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Department of Experimental Medical Science, Biomedical Centre, C11, Lund University, SE-221 84 Lund, Sweden
¹ Pulmonary/Critical-Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA
² Department of Medical Physiology, the Panum Institute, DK-2200 Copenhagen, Denmark
³ Department of Clinical Sciences, Lund, Biomedical Centre, B11, Lund University, SE-221 84 Lund, Sweden

(Requests for offprints should be addressed to H A Walz; Email: helena.walz{at}med.lu.se)

(L Härndahl is now at AstraZeneca, 3S36A Mereside, Alderly Park, Macclesfield, Cheshire, SK10 4TG, UK)

^* (H A Walz and L Härndahl contributed equally to this work)

Inadequate islet adaptation to insulin resistance leads to glucose intolerance and type 2 diabetes. Here we investigate whether ß-cell cAMP is crucial for islet adaptation and prevention of glucose intolerance in mice. Mice with a ß-cell-specific, 2-fold overexpression of the cAMP-degrading enzyme phosphodiesterase 3B (RIP-PDE3B/2 mice) were metabolically challenged with a high-fat diet. We found that RIP-PDE3B/2 mice early and rapidly develop glucose intolerance and insulin resistance, as compared with wild-type littermates, after 2 months of high-fat feeding. This was evident from advanced fasting hyperinsulinemia and early development of hyper-glycemia, in spite of hyperinsulinemia, as well as impaired capacity of insulin to suppress plasma glucose in an insulin tolerance test. In vitro analyses of insulin-stimulated lipogenesis in adipocytes and glucose uptake in skeletal muscle did not reveal reduced insulin sensitivity in these tissues. Significant steatosis was noted in livers from high-fat-fed wild-type and RIP-PDE3B/2 mice and liver triacyl-glycerol content was 3-fold higher than in wild-type mice fed a control diet. Histochemical analysis revealed severe islet perturbations, such as centrally located -cells and reduced immunostaining for insulin and GLUT2 in islets from RIP-PDE3B/2 mice. Additionally, in vitro experiments revealed that the insulin secretory response to glucagon-like peptide-1 stimulation was markedly reduced in islets from high-fat-fed RIP-PDE3B/2 mice. We conclude that accurate regulation of ß-cell cAMP is necessary for adequate islet adaptation to a perturbed metabolic environment and protective for the development of glucose intolerance and insulin resistance.

This article has been cited by other articles:

				A. Dov, E. Abramovitch, N. Warwar, and R. Nesher Diminished Phosphodiesterase-8B Potentiates Biphasic Insulin Response to Glucose Endocrinology, February 1, 2008; 149(2): 741 - 748. [Abstract] [Full Text] [PDF]