Role of autophagy in diabetes and mitochondria

Abstract

Type 2 diabetes mellitus is characterized by insulin resistance and failure of pancreatic beta-cells producing insulin. Mitochondrial dysfunction may play a role in both processes of diabetes. Autophagy maintains cellular homeostasis through degradation and recycling of organelles such as mitochondria. As dysfunctional mitochondria are the main organelles removed by autophagy, we studied the role of autophagy in diabetes using mice with beta-cell-specific deletion of the Atg7 gene. Atg7-mutant mice showed reduction in beta-cell mass and pancreatic insulin content. Electron microscopy showed swollen mitochondria and other ultrastructural changes in autophagy-deficient beta-cells. Insulin secretory function ex vivo was also impaired. As a result, Atg7-mutant mice showed hypoinsulinemia and hyperglycemia. These results suggest that autophagy is necessary to maintain structure, mass, and function of beta-cells. Besides its effect on beta-cells, autophagy may affect insulin sensitivity because mitochondrial dysfunction has been implicated in insulin resistance and autophagy is involved in the maintenance of the organelles. Furthermore, since aging is associated with impaired glucose tolerance, decline of autophagic activity may be involved in age-associated reduction of glucose tolerance.