Modulation of Insulin Secretion and Glycemia by Selective Inhibition of Cyclic AMP Phosphodiesterase III

Parker, Janice C.; Vanvolkenburg, Maria A.; Nardone, Nancy A.; Hargrove, Diane M.; Andrews, Kim

doi:10.1006/bbrc.1997.7034

Cited by 28 publications

(14 citation statements)

References 14 publications

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“…Indeed, our in vivo work showed that a potent PDE3 inhibitor, Org 9935, considerably augmented glucose-induced increases in plasma insulin concentrations, but did not modify plasma glucose concentrations, possibly due to concomitant inhibition of hepatic and adipose tissue PDE3 [90]. Milrinone improved glucose tolerance in the normal mouse but was hyperglycaemic in the ob/ob mouse, despite increases in plasma insulin [91]. This group also showed milrinone to antagonise insulin-mediated inhibition of lipolysis in isolated adipocytes and insulin-mediated inhibition of glucose production in isolated hepatocytes.…”

Section: Pdes In Other Islet Cell Typesmentioning

confidence: 78%

Cyclic nucleotide phosphodiesterases in pancreatic islets

Pyne

Furman

2003

Diabetologia

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Cyclic nucleotide phosphodiesterases (PDEs) comprise a family of enzymes (PDE1-PDE11) which hydrolyse cyclic AMP and cyclic GMP to their biologically inactive 5′ derivatives. Cyclic AMP is an important physiological amplifier of glucose-induced insulin secretion. As PDEs are the only known mechanism for inactivating cyclic nucleotides, it is important to characterise the PDEs present in the pancreatic islet beta cells. Several studies have shown pancreatic islets or beta cells to contain PDE1C, PDE3B and PDE4, with some evidence for PDE10A. Most evidence suggests that PDE3B is the most important in relation to the regulation of insulin release, although PDE1C could have a role. PDE3-selective inhibitors augment glucose-induced insulin secretion. In contrast, activation of beta-cell PDE3B could mediate the inhibitory effect of IGF-1 and leptin on insulin secretion. In vivo, although PDE3 inhibitors augment glucose-induced insulin secretion, concomitant inhibition of PDE3B in liver and adipose tissue induce insulin resistance and PDE3 inhibitors do not induce hypoglycaemia. The development of PDE3 inhibitors as anti-diabetic agents would require differentiation between PDE3B in the beta cell and that in hepatocytes and adipocytes. Through their effects in regulating beta-cell cyclic nucleotide concentrations, PDEs could modulate beta-cell growth, differentiation and survival; some work has shown that selective inhibition of PDE4 prevents diabetes in NOD mice and that selective PDE3 inhibition blocks cytokine-induced nitric oxide production in islet cells. Further work is required to understand the mechanism of regulation and role of the various PDEs in islet-cell function and to validate them as targets for drugs to treat and prevent diabetes. [Diabetologia (2003[Diabetologia ( ) 46:1179[Diabetologia ( -1189

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Section: Pdes In Other Islet Cell Typesmentioning

confidence: 78%

Cyclic nucleotide phosphodiesterases in pancreatic islets

Pyne

Furman

2003

Diabetologia

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“…An important role of the PDE3B isoform in regulating insulin secretion has been inferred from studies demonstrating that inhibitors selective for PDE3 increase insulin secretion in mice (Parker et al 1997) as well as in human and rat islets (ElMetwally et al 1997, Ahmad et al 2000. Furthermore, overexpression of PDE3B in clonal -cells and rat islets has been shown to reduce cAMP and the insulinotropic response to glucose and GLP-1 (Härndahl et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Early and rapid development of insulin resistance, islet dysfunction and glucose intolerance after high-fat feeding in mice overexpressing phosphodiesterase 3B

Walz

Härndahl²,

Wierup³

et al. 2006

Journal of Endocrinology

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Inadequate islet adaptation to insulin resistance leads to glucose intolerance and type 2 diabetes. Here we investigate whether -cell cAMP is crucial for islet adaptation and prevention of glucose intolerance in mice. Mice with a -cell-specific, 2-fold overexpression of the cAMPdegrading 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 hyperglycemia, 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 triacylglycerol 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 -cell cAMP is necessary for adequate islet adaptation to a perturbed metabolic environment and protective for the development of glucose intolerance and insulin resistance.

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“…Inhibitors of PDE, some of which are in clinical use, are well known cAMP elevating tools. One effect of PDE inhibition is augmented insulin secretion (12)(13)(14).…”

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confidence: 99%

β-Cell-targeted Overexpression of Phosphodiesterase 3B in Mice Causes Impaired Insulin Secretion, Glucose Intolerance, and Deranged Islet Morphology

Härndahl

Wierup

Enerbäck

et al. 2004

Journal of Biological Chemistry

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The second messenger cAMP mediates potentiation of glucose-stimulated insulin release. Use of inhibitors of cAMP-hydrolyzing phosphodiesterase (PDE) 3 and overexpression of PDE3B in vitro have demonstrated a regulatory role for this enzyme in insulin secretion. In this work, the physiological significance of PDE3B-mediated degradation of cAMP for the regulation of insulin secretion in vivo and glucose homeostasis was investigated in transgenic mice overexpressing PDE3B in pancreatic ␤-cells. A 2-fold overexpression of PDE3B protein and activity blunted the insulin response to intravenous glucose, resulting in reduced glucose disposal. The effects were "dose"-dependent because mice overexpressing PDE3B 7-fold failed to increase insulin in response to glucose and hence exhibited pronounced glucose intolerance. Also, the insulin secretory response to intravenous glucagon-like peptide 1 was reduced in vivo. Similarly, islets stimulated in vitro exhibited reduced insulin secretory capacity in response to glucose and glucagonlike peptide 1. Perifusion experiments revealed that the reduction specifically affected the first phase of glucosestimulated insulin secretion. Furthermore, morphological examinations demonstrated deranged islet cytoarchitecture. In conclusion, these results are consistent with an essential role for PDE3B in cAMP-mediated regulation of insulin release and glucose homeostasis.

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Modulation of Insulin Secretion and Glycemia by Selective Inhibition of Cyclic AMP Phosphodiesterase III

Cited by 28 publications

References 14 publications

Cyclic nucleotide phosphodiesterases in pancreatic islets

Cyclic nucleotide phosphodiesterases in pancreatic islets

Early and rapid development of insulin resistance, islet dysfunction and glucose intolerance after high-fat feeding in mice overexpressing phosphodiesterase 3B

β-Cell-targeted Overexpression of Phosphodiesterase 3B in Mice Causes Impaired Insulin Secretion, Glucose Intolerance, and Deranged Islet Morphology

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