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J. Biol. Chem., Vol. 279, Issue 15, 15214-15222, April 9, 2004

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-Cell-targeted Overexpression of Phosphodiesterase 3B in Mice Causes Impaired Insulin Secretion, Glucose Intolerance, and Deranged Islet Morphology^*

Linda Härndahl, Nils Wierup, Sven Enerbäck¶, Hindrik Mulder, Vincent C. Manganiello||, Frank Sundler, Eva Degerman, Bo Ahrén**, and Lena Stenson Holst

From the Departments of Cell and Molecular Biology, Biomedical Center, C11, Physiological Sciences, Biomedical Center, F10, and ^**Medicine, Biomedical Centre, B11, Lund University, SE-221 84 Lund, Sweden, the ^¶Department of Medical Biochemistry, Medical Genetics, Göteborg University, Box 440, SE-405 30 Göteborg, Sweden, and the ^||Pulmonary/Critical Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892

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 -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.

Received for publication, August 13, 2003 , and in revised form, December 22, 2003.

^* This work was supported by Swedish Research Council Grants 3362 (to E. D.), 6834 (to B. A.), and 4499 (to F. S. and N. W.), a Center of Excellence grant from the Juvenile Diabetes Foundation, USA, the Knut and Alice Wallenberg Foundation, Sweden, the Swedish Society of Medicine, the Swedish Diabetes Association, the A. Påhlsson, M. Bergwall, Å. Wiberg, T. Zoega, and Crafoord Foundations, Sweden, and the Novo Nordisk Foundation, Denmark. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Biomedical Center, C11, SE-221 84 Lund, Sweden. Tel.: 46-46-222-89-84; Fax: 46-46-222-40-22; E-mail: Lena.Stenson-Holst{at}medkem.lu.se.

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