β-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment

Abstract

Objective: This article examines the foundation of β-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment.

Research design and methods: A group of experts participated in a conference on 14-16 October 2013 cosponsored by the Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations.

Results: The writing group based this article on conference presentations, discussion, and debate. Topics covered include genetic predisposition, foundations of β-cell failure, natural history of β-cell failure, and impact of therapeutic interventions.

Conclusions: β-Cell failure is central to the development and progression of T2D. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased β-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include to (1) impact the natural history of β-cell failure; (2) identify and characterize genetic loci for T2D; (3) target β-cell signaling, metabolic, and genetic pathways to improve function/mass; (4) develop alternative sources of β-cells for cell-based therapy; (5) focus on metabolic environment to provide indirect benefit to β-cells; (6) improve understanding of the physiology of responses to bypass surgery; and (7) identify circulating factors and neuronal circuits underlying the axis of communication between the brain and β-cells.

Figure 1

Stressors on the β-cell in the pathogenesis of T2D. In the excessive nutritional state found in obesity, hyperglycemia and hyperlipidemia develop, increasing metabolic load coupled with concurrent inherent insulin resistance and chronic inflammation. The pancreatic islet response to this new environment is likely variable among individuals with differing genetic susceptibility but may include inflammatory stress, ER stress, metabolic and oxidative stress (e.g., glucotoxicity, lipotoxicity, and glucolipotoxicity), amyloid stress, and loss of islet cell integrity. If untreated, these interrelated stressors increase with time, promoting β-cell dysfunction (coupled with increased glucagon secretion) and ultimately loss of β-cell mass and possibly dedifferentiation that mark the onset of T2D.