Loss of Autophagy Diminishes Pancreatic β Cell Mass and Function with Resultant Hyperglycemia (original) (raw)

Autophagy is a cellular degradation-recycling system for aggregated proteins and damaged organelles. Although dysregulated autophagy is implicated in various diseases including neurodegeneration, its role in pancreatic b cells and glucose homeostasis has not been described. We produced mice with b cell-specific deletion of Atg7 (autophagy-related 7). Atg7 mutant mice showed impaired glucose tolerance and decreased serum insulin level. b cell mass and pancreatic insulin content were reduced because of increased apoptosis and decreased proliferation of b cells. Physiological studies showed reduced basal and glucose-stimulated insulin secretion and impaired glucose-induced cytosolic Ca 2+ transients in autophagy-deficient b cells. Morphologic analysis revealed accumulation of ubiquitinated protein aggregates colocalized with p62, which was accompanied by mitochondrial swelling, endoplasmic reticulum distension, and vacuolar changes in b cells. These results suggest that autophagy is necessary to maintain structure, mass and function of pancreatic b cells, and its impairment causes insulin deficiency and hyperglycemia because of abnormal turnover and function of cellular organelles.