Roles of autophagy in pancreatic β-cell function and type 2 diabetes

Abstract

The onset and progression of type 2 diabetes largely depends on pancreatic β-cell failure in the setting of insulin resistance. In most type 2 diabetic patients, loss of β-cell function and mass is associated with worsening of glycemic control. In this regard, type 2 diabetes could be regarded as a disease of pancreatic β-cell failure. This concept was further supported by the results of recent genome-wide association studies that identified genes that potentially regulate β-cell function and growth as type 2 diabetes susceptibility loci. The response of normal β cells to increased insulin demands includes both enhanced insulin secretion per cell and expansion of β-cell mass. Whereas the precise molecular mechanism underlying the compensatory response of β cells is unknown, recent studies using autophagy-deficient animal models have highlighted the importance of autophagy in the preservation of normal islet architecture and enhancement of β-cell function, especially under insulin-resistant states. Furthermore, normal autophagy function has been shown to play important roles in maintaining hepatic insulin sensitivity by counteracting endoplasmic reticulum stress. In this article, we review knowledge of the role of autophagy in maintaining β-cell function, hepatic insulin sensitivity, and its possible implication in diabetes pathogenesis. Identifying autophagy as a critical modulator of the two major pathological arms of type 2 diabetes—impaired insulin secretion and insulin sensitivity—may direct the development of future therapeutic strategies for this disease.