Faculty Bibliography

In view of the global shift from communicable to chronic, non-communicable diseases including obesity, prediabetes, and type 2 diabetes mellitus, the increasing prevalence of the latter creates a considerable challenge to the clinician and public health infrastructure. Despite the substantial research efforts in the last 10-15 years highlighting the considerable benefit of lifestyle modification in thwarting the insidious progression to diabetes and its complications, many individuals will ineluctably progress even when initially responsive. Furthermore, the vast majority of individuals with prediabetes remain undiagnosed and untreated. Therefore, the responsibilities of the medical and public health communities involve identifying new methods for screening and identifying those at risk as well as refining therapeutic approaches availing as many high-risk individuals as possible to novel treatment modalities.

Diagnosis of dysglycemic states is likely delayed as current diagnostic criteria apply absolute threshold values to a process that is continuous. The importance of this relates to forestalling opportunities for earlier diagnosis when prevention and reversibility are more likely to occur by preventing further beta cell dysfunction. Although the optimal method for earlier identification of individuals at risk remains uncertain, the paper suggests novel approaches.

Type 2 diabetes and other non-communicable diseases (NCD) are a growing public health challenge globally. An estimated 285 million people, corresponding to 6.4 % of the world's adult population has diabetes. This is expected to reach 552 million by 2030, 7.8 % of the adult population, with the African region expected to experience the greatest increase. A much larger segment of the world's population, approximating 79 million individuals in the US alone, has prediabetes. Multiple factors including genetic predisposition, insulin resistance, increased insulin secretory demand, glucotoxicity, lipotoxicity, impaired incretin release/action, amylin accumulation, and decreased beta-cell mass play a causative role in the progressive beta-cell dysfunction characteristic of prediabetes. Interventions preventing progression to type 2 diabetes should therefore delay or prevent beta-cell failure. This article will first review the principal pathophysiological mechanisms underlying prediabetes and subsequently address treatment considerations based on these in the prevention of type 2 diabetes. In view of long-standing safety data with demonstrated efficacy and cost-effectiveness in the prevention of type 2 diabetes in high-risk individuals, metformin should be considered as initial therapy for those unable to comply with or lifestyle modification or where the latter has been ineffective in decreasing progression to type 2 diabetes.

HbA1c testing has become an accepted means of diagnosing diabetes, as an alternative to blood glucose levels. However, population based norms of glucose and of HbA1c levels do not enable the detection of diabetes at an early enough stage to thwart complications. Personal trajectories of glucose levels show steep increases a number of years prior to diabetes diagnosis. Here, we hypothesize that a comparable time-dependent deviation in an individual's HbA1c level may be an early manifestation of disease that should prompt lifestyle modifications. We predict that analysis of personal trajectories of glucose and of HbA1c will promote earlier intervention and a greater reduction in disease complications, than do current standards, which are based on population based norms

OBJECTIVE: We prospectively analysed HbA1c changes after 12 months of exenatide therapy and determined which baseline clinical and/or biological factors predict response. RESEARCH DESIGN AND METHODS: Open-label cohort of 41 subjects with type 2 diabetes (56% male) poorly-controlled on maximally-tolerated oral dual therapy. Age (mean +/- 1SD) was 60 +/- 10 years, and known diabetes duration 11 +/- 8 years (mean +/- 1SD). Biometric changes in weight, body mass index (BMI), waist circumference (WC), HOMA modeling (Homeostasis Model Assessment) of beta-cell function (HOMA-B) and insulin sensitivity (HOMA-S) as well as in HbA1c were assessed at baseline, and after 6 or 12 months exenatide therapy. Patients were divided into three groups: goal-achievers (GA, n = 15), defined as achieving HbA1c 7.5% (58 mmol/mol) at 12 months); and primary failure to exenatide therapy (early lack of efficacy; PF, n = 9). Non-responders represented the combined NGA plus PF patients. RESULTS: The addition of exenatide to maximally-tolerated oral dual therapy led to target HbA1c attainment (