DAROC : DAROC 40th Anniversary DAROC – AASD Joint Symposium

DAROC-2 ENDOTHELIN-1 AS A TARGET FOR INTERVENTION IN METABOLIC SYNDROME

LOW-TONE HO

Departments of Medical Research and Internal Medicine, Taipei Veterans General Hospital, and National YangMing University School of Medicine

“Metabolic Syndrome” (Mets) is a cluster of “pre-disease states” including diabetes, hypertension, dyslipidemia and obesity, with common roots in insulin resistance (IR) and low grade systemic inflammation (LGSI). The molecular mechanism linking high blood pressure (BP) and glucose (PG) in Mets is still not clear. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictive polypeptide with action much longer than another similarly potent angiotensin-II (AT2). Both ET-1 and AT2 are well known deeply involved in pathophysiology of hypertension and many other cardiovascular events. We firstly discovered ET-1 inhibited insulin-stimulated-glucose-uptake (ISGU) in rat adipocyte via ET-1 receptor and post-insulin binding mechanism. A series of subsequent experiments have accumulated convincing evidences supporting its pivotal role in the development of Mets in rats. These include as following: (1) Modest hyperinsulinemia (HI) induced by exogenous insulin caused sequential elevations in order of plasma triglyceride (TG) and ET-1 levels, then BP and PG finally, of which BP elevation was abolished by pretreatment with ET-1 receptor A antagonist (ETARA). (2) Similarly an endogenous HI model of fructose fed rat (FFR) also showed same phenomena. (3) Increase of plasma ET-1 level and sensitivity to ET-1 induced aortic ring constriction was found in the FFR and also upregulation of mRNA of ET-1 and ETAR in their tail vessel walls. (4) Infusion of physiological doses of ET-1 in conscious rats induced IR shown by glucose clamp and mild PG elevation. (5) AT2 enhanced ET-I induced vasoconstriction via upregulating ETAR in aortic ring, and via increase of binding capacity and decrease of binding affinity to ETAR in the aortic tissue of a high fat rat (HFR) model of Mets. (6) Combination of sub-pressor doses of ET-1 and AT2 caused persistent hypertension. (7) Other evidence related to ET-1’s role in atherosclerosis: enhance lipolysis in vivo and in vitro; decrease of cholesterol efflux from macrophages via degradation of ABCG1; and stimulation of proliferation and migration of vascular smooth muscle cells (VSMC), etc.

In summary of these evidences, a hypothesis may be formed so that ET-1 may negatively interact with insulin in its metabolic pathway, i.e., IR, in conjunction with its vasoconstrictive potency to induce hypertension, and meanwhile synergistically with its mitogenic pathway, e.g., proliferation and migration of VSMC, fatty acid metabolism interact with inflammatory macrophage and foam cells to induce atherosclerosis. Suffice it to say, ET-1 serves well as a target for intervention of Mets in animal models. Although there are a few ET-1 receptor antagonists are available in clinical use, better efficacy and safety profiles are yet to find, in aspects of either intervention or prevention of Mets in clinical trials. A platform of high throughput cell based drug screening system has been established, which composed of ETAR and ETBR transfected cell lines for both screening and counter-screening purposes. However, it always needs luck in the realm of drug discovery.

DAROC-3 THE WHOLE PICTURE OF YOUNG-ONSET DIABETES IN HONG KONG

ANDREA LUK

Department of Medicine & Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong

The burden of type 2 diabetes is rising in all parts of the world with rapid increases observed in Asia. Using territory-wide database of over 0.5 million Hong Kong people with diabetes, we detected increases in incidence rates of type 2 diabetes in youth and young adults but not in older groups. In wider Asia, up to one in five people with diabetes were diagnosed before the age of 40 years. People with young-onset diabetes have higher lifetime risks of diabetes-related complications and consume more healthcare resources than their usual-onset counterparts. We estimated that a person with youngonset diabetes will spend approximately 100 days in hospital by the age of 75 years. Furthermore, the life expectancy of a person with diabetes at the age of 40 years is shortened by 7-8 years. Whilst complication and mortality rates have declined for most people with diabetes over the past two decades, improvements were not observed in the young. This is in part related to suboptimal control of blood glucose due to poorer adherence to diabetes self-management and therapeutic inertia. Undertreatment also pertains to other metabolic risk factors. The challenge in the management of youngonset diabetes is compounded by the heterogeneity in the underlying cause and clinical phenotypes. From the Hong Kong Diabetes Register, among people with young-onset diabetes, 10% have type 1 diabetes based on classical presentation with diabetic ketoacidosis, and another 8% habour antiislet autoantibodies and have latent autoimmune diabetes. The mechanisms underlying progression of diabetes determine response to glucose-lowering treatment and prognosis. Treatment algorithms incorporating genetic and clinical biomarkers to guide drug therapy in young people are desirable but this will require vigorous evaluation in well-executed clinical trials. There are windows of opportunity to intervene early in the clinical trajectory of people with young-onset diabetes who are most likely to benefit from metabolic legacy.

DAROC-4 APPLICATION OF NEW TECHNOLOGY IN THE MANAGEMENT OF DIABETES PATIENT: KOREA EXPERIENCE

YOUNG MIN CHO

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

Diabetes is a chronic disease requiring lifelong management with lifestyle modification, medication, or both; therefore, diabetes self-management education and adherence to the treatment plans are considered key components in the management of diabetes. As information technology (IT) advances, medical services using IT devices such as mobile healthcare (mHealth) systems have been developed to aid chronic disease management. Currently, approximately 259,000 mHealth applications are available from major application stores. Among various chronic diseases, an IT-based intervention has most frequently been applied to diabetes. Although there was considerable heterogeneity among different applications and patient characteristics, a recent systematic review and meta-analysis of the mHealth application for diabetes self-management (which included 13 randomized, controlled studies with 1,022 patients with type 2 diabetes) showed that the overall HbA1c reduction was -0.40% (95% CI: -0.69 to -0.11%). However, smartphone applications for the management of type 2 diabetes that deal with diet, physical acitivity, glucose monitoring, insulin titration, and social networking service altogether are not common. In addition, although there are numerous commercial smartphone applications for diabetes management, only a few small-scale, randomized, controlled trials have examined their glucose-lowering efficacy. We also developed a smartphone-based, patient-centered diabetes care system (mDiabetes) featuring an individualized diabetes management algorithm, automatic input of daily glucose levels and physical activity, guidance for basal insulin dosage, and a range of interactive components, including a social networking service. In the 12-week, single arm, non-controlled pilot study, HbA1c decreased by 0.6% from baseline and was accompanied by significantly improved diabetes self-management in areas including diet, exercise, and blood glucose monitoring. Recently, we upgraded the mDiabetes system and conducted a 24-week, multicenter, randomized, controlled trial to evaluate its efficacy and safety. HbA1c reduction from baseline was greater in the mDiabetes group (-0.40 ± 0.09%, n = 90) than in the control group (-0.06 ± 0.10%, n = 82). The difference of adjusted mean changes was 0.35% (95% CI: 0.14-0.55, p = 0.001). The proportion of patients whose HbA1c fell below 7.0% (53 mmol/mol) was 41.1% for the mDiabetes group and 20.7% for the control group (OR = 2.01, 95% CI: 1.240-3.25, p = 0.003). The number of patients who attained HbA1c levels below 7.0% (53 mmol/mol) without hypoglycemia was 31.1% in the mDiabetes group and 17.1% in the control group (OR = 1.82, 95% CI: 1.03–3.21, p = 0.024). There was no difference in the event numbers of severe hyperglycemia and hypoglycemia between the two groups. From our experience, we may conclude that the implementation of the mDiabetes for patients with inadequately controlled type 2 diabetes resulted in a significant reduction in HbA1c levels, with tolerable safety profiles.