title: Early and rapid development of insulin resistance, islet dysfunction and glucose intolerance after high-fat feeding in mice overexpressing phosphodiesterase 3B.
abstract: 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.
authors.affiliation: Department of Experimental Medical Science, Biomedical Centre, C11, Lund University, SE-221 84 Lund, Sweden. helena.walz@med.lu.se
authors.forename: Helena A
authors.initials: HA
authors.lastname: Walz
authors.forename: Linda
authors.initials: L
authors.lastname: Härndahl
authors.forename: Nils
authors.initials: N
authors.lastname: Wierup
authors.forename: Emilia
authors.initials: E
authors.lastname: Zmuda-Trzebiatowska
authors.forename: Fredrik
authors.initials: F
authors.lastname: Svennelid
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Manganiello
authors.forename: Thorkil
authors.initials: T
authors.lastname: Ploug
authors.forename: Frank
authors.initials: F
authors.lastname: Sundler
authors.forename: Eva
authors.initials: E
authors.lastname: Degerman
authors.forename: Bo
authors.initials: B
authors.lastname: Ahrén
authors.forename: Lena Stenson
authors.initials: LS
authors.lastname: Holst
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics / Q000378:metabolism*; D000222:Adaptation, Physiological; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D000242:Cyclic AMP / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004041:Dietary Fats / Q000008:administration & dosage*; D015870:Gene Expression; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D051273:Glucose Transporter Type 2 / Q000032:analysis; D007150:Immunohistochemistry / Q000379:methods; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D014280:Triglycerides / Q000032:analysis
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D051273:Glucose Transporter Type 2; D007328:Insulin; D014280:Triglycerides; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517293:Pde3b protein, mouse