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To study whether the incretin effect is involved in adaptively increased insulin secretion in insulin resistance, glucose was infused at a variable rate to match glucose levels after oral glucose (25 mg) in normal anesthetized C57BL/6J female mice or in mice rendered insulin resistant by 8 weeks of high-fat feeding. Insulin response was markedly higher after oral than i.v. glucose in both groups, and this augmentation was even higher in high-fat fed than normal mice. In normal mice, the area under the curve (AUCinsulin) was augmented from 4.0±0.8 to 8.0±1.8 nmol/l×60 min by the oral glucose, i.e. by a factor of 2 (P=0.023), whereas in the high-fat fed mice, AUCinsulin was augmented from 0.70±0.4 to 12.4±2.5 nmol/l×60 min, i.e. by a factor of 17 (P<0.001). To examine whether the incretin hormone glucagon-like peptide-1 (GLP-1) is responsible for this difference, the effect of i.v. GLP-1 was compared in normal and high-fat fed mice. The sensitivity to i.v. GLP-1 in stimulating insulin secretion was increased in the high-fat diet fed mice: the lowest effective dose of GLP-1 was 650 pmol/kg in normal mice and 13 pmol/kg in the high-fat diet fed mice. We conclude that 1) the incretin effect contributes by ∼50% to insulin secretion by the oral glucose in normal mice, 2) this effect is markedly exaggerated in insulin-resistant mice fed a high-fat diet, and 3) this augmented incretin contribution in the high-fat fed mice may partially be explained by GLP-1.
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Stimulation of insulin secretion by short-term glucagon receptor (GCGR) activation is well characterized; however, the effect of long-term GCGR activation on β-cell function is not known, but of interest, since hyperglucagonemia occurs early during development of type 2 diabetes. Therefore, we examined whether chronic GCGR activation affects insulin secretion in glucose intolerant mice. To induce chronic GCGR activation, high-fat diet fed mice were continuously (2 weeks) infused with the stable glucagon analog ZP-GA-1 and challenged with oral glucose and intravenous glucose±glucagon-like peptide 1 (GLP1). Islets were isolated to evaluate the insulin secretory response to glucose±GLP1 and their pancreas were collected for immunohistochemical analysis. Two weeks of ZP-GA-1 infusion reduced insulin secretion both after oral and intravenous glucose challenges in vivo and in isolated islets. These inhibitory effects were corrected for by GLP1. Also, we observed increased β-cell area and islet size. We conclude that induction of chronic ZP-GA-1 levels in glucose intolerant mice markedly reduces insulin secretion, and thus, we suggest that chronic activation of the GCGR may contribute to the failure of β-cell function during development of type 2 diabetes.
Pulmonary/Critical-Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA
Department of Medical Physiology, the Panum Institute, DK-2200 Copenhagen, Denmark
Department of Clinical Sciences, Lund, Biomedical Centre, B11, Lund University, SE-221 84 Lund, Sweden
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Pulmonary/Critical-Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA
Department of Medical Physiology, the Panum Institute, DK-2200 Copenhagen, Denmark
Department of Clinical Sciences, Lund, Biomedical Centre, B11, Lund University, SE-221 84 Lund, Sweden
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Pulmonary/Critical-Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA
Department of Medical Physiology, the Panum Institute, DK-2200 Copenhagen, Denmark
Department of Clinical Sciences, Lund, Biomedical Centre, B11, Lund University, SE-221 84 Lund, Sweden
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Pulmonary/Critical-Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA
Department of Medical Physiology, the Panum Institute, DK-2200 Copenhagen, Denmark
Department of Clinical Sciences, Lund, Biomedical Centre, B11, Lund University, SE-221 84 Lund, Sweden
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Pulmonary/Critical-Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA
Department of Medical Physiology, the Panum Institute, DK-2200 Copenhagen, Denmark
Department of Clinical Sciences, Lund, Biomedical Centre, B11, Lund University, SE-221 84 Lund, Sweden
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Pulmonary/Critical-Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA
Department of Medical Physiology, the Panum Institute, DK-2200 Copenhagen, Denmark
Department of Clinical Sciences, Lund, Biomedical Centre, B11, Lund University, SE-221 84 Lund, Sweden
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Pulmonary/Critical-Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA
Department of Medical Physiology, the Panum Institute, DK-2200 Copenhagen, Denmark
Department of Clinical Sciences, Lund, Biomedical Centre, B11, Lund University, SE-221 84 Lund, Sweden
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Pulmonary/Critical-Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA
Department of Medical Physiology, the Panum Institute, DK-2200 Copenhagen, Denmark
Department of Clinical Sciences, Lund, Biomedical Centre, B11, Lund University, SE-221 84 Lund, Sweden
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Pulmonary/Critical-Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA
Department of Medical Physiology, the Panum Institute, DK-2200 Copenhagen, Denmark
Department of Clinical Sciences, Lund, Biomedical Centre, B11, Lund University, SE-221 84 Lund, Sweden
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Pulmonary/Critical-Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA
Department of Medical Physiology, the Panum Institute, DK-2200 Copenhagen, Denmark
Department of Clinical Sciences, Lund, Biomedical Centre, B11, Lund University, SE-221 84 Lund, Sweden
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Pulmonary/Critical-Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA
Department of Medical Physiology, the Panum Institute, DK-2200 Copenhagen, Denmark
Department of Clinical Sciences, Lund, Biomedical Centre, B11, Lund University, SE-221 84 Lund, Sweden
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Inadequate islet adaptation to insulin resistance leads to glucose intolerance and type 2 diabetes. Here we investigate whether β-cell cAMP is crucial for islet adaptation and prevention of glucose intolerance in mice. Mice with a β-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 α-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 β-cell cAMP is necessary for adequate islet adaptation to a perturbed metabolic environment and protective for the development of glucose intolerance and insulin resistance.
