The role of impaired early insulin secretion in the pathogenesis of Type II diabetes mellitus

Abstract

Normal glucose tolerance is maintained by a precise balance between insulin secretion from pancreatic beta cells and insulin action on sensitive tissues, principally muscle, adipose tissue and liver [1,2]. Patients with Type II (non-insulin-dependent) diabetes mellitus manifest impairments in insulin secretion and insulin action and an increased rate of endogenous glucose production [1±3]. The relative importance of these abnormalities in the pathogenesis of the disease has been debated for many years. It is now generally accepted that abnormalities in insulin secretion and insulin action contribute to the development of Type II diabetes, whereas the increase in endogenous glucose production is a later phenomenon. Insulin secretory dysfunction in Type II diabetes is both quantitative and qualitative [3±4]. In addition to a relative impairment in the amount of insulin released, the pattern of insulin secretion is abnormal. In this review, we focus on the critical role of impaired early insulin secretion in the pathogenesis of Type II diabetes.Current understanding of the pathophysiology of Type II diabetes is based on the contributions of many laboratories working with different populations around the world. Since 1982, the National Institutes of Health has conducted a longitudinal study of the metabolic predictors of Type II diabetes in the Pima Indians of Arizona [5], a population uniquely suited for such studies because of their extraordinarily high Diabetologia (2001) AbstractPatients with Type II (non-insulin-dependent) diabetes mellitus manifest abnormalities in insulin action and insulin secretion. It is widely accepted that insulin resistance is an early finding, evident before the onset of hyperglycaemia and predictive of the subsequent development of diabetes. Whether abnormalities in insulin secretion also precede and predict diabetes has been debated. However, recent studies clearly indicate that early insulin secretion plays a critical role in maintaining normal glucose homeostasis. Crosssectional analyses show that acute insulin secretory responses (AIR) to intravenous glucose are lower in subjects with impaired glucose tolerance and those at high risk for developing diabetes. Prospectively, a low AIR predicts the development of diabetes in several populations. In longitudinal studies, AIR declines dramatically as patients progress from normal to impaired glucose tolerance and ultimately to diabetes. Early insulin secretion is important for the rapid and efficient suppression of endogenous glucose production after a meal. Thus, loss of early insulin secretion initially leads to post-prandial hyperglycaemia which, as the disease progresses, worsens to clinical hyperglycaemia. Strategies that enhance early insulin secretion improve glucose tolerance and represent a novel and more physiologic approach to improving glycaemic control in patients with Type II diabetes mellitus. [Diabetologia (2001) 44: 929±945]

Beta cell dysfunction in patients with acute myocardial infarction but without previously known type 2 diabetes: a report from the GAMI study

“…In comparative studies of several indices of beta cell function, the IGI index was closely correlated with insulin secretion [29]. Recent studies have presented results that indicate that beta cell dysfunction in early stages of AGT is present independently of insulin resistance and is already present in obese patients with NGT [30][31][32]. In addition, a study of type 2 diabetic Japanese patients recently showed that decreased insulin secretion had a more pronounced impact on glucose tolerance than insulin sensitivity [33].…”

Loss of beta cell function as fasting glucose increases in the non-diabetic range

“…The respective roles of insulin deficiency and insulin resistance in the development of Type 2 diabetes mellitus remain controversial [1,2]. In response to a glucose stimulus, two phases of insulin secretion may be distinguished [3].…”

High normal 2-hour plasma glucose is associated with insulin sensitivity and secretion that may predispose to type 2 diabetes

“…Both impaired insulin sensitivity and insulin secretion are involved in the deterioration of glucose tolerance from the normal to the glucose intolerant state [12]. Whether defects in these glucose-insulin metabolism parameters are present in subjects with high normal 2hPG (NPG) is not well known.…”