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

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.

• Författare: Linda Härndahl; Nils Wierup; Sven Enerbäck; Hindrik Mulder; Vincent C Manganiello; Frank Sundler; Eva Degerman; Bo Ahrén; Lena Stenson Holst
• Avdelning/ar: Institutionen för experimentell medicinsk vetenskap; Diabetes - molekylär metabolism; Signaltransduktionsforskning; Medicin/akutsjukvård, Lund
• Publiceringsår: 2004
• Språk: Engelska
• Sidor: 15214-15222
• Publikation/Tidskrift/Serie: Journal of Biological Chemistry
• Volym: 279
• Issue: 15
• Länkar: http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=14736883&ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum; http://dx.doi.org/10.1074/jbc.M308952200
• Dokumenttyp: Artikel i tidskrift
• Förlag: American Society for Biochemistry and Molecular Biology
• Ämne: Cell and Molecular Biology
• Status: Published
• Forskningsgrupp: Diabetes - Molecular Metabolism; Insulin Signal Transduction
• ISBN/ISSN/Övrigt: ISSN: 1083-351X