Gp130 receptor signaling mediates α cell dysfunction in a rodent model of type 2 diabetes

  1. Jan A. Ehses1
  1. 1Department of Surgery, Faculty of Medicine, University of British Columbia, Child & Family Research Institute, Vancouver, BC, Canada.
  2. 2Diabetes Research Unit, Novo Nordisk A/S, Måløv, Denmark.
  3. 3Institute of Biochemistry, Medical Faculty, Christian Albrechts University of Kiel, Kiel, Germany.
  4. 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.
  5. 5Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
  6. 6Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
  7. 7The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Denmark.
  1. #Corresponding Author: Jan A. Ehses, E-mail: ehses{at}


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.

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