Diabetes – IS IT THE NEXT GLOBAL PANDEMIC?

Products & Procedures under the microscope

With Gaynor Wooldridge

Chair of the Medicines and Procedures Panel (MaPP) of the Institute of Chiropodists and Podiatrists

Diabetes – IS IT THE NEXT GLOBAL PANDEMIC?

On March 11, 2020, the World Health Organisation (WHO) declared the novel coronavirus (COVID-19) outbreak a global pandemic after the numbers of cases outside of China increased 13-fold, and the number of countries with cases increased 3-fold (Cucinotta et al. 2020). To date (27 October 2022) 6,588, 474 people have been confirmed to have died so far from the coronavirus COVID -19 outbreak, in 228 countries and territories (worldometers, 2021).

Fig.1

The novel coronavirus pandemic is a perfect model for understanding what a pandemic is, and how it impacts life on a global scale. WHO declares a pandemic when a disease’s growth is exponential; its definition is based on the rate and spread of the disease, and not the severity (WHO, 2020). The Black Death was one of the most devastating pandemics in human history and killed as many as 20% of the world’s population in the 14th century (Benedictow, 2004). Diabetes was responsible for 6.7m deaths in 2021 alone (International Diabetes Federation, 2021). Diabetes is an underrated, global health issue and the world can surely no longer ignore the ‘rise and rise’ (Zimmet, 2017) of diabetes mellitus type 2 (DMT2). A much clearer understanding of its drivers are urgently needed, with the discovery of vital, novel approaches to prevent a global pandemic. DMT2 is a metabolic disorder that causes blood sugar levels to increase. There are two main types of diabetes mellitus. Type 1 (DMT1) usually develops in childhood or teenage years and is an autoimmune disorder where the resulting damage to the pancreas leaves it producing little or no insulin. In DMT2, which is the focus of this article, insulin is produced by the pancreas, but the body’s cells gradually lose the ability to absorb and use the insulin. DMT2 is much more common than DMT1, affecting approximately 90% of people diagnosed with diabetes (Murfet, 2017). This article seeks to investigate exactly what DMT2 (once called late onset diabetes) is, some fascinating historical milestones to present day, and past and current treatments. We will also discuss some of the very exciting clinical trials underway targeting insulin resistance instead of focusing on hyperglycemia (Joubert, 2022).

What is diabetes?

DMT2 is fast becoming one of the biggest epidemics in the world (Murfet, 2017). During the recent COVID-19 pandemic, diabetes contributed to 1 in 3 deaths. The International Diabetes Federation (2019) described diabetes as a life-style disease affecting 9.3% (463m people globally) of the adult population, which is increasing at an ‘alarming rate’. They went on to state that it is one of the most common, non-communicable diseases of the current era.

Diabetes is a chronic health condition that affects how the body turns food into energy.

The pancreas is located in the upper abdomen behind the stomach and it has two important functions. It produces enzymes (lipases, Fig.2 Fig.3 proteases and amylases) to break down food in the intestines (exocrine=secreting externally); it also releases hormones (insulin and glucagon) to regulate blood sugar levels (endocrine=secreting internally). Normally, the body breaks down most of the carbohydrate food we eat into sugar and releases it into our blood stream. When the sugar levels increase, it initiates a response from the pancreas to release insulin from the beta cells, found within clusters of cells known as the Islets of Langerhans in the pancreas. Primarily, the role of the beta cells is to produce and secrete insulin in a tightly regulated manner in order to maintain circulating glucose concentrations in a narrow, physiological range (Saisho, 2015). The alpha cells make the hormone glucagon, which raises the glucose levels in the blood. Insulin acts like a key to allow the blood sugar into the cells of the body for use as energy.

Fig.5

In DMT2, there is an impairment in the way the body regulates and uses sugar (glucose) as a fuel. Primarily, this is caused by two problems: the pancreas does not produce enough insulin and, also, the body’s cells respond poorly to insulin and take in less sugar. These are the main defects for DMT2: insulin resistance and beta cell dysfunction (Zyoud et al. 2022; Zinn and Crofts, 2022).

Diabetes through the Ages

“Diabetes is a remarkable The first accurate affliction… the course is the description of the common one, namely, the kidneys symptoms of diabetes was and the bladder … one cannot found in a collection of stop drinking or making water… medical texts written the disease appears to me to have around 1552 BCE called the name diabetes as if from the the Ebers Papyrus

Greek word (meaning siphon). (Karamanou et a. 2016) ;

Aretaeus of Cappodocia it was noted that ants (1st - 2nd century) seemed to be attracted to the urine of people who had this disease (Zayac et al. 2009). The papyrus proposed a 4-day treatment of a concoction of bones, wheat, grain, grit, green lead and earth (Quionzon and Cheikh, 2012). This method of diagnostic practice of attracting ants continued in ancient India; they called this condition ‘madhumaha’, meaning honey urine (Guddoye et al. 2013; Kumar et al. 2018). The Indian physician, Sushruta, and the surgeon, Charaka (400-500 BCE) were able to distinguish between type 1 and 2 (Vecchio et al, 2018). The first written recorded history of the term ‘diabetes’ can be attributed to Aretaeus the Cappodocian, one of the most celebrated Greek physicians (Tekiner, 2015). Cappodocia’s text displays great accuracy in the detail of symptoms and of the diagnostic character of the disease. Two of his manuscripts were discovered and published, in a Latin translation, in 1554. In these manuscripts, he gave diabetes its name; it was the earliest clearest account of diabetes.

Thomas Willis added the term ‘mellitus’ to the disease in 1674, in an attempt to differentiate the sweet urine of mellitus from the unrelated diabetes insipidus (Eknoyan et al. 2005). A century later, Matthew Dobson (1732-1784) experimentally demonstrated the presence of sugar in urine, but the disease continued to be attributed to the kidneys well into the middle of the 19th century. It was the French physiologist Claude Bernard’s discoveries concerning the role of the pancreas in digestion, and the glycaemic action of the liver, that paved the way for further progress (Habert, 2022). Bernard’s concepts and discoveries were numerous and varied. He fiercely and passionately denied the accepted dominant medical philosophy, vitalism, that can be traced back to Aristotle. Vitalism continued to have advocates into the 19th century (Bechtel and Richardson, 1998; Normanden, 2007).

In 1889, Oskar Minkowski and Joseph von Mening performed their famous experiment of removing the pancreas from a dog. Sadly, this produced a fatal diabetes. Their work did, however, demonstrate that the pancreas was a gland of internal secretion (endocrine), and they presented the first proof of the impact of the pancreas in diabetes (Ceranowicz, 2015). This paved the way for the pioneering work of Frederick Banting and Charles Best in 1921, with their discovery of insulin (Karamanou et al, 2016). They were able to isolate insulin from pancreatic islets and administer it to patients suffering from diabetes, thus inaugurating a new era in diabetes treatment.

As we know today, the Islets of Langerhans, with their alpha and beta cells, play a synergistic role in a paracrine manner. The release of insulin from the beta cells inhibit the alpha cell function and the alpha cells are stimulating for the beta cells in order to maintain blood glucose homeostasis (Baskin, 2015). However, nothing was known about the Islets of Langerhans until Edouard Laguesse suggested these ‘little heaps of cells’ (Paul Langerhans, 1869) might play a regulatory role in digestion in 1893, and named them the ‘Islets of Langerhans’ after their initial discoverer. Langerhans was also the first to describe dendritic cells in the supra basal region of the epidermis (Doebel et al. 2017; Jorgens, 2020). Over the years following, insulin purification methods improved and new formulations were developed (White, 2014).

Current Understanding and Treatments

Metformin was introduced in 1959 as an antihyperglycaemic agent. Today, it is the only biguanide and is the most widely used antihyperglycaemic agent in the world. Its primary mechanism of action is to reduce hepatic glucose production, and also reduce glucose via a mild increase in insulinstimulated glucose uptake (White, 2008). There are now more than 11 different categories of medications directed at managing DMT2, some of which are frequently used by patients within our foot health practices (Table 1). These compounds have been developed during the past 90 years, with many subtypes also existing within these categories.

Advances in pharmacotherapy have made an incredible difference to the lives of people with diabetes, but it must be kept in mind that the treatment of DMT2 is multifactorial (Aschner, 2017).

Hammed et al.(2015) discussed the alarmingly increasing rate of T2DM and the chronic, low-grade inflammation it creates, leading to insulin resistance and beta cell dysfunction. The risk factors are many and include: being overweight, smoking, poor diet, ethnicity, gestational predisposition, some medications that affect sugar metabolism and genetic factors (NICE, 2022). Obesity and DMT2 are strongly intertwined however, and Surugue (2020) found that approximately 80% of obese subjects develop the disease. Metabolic syndrome is closely linked to insulin resistance.

Recent studies from the UK, US and Germany also point to a raised risk of developing DMT2 following the coronavirus

Drug Type of drug How it works Possible Side Effects

Metformin Biguanide Usually first medication prescribed. Lowers glucose production in the liver and improves B12 deficiency, nausea, abdominal body’s sensitivity to insulin, so the body uses it more effectively. pain, diarrhoea

Glybunide Sulphonylureas Helps the body secrete more insulin Glipizide Low blood sugar, weight gain

Repaglinide Glynides Nateglinide Stimulate pancreas to secrete more insulin. Faster acting than sulphonylureas, but duration of effect shorter Low blood sugar, weight gain

Rosiglitazone Thiozolidinediones Makes the body’s tissues more sensitive to insulin

Pioglitazone Risk of: congestive heart failure, bladder cancer, bone fractures, high cholesterol, weight gain

Janumet (fixed Gliptins (DPP-4 Help blood sugar levels by blocking action of DPP-4 (enzyme that destroys the hormone, Gastrointestinal, hepatitis, rash, back combination inhibitors) incretin), but modest effect pain, infections dose metformin & sitagliptin)

Vildagliptin

Liraglutide Incretin Mimetics Helps the pancreas produce more insulin, reduces the amount of sugar the Sitagliptin (GLP-1 analogues) liver produces and slows digestion speed. Also reduces appetite Alogliptin Diarrhoea, nausea, headaches, loss of appetite

Dapagliflozin SGLT2 inhibitors Reduces the amount of sugar the kidneys absorb and passed it out In urine so less in Genital yeast infections, flu like, Ertugliflozin (Sodium-glucose blood. Urine test will be glucose +ve because of how they work symptoms rare but can cause kidney Canaglifllozin transporter 2) injury and lead to amputations

Simvastatin Statins Pravastatin Ezetimibe Injected evolocumab Diabetes can increase the risk of heart diseases. Statins reduce the ability for the Low platelets, headache, digestive body to manufacture LDL cholesterol. They reduce risk of cardiovascular event by 48% problems, nausea, unusually tired

infection (Riley, 2022); this is perhaps caused by inflammation in the body from the virus, creating insulin resistance. It is also possible that the virus directly infects and damages the insulinmaking beta cells (Cutolo et al, 2020). For all of us working within the foot health profession, seeing and treating patients with diabetes is a regular part of our working lives. We are all aware that poor diabetic care increases the risk of ulceration, infection and limb loss. Our patients with diabetes mellitus have an increased risk for pedal ulceration due to microvascular, neuropathic and biomechanical changes to the foot. Neuropathic changes to the body result in decreased pedal sensation, making the diabetic foot prone to wounds from pressure injuries. Microvascular changes can also result in reduced blood flow to the lower extremities, delaying the healing of wounds. Hirpha et al (2020) studied diabetic foot practices among adult patients and their findings showed that they were not adequately self-inspecting and washing their feet daily, drying after washing or using moisturizing creams. They also highlighted that they were likely to walk bare foot, and wear shoes, sandals and slippers without socks for protection. As clinicians, we should make every DMT2 patient aware of the importance of foot inspection and hygiene, and advise on the risks of walking bare foot at each visit.

New breakthroughs – will there be a cure in the future?

There is currently no cure for diabetes. Scientists working on a ground breaking management study are hoping to be able to help people maintain remission (ReTune, 2018-2022), and maintain HbA1C levels below 6.5% without the need for medication.

There are some exciting new collaborative developments currently being undertaken by the University of Birmingham, Monash University, Australia and the Diabetes Division of the US Food and Drugs Agency. They are looking at a completely new approach by targeting the underlying biologic mechanism responsible, rather than treatments attempting to mitigate the consequences of DMT2, which currently focuses primarily on glycaemic regulation. PATAS is an exciting, innovative peptide that works by specifically targeting the adipocytes (fat cells). Insulin resistance prevents fat cells from allowing glucose to enter the cells and, instead, creates an overspill of toxic fat which leads to higher blood sugar levels and the storage of fat in the wrong place; this causes a number of other serious issues. When the adipocytes become insulin resistant, glucose is blocked from entering. PATAS works like a passcode to restore the usual function and allow glucose to flow into the cells (Hiwot, 2022).

Fig.7

Fat cells control insulin resistance by absorbing 10% of the circulating glucose; this fuels a process called lipogenesis. PATAS is not an antihyperglycaemic-resistance treatment, but rather an insulin-resistance treatment (Schreyer et al. 2022). Adipose tissue is a key regulator of whole body metabolic fitness because of its role in controlling insulin sensitivity. Obesity is associated with hypertrophic adipocytes with impaired glucose absorption (Joubert, 2022). PATAS reduces insulin resistance and provides vital cardiovascular benefits. Phase 1 clinical trials will begin in 2023 to hopefully bring PATAS to the market as quickly as possible, and as the only drug to directly treat insulin resistance (AdipoPharma, 2022). It will hopefully restore the metabolic fitness of the adipose tissue, and also have significant beneficial effects on pancreatic beta cell plaque removal, liver steatosis and fibrosis.

There are also a new generation of drugs that have been developed as a weaponised gut hormone. These medications are known as incretins, and one of their physiological roles is to regulate the amount of insulin secreted after eating (Wook and Egan, 2008). They are accepted as routine treatments for diabetes and obesity. Tirzepatide, a once weekly drug that has been described as a ‘first if its kind’, has just been approved by the Medicines and Healthcare products Regulatory Agency (Jelley, 2022). It is a single novel molecule that activates the body’s receptors for GIP and GLP -1, which are the natural incretin hormones. Critical improvements were made in comparison to the first generation GLP-1 agonists, such as semaglutide, and its effects proved to be statistically significant and clinically meaningful (Vadher et al. 2022).

Final Thoughts

Diabetes is a complex disease and, subsequently, requires a multifaceted approach to treatment. Available evidence would indicate that lifestyle interventions are significant for its development and for the prevention of further complications. However, it is obvious that in order to prevent the high risk of these subsequent complications, permanent life-style change, alongside appropriate medication, is imperative. Until very recently, the scope of the problem was not really fully understood. Insulin resistance was the accepted cause. However, research has proven that part of the problem lies with the beta cells in the pancreas, and the new and future developments can hopefully make living with DMT2 more manageable. Many specialists discuss diabetes in similar terms to cancer: remission and not cure.

Unfortunately, diabetes had reached epidemic proportions in 1994 (CDC, 1997), yet over the past 25 years we have failed to apply a dedicated and focused health approach, and DMT2 has tripled, with deaths and serious complications now at out-of-control proportions. Perhaps a universal screening to highlight those already pre-diabetic is needed, and an urgent assessment of social and community factors that might increase the risk?

Glossary

GIP: gastric inhibitors polypeptide – stimulates insulin production. GLP-1 receptor agonists: stimulate the release of insulin and suppress glucagon secretion when blood glucose concentrations are elevated. Homeostasis: from the Greek word for ‘same’ or ‘steady’. Refers to any process that living things use to actively maintain stable conditions for survival. Metabolic syndrome: the medical term for a combination of diabetes, hypertension and obesity. Paracrine signalling: cellular communication. Peptide: long or short chains of amino acids. Long chains are called proteins. Vitalism: belief that living entities contain some fluid or a distinctive ‘spirit’. It would seem that at this critical stage, only by combining clinical interventions with behavioural modifications, can this complex, multifactorial disease be possibly mitigated.

Figures and Tables

Fig 1: Coronavirus: www.shutteestock.com Image ID 1643947495 Fig. 2: Diabetes symptoms: www.shutterstock.com Image ID 1140753038 Fig. 3: Pancreas: www.shutterstock.com Image ID 635022062 Fig. 4: How insulin works: www.shutterstock.com Image ID 2000998226 Fig. 5: Insulin resistance: www.shutterstock.com Image ID 1342319067 Fig. 6: Islets of Langerhans: www.shutterstock.com Image ID 186698168 Fig. 7: Adipocyte cell: www.shutterstock.com Image ID 1906807798

Table 1: Compiled from information Diabetes UK. [Accessed 10 November @17:06]Gaynor Wooldridge

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