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Important role of phosphodiesterase 3B for the stimulatory action of cAMP on pancreatic beta -cell exocytosis and release of insulin.

Author:
  • Linda Härndahl
  • Xingjun Jing
  • Rosita Ivarsson
  • Eva Degerman
  • Bo Ahrén
  • Vincent C. Manganiello
  • Erik Renström
  • Lena Stenson Holst
Publishing year: 2002
Language: English
Pages: 37446-37455
Publication/Series: Journal of Biological Chemistry
Volume: 277
Issue: 40
Document type: Journal article
Publisher: ASBMB

Abstract english

Cyclic AMP potentiates glucose-stimulated insulin release and mediates the stimulatory effects of hormones such as glucagon-like peptide 1 (GLP-1) on pancreatic b-cells. By inhibition of cAMP-degrading phosphodiesterase (PDE) and, in particular, selective inhibition of PDE3 activity, stimulatory effects on insulin secretion have been observed. Molecular and functional information on b-cell PDE3 is, however, scarce. To provide such information, we have studied the specific effects of the PDE3B isoform by adenovirus-mediated overexpression. In rat islets and rat insulinoma cells, approximate 10-fold overexpression of PDE3B was accompanied by a 6-8-fold increase in membrane-associated PDE3B activity. The cAMP concentration was significantly lowered in transduced cells (INS-1(832/13), and insulin secretion in response to stimulation with high glucose (11.1 mM) was reduced by 40% (islets) and 50% (INS-1). Further, the ability of GLP-1 (100 nM) to augment glucose-stimulated insulin secretion was inhibited by approximately 30% (islets) and 70% (INS-1). Accordingly, when stimulating with cAMP, a substantial decrease (65%) in exocytotic capacity was demonstrated in patch-clamped single b-cells. In untransduced insulinoma cells, application of the PDE3-selective inhibitor OPC3911 (10 mM) was shown to increase glucose-stimulated insulin release as well as cAMP-enhanced exocytosis. The findings suggest a significant role of PDE3B as an important regulator of insulin secretory processes.

Keywords

  • Endocrinology and Diabetes

Other

Published
  • Islet patophysiology
  • Insulin Signal Transduction
  • ISSN: 1083-351X
Eva Degerman
E-mail: eva.degerman [at] med.lu.se

Professor

Insulin Signal Transduction

+46 46 222 85 83

+46 70 885 83 62

BMC C1121b

66

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00