Loss of Autophagy Diminishes Pancreatic β Cell Mass and Function with Resultant Hyperglycemia

Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Kangnam-ku, Seoul 135-710, Korea.
Cell metabolism (Impact Factor: 17.57). 11/2008; 8(4):318-24. DOI: 10.1016/j.cmet.2008.08.013
Source: PubMed


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 beta cells and glucose homeostasis has not been described. We produced mice with beta cell-specific deletion of Atg7 (autophagy-related 7). Atg7 mutant mice showed impaired glucose tolerance and decreased serum insulin level. beta cell mass and pancreatic insulin content were reduced because of increased apoptosis and decreased proliferation of beta cells. Physiological studies showed reduced basal and glucose-stimulated insulin secretion and impaired glucose-induced cytosolic Ca2+ transients in autophagy-deficient beta 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 beta cells. These results suggest that autophagy is necessary to maintain structure, mass and function of pancreatic beta cells, and its impairment causes insulin deficiency and hyperglycemia because of abnormal turnover and function of cellular organelles.

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    • "The defect in insulin secretion appeared to be due to defective mitochondrial function as ATP production was lower from mutant b cells (Ebato et al., 2008). Electron microscopy demonstrated mitochondrial swelling and cisternal distention of the rough ER and Golgi complex ( Jung et al., 2008). Together, these results suggest that autophagy in b cells acts as a defense mechanism by constantly clearing potentially toxic ubiquitinated proteins, damaged organelles, and p62. "
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