title: PTEN deletion in pancreatic α-cells protects against high-fat diet-induced hyperglucagonemia and insulin resistance.
abstract: An aberrant increase in circulating catabolic hormone glucagon contributes to type 2 diabetes pathogenesis. However, mechanisms regulating glucagon secretion and α-cell mass are not well understood. In this study, we aimed to demonstrate that phosphatidylinositol 3-kinase (PI3K) signaling is an important regulator of α-cell function. Mice with deletion of PTEN, a negative regulator of this pathway, in α-cells show reduced circulating glucagon levels and attenuated l-arginine-stimulated glucagon secretion both in vivo and in vitro. This hypoglucagonemic state is maintained after high-fat-diet feeding, leading to reduced expression of hepatic glycogenolytic and gluconeogenic genes. These beneficial effects protected high-fat diet-fed mice against hyperglycemia and insulin resistance. The data demonstrate an inhibitory role of PI3K signaling on α-cell function and provide experimental evidence for enhancing α-cell PI3K signaling for diabetes treatment.
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON, Canada Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Linyuan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON, Canada Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Cynthia T
authors.initials: CT
authors.lastname: Luk
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON, Canada Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Erica P
authors.initials: EP
authors.lastname: Cai
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON, Canada.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Schroer
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Emma M
authors.initials: EM
authors.lastname: Allister
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON, Canada Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Sally Y
authors.initials: SY
authors.lastname: Shi
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Wheeler
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Gaisano
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON, Canada Institute of Medical Science, University of Toronto, Toronto, ON, Canada Division of Endocrinology & Metabolism, Department of Medicine, University Health Network, Toronto, ON, Canada mwoo@uhnresearch.ca.
authors.forename: Minna
authors.initials: M
authors.lastname: Woo
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat; D005260:Female; D005934:Glucagon / Q000097:blood* / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology
chemical_list: D034741:RNA, Small Interfering; D005934:Glucagon; D001120:Arginine; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse