The role of autophagy in pancreatic beta-cell and diabetes.
Pancreatic beta-cells play a key role in glucose homeostasis in mammals. Although large-scale protein synthesis and degradation occur in pancreatic beta-cells, the mechanism underlying dynamic protein turnover in beta-cells remains largely unknown. We found low-level constitutive autophagy in beta-cells of C57BL/6 mice fed a standard diet; however, autophagy was markedly upregulated in mice fed a high-fat diet. beta-cells of diabetic db/db mice contained large numbers of autophagosomes, compared with nondiabetic db/misty controls. The functional importance of autophagy was analyzed using beta-cell-specific Atg7 knockout mice. Autophagy-deficient mice showed degeneration of beta-cells and impaired glucose tolerance with reduced insulin secretion. While a high-fat diet stimulated beta-cell autophagy in control mice, it induced a profound deterioration of glucose intolerance in beta-cell autophagy-deficient mutants, partly because of the lack of a compensatory increase in beta-cell mass. These results suggest that the degradation of unnecessary cellular components by autophagy is essential for maintenance of the architecture and function of beta-cells. Autophagy also serves as a crucial element of stress responses to protect beta-cells under insulin-resistant states. Impairment of autophagic machinery could thus predispose individuals to type 2 diabetes.
Fujitani
Yoshio
Y
Department of Medicine, Metabolism & Endocrinology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan. hwatada@juntendo.ac.jp
Kawamori
Ryuzo
R
Watada
Hirotaka
H
D000818:Animals; D001343:Autophagy; D048430:Cell Shape; D003920:Diabetes Mellitus / Q000473:pathology*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000473:pathology*; D051379:Mice; D010588:Phagosomes / Q000378:metabolism / Q000473:pathology