PMID:14736883

Citation	Härndahl, L, Wierup, N, Enerbäck, S, Mulder, H, Manganiello, VC, Sundler, F, Degerman, E, Ahrén, B and Holst, LS (2004) Beta-cell-targeted overexpression of phosphodiesterase 3B in mice causes impaired insulin secretion, glucose intolerance, and deranged islet morphology. J. Biol. Chem. 279:15214-22
Abstract	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.
Links	PubMed Online version:10.1074/jbc.M308952200
Keywords	3',5'-Cyclic-AMP Phosphodiesterases/biosynthesis; Animals; Blotting, Western; Cyclic AMP/metabolism; Cyclic Nucleotide Phosphodiesterases, Type 3; DNA, Complementary/metabolism; Dose-Response Relationship, Drug; Glucagon/chemistry; Glucagon-Like Peptide 1; Glucose/metabolism; Immunohistochemistry; Insulin/metabolism; Insulin/secretion; Islets of Langerhans/cytology; Islets of Langerhans/metabolism; Mice; Mice, Inbred CBA; Mice, Transgenic; Microscopy, Fluorescence; Peptide Fragments/chemistry; Protein Precursors/chemistry; Reverse Transcriptase Polymerase Chain Reaction; Time Factors
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