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Diabetes. 2014 Sep;63(9):2984-95. doi: 10.2337/db13-1121. Epub 2014 May 8.

Glycoprotein 130 receptor signaling mediates α-cell dysfunction in a rodent model of type 2 diabetes.

Author information

1
Department of Surgery, Faculty of Medicine, University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, Canada.
2
Diabetes Research Unit, Novo Nordisk A/S, Måløv, Denmark.
3
Institute of Biochemistry, Medical Faculty, Christian Albrechts University of Kiel, Kiel, Germany.
4
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.
5
Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
6
Faculty of Life Sciences, University of Manchester, Manchester, U.K.
7
The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
8
Department of Surgery, Faculty of Medicine, University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, Canada ehses@mail.ubc.ca.

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.

PMID:
24812426
DOI:
10.2337/db13-1121
[Indexed for MEDLINE]
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