Role of autophagy in diabetes and mitochondria

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.Liu HY, 2009, J BIOL CHEM, V284, P31484, DOI 10.1074/jbc.M109.033936Zhou LJ, 2009, MOL PHARMACOL, V76, P596, DOI 10.1124/mol.109.057067Kanki T, 2009, DEV CELL, V17, P98, DOI 10.1016/j.devcel.2009.06.014Okamoto K, 2009, DEV CELL, V17, P87, DOI 10.1016/j.devcel.2009.06.013Kirkin V, 2009, MOL CELL, V34, P259, DOI 10.1016/j.molcel.2009.04.026Jung HS, 2008, CELL METAB, V8, P318, DOI 10.1016/j.cmet.2008.08.013Ebato C, 2008, CELL METAB, V8, P325, DOI 10.1016/j.cmet.2008.08.009Ichimura Y, 2008, J BIOL CHEM, V283, P22847, DOI 10.1074/jbc.M802182200Levine B, 2008, CELL, V132, P27, DOI 10.1016/j.cell.2007.12.018Komatsu M, 2007, CELL, V131, P1149, DOI 10.1016/j.cell.2007.10.035Levine B, 2007, NAT REV IMMUNOL, V7, P767, DOI 10.1038/nri2161Nakai A, 2007, NAT MED, V13, P619, DOI 10.1038/nm1574Bernales S, 2007, AUTOPHAGY, V3, P285Laybutt DR, 2007, DIABETOLOGIA, V50, P752, DOI 10.1007/s00125-006-0590-zKaniuk NA, 2007, DIABETES, V56, P930, DOI 10.2337/db06-1160Ozcan U, 2006, SCIENCE, V313, P1137, DOI 10.1126/science.1128294Komatsu M, 2006, NATURE, V441, P880, DOI 10.1038/nature04723Rodriguez-Enriquez S, 2006, AUTOPHAGY, V2, P39Bjorkoy G, 2005, J CELL BIOL, V171, P603, DOI 10.1083/jcb.200507002Levine B, 2005, J CLIN INVEST, V115, P2679, DOI 10.1172/JC126390Komatsu M, 2005, J CELL BIOL, V169, P425, DOI 10.1083/jcb.200412022Boya P, 2005, MOL CELL BIOL, V25, P1025, DOI 10.1128/MCB.25.3.1025-1040.2005Lum JJ, 2005, CELL, V120, P237, DOI 10.1016/j.cell.2004.11.046Ozcan U, 2004, SCIENCE, V306, P457Levine B, 2004, DEV CELL, V6, P463Petersen KF, 2004, NEW ENGL J MED, V350, P664Petersen KF, 2003, SCIENCE, V300, P1140Klionsky DJ, 2000, SCIENCE, V290, P1717Maechler P, 1999, NATURE, V402, P685ASHFORD TP, 1962, J CELL BIOL, V12, P198