title: Glycoprotein 130 receptor signaling mediates α-cell dysfunction in a rodent model of type 2 diabetes.
abstract: Dysregulated glucagon secretion accompanies islet inflammation in type 2 diabetes. We recently discovered that interleukin (IL)-6 stimulates glucagon secretion from human and rodent islets. IL-6 family cytokines require the glycoprotein 130 (gp130) receptor to signal. In this study, we elucidated the effects of α-cell gp130 receptor signaling on glycemic control in type 2 diabetes. IL-6 family cytokines were elevated in islets in rodent models of this disease. gp130 receptor activation increased STAT3 phosphorylation in primary α-cells and stimulated glucagon secretion. Pancreatic α-cell gp130 knockout (αgp130KO) mice showed no differences in glycemic control, α-cell function, or α-cell mass. However, when subjected to streptozotocin plus high-fat diet to induce islet inflammation and pathophysiology modeling type 2 diabetes, αgp130KO mice had reduced fasting glycemia, improved glucose tolerance, reduced fasting insulin, and improved α-cell function. Hyperinsulinemic-euglycemic clamps revealed no differences in insulin sensitivity. We conclude that in a setting of islet inflammation and pathophysiology modeling type 2 diabetes, activation of α-cell gp130 receptor signaling has deleterious effects on α-cell function, promoting hyperglycemia. Antagonism of α-cell gp130 receptor signaling may be useful for the treatment of type 2 diabetes.
authors.affiliation: Department of Surgery, Faculty of Medicine, University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Samuel Z
authors.initials: SZ
authors.lastname: Chow
authors.affiliation: Department of Surgery, Faculty of Medicine, University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Speck
authors.affiliation: Department of Surgery, Faculty of Medicine, University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Piriya
authors.initials: P
authors.lastname: Yoganathan
authors.affiliation: Department of Surgery, Faculty of Medicine, University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Dominika
authors.initials: D
authors.lastname: Nackiewicz
authors.affiliation: Diabetes Research Unit, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: Ann Maria
authors.initials: AM
authors.lastname: Hansen
authors.affiliation: Diabetes Research Unit, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Ladefoged
authors.affiliation: Institute of Biochemistry, Medical Faculty, Christian Albrechts University of Kiel, Kiel, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Rabe
authors.affiliation: Institute of Biochemistry, Medical Faculty, Christian Albrechts University of Kiel, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Institute of Metabolic Science, University of Cambridge Metabolic Research Laboratories and National Institute for Health Research Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, U.K.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Voshol
authors.affiliation: Department of Surgery, Faculty of Medicine, University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Francis C
authors.initials: FC
authors.lastname: Lynn
authors.affiliation: Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Herrera
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, U.K.
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.affiliation: The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Helga
authors.initials: H
authors.lastname: Ellingsgaard
authors.affiliation: Department of Surgery, Faculty of Medicine, University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, Canada ehses@mail.ubc.ca.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Ehses
mesh_terms: D000818:Animals; D050822:Cytokine Receptor gp130 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D059305:Diet, High-Fat; D005934:Glucagon / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: C494200:Il6st protein, mouse; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D050822:Cytokine Receptor gp130; D005934:Glucagon