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Nils Wierup

Nils Wierup

Senior lecturer

Nils Wierup

Beta-cell-targeted overexpression of phosphodiesterase 3B in mice causes impaired insulin secretion, glucose intolerance and deranged glucose morphology.

Author

  • Linda Härndahl
  • Nils Wierup
  • Sven Enerbäck
  • Hindrik Mulder
  • Vincent C Manganiello
  • Frank Sundler
  • Eva Degerman
  • Bo Ahrén
  • Lena Stenson Holst

Summary, in English

The second messenger cAMP mediates potentiation of glucose-stimulated insulin release. Use of inhibitors of cAMP-hydrolyzing phosphodiesterase (PDE) 3 and overexpression of PDE3B in vitro have demonstrated a regulatory role for this enzyme in insulin secretion. In this work, the physiological significance of PDE3B-mediated degradation of cAMP for the regulation of insulin secretion in vivo and glucose homeostasis was investigated in transgenic mice overexpressing PDE3B in pancreatic beta-cells. A 2-fold overexpression of PDE3B protein and activity blunted the insulin response to intravenous glucose, resulting in reduced glucose disposal. The effects were "dose"-dependent because mice overexpressing PDE3B 7-fold failed to increase insulin in response to glucose and hence exhibited pronounced glucose intolerance. Also, the insulin secretory response to intravenous glucagon-like peptide 1 was reduced in vivo. Similarly, islets stimulated in vitro exhibited reduced insulin secretory capacity in response to glucose and glucagon-like peptide 1. Perifusion experiments revealed that the reduction specifically affected the first phase of glucose-stimulated insulin secretion. Furthermore, morphological examinations demonstrated deranged islet cytoarchitecture. In conclusion, these results are consistent with an essential role for PDE3B in cAMP-mediated regulation of insulin release and glucose homeostasis.

Department/s

  • Department of Experimental Medical Science
  • Diabetes - Molecular Metabolism
  • Insulin Signal Transduction
  • Medicine, Lund

Publishing year

2004

Language

English

Pages

15214-15222

Publication/Series

Journal of Biological Chemistry

Volume

279

Issue

15

Document type

Journal article

Publisher

ASBMB

Topic

  • Cell and Molecular Biology

Status

Published

Research group

  • Diabetes - Molecular Metabolism
  • Insulin Signal Transduction

ISBN/ISSN/Other

  • ISSN: 1083-351X