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Cecilia Holm

Professor

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Long-term exposure to glucose and lipids inhibits glucose-induced insulin secretion downstream of granule fusion with plasma membrane.

Author

  • Charlotta Olofsson
  • Stephan Collins
  • Martin Bengtsson
  • Lena Eliasson
  • S Albert Salehi
  • Kenju Shimomura
  • Andrei Tarasov
  • Cecilia Holm
  • Frances Ashcroft
  • Patrik Rorsman

Summary, in English

Mouse beta-cells cultured at 15 mmol/l glucose for 72 h had reduced ATP-sensitive K+ (K-ATP) channel activity (-30%), increased voltage-gated Ca2+ currents, higher intracellular free Ca2+ concentration ([Ca-i(2+]) +160%), more exocytosis (monitored by capacitance measurements, +100%), and greater insulin content (+230%) than those cultured at 4.5 mmol/l glucose. However, they released 20% less insulin when challenged with 20 mmol/l glucose. Glucose-induced (20 mmol/l) insulin secretion was reduced by 60-90% in islets cocultured at 4.5 or 15 mmol/l glucose and either oleate or palmitate (0.5 mmol/l). Free fatty acid (FFA)induced inhibition of secretion was not associated with any major changes in [Ca2+](i) or islet ATP content. Palmitate stimulated exocytosis by twofold or more but reduced V-induced secretion by up to 60%. Basal (1 mmol/l glucose) K-ATP channel activity was 40% lower in islets cultured at 4.5 mmol/l glucose plus palmitate and 60% lower in islets cultured at 15 mmol/l glucose plus either of the FFAs. Insulin content decreased by 75% in islets exposed to FFAs in the presence of high (15 mmol/l), but not low (4.5 mmol/l), glucose concentrations, but the number of secre tory granules was unchanged. FFA-induced inhibition of insulin secretion was not associated with increased tran script levels of the apoptosis markers Bax (BclII-associated X protein) and caspase-3. We conclude that glucose and FFAs reduce insulin secretion by interference with the exit of insulin via the fusion pore.

Department/s

  • Faculty of Medicine
  • Islet cell physiology
  • Diabetes - Islet Cell Exocytosis
  • Molecular Endocrinology

Publishing year

2007

Language

English

Pages

1888-1897

Publication/Series

Diabetes

Volume

56

Issue

7

Document type

Journal article

Publisher

American Diabetes Association Inc.

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Islet cell physiology
  • Diabetes - Islet Cell Exocytosis
  • Molecular Endocrinology

ISBN/ISSN/Other

  • ISSN: 1939-327X