Early and rapid development of insulin resistance, islet dysfunction and glucose intolerance after high-fat feeding in mice overexpressing phosphodiesterase 3B.
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Inadequate islet adaptation to insulin resistance leads to glucose intolerance and type 2 diabetes. Here we investigate whether beta-cell cAMP is crucial for islet adaptation and prevention of glucose intolerance in mice. Mice with a beta-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 alpha-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 beta-cell cAMP is necessary for adequate islet adaptation to a perturbed metabolic environment and protective for the development of glucose intolerance and insulin resistance.
Original language | English |
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Journal | Journal of Endocrinology |
Volume | 189 |
Issue number | 3 |
Pages (from-to) | 629-41 |
Number of pages | 12 |
ISSN | 0022-0795 |
DOIs | |
Publication status | Published - 2006 |
Bibliographical note
Keywords: 3',5'-Cyclic-AMP Phosphodiesterases; Adaptation, Physiological; Animals; Blood Glucose; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 3; Diabetes Mellitus, Type 2; Dietary Fats; Gene Expression; Glucagon-Like Peptide 1; Glucose Transporter Type 2; Immunohistochemistry; Insulin; Insulin Resistance; Insulin-Secreting Cells; Liver; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Triglycerides
ID: 8462248