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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    • "As a regulator of lipid and glucose metabolism [104], loss of autophagy caused abnormal accumulation of lipids in mouse hepatocytes and a significant increase in plasma triglycerides, with reductions in fatty acid beta-oxidation [105] and pancreatic β-cell mass [106]. Coincidently, saikosaponins increased hepatic uptake of cholesterol and decreased plasma levels of cholesterol and triglycerides [107]. "
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    • "Inhibition of autophagic proteins, such as Atg1, Atg7, Atg18, and Beclin1, significantly shortens life span in lower organisms [70]. In mammals, deletion of autophagic proteins in organs, such as the liver [71, 72], brain [73, 74], pancreas [75], and heart [76], is associated with early signs of senescence and dysfunction characterized by intracellular misfolded protein accumulation and the presence of aberrant mitochondria. On the other hand, whether autophagy activation is sufficient to extend life span in mammals is still under investigation. "
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    • "The LC3 conjugation enzymes ATG7 and ATG3, and lysosomal cysteine proteases, depend on cysteines for their activities ; however how they are modified by cellular redox status is unknown [66]. Loss of function due to thiol oxidation is likely detrimental since loss of function of ATG3 or ATG7 has been shown to result in mitochondrial dysfunction in T cells and β cells, respectively [67] [68] [69]. Future studies to determine whether ATG4, DJ-1, ATG3, ATG7 or other autophagy proteins are modified at cysteine residues in vivo in different cells and in response to different redox signals, and whether their oxidation attenuates autophagy and cell survival are needed. "
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