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  • Title: Autophagy deficiency in β cells blunts incretin-induced suppression of glucagon release from α cells.
    Author: Kim MJ, Choi OK, Chae KS, Lee H, Chung SS, Ham DS, Kim JW, Yoon KH, Park KS, Jung HS.
    Journal: Islets; 2015; 7(5):e1129096. PubMed ID: 26744903.
    Abstract:
    Incretin-based therapy such as GLP-1 receptor agonists and DPP-4 inhibitors for type 2 diabetes mellitus is characterized by glucose-dependent insulin secretion and glucose-inhibited glucagon secretion. Recently, autophagy deficiency in islet β cells has been shown to contribute to the pathogenesis of type 2 diabetes mellitus however, with the role of incretin has not been established. To evaluate the role of autophagy in incretin effects, 8-week-old male β cell-specific Atg7 knockout (Atg7(Δβ cell)) mice and wild-type mice were administered vildagliptin for 12 weeks. Vildagliptin treatment improved glucose intolerance and hypoinsulinemia; however, it failed to suppress serum glucagon levels after glucose loading in the Atg7(Δβ cell) mice. Ex vivo glucose-induced glucagon suppression was also blunted in the islets from vildagliptin-treated Atg7(Δβ cell) mice. The α cell mass was not affected by β cell autophagy deficiency or vildagliptin. However, glucagon mRNA expression was significantly increased by vildagliptin in the autophagy-deficient islets, and was significantly reduced by vildagliptin in wild-type islets. Pancreatic glucagon contents were not in agreement with the changes in mRNA expression, suggesting a dysregulation in glucagon translation and secretion. In vitro studies revealed that glucose-stimulated cAMP production was impaired in the autophagy-deficient islets exposed to exendin-4. Taken together, the results suggest that the constitutive autophagy in β cells could regulate incretin-induced glucagon expression and release in α cells, and that cAMP may play a role in this process.
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