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

다국어 초록 (Multilingual Abstract)

<P><B>Summary</B></P><P>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 β cells and glucose homeostasis has not been described. We produced mice with β cell-specific deletion of <I>Atg7</I> (<I>autophagy-related 7</I>). <I>Atg7</I> mutant mice showed impaired glucose tolerance and decreased serum insulin level. β cell mass and pancreatic insulin content were reduced because of increased apoptosis and decreased proliferation of β cells. Physiological studies showed reduced basal and glucose-stimulated insulin secretion and impaired glucose-induced cytosolic Ca<SUP>2+</SUP> transients in autophagy-deficient β 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 β cells. These results suggest that autophagy is necessary to maintain structure, mass and function of pancreatic β cells, and its impairment causes insulin deficiency and hyperglycemia because of abnormal turnover and function of cellular organelles.</P>