Gp130 receptor signaling mediates α cell dysfunction in a rodent model of type 2 diabetes
- Samuel Z. Chow1,*,
- Madeleine Speck1,*,
- Priya Yoganathan1,
- Dominika Nackiewicz1,
- Ann Maria Hansen2,
- Mette Ladefoged2,
- Bjorn Rabe3,
- Stefan Rose-John3,
- Peter J. Voshol4,
- Francis C. Lynn1,
- Pedro L. Herrera5,
- Werner Müller6,
- Helga Ellingsgaard7 and
- Jan A. Ehses1
- 1Department of Surgery, Faculty of Medicine, University of British Columbia, Child & Family Research Institute, Vancouver, BC, Canada.
- 2Diabetes Research Unit, Novo Nordisk A/S, Måløv, Denmark.
- 3Institute of Biochemistry, Medical Faculty, Christian Albrechts University of Kiel, Kiel, Germany.
- 4Institute of Metabolic Science, University of Cambridge Metabolic Research Laboratories and National Institute for Health Research Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, United Kingdom.
- 5Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
- 6Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
- 7The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Denmark.
- #Corresponding Author: Jan A. Ehses, E-mail:
Dysregulated glucagon secretion accompanies islet inflammation in type 2 diabetes. We recently discovered that IL-6 stimulates glucagon secretion from human and rodent islets. IL-6 family cytokines require the 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 knock out (αgp130KO) mice showed no differences in glycemic control, α cell function or α cell mass. However, when subjected to streptozotocin (STZ) plus high fat diet (HFD) to induce islet inflammation and pathophysiology modelling 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.
- Received July 19, 2013.
- Accepted April 7, 2014.
- © 2014 by the American Diabetes Association.
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