Beta-cell mass plasticity in type 2 diabetes.

Abstract

Prospective studies have shown that insulin resistance (IR) and impaired insulin secretion are independent predecessors and predictors of overt diabetes in genetically predisposed individuals [1–3]. Studies involving subjects at high risk of progression to type 2 diabetes (T2D) have shown that b-cell function begins to decline prior to presentation of elevated, fasting plasma glucose levels, thus predicting the subsequent development of T2D [4]. With the onset of IR, rates of both insulin biosynthesis and secretion are amplified, coupled with increases in b-cell mass and hypertrophy of existing b-cells to meet the increase in demand [5]. As the b-cell mass reaches its threshold to compensate, the burden of IR can no longer be overcome [6]. In those individuals with a genetic predisposition, this lack of pancreatic plasticity ultimately leads to hyperglycaemia [7]. After years of controversy regarding the primacy of either a b-cell defect or IR in the pathogenesis of T2D, we now recognize that various degrees of both alterations must coexist for hyperglycaemia to become manifest. While much is known about the mechanisms of IR, the causes for b-cell defects remain poorly understood. Still more enigmatic is the clinical relationship of the functional b-cell defect to actual b-cell mass. Vague terms such as b-cell exhaustion and fatigue, b-cell rest and survival and b-cell preservation provide little direction towards the effective therapeutic strategies for preserving b-cell function and mass. As the incidence of T2D continues to increase at an alarming rate, it is becoming imperative that the clinical focus shift towards the preservation of b-cell function and mass. Widespread efforts are being undertaken in an attempt to understand the mechanisms that regulate b-cell mass and to determine precisely what goes awry in T2D. Clinicians, however, are limited by the fact that there is no method for monitoring b-cell mass. In the following review, we discuss factors that influence b-cell mass and potential strategies for therapeutic intervention in the preservation of b-cell mass.