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

Artikel i vetenskaplig tidskrift
Författare Linda Härndahl
Nils Wierup
Sven Enerbäck
Hindrik Mulder
Vincent C Manganiello
Frank Sundler
Eva Degerman
Bo Ahrén
Lena Holst Stenson
Publicerad i The Journal of biological chemistry
Volym 279
Nummer/häfte 15
Sidor 15214-22
ISSN 0021-9258
Publiceringsår 2004
Publicerad vid Institutionen för medicinsk och fysiologisk kemi
Sidor 15214-22
Språk en
Länkar dx.doi.org/10.1074/jbc.M308952200
Ämnesord 3',5'-Cyclic-Nucleotide Phosphodiesterase, biosynthesis, Animals, Blotting, Western, Cyclic AMP, metabolism, DNA, Complementary, metabolism, Dose-Response Relationship, Drug, Glucagon, chemistry, Glucagon-Like Peptide 1, Glucose, metabolism, Immunohistochemistry, Insulin, metabolism, secretion, Islets of Langerhans, cytology, metabolism, Mice, Mice, Inbred CBA, Mice, Transgenic, Microscopy, Fluorescence, Peptide Fragments, chemistry, Protein Precursors, chemistry, Reverse Transcriptase Polymerase Chain Reaction, Time Factors
Ämneskategorier Medicin och Hälsovetenskap

Sammanfattning

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.

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