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Nils Wierup

Nils Wierup

Senior lecturer

Nils Wierup

Glucagon receptor antagonism improves islet function in mice with insulin resistance induced by a high-fat diet.

Author

  • Maria Sörhede Winzell
  • C Brand
  • Nils Wierup
  • U Sidelmann
  • Frank Sundler
  • E Nishimura
  • Bo Ahrén

Summary, in English

Aims/hypothesis Increased glucagon secretion predicts deterioration of glucose tolerance, and high glucagon levels contribute to hyperglycaemia in type 2 diabetes. Inhibition of glucagon action may therefore be a potential novel target to reduce hyperglycaemia. Here, we investigated whether chronic treatment with a glucagon receptor antagonist (GRA) improves islet dysfunction in female mice on a high-fat diet (HFD). Materials and methods After 8 weeks of HFD, mice were treated with a small molecule GRA ( 300 mg/kg, gavage once daily) for up to 30 days. Insulin secretion was studied after oral and intravenous administration of glucose and glucagon secretion after intravenous arginine. Islet morphology was examined and insulin secretion and glucose oxidation were measured in isolated islets. Results Fasting plasma glucose levels were reduced by GRA (6.0 +/- 0.2 vs 7.4 +/- 0.5 mmol/l; p= 0.017). The acute insulin response to intravenous glucose was augmented ( 1,300 +/- 110 vs 790 +/- 64 pmol/l; p < 0.001). The early insulin response to oral glucose was reduced in mice on HFD + GRA ( 1,890 +/- 160 vs 3,040 +/- 420 pmol/ l; p= 0.012), but glucose excursions were improved. Intravenous arginine significantly increased the acute glucagon response ( 129 +/- 12 vs 36 +/- 6 ng/l in controls; p < 0.01), notably without affecting plasma glucose. GRA caused a modest increase in alpha cell mass, while beta cell mass was similar to that in mice on HFD + vehicle. Isolated islets displayed improved glucose-stimulated insulin secretion after GRA treatment (0.061 +/- 0.007 vs 0.030 +/- 0.004 pmol islet(-1) h(-1) at 16.7 mmol/l glucose; p < 0.001), without affecting islet glucose oxidation. Conclusions/interpretation Chronic glucagon receptor antagonism in HFD-fed mice improves islet sensitivity to glucose and increases insulin secretion, suggesting improvement of key defects underlying impaired glucose tolerance and type 2 diabetes.

Department/s

  • Medicine, Lund
  • Neuroendocrine Cell Biology

Publishing year

2007

Language

English

Pages

1453-1462

Publication/Series

Diabetologia

Volume

50

Document type

Journal article

Publisher

Springer

Topic

  • Endocrinology and Diabetes

Keywords

  • diabetes
  • type 2
  • islet
  • insulin sensitivity
  • glucagon
  • glucose tolerance
  • glycaemia
  • insulin secretion
  • diabetes treatment
  • beta cell
  • alpha cell

Status

Published

Research group

  • Neuroendocrine Cell Biology

ISBN/ISSN/Other

  • ISSN: 1432-0428