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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Early and rapid development of insulin resistance, islet dysfunction and glucose intolerance after high-fat feeding in mice overexpressing phosphodiesterase 3B. / Walz, Helena A; Härndahl, Linda; Wierup, Nils; Zmuda-Trzebiatowska, Emilia; Svennelid, Fredrik; Manganiello, Vincent C; Ploug, Thorkil; Sundler, Frank; Degerman, Eva; Ahrén, Bo; Holst, Lena Stenson.
I: Journal of Endocrinology, Bind 189, Nr. 3, 2006, s. 629-41.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Early and rapid development of insulin resistance, islet dysfunction and glucose intolerance after high-fat feeding in mice overexpressing phosphodiesterase 3B.
AU - Walz, Helena A
AU - Härndahl, Linda
AU - Wierup, Nils
AU - Zmuda-Trzebiatowska, Emilia
AU - Svennelid, Fredrik
AU - Manganiello, Vincent C
AU - Ploug, Thorkil
AU - Sundler, Frank
AU - Degerman, Eva
AU - Ahrén, Bo
AU - Holst, Lena Stenson
N1 - 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
PY - 2006
Y1 - 2006
N2 - 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.
AB - 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.
U2 - 10.1677/joe.1.06522
DO - 10.1677/joe.1.06522
M3 - Journal article
C2 - 16731793
VL - 189
SP - 629
EP - 641
JO - Journal of Endocrinology
JF - Journal of Endocrinology
SN - 0022-0795
IS - 3
ER -
ID: 8462248