Islet beta cell failure in type 2 diabetes

Abstract

The major focus of this Review is on the mechanisms of islet beta cell failure in the pathogenesis of obesity-associated type 2 diabetes (T2D). As this demise occurs within the context of beta cell compensation for insulin resistance, consideration is also given to the mechanisms involved in the compensation process, including mechanisms for expansion of beta cell mass and for enhanced beta cell performance. The importance of genetic, intrauterine, and environmental factors in the determination of "susceptible" islets and overall risk for T2D is reviewed. The likely mechanisms of beta cell failure are discussed within the two broad categories: those with initiation and those with progression roles.

Figure 1. Islet β cell failure and the natural history of T2D.

T2D develops in response to overnutriton and lack of physical activity in subjects that have underlying genetic and acquired predispositions to both insulin resistance (and/or hyperinsulinemia) and β cell dysfunction. Over time, islet β cell compensation for the insulin resistance fails, resulting in a progressive decline in β cell function. As a consequence, subjects progress from normal glucose tolerance (NGT) to IGT and finally to established T2D. Even after diagnosis of T2D, β cell function continues to worsen such that subjects progress from needing changes in diet/exercise only to requiring oral hypoglycemic agents and eventually insulin for achievement of adequate glycemic control. Future therapies will be directed not only to achievement of euglycemia, but also changing the course of the disease by reversing the processes of β cell failure.

Figure 2. Mechanisms of β cell compensation for insulin resistance.

Normally islet β cells respond to insulin resistance by increased secretion through the processes of compensation. These include an expansion of β cell mass, increased insulin biosynthesis, and enhanced nutrient secretion coupling processes with increased sensitivity to glucose, FFAs, and GLP-1 stimuli. Enhanced glucose utilization, glucose oxidation, anaplerosis/cataplerosis, and TG/FFA cycling result in increased production of coupling signals necessary for insulin exocytosis. For expansion of β cell mass, roles are evident for increased activity of growth factor signaling pathways, postprandial glucose, and GLP-1 signaling that promote β cell proliferation and neogenesis and prevent apoptosis. Furthermore, signaling for growth may occur in response to FFAs, via the FFA receptors (FFAR) and via lipid signaling molecules derived from TG/FFA cycling. adr, adrenergic; ANS, autonomic nervous system; chol, cholinergic; CREB, cAMP response element–binding protein; DAG, diacylglycerol; GF, growth factor; GLP1R, GLP-1 receptor; GHR, growth hormone receptor; IGFR, insulin-like growth factor receptor; IR, insulin receptor, IRS-2, insulin receptor substrate 2; MCF, metabolic coupling factors; npt, neuropeptide; PKB, phosphokinase B; PL, phospholipids.

Figure 3. Mechanisms of β cell failure in T2D.

Islet β cell compensation for insulin resistance is sustained provided β cells are robust, resulting in long-term maintenance of NGT. Compensation processes, however, fail if there are genetic or acquired factors that result in susceptible β cells. The defect(s) create weak link(s) in the compensation process that promote β cell dysfunction by mechanisms with initiator roles that result in IGT and early T2D. Hyperglycemia, once established, promotes a further series of mechanisms, under the umbrella of glucotoxicity, that cause severe β cell failure and overt and late T2D. AMPK/Mal-CoA, AMPK/malonyl-CoA signaling network.