Diabetes Voice by International Diabetes Federation

Volume 56 â&#x20AC;&#x201C; December 2011

TYPE 1 DIABETES

A very special issue

SPECIAL ISS U E

Global perspectives on diabetes

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Contents

Diabetes Views

T h e g l o b a l i m pa c t

International Diabetes Federation Promoting diabetes care, prevention and a cure worldwide

Estimating the worldwide burden of type 1 diabetes

Diabetes Voice is published quarterly and is freely available online at www.diabetesvoice.org.

Hope springs for young people with type 1 diabetes

The production of this Special Issue has been made possible thanks to the support of Sanofi Diabetes.

The 3-C Study – strong partnerships to improve care for people with type 1 diabetes in China

Leonor Guariguata

Graham Ogle and Larry Deeb

Linong Ji and Helen McGuire

m a n a g e m e n t, c a r e a n d p r e v e n t i o n The key to managing diabetes without tears – the treatment and teaching programme for flexible insulin therapy in Germany 16

Ulrich Alfons Müller

Taking the benefits of DAFNE to the UK and beyond

Stephanie A Amiel, Julia Lawton, Simon Heller

Positive results in Australia – OzDAFNE takes up the challenge

Never say never – implementing DAFNE in Kuwait

Dianne Harvey

Ebaa Alozairi

Great results for DAFNE Singapore – next stop, South-East Asia

Making progress with immune therapies for type 1 diabetes

Su-Yen Goh and Daphne Gardner

Mark Peakman

All that glitters is not gold – why we need better trials and reporting 32

Rury R Holman

Back to the future: investigating new treatments for type 1 diabetes using old inexpensive drugs 37

Denise Faustman and Miriam Davis

c a u s e s a n d e ff e c t s From victim to protector – what the brain does with hypoglycaemia 40

Stephanie A Amiel

Epilepsy in children and adolescents with type 1 diabetes

Edith Schober and Reinhard Holl

diabetes champions Breakthrough – the story of Elizabeth Hughes and the making of a medical miracle

Arthur Ainsberg

In the race for a glittering prize – Team Type 1 hits the road

Phil Southerland

This publication is also available in French, Spanish and Chinese. Editor-in-Chief: Stephanie A Amiel, UK Managing Editor: Olivier Jacqmain, olivier@idf.org Editor: Tim Nolan, tim@idf.org Advisory group: Pablo Aschner (Colombia), Ruth Colagiuri (Australia), Patricia Fokumlah (Cameroon), Attila József (Hungary), Viswanathan Mohan (India). Layout and printing: Luc Vandensteene, Ex Nihilo, Belgium, www.exnihilo.be All correspondence and advertising enquiries should be addressed to the Managing Editor: International Diabetes Federation, Chaussée de La Hulpe 166, 1170 Brussels, Belgium Phone: +32-2-5431626 – Fax: +32-2-5385114 – olivier@idf.org

© International Diabetes Federation, 2010 – All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means without the written prior permission of the International Diabetes Federation (IDF). Requests to reproduce or translate IDF publications should be addressed to the IDF Communications Unit, Chaussée de La Hulpe 166, B-1170 Brussels, by fax +32-2-5385114, or by e-mail at communications@idf.org. The information in this magazine is for information purposes only. IDF makes no representations or warranties about the accuracy and reliability of any content in the magazine. Any opinions expressed are those of their authors, and do not necessarily represent the views of IDF. IDF shall not be liable for any loss or damage in connection with your use of this magazine. Through this magazine, you may link to third-party websites, which are not under IDF’s control. The inclusion of such links does not imply a recommendation or an endorsement by IDF of any material, information, products and services advertised on third-party websites, and IDF disclaims any liability with regard to your access of such linked websites and use of any products or services advertised there. While some information in Diabetes Voice is about medical issues, it is not medical advice and should not be construed as such.

ISSN: 1437-4064 Cover photo © Wong Sze Yuen - istockphoto.com

From diabetes education and prevention all the way to sporting excellence – Italy’s BCD Campaign 49

Massimo Massi-Benedetti

December 2011 • Volume 56 • Special Issue 2

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Diabetes views

A very special issue in a stellar year for diabetes

the diabetes pandemic that maximizes the resources available to tackle the causes and consequences of the upsurge in type 2 diabetes and prioritizes the needs of people with type 1 diabetes. The diagnosis, treatment and management of non-preventable diabetes require integrated health systems, delivery of care down to primary care level and supportive policies outside the health sector.

The 5th edition of the IDF Diabetes Atlas, which was launched on World Diabetes Day, 14 November 2011, presented some daunting figures: the estimated number of adults living with diabetes has soared to 366 million – more than 8% of the global adult population – and is projected to rise to 552 million people by 2030 – just short of 10% of all adults. That means that diabetes is growing at the extraordinary rate of approximately three new cases every 10 seconds. The Atlas estimates confirm that diabetes continues to affect disproportionately the socially disadvantaged and continues to increase especially rapidly in low- and middle-income countries – where the health system is already ill equipped to provide care and resources for people with any type of diabetes.

While type 2 diabetes dominates in sheer numbers, type 1 diabetes remains a very special issue. With 70,000 newly diagnosed young people every year, the prevalence of type 1 diabetes is growing globally – not just in northern Europe. Those affected have very particular needs. The bottom line could not be more crude: unless they are diagnosed quickly and then receive insulin and skilled instruction on how to use it, people with type 1 diabetes die very quickly. That adults and children should be dying every day because they go undiagnosed or do not have access to insulin is deplorable. In various partnerships with other non-profit groups and public and private entities IDF is working to bridge some of the gaps. IDF’s child sponsorship programme, Life for a Child, supports services for children with diabetes and their families in resourcepoor communities worldwide. And in collaboration with the International Society for Pediatric and Adolescent Diabetes (ISPAD), IDF has produced the brand new Guideline for Diabetes in Childhood and Adolescence – which covers all diabetes in young people. The desired role of the guideline is not only to assist individual healthcare providers in managing young people with diabetes; it aims to improve awareness among governments and state healthcare providers of the essential resources needed for optimal care. These activities are vital and our involvement can only increase. But our fight for diabetes will take us further – beyond the diabetes community. Societies in general must build a concerted response to

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In terms of our campaign to achieve those long-term objectives, 2011 has been a landmark year for diabetes. In September, I attended an historic meeting of world leaders at the UN Summit, where they adopted the first ever Political Declaration on Non-Communicable Diseases. The standard bearer for diabetes throughout, IDF has been a principal figure in the NCD Alliance largely responsible for that historic accomplishment in New York. And we are among the ‘NCD revolutionaries’ – as described recently by Richard Horton, Editor of The Lancet – who are striving to ensure that the promises made by governments can be turned into action for people with diabetes of any type. Diabetes needs the reach, the voice and the power to generate government interest in health-protective policies beyond the health sector – and then to actually legislate for them. A broad coalition of aligned groups will be fundamental; inter-sectoral alliance is a significant recommendation of the 2011 Political Declaration. IDF provides the platform for that much needed collaboration. IDF engages in ‘triple p partnerships’ (public-private-people) that bring together non-health actors and key stakeholders, including the private sector where appropriate, and civil society in proactive partnerships to promote and protect health. As we look forward to a new year and welcome a new springtime in the fight against diabetes, we must act as a global community. We are all part of the solution!

Jean Claude Mbanya is IDF President for the period 2009 to 2012. He is Professor of endocrinology at the University of Yaounde, Cameroon, and Chief of the Endocrinology and Metabolic Diseases Unit at the Hospital Central in Yaounde.

December 2011 • Volume 56 • Special Issue 2

Diabetes views

Type 1 diabetes: quo vadis? In this special issue of Diabetes Voice, there is a focus on type 1 diabetes. In tackling the world pandemic of diabetes, and the critical importance of making societal change to arrest the staggering rise in the prevalence of type 2 diabetes, it is easy for the needs of the 10% of people with diabetes who have type 1 diabetes to be forgotten. Yet incidence of type 1 diabetes is also rising – at 3% per year (see page 6) - and as Professor M'Banya points out in his editorial, people with type 1 diabetes worldwide are still dying because of missed diagnoses or inadequate insulin supply. The disease particularly affects children: IDF estimates that there are over half a million children with type 1 diabetes currently. But another danger exists in forgetting that type 1 diabetes can arise at any age and that focusing attention only on children may disenfranchise adults living with the disease. Be they children or adults, the needs of the people with type 1 diabetes are different from those of the majority of people with diabetes and have to be be addressed separately. As exemplified by this special issue, IDF has not forgotten the 10%. At our international meeting in Dubai, IDF presented data on type 1 diabetes in China from a collaboration that started in July, in partnership with the Chinese Diabetes Society and insulin manufacturers Sanofi Aventis, sponsors of this issue of Diabetes Voice. We are excited that this issue of Diabetes Voice is published in Mandarin. It is now 90 years since the discovery of insulin. One of the remarkable things about the insulin story is how quickly it moved from bench to bedside – one might be forgiven for wondering how it would have fared in today’s regulatory environment! It is sobering to reflect that the first recipient of insulin – Leonard Thompson – died of pneumonia in the era before the discovery of antibiotics. On page 45, Thea Cooper and Arthur Ainsberg review the history of the discovery of insulin from the perspective of one of the people whose life it saved – touching also on the limitations of insulin as a therapy. Since Elizabeth Hughes received her first insulin injection, we have learned much about how to use insulin most appropriately – now we need to learn how to transfer that information to our colleagues – and to our patients. And we need the funding to do it effectively. As with any long-term condition, and certainly as with other forms of diabetes, the best – indeed the only – person who can properly manage the disease is the person who lives with it, day by day, month by month, year by year. It is the role of the healthcare professional to equip the patient (and often their family) with the tools to do this. This is much more than a prescription for insulin and blood glucose monitoring equipment. Good outcomes also need the users of these

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items – which, although they are essential, are not easy to come by for everyone – to have a high degree of knowledge and enough confidence to apply that knowledge and the emotional security to be able to handle it all. Providing that support takes time – another commodity not always in great supply – and expertise, from healthcare professionals as well as people with diabetes. Helping our patients to learn how to manage their life on insulin injections is too important to leave to chance or to random, wellmeaning interventions of unproven validity. It needs resourcing. On pages 16 to 28, we look at the globalization of one strategy for helping people with type 1 diabetes to live more healthily, using structured education to help patients use insulin flexibly. The Dusseldorf DAFNE programme can help people with type 1 diabetes achieve the glucose targets that reduce the risk of complications, while reducing hypoglycaemia risks and allowing people to live the life they choose with measurable benefit to quality of life. It is founded in well-validated principles of insulin action and educational strategies that work for adults, and has a good evidence base for its efficacy. Delivering such programmes requires skilled healthcare professionals who understand education as well as physiology and metabolism. The need for an expert multidisciplinary team has never been stronger. Developing such programmes for children and adolescents, who require different educational approaches, has been slow but is evolving. Many throughout the diabetes community will be keeping an eye out for future developments. I have no doubt that the editors of this special issue would like to hear of successes in this area! Access to good therapy for people with type 1 diabetes should not be a lottery. Nor should it be dependent upon charitable works and humanitarian organizations. Health organizations, in trying to reduce costs by re-structuring services for people with other forms of diabetes, must not allow the support needed by people with type one to be the baby that gets thrown out with the bath-water!

Professor Sir K George M M Alberti Chairman of Diabetes UK and Past-President of IDF

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Diabetes views

Estimating the worldwide burden of type 1 diabetes Leonor Guariguata

Providing an accurate estimate of the number of children with type 1 diabetes is an essential component of planning health policy, assessing the quality of care and driving research. There is good evidence that the incidence of type 1 diabetes among children is increasing in many parts of the world. The International Diabetes Federation’s Diabetes Atlas, 5th edition, estimates that increase to be 3% per year. The cause of this rise is unknown, although it may be linked to a number of factors. Studies have found associations with older mothers, early exposure to dietary components, such as cow’s milk, and a reduction in the frequency of early infections. Many of these factors can be linked to socioeconomic development and changes in environments. However, there are important geographic differences in the trends, which may reflect underlying differences in ethnicity, exposure to potential risk factors and the capacity of health systems to identify and record people diagnosed with type 1 diabetes. Leonor Guariguata reports on the global status of type 1 diabetes in children and looks at some the key issues behind the latest figures.

Type 1 diabetes is one of the most common endocrine and metabolic conditions among children. According to the latest edition of the Diabetes Atlas, an estimated 490,100 children below the age of 15 years are living with type 1 diabetes.1 A further 77,800 children under the age of 15 are expected to develop the disease in 2011 and there is evidence

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that the incidence is rising rapidly, especially among the youngest children.2-4 Type 1 diabetes is increasing steeply in some central and eastern European countries, where the disease remains less common than in other regions.5 If these trends continue, it is inevitable that the total prevalence of people with type 1 diabetes will increase in coming years.

Regional trends An estimated 24% of all children with type 1 diabetes live in the European region, where the most reliable and up-to-date estimates of the burden of diabetes are available. Two large international collaborative projects, the Diabetes Mondiale study (DiaMond) and the Europe and Diabetes study (EURODIAB) have been instrumental in monitoring developments in the incidence of type 1 diabetes in children, providing us with some of the best evidence on trends and prevalence for any region. These studies have shown that the rate of new cases in many countries is highest among younger children.2

In many countries, the rate of newly diagnosed type 1 diabetes is highest among younger children. There are a number of clinical implications for this overall drop in the ages at which young people are being diagnosed with type 1 diabetes. Diagnosis

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THE GLOBAL IMPACT

in a young child may be delayed or missed because of subtle and misleading symptoms. In many cases, it can be impossible for a child to be stabilized and begin receiving care outside hospital – which, in many parts of the world, presents a serious barrier to seeing a qualified health professional. Moreover, younger children with diabetes may be more likely than their older peers to present with ketoacidosis at the time of diagnosis and may face more years of hyperglycaemia with increased risk of complications. These combined factors place a significant burden on health systems and may increase the costs of care. Europe is followed closely by SouthEast Asia, with 23% of the world’s young people with type 1 diabetes, and North America and the Caribbean, with 19%. However, the lack of data in other parts of the world makes it difficult to estimate the true burden. In sub-Saharan Africa and many low-resource countries, diagnosis may be missed and children may

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be dying from a lack of insulin before they are identified. One study in Sudan showed a mortality rate of 42.6 deaths per 100,000 children with type 1 diabetes.6 This is compared to 0.63 deaths per 100,000 children with type 1 diabetes in the USA.7 It is almost impossible to determine the true incidence and prevalence in these regions; special efforts must be made to record and report on this problem. Regardless, even in studies from high-income countries, children with type 1 diabetes had at least twice the mortality rate of children without the disease.8

Even in high-income countries, children with type 1 diabetes died at twice the rate of children without the disease. Mortality This early mortality is almost certainly linked to a severe lack of access to insulin

and quality care. A study by the International Insulin Foundation, the Rapid Assessment Protocol for Insulin Access, conducted in five countries (Mali, Mozambique, Nicaragua, Vietnam, and Zambia), found several barriers to access to good care, including a lack of availability of quality insulin, syringes, and monitoring devices.9 These barriers pose a direct threat to children with type 1 diabetes, who must rely on caregivers to help manage their disease and obtain the materials necessary to keep them alive. A number of other factors can have a strong influence on estimates of type 1 diabetes. For older children moving into adolescence, distinguishing between type 1 diabetes and type 2 diabetes becomes more difficult; problems of misclassification can hamper efforts to estimate accurately the status of diabetes. Type 2 diabetes is emerging as a serious problem for adolescents worldwide. As a result, children who present with type 2 diabetes, a disease traditionally associated

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THE GLOBAL IMPACT

with adults, may be misclassified as having type 1 diabetes. Similarly, as global trends in obesity also increase in children and adolescents, some young people who are obese but present with type 1 diabetes may be misclassified as having type 2 diabetes because of the latter’s strong links with obesity.10 Generating the figures All the estimates and figures produced by IDF and published in the Diabetes Atlas are based on studies carried out in regions and countries. For the 5th edition, a total 88 studies were used to generate the estimates for diabetes in children. The majority of those studies were carried out in Europe, North America and South-East Asia. There are serious gaps in the availability of studies from sub-Saharan Africa and parts of the Western Pacific, which influences the figures for those regions. The quality and reliability of studies can vary greatly depending on the methods used and the representation of the population. Most of the studies used for global estimates draw on population-

based diabetes registries, which record newly diagnosed people with diabetes. These numbers are then used to estimate the prevalence of type 1 diabetes in children. The Atlas reports type 1 diabetes estimates only for children between 0 and 14 years – and no older – because the majority of studies include this information. There are few studies estimating the burden of type 1 diabetes among young people aged between 15 and 19, and even fewer capturing estimates for type 1 diabetes in adults. However, there is some indication that in high-income countries, between 10% and 15% of all diabetes is attributable to type 1 diabetes, while the estimate is likely to be lower in low- and middle-income countries. The way forward Despite gaps in the evidence and the need for more high-quality studies, it is clear that type 1 diabetes is a serious health priority all over the world. It is essential to map the disease in order to set priorities for care and improve the

life of people with type 1 diabetes, including, perhaps especially, the children with diabetes and their families through improved access to medicines, social support and diabetes education. With type 1 diabetes on the rise in many parts of the world, resources must be developed to meet the needs of this growing population. Leonor Guariguata Leonor Guariguata is biostatistician at the International Diabetes Federation.

References 1 I nternational Diabetes Federation. Diabetes Atlas, 5th ed. IDF. Brussels, 2011. 2 T uomilehto J, Virtala E, Karvonen M, et al. Increase in incidence of insulin-dependent diabetes mellitus among children in Finland. Int J Epidemiol 1995; 24: 984-92. 3 G ardner SG, Bingley PJ, Sawtell PA, et al. Rising incidence of insulin dependent diabetes in children aged under 5 years in the Oxford region: time trend analysis. The Bart’s Oxford Study Group. BMJ 1997; 315: 713-7. 4 D ahlquist G, Mustonen L. Analysis of 20 years of prospective registration of childhood onset diabetes time trends and birth cohort effects. Swedish Childhood Diabetes Study Group. Acta Paediatr 2000; 89: 1231-7. 5 E URODIAB ACE Study Group. Variation and trends in incidence of childhood diabetes in Europe. Lancet 2000; 355: 873-6. 6 E lamin A, Altahir H, Ismail B, Tuvemo T. Clinical pattern of childhood type 1 (insulin-dependent) diabetes mellitus in the Sudan. Diabetologia 1992; 35: 645-8. 7 N ishimura R, LaPorte RE, Dorman JS, et al. Mortality Trends in Type 1 Diabetes: The Allegheny County (Pennsylvania) Registry 1965-1999. Diabetes Care 2001; 24: 823-7. 8 I nternational Diabetes Federation. Diabetes Atlas, 3rd ed. IDF. Brussels, 2007. 9 B eran D, Yudkin JS, de Courten M. Access to care for patients with insulin-requiring diabetes in developing countries: case studies of Mozambique and Zambia. Diabetes Care 2005; 28: 2136-40. 10 Rosenbloom AL, Silverstein JH, Amemiya S, et al. Type 2 diabetes mellitus in the child and adolescent. Pediatric Diabetes 2008; 9: 512-26.

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Hope springs for young people with type 1 diabetes Graham Ogle and Larry Deeb

The IDF Diabetes Atlas, 5 edition, estimates that th

worldwide 495,100 children below 15 years of age are living with diabetes. Added to this number would be as many or more young people aged between 15 and 25 years. Together with adults with type 1 diabetes, these 1 million plus children and young people face the challenge of living with a complex, life-threatening chronic disease, but in widely different circumstances. The authors reflect on the latest figures from around the world for type 1 diabetes in young people, describe some of the challenges to providing universal care and treatment, and deliver good news about some positive trends in the developing world.

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In the developed world, the outlook for a child with type 1 diabetes has changed dramatically over the 90 years since insulin was discovered. The diagnosis used to be a death sentence, with life expectancy measured in months. As reported elsewhere in this issue, there have been steady advances since then, including: longer-acting animal insulin, blood glucose self-monitoring, HbA1c testing, understanding of complications and the importance of blood glucose control, appreciation of the role of different diets and exercise regimens, human insulin, diabetes education and empowerment (including associations of people with diabetes and diabetes camps), the multidisciplinary team, analogue insulins and insulin pump therapy. In parallel with this, scientific understanding of immunological and pathological mechanisms and determination of best-practice care have occurred. Extensive research is underway into all dimensions of type 1 diabetes, with much attention focused on closing the loop between blood glucose measurement and insulin delivery, prediction and prevention, and possibilities for a

cure, such as islet cell transplantation. Nowadays, many people live with type 1 diabetes for 60 or 70 years, or more, and long-term studies of adults who developed diabetes during childhood show steady reductions in mortality rates with time, with the likelihood that this will continue to improve.1

More than a quarter of a million children with type 1 diabetes – 50% of the global population – live in the developing world. Examination of the Diabetes Atlas figures reveals interesting details. Incidence varies markedly around the world and, on average, is increasing at between 3% and 4% per year.2,3 Of the estimated 495,100 children with type 1 diabetes, around 230,000 (some 46%) live in developed countries – the European nations, USA and Canada, Australia, New Zealand, Japan, Singapore, Saudi Arabia, and other high-income nations. The remaining 260,000 children with diabetes live in middle- and low-income

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countries. India is estimated to have 97,700 and China 8,700 (reflecting the stark difference in measured incidence between these two countries). Africa has an estimated 36,000 cases.

(particularly in Africa) – presumably due to high mortality rates. In others (for instance in Central America), the incidence may be considerably higher than the few studies (often relatively old) would suggest.

These estimates are the best that can be made with the available data. However, there are, by necessity, many extrapolations where there are gaps in the data; 129 of the 202 countries listed have no incidence data. For a number of others, the data are relatively old and determined from a region or city rather than the whole country.

Lack of access to insulin, limited medical expertise and education, and extreme poverty combined lead to very poor outcomes.

Even when the rate of incidence is known, prevalence is very difficult to calculate in poor countries, as few have a complete registry or any published information on mortality rates. Direct experience of the IDF Life for a Child programme suggests that the Atlas may markedly overestimate the existing numbers in some countries

Children in high-income countries have access to comprehensive care – the most up-to-date and complete range of health technologies that can be offered to people with diabetes with the aim of achieving best possible outcomes. In many middle-income countries and some low-income countries, quality care is also achieved - through well-designed cost-effective approaches consistent

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with available resources. However, there are number of countries, particularly in sub-Saharan Africa but also in Asia and the Americas, where such care is only available to wealthy families. Lack of access to, and the high cost of, insulin and other supplies, limited health professional expertise concerning childhood diabetes, lack of diabetes education, geographic isolation and extreme poverty can result in very poor outcomes – starting with frequent misdiagnosis at disease onset so the child dies untreated; then a high risk of early death from hypoglycaemia or ketoacidosis; and for those who survive, very poor blood glucose control. Such sustained poor control leads to impaired quality of life – many children drop out of school, cannot find employment or a marriage partner and develop severe complications (such as loss of vision, end-stage renal failure and severe neuropathy) in their 20s or even earlier.

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In the last 10 years, however, progress has been made in some low-income countries concerning access to insulin for children and adolescents. Various factors are helping this trend: economic growth in some countries, more market competition, the availability of reduced prices to developing nations in certain circumstances and the impact of Life for a Child and other programmes (which receive and deploy donated supplies).

There is an alarming trend in at least a few countries towards purchasing analogue and other expensive insulin preparations. However, many children do not receive enough insulin and have insecure, intermittent access, particularly in outlying and rural areas of developing countries, and in developing countries that have not yet been able to develop a diabetes service. Self-monitoring of blood glucose is also beyond the reach of many thousands of children and adolescents with diabetes, as neither their government health system nor their own family’s finances can afford to buy test strips – which, paradoxically, are more expensive than insulin. Transnational solutions are urgently needed in this area. Further challenges occur in the availability of HbA1c testing and screening for complications, such as for microalbuminuria. Equal to the problem of access to insulin and other supplies is the lack of available diabetes education in many countries. Few physicians are familiar with childhood diabetes, and children are often treated by adult internists or general practitioners. Many countries

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have no specialty diabetes nurse educators. Skills and settings to educate families and young people affected by diabetes are lacking, and often there are no education materials available. Diversity of languages and educational levels compound the challenges. However, we can report with pleasure that the situation is changing. The diabetes landscape is being transformed by the dedicated efforts of local champions – doctors and non-medical people determined to make childhood diabetes a focus – combined with support from the international diabetes community (health professionals, developed-country associations, industry).

We can report with pleasure that the situation is changing; a watershed has been reached for care of childhood diabetes worldwide. For instance in Mali, the intervention of Santé Diabète and the Government health services, with support from the Life for a Child Program, has led to dramatic improvements in survival. In Mali in 2007, only 14 young people aged below 23 years were known to the diabetes community. With the provision of adequate insulin, test strips, HbA1c testing equipment and other supplies, this number has risen to more than 140 – most of the increase being new cases. Mortality rates are now low. Similarly, in Rwanda, there are improvements in care4 and sharp increases in numbers. Life for a Child is supporting diabetes services in 36 countries and has developed a website for childhood and adolescent diabetes education resources

in major world languages. A range of other initiatives is also underway: the International Society for Pediatric and Adolescent Diabetes (ISPAD) is conducting training and developing guidelines; the Changing Diabetes in Children programme is assisting diabetes centres in a number of countries; and the International Insulin Foundation is working to improve access to supplies. There is an increasing emphasis on training paediatric endocrinologists, including the successful ISPAD/European Society of Paediatric Endocrinology School in Nairobi, Kenya. Very much more remains to be done. However, due to the coordinated collaborative efforts of the international diabetes community to effect change, a watershed has been reached for care of childhood diabetes worldwide. Graham Ogle and Larry Deeb Graham Ogle is a paediatric endocrinologist. He is General Manager of the IDF Life for a Child programme and Director of Health and Social Services at HOPE worldwide (Australia). Larry Deeb is Clinical Professor of Pediatrics at the University of Florida and Clinical Professor of Behavioral Medicine at Florida State University, USA. He is also the chair of the IDF Task Force for Insulin, Test Strips, and other Diabetes Supplies.

References 1 S ecrest AM, Becker DJ, Kelsey SF, et al. All-cause mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes. Diabetes Care 2010; 33: 2573-9. 2 D IAMOND Project Group. Incidence and trends of childhood Type 1 diabetes worldwide 1990-1999. Diabet Med 2006; 23: 857-66. 3 P atterson CC, Dahlquist GG, Gyurus E, et al. Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted newcases 2005-20: a multicentre prospective registration study. Lancet 2009; 373: 2027-33. 4 M arshall SL, Sharma, V, Ogle G, Orchard T. Improvements of Glucose Control Seen in Children with Type 1 Diabetes in Rwanda, Africa. Diabetes 2011; 60(Suppl1): Abstract 1165-P, A320.

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Diabetes view from the field

CDS facing down challenges to improved care for type 1 diabetes

Despite these efforts, many unmet needs remain. Discrimination against people with type 1 diabetes is still common, for instance. People with type 1 diabetes face great difficulties accessing higher education and employment. This social unfairness not only has a negative impact on personal lives, it hinders disease management. For example, in order to hide their condition, many students and employees with type 1 diabetes never test blood glucose and inject insulin at school or the work place, making intensive glucose control impossible.

China is experiencing an increase in the number of people with type 1 diabetes. New cases as well as improved life expectancy among people with established diabetes are behind the rising prevalence. The incidence of type 1 diabetes among children has been put at 0.59 per 100,000 people per year. Although this is far lower than in some other regions, such as northern Europe, our numbers are huge because China has such a large population – in excess of 1.3 billion.

The Chinese Diabetes Society (CDS) is dedicated to improving diabetes care for people with type 1 diabetes through education and good clinical practice. CDS members have organized a national programme to train medical professionals in the management of type 1 diabetes. The CDS Guideline for diagnosis and treatment of diabetic ketoacidosis in childhood type 1 diabetes and Consensus of insulin treatment in childhood type 1 diabetes were developed in 2009 and 2010, respectively. CDS has made education one of its priorities. A CDS task-force, which was founded in 2003, focuses on enhancing and extending training for diabetes educators and certifying those who are qualified. Educators play more and more important roles in diabetes management, especially in improving people’s ability to follow professional diabetes management advice. Beijing Children’s Hospital is a good example. In the past five years, the educator at that hospital designed a structured course covering contents from fundamental survival skills to advanced self-management. Following structured education, blood glucose control has improved dramatically among young people with diabetes at the centre. Many tertiary care centres in large cities organize summer camps for children with type 1 diabetes and their parents, providing activities that teach kids with type 1 diabetes and their parents how to cope with the disease, and giving the children the confidence they need to fight the disease, safe in the knowledge that they are not alone.

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Special care for people with type 1 diabetes is available only in the large clinical centres located in major cities. The type 1 diabetes management capabilities of primary and secondary healthcare centres are still very limited. Even in the larger clinics, standards of care for type 1 diabetes have not been well implemented throughout. Moreover, the way in which people with type 1 diabetes are identified remains an area for serious attention. There are multiple reports of misdiagnoses of type 1 diabetes leading to fatalities. The personal financial burden of disease management is high. For example, throughout most of the country, glucose test strips and disposable insulin pen lancets are not reimbursed. As a result, people with type 1 diabetes reportedly are using the disposable needles for several days. CDS is fully committed to ongoing efforts to promote standards of care and education to improve the life of young people with type 1 diabetes. We will continue to work closely with the government and other sectors of society to improve quality of life and welfare of all people with the condition in China.

Linong Ji, Director of the Department of Endocrinology and Metabolism Peking University People’s Hospital and President of the Chinese Diabetes Society

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The 3-C Study – strong partnerships to improve care for people with type 1 diabetes in China Helen McGuire and Linong Ji

In March 2010, investigators from the Chinese Diabetes Society (CDS) published a study that captured headlines in the popular as well as the medical media around the world. It estimated that the number of people with diabetes in China had risen in excess of 92 million. With the release of those findings, China took over from India the dubious mantle of diabetes capital of the world. The authors look at the epidemiological contribution of type 1 diabetes to the national and global figures, and present a major new study aimed ultimately at improving care for people with the disease in China.

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On World Diabetes Day this year, 14 November 2011, the 5th edition of the International Diabetes Federation Diabetes Atlas was released containing the estimate that 8,700 children under 14 years of age in China have type 1 diabetes – an incidence rate of 0.6 per 100,000 per year.1 Although the prevalence and incidence rates are relatively low in China, the number of people with type 1 diabetes represents more than half the total number of young people with type 1 diabetes in the Western Pacific Region. In 2000, a large study was conducted over several countries including China that looked at trends in the incidence and prevalence of type 1 diabetes in children 14 and under.2 Within China, the highest incidence was found in the region of Wuhan (4.6 per 100,000 per year) and lowest in Zunyi (0.1 per 100000 per year).

Incidence was highest in children aged between 10 and 14 years of age, and there was no statistically significant genderbased difference in the rate.

Opportunities exist to achieve earlier diagnosis and strengthen secondary prevention efforts in China. Recent studies in China on clinical presentation and outcomes of people with type 1 diabetes suggest that opportunities exist to achieve earlier diagnosis and strengthen secondary prevention efforts. A 2007 study found that children under 18 years of age in China had generally poorer outcomes than the average values of young people in 11 countries in the Western Pacific Region (Figure).3 Severe hypoglycaemia was

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THE GLOBAL IMPACT

the exception, with a regional average of 74 events per 100 patient years compared with 39 events per person years in China. A more recent study, carried out in Shenyang found that 41% of children with type 1 diabetes present with ketoacidosis and that the average duration of symptoms before going to hospital was 24.5 days.4 Type 1 diabetes in China is an important area for research due to the paucity of available data. Moreover, investigating type 1 diabetes has the potential to influence the changing healthcare environment in China to improve care and clinical outcomes for people with the disease throughout the country. IDF is active in building the global diabetes evidence base and advocating for improved care for people with diabetes. An umbrella organization of more than 200 national diabetes associations around the world, IDF represents the interests of the growing number of people with diabetes and those at risk. Leading the global diabetes community since 1950, IDF’s mission is to promote diabetes care, prevention and a cure worldwide. IDF collaborates with its Member Associations to support their efforts to advance their strategic priorities and transfer knowledge from one region of the world to another. In 2009, IDF conceived a project to assess the current status of care, including the costs involved in coverage for people with type 1 diabetes, in order to influence change and ultimately improve outcomes for people with diabetes. IDF and Sanofi agreed to work together to realize a timely and innovative type 1 diabetes research project.

and CDS was contacted to determine their interest. A Member Association of IDF founded in 1991, CDS conducts various public education programmes, epidemiological surveys and research in China. The mission of CDS is to prevent and treat diabetes and provide information to help educate people living with diabetes, their families, healthcare professionals and the public about this disease. Led by IDF and with CDS collaboration and Sanofi support, the triparty partnership was formed.

The network of participating healthcare facilities is a testament of the power of effective partnerships. To advance the project design, the IDF specialist team, Helen McGuire, David Whiting and Katia Skarbek travelled to China on several occasions to meet with stakeholders and refine the protocol to match local realities. Professors Linong Ji (in Beijing) and Weng (in Shantou) represented CDS, and, along with IDF, led the establishment of the

project in China. An academic research organization in China was contracted to assist with implementation in Beijing and Shantou. The potential strength of partnerships became clear as the IDF team worked closely with healthcare professionals and investigators in China to launch the project. CDS brought together a network of 19 committed hospitals and primary health centres to participate in the project. These include: Peking University People's Hospital, Military Hospital, Peking Union Hospital, Beijing Children's Hospital, Peking University First Hospital, Peking University Third Hospital, Beijing Haidian Hospital, the Luhe Teaching Hospital of the Capital Medical University, Pinggu Hospital, Zhanlan Road Community Health Service Centre, the Second Hospital of Tongzhou district, Pinggu Town Community Health Service Centre, Pingguoyuan Community Health Service Centre, the First Affiliated Hospital of Shantou University Medical College, the Second Affiliated Hospital of Shantou University Medical College, Chaonan Minsheng Hospital, Chenghai

under n with type 1 diabetes re ild ch in es m co ut O Figure: vs 11 countries in the 18 years of age in China3 n Western Pacific Regio WPR HbA1c Microalbuminuria Hypertension

8.8% 2.5% 21.6%

China 9.5% 13.0% 23.9%

China was identified as the appropriate country to launch such a project

DiabetesVoice

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THE GLOBAL IMPACT

Huaqiao Hospital, Chaonan Longtian Health Service Centre, Chenghai Dongli Health Service Centre. This comprehensive network of committed healthcare facilities is a testament of the power of effective partnerships.

This global-to-local partnership represents an important model for advancing diabetes care worldwide. In July 2011, the 3-C Study: Coverage, Cost and Care of Type 1 Diabetes in China5 was launched in Beijing at a press conference featuring Jean Claude Mbanya, IDF President, Linong Ji, CDS President and Riccardo Perfetti, Vice President of Global Medical Affairs, Diabetes Division, Sanofi. The globalto-local partnership achieved in this project represents an important model for advancing diabetes care worldwide: National member associations provide in-country expertise and networking IDF provides the global perspective and facilitates knowledge transfer from one region of the world to another Industry makes a positive contribution to the advancement of care by supporting organizations to develop and implement projects without interference from the funder. The 3-C Study will provide data to inform policy and decisions on the advancement of treatment of type 1 diabetes in China. Its key objectives are as follows: Describe coverage, cost and care for type 1 diabetes Estimate the number of people with type 1 diabetes Estimate the economic burden from type 1 diabetes and financial barriers to care

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Training session for study investigators in Shantou

I dentify the scale of government investment needed to improve healthcare coverage Define the burden of disease in terms of clinical outcomes Describe the educational and care experiences of people with type 1 diabetes compared with selected clinical practice guidelines Describe the information processes associated with diabetes care and education. This is the first research initiative to study a chronic disease from a range of angles. The model established and experience gained in this study will be invaluable in studying other chronic conditions, such as type 2 diabetes. The gaps identified between what should be happening in type 1 diabetes care and day-to-day reality will lay the foundations for future translational research into the implementation of care standards for people with type 1 diabetes in China. The tri-party partnership led by IDF has achieved a culturally relevant and scalable project. With 366 million people in the world living with diabetes and many

questions about the disease unanswered, such collaborations are vital. We must speak with a common voice if we are going to make a real difference. Helen McGuire and Linong Ji Helen McGuire is Senior Diabetes Education and Health Systems Specialist at IDF and a member of the IDF team leading the 3-C Study. Linong Ji is Director of the Department of Endocrinology and Metabolism at Peking University People’s Hospital, Beijing, People’s Republic of China.

References 1 I nternational Diabetes Federation. Diabetes Atlas 5th edition. IDF. Brussels, 2011. 2 Y ang Z, Wang K, Li T, et al. Childhood diabetes in China. Enormous variation by place and ethnic group. Diabetes Care 1998; 21: 525-9. 3 C raig ME, Jones TW, Silink M, Ping YJ. Diabetes care, glycemic control, and complications in children with type 1 diabetes from Asia and the Western Pacific Region. J Diabetes Complications 2007; 21: 280-7. 4 X in Y, Yang M, Chen XJ, et al. Clinical features at the onset of childhood type 1 diabetes mellitus in Shenyang, China. J Paediatr Child Health 2010; 46: 171-5. 5 M cGuire H, Kissimova-Skarbek K, Whiting D, Ji L. The 3C Study: Coverage cost and care of type 1diabetes in China – Study Design and Implementation. Diab Res Clin Pract 2011; Doi:10.1016.

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The key to managing diabetes without tears – the treatment and teaching programme for flexible insulin therapy in Germany Ulrich Alfons Müller

Successful implementation of structured education programmes that teach people with type 1 diabetes to use insulin flexibly around normal lifestyle behaviours is the subject of this and the following four articles in this special issue. Programmes such as the UK's Dose Adjustment for Normal Eating (DAFNE), in which the person affected by type 1 diabetes is central to all disease management decisions, are the object of a number of projects in different countries. While such programmes are increasingly regarded as the state-of-the-art deployment of diabetes resources, their origins lay in Germany early in the last century. Ulrich Müller looks back at the birth and initially arrested development of flexible insulin therapy programmes, describes the approach itself and demonstrates what makes it an optimum therapeutic approach.

DiabetesVoice

It was the paediatrician, Karl Stolte, who, using pre-meal urine tests to target insulin dose adjustment, first provided people affected by diabetes with education to adapt their insulin regimen to be able to eat normally. 1 His idea to increase the dose of soluble (regular) insulin to allow dietary freedom came in 1928, when a birthday cake was brought to a hospital ward for a child without diabetes and shared with eight children with the disease. His work and his conviction that “people with diabetes should not eat like laboratory animals, which day after day get food calculated down to the gram” were rejected by most German paediatricians and diabetologists at the time – and until as late as the 1980s! The first diabetes teaching unit in a European country was founded by Jean Philippe Assal at the University Hospital in Geneva, Switzerland, in 1970. A paradigmatic change was underway in theories about diabetes therapy. ‘Patient education’, which took the form of obedience training, was replaced by an approach based on empathy, empow-

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erment and autonomy. In 1979, the Diabetes Education Study Group of the European Association for the Study of Diabetes was founded. Its major goal was to make skills and knowledge training for effective disease management an integral part of any affected person’s diabetes therapy. The emphasis for people with type 1 diabetes was on a five-day inpatient treatment and teaching programme in groups of 6 to 10 people.

A paradigmatic change was underway in theories about diabetes therapy. A structured programme – development and evaluation Between 1980 and 1990, Michael Berger and his team at the University of Düsseldorf developed the original Geneva programme for general use in Germany. The overarching objective was to provide education, skills training and motivation that could enable people with diabetes to take over aspects of their therapy, and manage their diabetes with growing autonomy from healthcare professionals and medical institutions. The resulting dose-adjustment for normal eating course, with a 12-unit curriculum, covers a range of issues: from understanding diabetes and the way insulin works, to understanding food quality and its interactions with insulin and managing on holiday (see Box).

In striking contrast to the DCCT, improvements in HbA1c were not associated with an increased risk of severe hypoglycaemia. During the early 1980s, the programme was based on intensified insulin therapy and ushered in the loosening of previously rigid rules for nutrition and daily schedules. Over the decades since then, the five-day programme has been translated into general hospitals throughout Germany, and has maintained its efficacy – significant reductions in HbA1c values, ketoacidosis, hospitalizations and sick leave.2 This success has been repeated in a number of other European countries.3,4,5 In striking contrast to the Diabetes Control and Complications Trial (DCCT), those improvements in HbA1c values were at no time associated with an increased risk of severe hypoglycaemia – quite the contrary: the incidence was halved. Implementing the German system During the 1990s, the treatment and teaching programme

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for intensified insulin therapy was rolled out to nearly all the specialist hospitals in Germany. The precondition for successful implementation countrywide was the provision of training for physicians, nurses and dietitians. To date, more than 3,000 people, primarily nurses and dietitians, have undertaken the 12-week course to become a diabetes educator. Over the years, about 200 departments of internal medicine have agreed to implement continuous quality assurance measures. These include re-examining a random sample of patients 12 to 15 months after they have taken part in the programme. Significant reductions have been seen in key endpoints in a sample of 9,583 people with type 1 diabetes.6 They showed for the first time that the inverse association between HbA1c and severe hypoglycaemia was not inevitable during intensive insulin therapy. Before the intervention, the incidence of severe hypoglycaemia was three times higher in the lowest compared with the highest quartile of HbA1c, whereas the risk was almost identical (but lower) across HbA1c ranges during the year after the DTTP. The programme was effective even in people with frequent episodes of severe hypoglycaemia or ketoacidosis.6 Although quality of life was not measured in the German programme, there is good evidence from the British DAFNE study7 and other trials that participants benefit psychologically from enjoying dietary freedom. In a recent trial, there were strong

BOX: The 12-unit curriculum P athophysiology, insulin and injection B lood glucose self-monitoring, diet and hypoglycaemia B asic diabetes information R educing insulin doses I ncreasing insulin doses and ketoacidosis P hysical activity H bA1c, complications, smoking and follow-up N utrition training and carbohydrate counting I nsulin pumps, contraception and pregnancy T ravelling and holidays C orrecting blood glucose S ocial issues

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indicators that differences in the quality of diabetes care that are caused by social inequalities disappear after treatment and education.8

Ulrich Alfons Müller Professor Müller leads the Working Group on Endocrinology and Metabolic Diseases in the Department of Internal Medicine III at the University Hospital Jena, Germany.

The Disease Management Programme In 2004, the Disease Management Programme for Diabetes was introduced into the German healthcare system, and structured diabetes education was an integral part of the Programme. As a result, people have the right to access diabetes education. Remuneration for the education programmes is EUR 600 per person per course. In one of the biggest German states, North Rhine-Westphalia, 18,441 people (65% of the of the type 1 diabetes population) registered in the Disease Management Programme in 2009.9

There is good evidence that participants benefit psychologically from enjoying dietary freedom. Diabetes education – what we can learn! There are some fundamental principles underpinning our vision for structured education programmes for people with long-term conditions like type 1 diabetes – or indeed type 2 diabetes. These should allow the healthcare professional to help the patient to identify his or her personal problems and issues with diabetes or hypertension, and their treatment. We must keep in mind that it is the ‘empowered’ patient who defines his or her own treatment goals and takes decisions relating to the treatment of diabetes or hypertension; our role as healthcare professionals is to inform and facilitate (provide the necessary tools). The principles we developed in the type 1 diabetes programme can be adopted to deliver specific strategies for people with type 2 diabetes – and within that group, for those who are on insulin and those who are not. Physicians and nurses and other healthcare professionals need training to deliver the programmes.

Our role as healthcare professionals is to inform and provide the necessary tools. Increasingly, computer programs and sophisticated technical devices are offered to manage diabetes. But we should all be aware that while the use of electronic records facilitates evaluation of the programme, those technologies could never replace a fully trained diabetes educator.

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References 1 S tolte K, Wolff J. Die Behandlung der kindlichen Zuckerkrankheit bei frei gewählter Kost. Ergebn Inn Med Kinderheilk 1939; 56: 154-93. 2 J örgens V, Grüßer M, Bott U, et al. Effective and safe translation of intensified insulin therapy to general internal medicine departments. Diabetologia 1993; 36: 99-105. 3 S tarostina EG, Antsiferov M, Galstyan GR, et al. Effectiveness and costbenefit analysis of intensive treatment and teaching programmes for Type 1 (insulin dependent) diabetes mellitus in Moscow - blood glucose versus urine glucose self-monitoring. Diabetologia 1994; 37: 170-6. 4 P ieber TR, Schattenberg S, Brunner A, et al. Evaluation of a structured outpatient group education programm for intensive insulin therapy. Diabetes Care 1995; 18: 625-30. 5 D AFNE Study Group. Training in flexible, intensive insulin management to enable dietary freedom in people with type 1 diabetes: dose adjustment for normal eating (DAFNE) randomised controlled trial. BMJ 2002; 325: 746. 6 S ämann A, Mühlhauser I, Bender R, et al. Glycaemic control and severe hypoglycaemia following training in flexible, intensive insulin therapy to enable dietary freedom in people with type 1 diabetes: a prospective implementation study. Diabetologia 2005; 48: 1965-70. 7 S peight J, Amiel SA, Bradley C, et al. Long-term biomedical and psychosocial outcomes following DAFNE (Dose Adjustment For Normal Eating) structured education to promote intensive insulin therapy in adults with sub-optimally controlled Type 1 diabetes. Diabetes Res Clin Pract 2010; 89: 22-9. 8 B äz L, Müller N, Beluchin E, et al. Differences in the quality of diabetes care caused by social inequalities disappear after treatment and education in a tertiary care centre. Diabet Med 2011. doi: 10.1111/j.1464-5491.2011.03455.x 9 H agen B, Altenhofen L, Blaschy S, et al. Qualitätssicherungsbericht 2008 Disease-Management-Programme in Nordrhein www.kvno.de/downloads/qualbe_dmp08.pdf

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Taking the benefits of DAFNE to the UK and beyond Stephanie A Amiel, Julia Lawton, Simon Heller

Two English diabetologists were among an international audience while Michael Berger told it to throw away the diet from the therapeutic approach to type 1 diabetes. That caught their attention. Berger was describing was a treatment programme that improved diabetes control in real terms. In contrast to the Diabetes Control and Complications Trial (DCCT), then still running, this was a programme that delivered lower average blood glucose concentrations and HbA1c and reduced the risk of severe hypoglycaemia. The DCCT seemed to show that this was not possible: the lower the HbA1c, the lower the risk of vascular complications but with a much higher risk of hypoglycaemia. Just over a year later, teams from King’s College Hospital London, Sheffield University and North Tyneside Hospital, all in the UK, visited Dusseldorf, Germany, to find out what Professor Berger’s team was doing.

As Ulrich Müller has described in the previous article, education underpinned the Dusseldorf approach. The UK teams observed a five-day programme of structured education in flexible insulin therapy, which aimed to transfer the healthcare professionals’ knowledge and skills in insulin therapy to the insulin user. Greatly impressed, and with

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the support of the German team, we brought their Treatment and Teaching Programme for Flexible Insulin Therapy to the UK. Taking DAFNE to England It took a grant from the charity Diabetes UK and more than a year of hard work to set up the Dose Adjustment for

Normal Eating (DAFNE) programme in England. A group of dietitians, specialist nurses and doctors translated the German teaching aids and received training in the principles of the programme and in the art and science of delivering education to adults. There were some challenges and we had to abandon some long-held beliefs of our own: dietitians were concerned about reducing the emphasis on healthy eating; doctors worried about abandoning the prescription of regular food intake and the classic meal-snack-meal-snack pattern we believed was necessary to minimize hypoglycaemia risk, and the need to inject soluble (regular) insulin 30 minutes before eating in doses decided by the doctor. But we made a decision early on that we should follow the evidence: the German programme worked and we should not change it. Compared to the German diet, the UK diet is much higher in carbohydrates, so we needed to revise the DAFNE food

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models and images. Professor Berger’s team supported us throughout and observed our first course.

UK findings added to evidence from across Europe and Latin America to show that DAFNE is effective. The rest is history. The Diabetes UKfunded trial of DAFNE demonstrated clinically relevant reductions in HbA1c at both six months and one year after courses, with other improvements in cardiovascular risk and no rise in severe hypoglycaemia.1 These findings contributed to the growing evidence base from Germany and other countries and regions, including Austria, Latin America and Eastern Europe, to show that the programme is effective. The improvements in diabetes control were found to be cost-effective.2 Importantly, DAFNE was the first programme to measure improvements in quality of life. The UK Department of Health funded the implementation of DAFNE to over 70 diabetes centres in England, while many more UK centres deliver variants on the Assal-Berger curriculum. In the UK, DAFNE is unique in having a health care professional training programme, a published evidence base for its efficacy, a peer-review system to ensure quality of teaching, a nationwide audit programme and a quality assurance programme to maintain the consistency of teaching. An annual meeting of educators and doctors from all the UK centres (and often visitors from elsewhere) reviews progress and considers new research. The curriculum evolves but we try only to modify the programme in ways that either already have an evidence base or that we can

DiabetesVoice

red Essential components of a structu 7 education programme P erson-centred philosophy A structured curriculum T rained educators A quality assurance programme A udited outcomes

audit in order to ensure that any changes result only in improvements. There are problems of course. Old habits die hard, and constant vigilance is required to ensure that all DAFNE courses remain true to the DAFNE principles. Newer insulins offer potential benefits but we do not yet have the data on how best to incorporate them into the DAFNE regimens. We made some obvious mistakes that, with hindsight, were rather obvious – the absence of a continuing education programme for the graduates of the DAFNE courses being a very obvious one that we are now addressing.

The group approach enhances learning, helps to overcome feelings of isolation and enables people to compare their experiences. Keys to success We do not know precisely what it is about the DAFNE-type programmes that deliver benefit. As Ebaa Alozairi points out in her article, the key lies

in bringing people with type 1 diabetes together to meet, learn and share experiences. This impression has been reinforced by research being undertaken in the UK, funded by the National Institute of Health Research (NIHR). The researchers found that the group approach enhances learning, helps to overcome feelings of isolation and enables people to compare their experiences of applying DAFNE principles, supporting more nervous people to ‘take the leap’ or making dose adjustments that have worked for others.3 Support from empathic educators, avoiding direct instruction but referring to DAFNE rules, is also important. Meanwhile, the DAFNE insulin regimen, which is by no means unique, gets as close to physiology as possible with conventional insulins: twice-daily injections of low-dose intermediateacting insulins to provide the basal insulin that controls endogenous glucose production; pre-meal doses of fastacting insulin that are adjusted every meal to match carbohydrate content – modified if indicated by a pre-meal blood test – injected before eating; and algorithms for dose adjustment that start with known physiology and are

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adjusted in predictable ways for each user, based on his or her own responses in pre-meal and pre-bed blood testing. We do know that both users and educators find value in the way the course includes and also extends beyond improved biomedical outcomes. DAFNE aims to put the person with diabetes in control and it appears to achieve this for most users. Maintaining the quality of the courses as the programme expands requires effort and resources – in terms of time and people as well as money. For users, sustaining in the long term the benefits derived from DAFNE courses can be a challenge and much effort is going in to understanding how we can support them to make this happen. The course graduates are the main movers in this: UK DAFNE graduates have created their own website and developed an application to support carbohydrate counting, which has been made freely available. The UK programme has provided training to healthcare professionals in other countries. It has developed a model in which larger centres can support smaller ones to obtain DAFNE with the engagement of all the professional teams involved.4 Meanwhile, the NIHR programme, which is being coordinated in Sheffield (UK), is exploring alternative forms of course delivery and ways of helping course graduates to sustain or improve on their outcomes. One area to

research is why some of the biomedical outcomes of the programme are less well sustained than the psychological and quality-of-life benefits5 and why biomedical outcomes vary between countries. Making DAFNE work worldwide Most importantly, the research programme is listening to what people with diabetes have to say. To date, we have found that most people were glad to have been able to 'do DAFNE', and remain keen on and committed to sustaining its approach. There is clear demand for ongoing support from health professionals who are trained in an approach that is responsive to people’s personal circumstances – suggesting that one-to-one, rather than group, follow-up, and being able to ask for help as and when needed, may be most appreciated.6 A national database is being maintained also, which collects information not just to ensure that the programmes are delivering benefit but also to facilitate research into which approaches and strategies are effective and which are not. That ongoing research and a growing number of committed and enthusiastic healthcare professionals and people with type 1 diabetes are working to establish, extend and improve DAFNE’s diabetes education web. Their endeavour needs resources and support but, as these pages hope to show, DAFNE is already flourishing internationally.

UK DAFNE graduates have created their own website and developed an application to support carbohydrate counting.

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Stephanie A Amiel, Julia Lawton, Simon Heller Stephanie A Amiel is the RD Lawrence Professor of Diabetic Medicine at King's College London, UK. Professor Amiel is Editor-in-Chief of Diabetes Voice and was chair of the DAFNE UK Executive Committee from 2001 to 2011. Julia Lawton is a Senior Research Fellow in the Public Health Sciences section of the Centre for Population Health Sciences at the Medical School of the University of Edinburgh, Scotland. Simon Heller is Professor of Clinical Diabetes at Sheffield University (UK) and Chief Investigator of the National Institute of Health Research Programme, ‘Improving management of Type 1 diabetes in the UK: the DAFNE programme as a research test-bed’.

References 1 D AFNE Study Group. Training in flexible, intensive insulin management to enable dietary freedom in people with type 1 diabetes: dose adjustment for normal eating (DAFNE) randomised controlled trial. BMJ 2002; 325: 746. 2 S hearer A, Bagust A, Sanderson D, et al. Cost-effectiveness of flexible intensive insulin management to enable dietary freedom in people with Type 1 diabetes in the UK. Diabet Med 2004; 21: 460-7. 3 L awton J, Rankin D. How do structured education programmes work? An ethnographic investigation of the dose adjustment for normal eating (DAFNE) programme for type 1 diabetes patients in the UK. Soc Sci Med 2010; 71: 486-93. 4 R ogers H, Turner E, Thompson G, et al. Huband-spoke model for a 5-day structured patient education programme for people with Type 1 diabetes. Diabet Med 2009; 26: 915-20. 5 T he DAFNE Study Group (2010). Long-term biomedical and psychosocial outcomes following DAFNE (Dose Adjustment For Normal Eating) structured education to promote intensive insulin therapy in adults with sub-optimally controlled Type 1 diabetes. Diab Res Clin Pract 2010; 89: 22-9. 6 R ankin D, Cooke DD, Clark M, et al; UK NIHR DAFNE Study Group. How and why do patients with Type 1 diabetes sustain their use of flexible intensive insulin therapy? A qualitative longitudinal investigation of patients' self-management practices following attendance at a Dose Adjustment for Normal Eating (DAFNE) course. Diabet Med 2011; 28: 532-8. 7 D iabetes UK, UK Department of Health, UK National Diabetes Support Team. How to Assess Structured Diabetes Education: An improvement toolkit for commissioners and local diabetes communities. www.diabetes.org.uk/ Professionals/Publications-reports-and-resources/ Reports-statistics-and-case-studies/Reports/ Structured-Education-Self-Assessment-Toolkit/

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Positive results in Australia – OzDAFNE takes up the challenge Dianne Harvey

Australian diabetes healthcare professionals in Melbourne learned about the DAFNE programme for people with type 1 diabetes in 2004, during a visit to the International Diabetes Institute there by Stephanie Amiel. Rather like the UK teams a few years earlier, a team of nine health professionals from four Australian centres undertook DAFNE training in the UK that year. Prior to this, there were no evidence-based group programmes providing structured education for people with type 1 in Australia. After the training period, the Australians returned home and ran their first courses: in early 2005, OzDAFNE was born.

DiabetesVoice

OzDAFNE has grown since its modest early stages, from the four original OzDAFNE centres to 20 centres countrywide, and the programme has provided training for centres in New Zealand and Singapore. An OzDAFNE collaborative was formed to link all Australian centres, provide governance for DAFNE at the national level and maintain links with UK DAFNE. The national coordinating centre, Diabetes Australia-Victoria, is partnered with Mater Health Services in Brisbane to oversee the training and peer review of new and existing centres, and contribute to research. One of the first and most important challenges in introducing DAFNE to an Australian audience was the development of ‘Australianized’ resources. Changes to the curriculum and handbook were minor but included, for example, regulatory guidelines around driving. The carbohydrate counting booklet was modified to allow for typical Australian foods and snacks, and the carbohydrate values were sourced from

an Australian database. Finally, we replaced the UK DAFNE ‘Jaffa cake’ (buscuit) logo with a picture of a traditional Australian sweet – the Lamington.

OzDAFNE has been integrated into community health centres, private practice and Diabetes Australia associations. With modifications to the resources complete, our focus shifted towards increasing the number of OzDAFNE centres in order to provide better access to courses for people with type 1 diabetes around the country. In the UK, DAFNE is normally run by hospitals in a clinical setting. However, major hospitals in Australia have struggled to incorporate DAFNE into their busy clinical environments within limited budgets. Although some hospital clinics have managed to do so, the OzDAFNE programme has also been integrated into a variety of other

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healthcare settings, such as community health centres, private practices and Diabetes Australia associations. As these non-clinical settings lack direct access to general practitioners and endocrinologists, a formal doctor’s consent process, including an insulin order form, was devised to allow the OzDAFNE educators to function. Different strokes… We also needed a different model for quality assurance. Australia is a vast country, so attempting to implement the UK DAFNE model of external peer review without adequate funding to support the travel and accommodation required was problematic. As a result, a modified quality assurance programme has been implemented that is based mainly on internal peer review, with external checks and administration carried out by the national coordinating centre. We are currently working towards a model in which there is a lead OzDAFNE centre in every state that takes responsibility for state training and quality assurance measures. The absence of dedicated funding for OzDAFNE affects our quality assurance programme and impacts on the adoption of OzDAFNE by new centres – as well as ongoing provision of DAFNE courses in existing centres. Currently, individual OzDAFNE centres self-fund their services through a variety of ad hoc methods and activities and participant contributions. For example, a number of community health centres have secured funding for OzDAFNE through chronic disease and self-management funding programmes; and one private practice model relies on pharmaceutical industry support. The National Diabetes and Supply Scheme provides the majority of funds to Diabetes Australia-Victoria as the coordinating centre. This con-

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tributes towards national ministration, training and quality assurance costs. Ongoing dedicated funding is needed to maintain finance for the OzDAFNE programme at the national level, and to assist individual centres to sustain it. Rebates from private health insurance companies are being investigated as a potential source of funding.

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Educators often comment that the DAFNE training was the best professional development they have ever experienced. … producing similar benefits Despite the particular challenges involved in bringing DAFNE to Australia, the OzDAFNE outcomes are quite similar to those shown in Germany and the UK. An audit of OzDAFNE data on clinical outcomes included 145 people (preDAFNE and 12 months post-DAFNE) with type 1 diabetes who participated in courses at seven Australian diabetes centres between February 2005 and March 2007. A year after taking part in DAFNE, our participants had better blood glucose control (average HbA1c fell from 8.2% to 7.8%), reduced incidence of severe hypoglycaemia, slightly reduced weight (average weight dropped from 75.1 kg to 74.2 kg) and reduced anxiety, depression and diabetes-related distress.1 OzDAFNE educators report enthusiasm for the DAFNE programme and often comment that the DAFNE training was the best professional development they have ever experienced. This enthusiasm was evident in June 2011, when

75% of DAFNE educators from all over Australia and New Zealand attended our inaugural OzDAFNE professional development day in Melbourne. Despite the many challenges involved in implementation in Australia, the outcomes of the course participants described above speak volumes for DAFNE’s efficacy and the potential benefits of its expansion. Those positive results and the passion of the OzDAFNE educators support the maintenance of the courses and the implementation of the programme throughout Australia.

Dianne Harvey Dianne Harvey is dietitian and OzDAFNE coordinator, Australia.

References 1 M cIntyre HD, Knight BA, Harvey DM,

et al. Dose adjustment for normal eating (DAFNE) – an audit of outcomes in Australia. MJA 2010; 11: 637-40.

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Never say never – implementing DAFNE in Kuwait Ebaa Alozairi

There is overwhelming evidence that improving HbA1c reduces the risk of longterm complications and improves quality of life. In Kuwait, however, few people with diabetes reach their target levels and, as a consequence, remain at risk of diabetes complications. Healthcare professionals ask the people in their care to test their blood glucose three or four times a day. Yet in many regions, very few people with diabetes have received education on how to adjust their insulin according to their blood glucose results. Unless appropriate education and skills training are provided, blood glucose outcomes will not be affected – however much encouragement is offered. Ebaa Alozairi describes successful efforts to bring to Kuwait an educational and therapeutic approach based on dose adjustment, the recent achievements and current progress of DAFNE trainers and graduates, and plans for expansion throughout the Middle East.

DiabetesVoice

There is lack of diabetes educators and dietitians in Kuwait, and resources vary according to geography. Some diabetes teams offer a substantial amount of education but this is delivered largely on a one-to-one basis and many hospitals lack facilities. Many dietitians in Kuwait either follow the North American methods – either an insulin-to-carbohydrate ratio of 1:15 or varying the ratio according to total daily dose. Both of these present mathematical challenges to people with diabetes, who often need to use a calculator to work out the correct dose. While I was in the UK receiving clinical diabetes and endocrine training a few years ago, I travelled to the Joslin Diabetes Center, Boston, USA, with a Fulbright grant. The Joslin offered an impressive variety of high-quality courses for people with diabetes. I observed many people who had travelled long distances across borders to attend sessions. Strikingly though, none of the courses had undergone randomized controlled trials or had external quality assurance. Back in the UK, I undertook training to become a DAFNE doctor. I was impressed by that programme too: it seemed highly practical – the use of 10 g rather than 15 g carbohydrate portions on which to base insulin, making it easier for people with diabetes to do the necessary maths. Firmly based on empowerment, the programme was methodologically sound, not unduly prescriptive and highly valued by the participants. I went on to complete the quality assurance training offered by the UK programme. My idea

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was to transfer the DAFNE model to Kuwait, where I was convinced it would bring considerable benefits to people with diabetes and the Ministry of Health.

Founded on empowerment, DAFNE is methodologically sound, not unduly prescriptive and highly valued by participants. Initially, I was concerned that the model might not work in Kuwait mainly due to cultural differences: patient empowerment is not standard practice for Middle Eastern doctors and people with diabetes in many cases prefer to depend on their healthcare professional for guidance. The change from a prescriptive approach to patient-centred care is difficult to implement and can be confusing from the patient's perspective. The UK team agreed to support the pilot programme us throughout its implementation in Kuwait. In 2009, two dietitians from the Al Amiri hospital made a structured observational visit to the UK and completed DAFNE training. Back in Kuwait, the DAFNE materials were translated into Arabic and adapted to Kuwaiti culture. With support from the head of the diabetes unit at Al Amiri, we were able to pilot DAFNE. Initially, two courses were conducted for groups of women and men separately; a third course was mixed gender. The first

sessions were held in the morning, like in the UK. However, we encountered difficulties recruiting, as participants generally were not able to take time off from work. Moreover, many people did not want to disclose their diabetes in the workplace due to the strong sense of stigma related to having the condition. So the sessions were moved to an afternoon and evening timetable, which was welcomed by participants. During the pilot study, all participants expressed their satisfaction – equipped, in many cases, for the first time, with the skills they needed to manage their own diabetes. Many course participants with type 2 diabetes, which is very prevalent in Kuwait, were happy to meet others with less-common type 1 diabetes, which generated a positive discussion. Never say never! Having completed our pilot, the team presented preliminary findings and a plan to extend DAFNE nationwide to the Kuwait Diabetes Society. Despite our positive results, some senior members objected to the idea of group education. They regarded people in Kuwait as very discreet and would be unwilling to discuss their diabetes in a group. So despite our findings, the model was not altogether welcomed. Also, some professionals were not happy that DAFNE educators were adjusting insulin dosages instead of the relevant physician. However, the positive experiences of people with diabetes engaged in DAFNE and our never-say-die attitude drove the educators on to continue delivering DAFNE – albeit in only one hospital.

Participants expressed their satisfaction – equipped for the first time with the skills they needed to manage their own diabetes.

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Having successfully presented our findings to the newly appointed Director General of the Dasman Diabetes Institute, the DAFNE programme was recognized as the national course for type 1 diabetes. To be held at the Dasman Institute, it the course is open to people from all regions of the country. All people with type 1 diabetes are welcomed to register and the referral is open to all doctors living and working in Kuwait. The DAFNE project was launched at the Dasman Institute in November 2010. The structured teaching programme is delivered to groups of between six and eight participants under the supervision of DAFNE-trained educators. Healthcare professionals are invited to attend as observers but with a maximum of two per course. Most of the training is built around group work, sharing and comparing experiences with other participants. However, there are opportunities for each person to speak to DAFNE educators individually. Acceptance has been remarkably good; a number of DAFNE graduates have requested that the course be extended to two weeks! To date, eight courses have been completed in 10 months. A special one-day Ramadan course recently gave participants the opportunity to practise estimating the carbohydrate content of particular complex foods that are eaten mainly during Ramadan. The DAFNE Kuwait collaborative has established strong links with the UK, keeping the UK DAFNE group informed at all stages, to ensure consistent standards of delivery. With supports from UK DAFNE and the Dasman Diabetes Institute, Kuwait has been made the training centre for the Middle East region. We are delighted to provide training to any centre wishing to adopt this very effective programme.

Acceptance has been remarkably good; a number of DAFNE graduates have requested that the course be extended to two weeks! Positive outcomes To date, 45 people with diabetes have completed the DAFNE course. None have required admission to hospital because of their blood glucose. There has been a marked reduction in rates of hypoglycaemia; most people are requiring fewer visits to the healthcare professionals and consuming less than half of their pre-course insulin dosages. Many have

DiabetesVoice

improved HbA1c. Most strikingly, some graduates want refresher courses, proposing that they be able to follow their HbA1c as a group. DAFNE is now part of the compulsory training for doctors during the Diabetes and Endocrinology degree programme in Kuwait. What do DAFNE graduates say? It is encouraging to read the universally positive feedback from people who have completed a DAFNE course in Kuwait. A few of the graduates, without any prompting, wrote an article in English and Arabic, which was published in a number of newspapers, describing their very positive experience. Another participant paid for all course members to dine together and refused offers of payment from his peers, saying that he was “relatively new to my diabetes journey and for the first time I feel normal”. The positive feedback here is stronger even that that I had observed in UK. Future plans Currently, all the various psychological questionnaires and biochemical data (weight, hypoglycaemic events, HbA1C) are collected both at baseline and at follow-up, and crosscultural differences will be examined. A Ramadan-specific trial will be carried out next year. People with type 1 diabetes and healthcare professionals from the Middle East are welcomed to attend DAFNE Kuwait to observe the positive impacts.

Ebaa Alozairi Ebaa Alozairi is Assistant Professor at Kuwait University, nutrition specialist on the American Board of Physician, a consultant in Diabetes and Endocrinology and lead DAFNE clinician in Kuwait (alozairi@hsc.edu.kw).

Acknowledgments

The author would like to thank Simon Heller and DAFNE UK, the Kuwait DAFNE educators, the Dasman Diabetes Institute, the Head of the Diabetes Unit at Al Amiri Hospital, DAFNE graduates and healthcare professionals in Kuwait.

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Great results for DAFNE Singapore – next stop, South-East Asia Su-Yen Goh and Daphne Gardner

In November 2010, a pioneering team comprising a nurse educator, a dietitian and an endocrinologist from Singapore General Hospital completed a DAFNE course and postcourse educator training in Australia, at the OzDAFNE centre, Diabetes AustraliaVictoria. This was the first step in a process that successfully took the DAFNE model Singapore. The Clinical Leads for the Singapore initiative describe the experience so far and look to the future and continental development of their growing programme.

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Upon returning to Singapore, the newly christened SgDAFNE team adapted the materials shared by OzDAFNE and developed a culturally relevant SgDAFNE programme, including a modified carbohydrate portion booklet for use in Singapore and the rest of South-East Asia. To the best of our knowledge, ours is the first centre in Asia to offer DAFNE, and we are growing and developing. With two courses given in 2011, and at least three more scheduled for 2012, we also provide healthcare professional DAFNE awareness events/ sessions, such as on World Diabetes Day this year. The inaugural course for SgDAFNE in April 2011 was conducted under the watchful eye of an auditor from Diabetes Australia, and OzDAFNE have included us in the OzDAFNE collaborative. We are committed to contributing to the OzDAFNE database until such time as the SgDAFNE

programme is able to establish its own independent collaborative.

DAFNE was a paradigm shift for people who were not attuned to the concept of empowerment. Many challenges have surfaced during the development and implementation of SgDAFNE. Prior to DAFNE, there were no structured or standardized education and self-management programmes for people with type 1 diabetes in Singapore. This was a paradigm shift for most people, some of whom functioned in a rather paternalistic and hierarchical doctor-patient relationship and were not attuned to the concept of empowerment. The programme demands a higher intensity of self-monitoring of blood glucose compared with routine care; purchases of glucometer and test

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strips are out-of-pocket expenses with no insurance reimbursement or government healthcare financing available. Some people previously had never done blood ketone testing, as the cost is prohibitive – up to USD 4 per test strip.

The very act of injecting insulin in public was a daunting barrier for some. Another major task was developing the carbohydrate counting material for the local context. The dietetics team laboured long and hard, and were thrilled to produce our own SgDAFNE carbohydrate portion booklet in the first quarter of 2011. In adapting the diabetes education material, we had to take into consideration the socio-cultural contexts of food and diabetes: many Singaporeans dine out for most meals of the day, and it was often challenging to calculate hidden carbohydrates (such as

DiabetesVoice

in sauces and gravies) or estimate accurately portion sizes. Many Singaporeans tend to be ‘grazers’, snacking throughout the day rather than eating a full meal at regular times. Although the DAFNE curriculum equips people with the ability to calculate and dose for snacks, difficulties arose in terms of interpreting pre-meal glucose concentrations and insulin stacking. The very act of injecting insulin in public, as well as weighing foods, was a daunting barrier for some.

To the delight of all involved, some people have had dose reductions of between 25% and 40%. With two groups of graduates, the SgDAFNE team has also found that the local people may be more insulin

sensitive (requiring 1:1 rather than 1.5:1 or 2:1 ratios) than previously thought. The issue of over-insulinization before entering the programme has also surfaced; to the delight of participants and the SgDAFNE team alike, some people have had dose reductions of between 25% and 40%. SgDAFNE has been an exciting journey for all involved and we look forward to extending the programme island-wide and throughout South-East Asia.

Su-Yen Goh and Daphne Gardner Su-Yen Goh and Daphne Gardner are the Clinical Leads for SgDAFNE at Singapore General Hospital.

Acknowledgement

SgDAFNE was supported by an unrestricted educational grant from sanofi-aventis Singapore with additional support from Abbott Diagnostics.

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Making progress with immune therapies for type 1 diabetes Mark Peakman

Thirty-five years on from the demonstration that type 1 diabetes has an autoimmune basis, we have learned an enormous amount about the disease. We know its genetic basis (immune genes), its pathological basis (immune cells) and we would expect to be converting this insight into therapeutic advances (immunebased). Certainly, the field of immunotherapy for type 1 diabetes is very active. Here, Mark Peakman reviews the progress being made and scans the horizon for the most likely future breakthroughs.

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In the mid-1970s, autoantibodies that bind to targets in cells in the islets of Langerhans were described in the scientific literature. They have since become established as a major biomarker for type 1 diabetes, both at diagnosis and in the preclinical prodrome. We have since learned that the disease results from autoimmune destruction of the insulin-secreting beta cells in the islets, a process involving the T and B lymphocytes and dendritic cells of the immune system (Figure). Focusing on the beta cells The disease arises on a distinctive genetic background, in which variants of genes that regulate immune responses are the predominant feature. This understanding, allied with a range of therapeutics (many arising from the field of transplantation), a better understanding of how immunological tolerance is maintained and lost, and several animal

models in which new therapies can be tested, has led to a period of intense activity as these advances are translated. Clinical trial consortia, such as Type 1 Diabetes TrialNet and the Immune Tolerance Network, linking centres with expertise in the field to do collaborative research, have been pivotal in promoting the acceptance of study designs that focus on, and are adequately powered to detect, the preservation of beta-cell function (measured as the C-peptide response to a challenge) in new-onset type 1 diabetes, typically measured at six, 12 and 24 months after the introduction of the novel therapy. Stimulated C peptide has proved an acceptable surrogate for any beneficial effects of therapy in preserving remaining beta cells, which would be expected to have an impact on glycaemic control if sufficient endogenous insulin production remains. A further emerging principle

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cytokines

3. Via blood

β cells

TREG CTL CTL 1. Islet

DC 2. Pancreatic lymph node

(shown in white) the pancreatic islet express proteins The insulin-secreting beta cells of B and cytotoxic (shown in pink) and activate T and that are picked up by dendritic cells cytokines as ) to destroy the beta cells, releasing lymphocytes (green, yellow and blue in black can damp down the process. they do. Regulatory T cells shown

is that trials are more likely to be able to show benefit if studies are started soon after diagnosis; 100 days from initial presentation to the first administration of the study drug is now the norm. What kind of therapeutic strategies are emerging? There are currently two main competing solutions being developed which target components of the immune system. The first is immune modulation via such strategies as biologics that target T lymphocytes, B lymphocytes, co-stimulatory molecules and cytokine pathways, among others (see Figure). This is ‘nonspecific immunotherapy’ is designed to act systemically, making no attempt to target only the minority of T lymphocytes that cause beta-cell damage. The lead compounds here have been two monoclonal antibodies directed against the CD3 protein on the surface of T cells. Although it is not exactly clear how anti-CD3 therapy works, two Phase II

DiabetesVoice

studies have indicated beneficial effects on C-peptide decline. Follow-up studies have even shown the potential for a prolonged effect, with preservation of C peptide for several years in some people. Unfortunately, the data emerging from subsequent Phase III studies ending in 2011 were mixed, although this may be attributable to the study design. Otelixizumab (GlaxoSmithKline/Tolerx, Inc) was reported to have failed Phase III trials in March 2011. The anti-CD3 antibody Teplizumab, developed by Macrogenics and Eli Lilly, also did not meet endpoints in a Phase III trial in type 1 diabetes but published data indicates that C peptide was nonetheless preserved. It is to be hoped that these drugs will undergo continued development to try and identify optimal conditions for their use. Another Phase II trial suggests that interfering in pathways of T-cell activation

with the drug Abatacept (an inhibitor of T-cell co-stimulation) also can be beneficial, and an earlier report had indicated that depletion of B lymphocytes using Rituximab has clear, but transient benefits. Thus, a small arsenal of agents is being identified. Importantly, safety and feasibility in the setting of newonset disease is becoming established, along with the precedent of enrolling adolescents and children into these studies – important, as new-onset type 1 diabetes is common in this age group. Antigen-specific immunotherapy The second approach is termed antigenspecific immunotherapy (ASI). It is well established that induction and restoration of immune tolerance is achieved by administering the very target (autoantigen) against which the destructive autoimmune response is directed. This may seem counter-intuitive and likely to ramp up the autoimmunity; but if the autoantigen is given under appropriate conditions, it seems to work, at least in model systems. There are different ASI strategies. Using short antigenic peptides representing sequences (epitopes) recognized by T lymphocytes – known as peptide immunotherapy (PIT) – is in Phase I-III development in clinical allergy and

Strategies for halting immune damage to beta cells Immune suppression with drugs that inhibit T lymphocyte function Immune modulation that promotes a better immune system balance Strategies to specifically promote immune regulation in islets Combinations of the above

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other autoimmune diseases. PIT has several advantages: highly efficient target delivery; avoidance of antibody development; relatively inexpensive synthesis costs; and the fact that the dose is not limited by the biological effects of the parent molecule. In Phase I studies in our centre, it appears safe and well tolerated. Future studies will be needed to evaluate its full potential and the best setting for its deployment. Alternatively, whole proteins from the beta cell have been used. The lead here is insulin, given orally to first-degree relatives without diabetes who already have islet cell autoantibodies. A clinical study conducted by TrialNet is based on sub-study data that suggest that firstdegree relatives who have high titres of anti-insulin autoantibodies might expect particular benefit from this approach in terms of reduced progression to clinical disease. Giving insulin by mouth has no metabolic effect at the dose used but takes advantage of the natural immunological phenomenon that ingested protein antigens are well tolerated by the immune system. The study will report in one or two years and, it is hoped, will provide better understanding of the mechanisms of oral immunological tolerance in humans. The other advanced drug in the ASI area was the whole beta-cell protein/ autoantigen GAD65 (glutamic acid decarboxylase isoform 65 kDa; Diamyd® GAD65). Although promising results (preservation of insulin reserve) were reported in a post-hoc analysis of a subset of cases treated with GAD65-alum prime and boost in 2008, a repeat conducted by TrialNet reported no benefit in 2011. Full reporting of the results of a Phase III study are expected, although preliminary reports suggest no preservation of C-peptide preservation.

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What does the future hold for type 1 diabetes therapeutic strategies? Can sense be made of these ebbs and flows of positive and negative clinical trial data? There is a picture emerging that non-specific, biologic-based therapies are effective when given close to diagnosis, whereas antigen-specific immunotherapy is not – probably because it operates sub-optimally in such an active inflammatory setting. Encouraging data from oral insulin studies suggest that building tolerance against beta-cell autoantigens may be useful if given early and for prolonged periods. Moreover, its excellent safety profile means that administration in at-risk groups is feasible. Future developments for ASI will centre on maximizing this potential, probably using multiple antigens or better delivery systems. New therapeutic modalities at very early stages of evaluation include attempts to bolster immune regulation using the approach of adoptive cell transfer. It seems probable that, like many complex human disorders of unknown aetiology, type 1 diabetes ultimately may be controlled via a therapeutic approach that combines multiple agents with different

modes of action. The advantages of such a strategy include minimizing the toxicities and realizing the synergies that enhance and prolong efficacy. The degree to which non-specific immunotherapy and antigen-specific therapy are combined may need to be different according to the stage of disease, for lower risk in the pre-diabetes setting and higher potency in newly diagnosed people.

Mark Peakman Mark Peakman is Professor of Clinical Immunology at King's College London, School of Medicine, UK..

Further reading Staeva-Vieira T, Peakman M, von Herrath M. Translational mini-review series on type 1 diabetes: Immune-based therapeutic approaches for type 1 diabetes. Clin Exp Immunol 2007; 148: 17-31. eakman M, von Herrath M. Antigen-specific P immunotherapy for type 1 diabetes: maximizing the potential. Diabetes 2003; 59: 2087-93. atthews JB, Staeva TP, Bernstein PL, et al. M Developing combination immunotherapies for type 1 diabetes: recommendations from the ITN-JDRF Type 1 Diabetes Combination Therapy Assessment Group. Clin Exp Immunol 2010; 160: 176-84. www.diabetestrialnet.org www.immunetolerance.org www.jdrf.org

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All that glitters is why we need bet trials and reporti Rury R Holman

In an age of increasing global information overload, it is becoming progressively more difficult to discern real health and safety signals, or potentially beneficial possibilities, from background noise. The explosion in exploratory analyses of emerging large-scale medical record databases and registries has helped to highlight many potential issues of interest. But establishing the reality of such uncontrolled ‘findings’ can be challenging. A major concern is that apparent associations, which are identified by these often opportunistic analyses, are frequently reported by the media and others as potential ‘medical breakthroughs’ or as possible ‘safety concerns’ for existing therapies. Remarkably, such reports often give equal (or greater) prominence to unsubstantiated exploratory findings than they do to robust results from properly designed and conducted trials. As a result, these reports can raise hopes or fears inappropriately in the population at large. In addition, the almost daily publication of frequently conflicting findings diminishes public faith in scientific pronouncements and may preclude people taking note of proven results that could be crucial to their future health.

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not gold – ter ng

An evidence-based approach to medicine has been adopted; it is recognized that intuition, unsystematic clinical experience and pathophysiological rationale are insufficient grounds for clinical decision making. Clinical observations can produce useful insights but are hindered by small sample sizes and the limitations in human processes for making inferences. Observational studies can provide compelling evidence but inevitably are limited by the possibility that apparent differences are really due to differences in patients’ prognoses secondary to the post hoc selection of treatment and control groups. One such example was the observational finding that women who took hormone replacement therapy appeared to have a reduced risk of coronary heart disease. A randomized controlled trial (RCT), however, showed the reality: that hormone replacement therapy increases rates of thromboembolic events and gallbladder disease.1 (The probable explanation is that early adopters of hormone replacement therapy were more likely to have been health-aware women with correspondingly healthier lifestyles.)

Randomization is too important to leave to chance. RCTs provide the highest level of evidence and remain the gold standard, although they are not always feasible: no one has yet conducted a RCT for parachutes! All trials attempt to discover ‘the truth’ but can only provide evidence of the truth, not absolute proof. ‘The truth’ would be the answer to a research question arrived at by conducting a perfectly executed study on everyone with the characteristics of interest. Participants in RCTs receive the interventions at random to help ensure similarity of characteristics both known and unknown

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– such as demographics, genetic make up, lifestyle choices – at the start of the comparison. Individuals, groups and the order in which measurements are obtained all can be randomized. Randomization must be conducted in such a way that the allocation of different interventions cannot be influenced by participants or those conducting the study – randomization is too important to leave to chance. Clinical trial design and reporting has improved immeasurably over time, especially with the widespread adoption of the CONSORT guidelines.2 RCTs seek to establish whether different interventions lead to different outcomes. However, in order for a difference to be a difference, it must make a difference! A numerical difference may be statistically significant but if the size of the effect is not clinically relevant, then it is of little import. Since the truth is rarely absolute, many decisions in medicine continue to be made on the balance of probabilities and epidemiological data. Observational data can identify signals of potential good or harm, but cannot assign causality. Meta-analyses, however well conducted, depend ultimately only on trials and studies that have been performed. If the appropriate trials have not been conducted, or indeed have not been reported, then the conclusions will be flawed. Fortunately, procedures for undertaking meta-analyses and systematic reviews have become much more robust, particularly with the aid of the Cochrane Collaboration,3 among others. Clearly, a more systematic approach is needed when assessing rapidly evolving data from a myriad of sources that have highly variable provenance. One such example is the Mini-Sentinel pilot,4 which is giving the US Food and Drink

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Adminsitration (FDA) the opportunity to develop the data infrastructure and scientific tools needed to conduct active safety surveillance of medical products within a distributed system of large private and public healthcare databases. Equally, trials are moving into a new era, particularly in diabetes. The FDA has issued industry guidance for the evaluation of cardiovascular risk in new therapies to treat type 2 diabetes.5 This requires that as they are assessed for possible licensing, new agents be studied in such a way as to ensure that their potential to increase cardiovascular risk does not exceed stipulated thresholds. This cardiovascular safety requirement, which has added greatly to the development costs of new drugs, has also led to a rapid increase in the number of cardiovascular outcome trials being performed, with some 14 studies currently recruiting over 110,000 participants. These large-scale, simple, mostly double-blind trials comparing new agents with placebo, will increase substantially the amount of clinically relevant information for treating type 2 diabetes.

The research community has a duty of care to report trials, studies and ‘incidental’ findings in context. However, smarter trials are needed. Testing multiple interventions in factorial or head-to-head designs would be more efficient, more informative and more cost-effective. While trials are likely to be powered based on the time to the first primary endpoint, subsequent events also should be captured routinely and evaluated in detail to maximize our understanding of the

full impact of treatments – with respect to both benefits and risks. The research community has a duty of care to report trials, studies and ‘incidental’ findings in context. In particular, a more rigorous approach for reporting observational findings is needed. In order to help provide guidance for the media and others when publicizing results from exploratory studies, systematic reviews, meta-analyses and RCTs, journals should consider adding an evidence level rating to relevant publications. Press releases issued by investigators, sponsors, funding bodies and journals could do much more to ensure a correct perspective is given to media coverage. Ultimately, routine sharing of individual-level data from completed trials will help to decide what it is that glitters and identify any hidden nuggets, as has been done successfully with the Cholesterol Treatment Trialists Collaboration and similar collaborative efforts.

Rury R Holman Rury R Holman is the Director of the University of Oxford Diabetes Trials Unit, Honorary Consultant Physician and a Senior Investigator at the UK National Institute for Health Research.

References 1 H ulley S, Grady D, Bush T, et al for

the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998; 280: 605-13.

2 A ltman DG, Schulz KF, Moher D,

et al for the CONSORT Group. The Revised CONSORT Statement for Reporting Randomized Trials: Explanation and Elaboration. Ann Intern Med 2001; 134: 663-94.

3 w w.cochrane.org 4 w ww.mini-sentinel.org 5 w w.fda.gov/downloads/Drugs/

GuidanceComplianceRegulatory Information/Guidances/UCM071627.pdf

December 2011 • Volume 56 • Special Issue 2

LANTUS ® Abbreviated Prescribing Information. 1. NAME AND PRESENTATION: Lantus 100 U/ml, solution for injection of insulin glargine is available in a vial of 5 & 10 ml, cartridge of 3 ml for the following reusable pens only: Optipen, ClikSTAR Autopen 24 or Tactipen, cartridge of 3 ml for Opticlik, and prefilled disposable pens of 3 ml for Lantus Optiset & Lantus Solostar. 2. THERAPEUTIC INDICATIONS: Treatment of adults, adolescents and children of 6 years or above with diabetes mellitus, where treatment with insulin is required. 3. POSOLOGY AND METHOD OF ADMINISTRATION: Lantus should be administered once daily at any time but at the same time each day. The dosage and timing of dose of Lantus should be individually adjusted. In patients with type 2 diabetes mellitus, Lantus can also be given together with orally active antidiabetic agents. In children older than 6 years Lantus should be given in the evening. In children below the age of 6 years, Lantus should only be used under careful medical supervision. When changing from a treatment regimen with an intermediate or long-acting insulin to a regimen with Lantus, a change of the dose of the basal insulin may be required and the concomitant antidiabetic treatment may need to be adjusted. Close metabolic monitoring is recommended. Administration: Lantus is administered subcutaneously, should not be administered intravenously and must not be mixed with any other insulin or diluted. For administration details see full SmPC. Patients must be educated to use proper injection techniques and insulin label must always be checked before each injection to avoid medication errors between Lantus and other insulins. Renal impairment & hepatic impairment: insulin requirements may be reduced. Elderly: deterioration of renal function may lead to a decrease in insulin requirements. 4. CONTRA-INDICATIONS: Hypersensitivity to the active substance or to any of the excipients. 5. SPECIAL WARNINGS AND PRECAUTIONS FOR USE: Lantus is not the insulin of choice for the treatment of diabetic ketoacidosis. Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand, type, origin and/or method of manufacture may result in the need for a change in dose. The warning symptoms of hypoglycaemia may be changed, less pronounced or absent in certain risk groups: for all details see the full SmPC. If pioglitazone is used in combination with insulin, especially in patients with CHF risk factors, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.6. DRUG INTERACTIONS: Substances that may enhance or reduce the blood-glucose-lowering activity and increase susceptibility to hypoglycaemia are detailed in the full SmPC. 7. PREGNANCY AND LACTATION: No clinical data from clinical trials are available. A moderate amount of data on pregnant women exposed indicates no adverse effects on pregnancy and no malformation nor feto/neonatal toxicity. Lantus may be considered during pregnancy, if necessary. Breastfeeding women may require adjustments in insulin dose and diet. 8. EFFECTS ON ABILITY TO DRIVE: Patients should take precautions to avoid hypoglycaemia whilst driving. 9. UNDESIRABLE EFFECTS: Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. Lipohypertrophy may occur at the injection site. Injection site reactions including redness, pain, itching, hives, swelling, or inflammation. For uncommon & rare adverse events please consult the full SmPC. 10. OVERDOSAGE: Mild episodes of hypoglycaemia can usually be treated with oral carbohydrates. More severe episodes may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. 11. PHARMACOLOGICAL PROPERTIES: ATC Code: A10A E04. 12. MARKETING AUTHORIZATION HOLDER: Sanofi-Aventis Deutschland GmbH, D-65926 Frankfurt am Main. Abbreviated Prescribing Information based on the EU SmPC as of Jan 2011. Always refer to the full Summary of Product Characteristics (SmPC) before prescribing.

- GLB.DIA.11.11.36 - 11/11

APIDRA® Abbreviated Prescribing Information. 1. NAME AND PRESENTATION: Apidra 100 U/ml, solution for injection of insuline glulisine is available in a vial of 10 ml, cartridge of 3 ml for reusable devices Optipen, ClikSTAR, Autopen 24 or Tactipen & cartridge for Opticlik, and prefilled disposable pens of 3ml for Optiset & Solostar. 2.THERAPEUTIC INDICATIONS: Treatment of adults, adolescents and children, 6 years or older with diabetes mellitus, where treatment with insulin is required. 3. POSOLOGY AND METHOD OF ADMINISTRATION: Apidra should be given by subcutaneous injection shortly (0-15 min) before or soon after meals or by continuous subcutaneous pump infusion. Apidra for injection in a vial can be administered intravenously. Apidra should be used in regimens that include an intermediate or long acting insulin or basal insulin analogue and can be used with oral hypoglycaemic agents. The dosage of Apidra should be individually adjusted. For administration details see full SmPC. Patients must be educated to use proper injection techniques and insulin label must always be checked before each injection to avoid medication errors between Apidra and other insulins. Renal impairment & hepatic impairment: insulin requirements may be reduced. Elderly: deterioration of renal function may lead to a decrease in insulin requirements. 4. CONTRA-INDICATIONS: Hypersensitivity to insulin glulisine or to any of the excipients. Hypoglycaemia. 5. SPECIAL WARNINGS AND PRECAUTIONS FOR USE: Transferring a patient to a new type or brand of insulin should be done under strict medical supervision. Changes in strength, brand, type, source and/or method of manufacture may result in the need for a change in dose. Concomitant oral antidiabetic treatment may need to be adjusted. Adjustment of dosage may be necessary if patients undertake increased physical activity or change their usual meal plan. Conditions which may take the early warning symptoms of hypoglycaemia different or less pronounced are detailed in the full SmPC. Contains less than 1 mmol sodium per dose. Contains metacresol. If pioglitazone is used in combination with insulin, especially in patients with CHF risk factors, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs. 6. DRUG INTERACTIONS: Substances that may enhance or reduce the blood-glucose-lowering activity and increase susceptibility to hypoglycaemia are detailed in the full SmPC. 7. PREGNANCY AND LACTATION: No adequate data are available. Insulin requirements may decrease during the first trimester and generally increase during the second and third trimesters. Breast-feeding mothers may require adjustements in insulin dose and diet. 8. ABILITY TO DRIVE: Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. 9. UNDESIRABLE EFFECTS: Hypoglycaemia is the most frequent undesirable effect of insulin therapy. Injection site reactions and local hypersensitivity reactions. For uncommon & rare adverse events, consult the full SmPC. 10. OVERDOSAGE: Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. Severe hypoglycaemic episodes can be treated by glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously or by glucose given intravenously. 11. PHARMACODYNAMIC PROPERTIES: ATC code: A10AB06. 12. MARKETING AUTHORIZATION HOLDER: Sanofi-Aventis Deutschland GmbH, D-65926 Frankfurt am Main. Abbreviated Prescribing Information based on the EU SmPC as of January 2011. Always refer to the full Summary of Product Characteristics (SmPC) before prescribing. INSUMAN®* Abbreviated Prescribing Information. 1. Name And Presentation: Insuman® (insulin human) 40 IU/ml or 100 IU/ml is a regular insulin solution (Rapid), or an isophane insulin suspension (Basal) or biphasic isophane insulin suspension (Comb 15-25-30-50) consisting of 15%, 25% , 30%, or 50% dissolved insulin and complementary portion of 85%, 75%. 70%, or 50% crystalline protamine insulin respectively. Insuman® is provided in a vial (5 or 10 ml) or cartridge (3 ml) for use with the reusable devices OptiPen, ClikSTAR, Autopen 24 or Tactipen and cartridge for OptiClik or pre-filled disposable pens (3 ml) SoloSTAR and OptiSet. Insuman® is also available as injection vial & cartridge for infusion (Insuman® Infusat 100 IU/ml). 2. Therapeutic Indications: Diabetes mellitus where treatment with insulin is required. Insuman® Rapid is suitable in hyperglycaemic coma & ketoacidosis, as well as for pre-, -intra- and post-operative stabilisation in patients with diabetes mellitus. 3. Posology And Method Of Administration: The dosage and timings should be individually adjusted. Daily doses and timing of administration: there are no fixed rules for insulin dose regimen. However, the average insulin requirement is often 0.5 to 1.0 IU per kg body weight per day. Insuman® is injected subcutaneously 15 to 20 minutes (Rapid) or 45 to 60 minutes (Basal) or 30 to 45 minutes (Comb 15-25-30) or 20 to 30 minutes (Comb 50) before a meal. Insuman® Rapid for injection in a vial may also be administered intravenously (intensive care conditions). Insuman® Basal and Comb must never be injected intravenously. Insuman® Infusat is used with an external pump, one part of the daily insulin dose is infused continuously (“basal rate”), and the rest is administered in the form of bolus injections before meals. Refer to the infusion pump operating instructions for detailed information. In the treatment of severe hyperglycaemia or ketoacidosis, insulin administration regimen requires close monitoring. Secondary dose adjustment: Improved metabolic control may result in increased insulin sensitivity, leading to a reduced insulin requirement. Dose adjustment may also be required, if the patient’s weight or life-style changes. Other circumstances arise that may promote an increased susceptibility to hypo- or hyperglycaemia. Patients must be educated to use proper injection techniques. For administration details see full SmPC. Hepatic or renal impairment and elderly: insulin requirements may be reduced. 4. Contra-Indications: Hypersensitivity to the active substance or to any of the excipients. Insuman® Rapid must not be used in external or implanted insulin pumps or in peristaltic pumps with silicone tubing. Insuman® Basal and Comb must not be administered intravenously and must not be used in infusion pumps or external or implanted insulin pumps. Insuman® Infusat must not be used in peristaltic pumps with silicone tubing. Refer to the technical manual for contraindications relating to the use of insulin pumps. 5. Special Warnings And Precautions For Use: Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand, type, origin and/or method of manufacture may result in the need for a change in dosage. Following transfer from an animal insulin to human insulin, dose regimen reduction may be required. The warning symptoms of hypoglycaemia may be changed, less pronounced or absent in certain risk groups: for all details see the full SmPC. 6. Drug Interactions: Substances that may enhance or reduce the blood-glucoselowering activity and increase susceptibility to hypoglycaemia are detailed in the full SmPC. 7. Pregnancy And Lactation: No clinical data on exposed pregnancies are available. Insulin does not cross the placental barrier. Caution should be exercised when prescribing to pregnant women. No effects on the suckling child are anticipated. Insuman® can be used during breast-feeding. Lactating women may require adjustments in insulin dose and diet. 8. Effects On Ability To Drive: Patients should take precautions to avoid hypoglycaemia whilst driving. 9. Undesirable Effects: Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. Oedema, injection site reactions. For uncommon & rare adverse events please consult the full SmPC. 10. Overdosage: Mild episodes of hypoglycaemia can usually be treated with oral carbohydrates. More severe episodes may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. 11. Pharmacodynamic Properties: ATC code:A10AC01. 12. Marketing Authorization Holder: Sanofi-Aventis Deutschland GmbH, D-65926 Frankfurt am Main, Germany. Abbreviated Prescribing Information based on the EU SmPC as of February 2011. Always refer to the full Summary of Product Characteristics (SmPC) before prescribing.

MANAGEMENT, CARE AND PREVENTION

Back to the future: investigating new treatments for type 1 diabetes using old inexpensive drugs Denise Faustman and Miriam Davis

"Great disappointments in medicine frequently give rise to great innovation – so the saying goes – but who expected a 20-year detour?" Denise Faustman and her team were disappointed by their findings from human islet cell transplantation trials and felt compelled to return to the bench for 20 years to understand why the trials had been less successful than had been hoped. They first turned to an animal model of type 1 diabetes, which, just as in people, features an autoimmune assault on the insulin-producing islet cells in the pancreas. The animal model provided an opportunity to tease apart the immune system that triggers the disease. Over the next 10 years, they turned to studying the blood of large numbers of people with type 1 diabetes, hoping that the promising mouse data could be replicated in people. Those years-long and human and mouse studies suggested a new trigger for diabetes and, thus, a new approach to designing a clinical trial to test a vaccine – a vaccine we all hope will be an advance in treatment for people with type 1 diabetes, and if successful, a remarkably affordable one.

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More than 20 years ago, we began studying islet transplants in people with longstanding type 1 diabetes. We hoped to replenish the pancreas with healthy islet cells and thereby restore normal blood glucose. To achieve this, we replaced people’s islet cells with the same cells modified to shield them from rejection by their own immune system. In type 1 diabetes and other autoimmune diseases, the immune system regards some tissues, such as the insulin-secreting islet cells, as foreign, not part of the self, and it erroneously rejects and destroys them. At first, like many other islet transplant researchers worldwide, we thought the transplanted islet cells could be modified to escape the host's dysfunctional immune attack when combined with immunosuppressive drugs.

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But we did not realize that the diseased immune system was relentless: it continued to attack the newly transplanted islet cells even decades after diagnosis of the original disease. The autoimmunity once again affected the transplanted insulin-secreting cells, even when the host received drugs to prevent kidney rejection. We decided to take a step back and turned to studying how type 1 diabetes occurs and how rogue white blood cells are produced in the first place.

At first, we used a wellknown rodent model of type 1 diabetes called the non-obese diabetic (NOD) mouse. We wanted to learn more about the basic science underlying type 1 diabetes in the hope of finding more targeted ways to treat the disease. At that time, little was known about the kinds of rogue T cells that caused type 1 diabetes – except that they provoked a self-reactive and autoimmune disease. Laboratory-based research using rodents does not attract the interest that human clinical trials do but it is the surest means to reveal the complex disease processes. The unusual suspects: CD8 T lymphocytes Our first major breakthrough came in 1991, when we discovered that a new type of immune cell was in part responsible for attacking the islet cells in the pancreas – and this immune cell was not the one most scientists pursued. Indeed, other scientists received our finding

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with a degree of scepticism. We identified a major culprit as a type of immune cell known as a CD8 T lymphocytes (or CD8 T cells) in mice as well as and humans.1 Other immune cells might participate, but small, potent CD8 T cells were a primary perpetrator. Initially, we thought only people with diabetes had these disease-provoking CD8 T cells since when we studied identical twins, only the twin with diabetes had CD8 T cells. However, there are many different types of CD8 T cells. In type 1 diabetes, only a particular subset of CD8 T cells is defective – the subset that targets specific proteins found almost exclusively on the surface of islet cells. The quest to find the abnormality in CD8 T cells lasted nearly a decade. In the late 1990s, we published our findings that the educator cell of CD8 T cells was defective and thus the subset of rogue CD8 T cells might also have similar proteins with the defect.1

worldwide research had uncovered the mechanism by which TNF usually does not harm normal cells. However, the mutant defective CD8 T cells in humans and mice with diabetes became susceptible to specific killing, much like way bacteria but not normal cells of the body are vulnerable to antibiotics.2,3 We tested these findings first in tissue culture with isolated cells from people with diabetes, and showed, at albeit in culture, evidence that TNF selectively killed only the auto-reactive T cells.4 So we hypothesized that TNF also could be used as a treatment to destroy the abnormal CD8 T cells that caused type 1 diabetes, while sparing healthy cells. Simply put, we hoped that TNF would act like a laser-guided missile or an ‘antibiotic for diabetes’. That was the rationale behind our first experiments in NOD mice, then later in human blood samples and now in clinical trials.5,6

The protein defects enabled the abnormal CD8 T cell to escape the process of ‘T cell education’ – the process of learning to be tolerant to cells belonging to one’s own body. So as they matured, poorly educated CD8 T cells attacked the body’s own islet cells. But it turned out that one of the dark clouds we had identified also had a silver lining: the CD8 T cells became exquisitely vulnerable to death by a normal protein of the immune system known as tumour necrosis factor or TNF. We knew about TNF from many basic science studies; previous

December 2011 • Volume 56 • Special Issue 2

Finding a fast track to the clinic In engaging in clinical trials, our overarching aim is to develop only new therapies that are safe and widely affordable. Clinical development is often very slow but a short cut can save time and money and ensure that safety is achieved at earlier stages. Instead of directly administering TNF, which is not an existing drug and would require years of validated manufacturing processes, or testing it for safety on live primates, we chose an indirect method for TNF exposures that showed us faster path to the clinic: we administered an agent that induced internal TNF production using an 80-year-old vaccine called Balcillus-Calmette-Guerin (BCG). In 2001 and 2003, we published our results showing that the TNF inducer injected into end-stage diabetic animals was capable of selectively killing the defective CD8 T cells responsible for killing islet cells.5,6 The TNF inducer was an old fashion vaccine that was originally developed for protection from tuberculosis and treatment of bladder cancer. It was so successful that after 15 weeks the animals with diabetes began to produce normal blood glucose levels for sustained periods of time. For the first time, killing rogue T cells using TNF was followed by brisk islet regeneration. The concept that diabetes might be treated by targeted disease removal was surprising and pleasing news, especially since it worked even in advanced disease. That additional finding was first met with widespread scepticism. Now, there is near uniform acceptance of worldwide data accumulated over the past eight years that the pancreas can show growth well into adulthood. Our results have been replicated in other animal models and in other autoimmune diseases and there is enormous and growing interest in the many different ways the pancreas can regenerate.

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The successes in killing the rogue T cells and showing pancreas regeneration emboldened us to conduct experiments with human blood samples. We studied blood samples from 675 people with type 1 diabetes and 512 people without diabetes. Using two different methods to measure cell death in people with diabetes, we showed that TNF killed a subpopulation of CD8 cells but did not kill a different population of T cells. The results applied across all six different doses of TNF.4 Furthermore, TNF was effective in selectively killing rogue CD8 T cells in several other autoimmune diseases.

TNF was effective in selectively killing rogue CD8 T cells in several autoimmune diseases. By this point, we felt ready to plan for a human clinical trial with a TNF-inducer. Unlike most other diabetes clinical trials, we focused on advanced type 1 diabetes. Our rationale was that if mice with advanced type 1 diabetes could be cured, we could choose people with the greatest need for treatment. Moreover, surmounting the toughest challenge would be the most rigorous way to support our hypothesis that TNF could selectively kill the disease-provoking T cells. Our choice of BCG, an established generic drug that was already on the market, gave us two advantages: BCG’s safety is very well established; the drug would be inexpensive. Our 20-year research programme had established so many mechanisms about the drug's effects that we were able to monitor those throughout the trial to ensure that BCG was working in the manner and with the purpose intended. This approach is known as translational medicine with biomarkers: by closely

monitoring people’s blood, we are able to determine whether the TNF is killing the disease-provoking cells – like seeing an antibiotic kill bacteria in the blood of an person with an infection. Real hope for the future As we progress with the testing of BCG, we hope to open up possibilities for treating people with long-standing diabetes using a universally affordable drug. Data from our Phase I trial, using only limited doses of BCG and regular blood glucose monitoring, are encouraging. Our aim is to carry out these trials quickly and costefficiently in order to develop a cheap generic drug for type 1 diabetes.

Denise Faustman and Miriam Davis Denise Faustman is Director of Immunobiology at the Massachusetts General Hospital and Harvard Medical School, Immunbiology Laboratories, Boston, USA. (faustman@helix.mgh.harvard.edu) Miriam Davis is a member of the Department of Medicine at Massachusetts General Hospital and Harvard Medical School, Immunbiology Laboratories, Boston, USA.

References 1 F austman D, Li X, Lin HY, et al. Linkage of faulty major histocompatibility complex class I to autoimmune diabetes. Science 1991; 254: 1756-61. 2 H ayashi T, Faustman D. Defective function of the proteasome in autoimmunity: Involvement of impaired NF-kB activation. Diabetes Tech Ther 2000; 2: 415-28. 3 H ayashi T, Kodama S, Faustman DL. Reply to 'LMP2 expression and proteasome activity in NOD mice'. Nat Med 2000; 6: 1065-6. 4 B an L, Zhang J, Wang L, et al. Selective death of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism. Proc Natl Acad Sci USA 2008; 105: 13644-9. 5 R yu S, Kodama S, Ryu K, et al. Reversal of established autoimmune diabetes by restoration of endogenous beta cell function. J Clin Invest 2001; 108: 63-72. 6 K odama S, Kuhtreiber W, Fujimura S, et al. Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science 2003; 302: 1223-7.

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From victim to protector – what the brain does with hypoglycaemia Stephanie A Amiel

The human brain depends on glucose to fuel all its functions. Although the brain can use other metabolic substrates, and babies’ brains do, glucose is its normal energy source. As the brain stores very little glucose, its proper function depends on a reliable supply from its circulation. If blood glucose concentrations fall too low, then brain malfunction results. But what is the plasma glucose concentration that is ‘too low’? Stephaine Amiel looks into this surprisingly controversial topic.

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December 2011 • Volume 56 • Special Issue 2

CAUSES AND EFFECTS

We know that the plasma glucose at which symptoms of hypoglycaemia occur is variable, depending heavily on a person’s recent glycaemic experience, although the evidence suggests that some degree of slowing of brain function is detectable in everyone once plasma glucose concentrations reach about 3 mmol/l (54 mg/dl). The American Diabetes Association has recommended that we consider any glucose concentration of less than 4 mmol/l (72 mg/ dl) as hypoglycaemia;1 the European Medicines Agency less than 3 mmol/l (54 mg/dl),2 elsewhere, less than 3.5 mmol/l (65 mg/dl) is considered diagnostic of a hypoglycaemic episode. Universally, however, it is agreed that people with diabetes using treatments that can cause hypoglycaemia should adjust their treatment regimens to avoid frequent exposure to concentrations below 4.5 mmol/l (approximately 80 mg/dl). It is certainly important to give people a lower limit to any glucose targets that we might recommend to them – as well as a higher limit!

cretion. The change in the insulin-toglucagon ratio in the blood leaving the pancreas and going to the liver immediately switches on glucose production by the liver cells, limiting the further development of the hypoglycaemia. If this does not work, and circulating glucose continues to fall, a more vigorous stress response occurs with secretion of stress hormones such as adrenaline (epinephrine); stimulation of the autonomic nervous system (which acts to increase the liver’s ability to make glucose and also adjusts the circulation to increase the blood flow to the brain) and the release of other hormones to help sustain the liver’s efforts and also slow the rate at which muscle and fat take glucose out of the circulation. Research using brain imaging techniques have shown that during symp-

date memories from the preceding day. Importantly, those brain regions that are active when we are enjoying ourselves are turned off by hypoglycaemia. Once the hypoglycaemia is treated, brain areas involved in arousal, stimulated by the low blood glucose, relax, perhaps explaining why people feel sleepy after an episode. Higher brain functions may not be fully re-established for some 40 minutes after plasma glucose concentrations return to normal. The protective stress responses to hypoglycaemia presumably evolved to protect brain glucose supplies during times of food shortage, or when muscle was using lots of glucose very rapidly, perhaps as primitive humans went chasing after lunch (or possibly escaping from being lunch for someone else). They efficiently protect the brain from glucose deprivation and make hypoglycaemia severe enough to cause cognitive impairment very rare in health.

The brain is the victim of falling plasma glucose and coordinator of the normal protective response.

The brain is not just a victim of falling plasma glucose; it is also the coordinator of the normal protective response. It is perhaps not surprising that the body’s most important glucose sensors are placed in the brain. Glucose-sensing neurones are found throughout the brain stem and most famously in the hypothalamus. These neurones are activated by changes in their glucose supply. When plasma glucose falls, these neurones initiate and coordinate a stress response that tends to correct the situation. The response starts with a message to the pancreas to shut down insulin production and increase glucagon se-

December 2011 • Volume 56 • Special Issue 2

tomatic hypoglycaemia, there is activation of the classical central stress pathways (hypothalamus and pituitary), hunger and appetite centres and also areas of the brain that are involved in monitoring how the body is behaving.3 Brain regions involved in aversion are also stimulated. The brain seems able to focus energy on these important functions, and diverts attention from such functions as memory and balance. Research suggests that people do not make a memory for an event that occurs when they are hypoglycaemic, and if hypoglycaemia occurs during sleep at night, they might not consoli-

For people with diabetes, however, hypoglycaemia is an all-too-familiar problem. Especially in circumstances of complete insulin deficiency (type 1 diabetes and late type 2 diabetes), defects in the above protective responses to a falling plasma glucose concentration allow the development of severe hypoglycaemia. Circulating insulin results from insulin injection, and concentrations do not fall just because the glucose concentration is falling. Because the cells making glucagon are driven as much by messages from insulin-secreting cells stopping work, as by the low glucose concentration itself, glucagon responses to hypoglycaemia are also lost. People with diabetes, therefore, depend most on the rest of the stress response and, most

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importantly, the generation and perception of symptoms of hypoglycaemia: stress symptoms and feelings of confusion and, importantly, hunger. Eating or drinking readily available carbohydrate is the best defence against a small hypoglycaemia becoming a big one.

Hypoglycaemia unawareness is associated with a sixfold increase in risk of severe hypoglycaemia. Sadly, for about a quarter of people with longstanding type 1 diabetes and an as yet undetermined number with type 2 diabetes, defects develop in these second-tier responses to hypoglycaemia. As well as not being able to suppress insulin or enhance glucagon, these people mount feeble stress responses that only start at much lower glucose concentrations than usual. In this situation, the stress responses start after the cognitive dysfunction has begun, and the person experiencing the hypoglycaemia does not have the opportunity to make a proper response and take carbohydrate before confusion and reduced consciousness occur. This ‘hypoglycaemia unawareness’ is associated with a six-fold increase in risk of severe hypoglycaemia (by definition hypoglycaemia that is so severe the person needs to be treated by someone else).4 There is failure of activation of the brain’s stress responses, and failure of activation of the symptom perception areas too. Moreover, research suggests that there is impaired shutdown of the reward circuitry and pleasure perception. In some victims of unawareness, these brain regions even may be stimulated! We know that hypoglycaemia unawareness can be induced and maintained by

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recurrent exposure to modest hypoglycaemia in daily life. Equally, if a person can adjust his or her diabetes therapy to avoid dropping plasma glucose below 3 mmol/l (54 mg/dl) too often, or for too long, the ability to perceive occasional subsequent hypoglycaemias can be restored. Structured education programmes (such as those described on pages 16 to 28 of this special issue) may help about half the participants with hypoglycaemia unawareness to regain awareness and they do reduce the amount of severe hypoglycaemia very substantially. It is thought that the failure to perceive the unpleasantness of each hypoglycaemia, as a result of the altered response of reward circuitry and pleasure perception, may block the other half from changing their behaviour enough to avoid future hypoglycaemia – rendering them resistant to the benefits of a purely educational approach.5 New strategies that help people change behaviours for more healthy ones are being developed.

We must improve our ability to help people with diabetes to minimize their risk for this distressing complication of diabetes therapies. What of the long-term effects of hypoglycaemia on the human brain? Again, neuroimaging and cognitive function tests are being deployed to determine whether recurrent hypoglycaemia has an impact on brain structure and function. The data are reassuring with regard to minor episodes, and probably to even severe hypoglycaemia in adults (as long as a full recovery is made at the time) but there are growing

concerns that severe hypoglycaemia in children with diabetes, which can be complicated by seizures, may result in impaired performance in some brain functions tested later on.6 (An article by Edith Schober and Reinhard Holl on page 43 of this special issue explores the links between diabetes and epilepsy in young people.) There is no doubt that we do need to improve on our ability to help all of our patients with diabetes to minimize their risk for this always distressing and sometimes dangerous complication of diabetes therapies. Stephanie A Amiel Stephanie A Amiel is RD Lawrence Professor of Diabetic Medicine, King’s College London (UK).

References 1 E uropean Medicines Agency, Committee for Proprietary Medicinal Products. Note for guidance on the clinical investigation of medicinal products in the treatment of diabetes mellitus. www.ema. europa.eu/docs/en_GB/document_library/ Scientific_guideline/2009/09/WC500003262.pdf 2 W orkgroup on Hypoglycemia, American Diabetes Association. Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care 2005; 28: 1245-9. 3 T eh MM, Dunn JT, Choudhary P, et al. Evolution and resolution of human brain perfusion responses to the stress of induced hypoglycemia. Neuroimage 2010; 53: 584-93. 4 S chopman JE, Geddes J, Frier BM. Frequency of symptomatic and asymptomatic hypoglycaemia in Type 1 diabetes: effect of impaired awareness of hypoglycaemia. Diabet Med 2011; 28: 352-5. 5 S mith CB, Choudhary P, Pernet A, et al. Hypoglycaemia unawareness is associated with reduced adherence to therapeutic decisions in patients with Type 1 diabetes: evidence from a clinical audit. Diabetes Care 2009; 32: 1196-8. 6 N ortham EA, Lin A. Hypoglycaemia in childhood onset type 1 diabetes--part villain, but not the only one. Pediatr Diabetes 2010; 11: 134-41.

December 2011 • Volume 56 • Special Issue 2

CAUSES AND EFFECTS

Epilepsy in children and adolescents with type 1 diabetes Edith Schober and Reinhard Holl

Seizures provoked by hypoglycaemia are relatively frequent in people with type 1 diabetes. Each year, up to 15% of children with type 1 diabetes experience a severe hypoglycaemic episode, or ‘hypo’, with seizures – often as a result of administering too much insulin. But seizures also can occur during diabetic ketoacidosis – when not enough insulin has been taken. These acute complications often constitute an obstacle to diagnosis of epilepsy in people, especially children and adolescents, with diabetes. The authors of this article look at some of the links between epilepsy and type 1 diabetes and report on a number of interesting findings from their recent study involving a large number of European children with type 1 diabetes.

December 2011 • Volume 56 • Special Issue 2

Epilepsy is a common chronic neurological condition, which affects the nervous system. Also referred to as a ‘seizure disorder’, epilepsy involves sporadic electrical storms in the brain, which cause sudden mild loss of attention or staring, and/or violent muscle contractions and loss of consciousness, known as grand mal seizures. There are several types of epilepsy, each with different causes, symptoms and treatments. Idiopathic generalized epilepsy is a group of disorders that tends to manifest itself in young people between early childhood and adolescence but which can develop in later life. The prevalence of idiopathic generalized epilepsy varies according to age. A peak prevalence of 1.1% occurs in adults over 50 years of age; in children and adolescents, the prevalence of epilepsy ranges between 0.2% and 0.4%.1 There is a recognized association between diabetes and idiopathic generalized epilepsy. In a UK study, a group of adults with epilepsy were found to have a four-fold higher prevalence of type 1 diabetes compared to the general population.2 In that group, diagnosis

of diabetes had preceded the onset of epilepsy by several years.

Epilepsy-related seizures in children may be mistaken for symptoms of hypoglycaemia. Recent studies in children have showed conflicting results. An Italian centre reported a higher prevalence of epilepsy in adolescents with diabetes compared to young people without diabetes. Again, diabetes had been diagnosed in these young people on average 2.8 years before epilepsy.3 On the other hand, an Australian study found no increase in risk for epilepsy in children and adolescents with diabetes.4 In many cases, epilepsy-related seizures in children may be mistaken for the symptoms of hypoglycaemia. Consequently, the diagnosis of epilepsy in children with diabetes is often delayed or underestimated. Generally, a diagnosis of epilepsy is based on at least two unprovoked seizures – not resulting from an external cause, such as injury or consumption of

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frequency of epileptic seizures in children and adolescents with diabetes than expected: twice as high as in children without diabetes. There was no difference between boys and girls.

We found a significantly higher frequency of epileptic seizures in children and adolescents with diabetes than expected.

prescribed medications or other drugs – in a person with normal blood glucose levels (above 3.9 mmol/l) and with an interval greater than 24 hours between the seizures. Although monitoring blood glucose is recommended when seizures or loss of consciousness occur in a child with diabetes, parents might not carry out a glucose test in such a frightening situation.

It could it be that people with repeated episodes of ketoacidosis are more prone to epilepsy. We had the opportunity to analyze the association between diabetes and epilepsy in a large group (45,847) of young people with type 1 diabetes aged between 0.1 and 20 years from Germany and Austria as part of the DPV initiative.5 We found a significantly higher

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Some interesting findings It was interesting to note that the children with both diabetes and epilepsy were younger at onset of diabetes than the children with diabetes alone. The reason for the increased frequency of epilepsy in children with type 1 diabetes is unknown and deserves further investigation. However, previous studies have shown that both severe hypoglycaemia and ketoacidosis can lead to abnormalities in an electroencephalogram (test to detect problems in the electrical activity of the brain) in children with diabetes. Given the risk of acute complications posed by both diseases, parents of children with epilepsy and diabetes might be expected to prevent convulsions in their child by attempting to avert hypoglycaemia using less insulin – with the consequence of higher overall blood glucose levels. However, among the children with both diseases, HbA1c levels and insulin dosage-to-body weight ratios were similar to those in the children without epilepsy and we saw no difference in the type of treatment – pump or injections. An interesting and unexplained result of our study was a significantly increased risk for diabetic ketoacidosis in children and adolescents with type 1 diabetes and epilepsy. They appear to be at twice the

risk compared to children with type 1 diabetes alone. The causes of this association are unclear. It could it be that people with repeated episodes of ketoacidosis are more prone to epilepsy. Education to prevent complications Close observation by parents of a child with diabetes and epilepsy could enable them to anticipate the symptoms of metabolic disturbances, allowing earlier diagnosis of (still mild) ketoacidosis. In reality, however, we found that rates of mild as well as severe ketoacidosis were higher in the children with both diseases. Children, their families and their healthcare providers need to be aware of this increased risk and should receive adequate and appropriate education to be able to detect and prevent ketoacidosis.

Edith Schober and Reinhard Holl Edith Schober is paediatric diabetologists in the Department of Paediatrics and Adolescent Medicine, Division of Paediatric Pulmology, Allergology and Endocrinology, Medical University Vienna, Austria. Reinhard Holl is paediatric diabetologist and epidemiologist at the Institute of Epidemiology and Medical Biometry, University of Ulm, Germany.

References 1 M artinez C, Sullivan T, Hauser WA. Prevalence of acute repetitive seizures (ARS) in the United Kingdom. Epilepsy Res 2009; 87: 137-43. 2 M cCorry D, Nicolson A, Smith D, et al. An Association between Type 1 Diabetes and Idiopathic Generalized Epilepsy. Ann Neurol 2006; 59: 204-6. 3 M ancardi MM, Striano P, Giannattasio A, et al. Type 1 diabetes and epilepsy: More than a casual association? Epilepsia 2010; 51: 319-322. 4 O ’Connell MA, Harvey AS, Mackay MT, Cameron FJ. Does epilepsy occur more frequently in children with Type 1 diabetes? J Paediatr Child Health 2008; 44: 586-9. 5 S chober E, Otto KP, Dost A, et al for the German/Austrian DPV Initiative and the BMBF competence network diabetes. Association of epilepsy and type 1 diabetes in children and adolescents. Is there an increased risk for DKA? Journal of Pediatrics (in press).

December 2011 • Volume 56 • Special Issue 2

Diabetes champions

Breakthrough – the story of Elizabeth Hughes and the making of a medical miracle Arthur Ainsberg

Of the many medical innovations seen in the 20th century, few were so pivotal as the discovery of insulin for the treatment for diabetes. A newly published book, Breakthrough, tells the story of a young girl who should have died as a child but survived to see seven grandchildren, and the drug that, for millions worldwide, has turned a death sentence into something more like a chronic irritation. A portion of the book’s proceeds is going to IDF’s Life for a Child Programme. The authors tell us more.

December 2011 • Volume 56 • Special Issue 2

Since its discovery in 1921, insulin has become the most widely prescribed drug in history. Many of the world’s estimated 366 million people with diabetes rely on this life-saving treatment. Although for millions administration of the drug has become a normal part of life, its discovery by four men at the University of Toronto – Frederick Banting, Charles Best, John James Rickard Macleod, James Collip – was anything but ordinary. They endured countless setbacks, disappointments and betrayals – even a fistfight! – before they discovered an effective extract. Their discovery transformed the life of nearly everyone around them, including their own. In 1920, Frederick Banting presented his idea for a diabetes treatment to John James Rickard Macleod at the University of Toronto. Banting believed that by tying off part of a dog’s pancreas, its tissues would degenerate and allow him to isolate a secretion that people with diabetes needed to survive. Although the process had been tried before, the recent advent of sophisticated glucose monitoring

methods would allow Banting to test accurately the effects of his treatment. Though cautious, Macleod granted him a research lab and assigned Best as his assistant. Neither Banting nor Best was a premier scientist or researcher. Banting had been a mediocre student at the University of Toronto’s Medical School and served as a medic in World War I. Best was a college student hoping for experience in a research lab. At the same time, an adolescent girl would be relying on the success of these two unlikely heroes. Elizabeth Hughes was the youngest daughter of one of the USA’s most famous politicians at that time, Charles Evans Hughes. To this day, her father remains the only man in American history to have served as New York Governor, US Secretary of State, Associate Justice and Chief Justice of the Supreme Court. In 1919, 11-year-old Elizabeth was diagnosed with ‘juvenile’ diabetes, now known as type 1 diabetes. Her prognosis looked grim. Before insulin, children with type 1

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diabetes survived an average of 11 months after diagnosis; from 1900 to 1919, half of all people with diabetes died within two years. Elizabeth’s parents turned to Frederick Allen, known then as a premier diabetes expert. Allen’s ‘starvation diet’ was one of the more effective treatments to prolong the short life of a person with diabetes. Before diabetes, Elizabeth’s recommended daily caloric intake was 2,200 calories; on the Allen diet, she sometimes dipped as low as 400. Incredibly, Elizabeth adhered perfectly to Allen’s diet, never wavering in her belief that if she could just stay alive long enough, a breakthrough would occur that would save her from this disease.

If Elizabeth could just stay alive long enough, a breakthrough would occur that would save her from this disease.

turned her down. Insulin was simply too experimental and too scarce. To meet the demand for mass manufacturing, the Toronto team entered into a partnership with Eli Lilly and Company – a radical idea at the time. However, insulin remained an unstable, experimental drug. People with diabetes continued to die. Elizabeth Hughes was to be one of the lucky ones. On 15 August 1922, Elizabeth, sat in Banting’s office in Toronto, became one of the first people to receive an insulin injection. Though initial supplies were sparse and dangerous, potentially deadly even, Elizabeth flourished. She gained weight quickly and grew taller, changes she described as “unspeakably wonderful”.

As Elizabeth wasted away, progress was being made in Toronto. Banting and Best’s new extract, which they named insulin, kept a dog with diabetes alive for 20 days. Researchers around the world began to take notice. With this new success, Macleod was finally convinced that Banting’s and Best’s discovery was worthy of a research team.

From the first failed experiment to its worldwide launch, insulin was developed in two years. Today, a new drug takes approximately 12 years and USD 1 billion to reach the end user (patient) – after successfully completing a series of government and regulatory reviews. But insulin is not a cure. It does not prevent or eradicate diabetes nor does it prevent the development of disabling and life-threatening complications. Insulindependent people with diabetes need to take great care in monitoring and managing their health.

The beginning of 1922 would pass in a whirlwind. Researchers lost the ability to make an effective extract; Banting, believing others were trying to take credit for his work, temporarily withdrew from the research team and began drinking heavily; Elizabeth Hughes’ weight dropped to 19.5 kg (43 lb). Her mother, desperate for help, wrote to Banting asking him to treat her daughter. As he did with all other requests, Banting

As we approach the 90th anniversary of the discovery of insulin, it is important to reflect on the importance of the drug and how much treatment options have changed since its inception. After centuries of ill-advised and even dangerous recommendations, insulin was the first truly effective treatment for people living with type 1 diabetes. It did not briefly delay an untimely, horrific death; it helped people to live normal, full lives.

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The lives of Elizabeth Hughes Three months after Frederick Banting injected her with insulin, Elizabeth Hughes left Toronto to begin a new life. It had been her dream to live as a normal girl, and insulin allowed her to live that dream – as long as she kept her diabetes a secret. That was no mean feat, given the demands of diabetes management, and this was long before the conveniences of glucose monitors and disposable syringes. Yet through exceptional determination and discipline, she succeeded in living the extraordinary, ordinary life that she had longed for during her agonizing, pre-insulin years of starvation. Just as remarkable as Elizabeth Hughes’s ‘disappearance’ in 1922, was the way that she re-emerged, after some 43,000 injections of insulin, 58 years later. This is recounted in Michael Bliss’s book, The Discovery of Insulin. Bliss, understandably, assumed that Elizabeth was dead and wrote to Elizabeth’s husband, William Gossett, hoping to obtain some information about her later years. Imagine his surprise when the reply came from Elizabeth herself! She was distressed that Bliss had found her and agreed to talk only after he promised to provide her with an alias in his book. Even her own children did not know of her diabetes until they were 18 years old. Among people with diabetes today, there are varying opinions about how public or private one should be in the quotidian management of diabetes. Some advocate injections at the dinner table; others adhere to a policy of privacy. Such debates were impossible before insulin. Whether or not one agrees with Elizabeth’s choice, one cannot help but appreciate her remarkable life – or one might say lives. Thea Cooper

Arthur Ainsberg Arthur Ainsberg , with Thea Cooper, is the co-author of Breakthrough - Elizabeth Hughes, the discovery of insulin, and the making of a medical miracle.

December 2011 • Volume 56 • Special Issue 2

Diabetes champions

In the race for a glittering prize – Team Type 1 hits the road Phil Southerland

Many people are shocked when I say that my diabetes is a gift – or that I would not take a cure if it were offered to me. But that is the truth. Diabetes is my life; I would not trade it for the world. Because of diabetes, I am healthier today than I would have been without the disease. Because of diabetes I live an incredible life – beyond my dreams – as the founder and chief executive officer of Team Type 1, a USA-based professional cycling team. Because of diabetes, I am able to play a part in helping to make life better for millions of people around the world. At Team Type 1, our goal is to show people that not only can people live their dreams with diabetes, but that diabetes combined with the resources and diligence it takes to manage the condition properly can be a path to achieving success in all aspects of life. Team Type 1 was conceived and established because of my friend, Joe Eldridge. When we met in college, Joe was not managing his diabetes well at all. To encourage him to do better, we

December 2011 • Volume 56 • Special Issue 2

made a sporting bet: at the end of the school day, the higher blood sugar pays for dinner. Joe bought me a lot of burritos that semester! But one day, the burritos stopped coming and Joe said, "Thank you

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for saving my life." That was the ‘game changer’ for me. Joe told me I was his hero; as far as I was concerned, he was the hero: he had taken control of his diabetes and his life. I grew up without a diabetes role model; diabetes had always seemed to me like a disease with no heroes. But I knew that Joe could be a powerful inspiration. We both liked cycling and I thought the bike could be a great platform to reach and motivate young people. Maybe we could provide a few diabetes heroes…

Prejudice and ignorance forces many people around the world are forced to hide their diabetes. Team Type 1 – we work to inspire A global sports organization was born out of that idea. Team Type 1-SANOFI has a world-class athletic programme with approximately 100 cyclists, runners and triathletes – more than 60 with type 1 diabetes and more than 20 with type 2 diabetes – all competing at the highest levels in their sports. We work to inspire. We train and compete against some of the best athletes on the planet to demonstrate to our peers everywhere that they can achieve their dreams if they can manage their condition and control their blood glucose, and to encourage others to take up physical exercise to prevent type 2 diabetes. I travel widely with Team Type 1 and have met people striving to live with diabetes in such countries, who, before meeting our athletes, have little hope for the future. When they see what our athletes have achieved and tell me of their newfound optimism, I feel a strong emotion that is difficult to measure or even describe. Whether I talk to a group of

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children or a room full of government officials, many audiences find it very hard to believe that I was diagnosed 29 complication-free years ago and that our athletes with type 1 diabetes are competing and winning in world-class events. "But you look normal", people say. And I reply that that is because we are normal – when we have the tools and education we need to control our disease we are.

tion in Macedoina will have, for the first time, free access to insulin and test strips. It is not a huge population but as a wise man once said, even the longest journey must begin with a single step. And for 2,500 people with diabetes, that journey now has very a different look to it.

Diabetes advocates at the top of their game Team Type 1 has a crucial role to play in advocating for the rights of people with diabetes. In the USA, people with diabetes have access to the supplies and medication we need, enabling us to live a healthy productive life without limitations – a basic human right. But that is not the case for the millions of people worldwide who do not have access to life-saving supplies. What is more, in many countries, outmoded and offensive discriminatory policies and widespread diabetes unawareness conspire to prevent people with the condition from attending school or having a job or even having a life partner. No wonder so many people around the world hide their diabetes – they are forced to.

We are bringing a powerful message that we hope will be the global game changer – for people with diabetes, people without diabetes, whole communities, employers, politicians and policy makers and media and diabetes stakeholders everywhere: if you have the right medicine, test strips and a decent meter and you know how to use them properly, diabetes is not a sickness; diabetes is a lifestyle.

In arenas of sporting excellence and at diabetes meetings and events worldwide, Team Type 1 is fighting to take the stigma out of diabetes and adding our voice to the global movement that is effectively pressuring governments to take real steps to improve the lives of their citizens with diabetes. During a recent trip to Macedonia, where I gave a presentation in the lead-up to the September 2011 UN High-Level Meeting on NCDs, representatives of the Ministry of Health requested a meeting at which they agreed to fund essential diabetes supplies. As a result, the entire type 1 diabetes popula-

Diabetes is not a sickness; diabetes is a lifestyle.

Eyes on the prize The recent UN summit was a step in the right direction but much work remains to be done. By continuing to offer an example, pushing the boundaries of possibility with diabetes and promoting education and empowerment, we intend to keep the diabetes advocacy pedals turning, to maintain the momentum of IDF’s campaign for recognition of diabetes and other NCDs at the very highest levels.

Phil Southerland Phil Southerland is founder and CEO of Team Type 1. He is also an IDF Blue Circle Champion.

December 2011 • Volume 56 • Special Issue 2

Diabetes champions

From diabetes education and prevention all the way to sporting excellence – Italy’s BCD Campaign Massimo Massi-Benedetti

Great strides have been made in our collective understanding of the benefits of well-managed diabetes and controlled blood glucose, and the key role in these that is played by physical activity. Yet slow progress has been made translating this knowledge into effective lifestyle education to engender healthful behaviour on a large scale. Very many young people remain at particularly high risk from the chronic effects of disabling diabetes complications. The threat of huge increases in the human and economic costs of diabetes demands a concerted response by multiple sectors of society to spot the warning signs and reduce the multiple health risks associated with this life-long condition. Massimo Massi-Benedetti describes a countrywide initiative in Italy, Campagna Buon Compenso del Diabete (BCD Campaign), which aims to spread a culture of diabetes prevention through healthy lifestyle education.

December 2011 • Volume 56 • Special Issue 2

The BCD Campaign is promoted by the International Diabetes Federation along with Italy’s professional diabetes organizations, the Association of Diabetologists (AMD) and the Italian Diabetology Association (SID), and groups representing people with diabetes, the Italian Diabetes Association (FAND-AID) and the Italian Association for Sports and Diabetes (ANIAD). The Campaign is supported by the Italian Association of Paediatric Endocrinology and Diabetology and the Ministry of Health and financed by Sanofi Italy.

The BCD Campaign promotes multiple partnerships involving a broad range of players in the fight against diabetes. The Campaign programme is a vehicle for activities that raise awareness by sharing information on prevention, control and treatment of diabetes through lifestyle education – with a special focus on sporting activities. The Campaign promotes multiple partnerships involving a broad range of players in the fight against diabetes: the medical-scientific community, institutions and healthcare professionals, volunteer associations, sports associations and the media.

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The AC Milan goalkeeper, Christian Abbiati (close up), who took part in several BCD activities. Young campers gather for a hike (main photo).

Since its inception in 2008, the BCD Campaign has reached more than 200,000 people in 80 Italian towns and cities, as well as major Italian companies and public institutions, carrying out screening and free tests (blood glucose, HbA1c, blood pressure, BMI) to assess people’s cardiometabolic risks, and providing them with educational materials. To date, some 14,000 visits have been conducted, involving 600 institutions, and 170,000 brochures distributed. More than 2,700 press articles and citations have given the BCD Campaign a visibility equivalent to nearly 360 million media contacts. People with diabetes can participate in any sporting activities, even at the very highest levels. The Campaign supports a range of sporting projects that carry a key message: when diabetes is managed well, it is not an obstacle; people with diabetes can participate in any sporting activities, even at the very highest levels. A new BCD project, Diabetes and Sports, aims to turn this message into reality for young people with diabetes in Italy. The project is the fruit of partnerships with the elite endurance sports outfit, Team Type 1 and the football club, AC Milan, via their Foundation. (An article on page 47 by the Team’s founder, Phil Southerland describes the origins aims and activities of Team Type 1). Thanks to these collaborations, 70 children

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with diabetes have the opportunity to spend a week at one of AC Milan’s residential summer camps, where ideal conditions have been created to guarantee children with diabetes (selected by Italian Association of Paediatric Endocrinology and Diabetology) the opportunity to train safely every day alongside children without diabetes. As you would expect from the best summer camps anywhere, the Milan camps provided a comprehensive range of sporting and leisure activities, as well as a social programme to fuel the bonding process among the children and promote empathy and self-confidence. The initiative has proved popular among the medical community and families, and has become a top hit on the Internet. Within days of the camps opening, the family members of children with diabetes began exchanging comments and writing blogs. Their general impression was very positive.

Massimo Massi-Benedetti Massimo Massi-Benedetti is Chair of the IDF Science Task Force.

December 2011 • Volume 56 • Special Issue 2