title: Autophagy deficiency in β cells blunts incretin-induced suppression of glucagon release from α cells.
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.
authors.affiliation: a Department of Internal Medicine ; Seoul National University College of Medicine ; Seoul , Republic of Korea.|b Department of Internal Medicine ; Korea Cancer Center Hospital ; Seoul , Republic of Korea.
authors.forename: Min Joo
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: c Innovative Research Institute for Cell Therapy ; Seoul , Republic of Korea.
authors.forename: Ok Kyong
authors.initials: OK
authors.lastname: Choi
authors.affiliation: c Innovative Research Institute for Cell Therapy ; Seoul , Republic of Korea.
authors.forename: Kyung Sil
authors.initials: KS
authors.lastname: Chae
authors.affiliation: c Innovative Research Institute for Cell Therapy ; Seoul , Republic of Korea.
authors.forename: Hakmo
authors.initials: H
authors.lastname: Lee
authors.affiliation: c Innovative Research Institute for Cell Therapy ; Seoul , Republic of Korea.
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Chung
authors.affiliation: d Department of Endocrinology and Metabolism ; The Catholic University of Korea ; Seoul , Republic of Korea.
authors.forename: Dong-Sik
authors.initials: DS
authors.lastname: Ham
authors.affiliation: d Department of Endocrinology and Metabolism ; The Catholic University of Korea ; Seoul , Republic of Korea.
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Kim
authors.affiliation: d Department of Endocrinology and Metabolism ; The Catholic University of Korea ; Seoul , Republic of Korea.
authors.forename: Kun-Ho
authors.initials: KH
authors.lastname: Yoon
authors.affiliation: a Department of Internal Medicine ; Seoul National University College of Medicine ; Seoul , Republic of Korea.|c Innovative Research Institute for Cell Therapy ; Seoul , Republic of Korea.
authors.forename: Kyong Soo
authors.initials: KS
authors.lastname: Park
authors.affiliation: a Department of Internal Medicine ; Seoul National University College of Medicine ; Seoul , Republic of Korea.|c Innovative Research Institute for Cell Therapy ; Seoul , Republic of Korea.
authors.forename: Hye Seung
authors.initials: HS
authors.lastname: Jung
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D018149:Glucose Intolerance / Q000378:metabolism; D054795:Incretins / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice
chemical_list: D054795:Incretins; D005934:Glucagon
keywords: autophagy; dipeptidyl-peptidase IV inhibitors; glucagon; incretins; vildagliptin; α cell