The effect of selective phosphodiesterase inhibitors on plasma insulin concentrations and insulin secretion in vitro in the rat

El-Metwally, M A; Shafiee-Nick, Reza; Pyne, Nigel J.; Furman, Brian L.

doi:10.1016/s0014-2999(97)00076-9

Cited by 24 publications

(15 citation statements)

References 23 publications

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“…Development of PDE3 inhibitors for this purpose will require their selectivity for islet beta cell PDE3, as PDE3 seems also to be the important isoenzyme in the liver and adipose tissue [89], where its activation mediates some of the effects of insulin. 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].…”

Section: Pdes In Other Islet Cell Typesmentioning

confidence: 77%

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: 77%

Cyclic nucleotide phosphodiesterases in pancreatic islets

Pyne

Furman

2003

Diabetologia

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“…Cell Culture, Treatments, and Measurements of Insulin Secretion-␤TC3 cells were cultured as described and early passages (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) were maintained (20). For measurements of insulin secretion cells were plated onto 24-well culture dishes 3-4 days, and refed 16 h prior to the assay.…”

Section: Preparation Of Cell Extracts and Mono Q-fplc Fractionation-cmentioning

confidence: 99%

“…Cyclic nucleotide PDEs present in ␤-cells were thus far investigated as total PDE activities of crude islet extracts and the presence of PDEs 3 and 4, and calcium-sensitive PDEs, in ␤-cells has been inferred from these studies (32)(33)(34)(35)(36). The involvement of PDE3 in glucose-induced insulin secretion from pancreatic islets has been demonstrated in studies using selective PDE3 inhibitors (32,33,37,38). The presence of PDE3B in pancreatic ␤-cells and its involvement in insulin-like growth factor-1 and in leptin-mediated inhibition of insulin secretion has been demonstrated recently (10,39).…”

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confidence: 99%

The Calcium/Calmodulin-dependent Phosphodiesterase PDE1C Down-regulates Glucose-induced Insulin Secretion

Han¹,

Werber²,

Surana

et al. 1999

Journal of Biological Chemistry

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To understand the role cAMP phosphodiesterases (PDEs) play in the regulation of insulin secretion, we analyzed cyclic nucleotide PDEs of a pancreatic ␤-cell line and used family and isozyme-specific PDE inhibitors to identify the PDEs that counteract glucose-stimulated insulin secretion. We demonstrate the presence of soluble PDE1C, PDE4A and 4D, a cGMP-specific PDE, and of particulate PDE3, activities in ␤TC3 insulinoma cells. Selective inhibition of PDE1C, but not of PDE4, augmentedglucose-stimulatedinsulinsecretioninadosedependent fashion thus demonstrating that PDE1C is the major PDE counteracting glucose-dependent insulin secretion from ␤TC3 cells. In pancreatic islets, inhibition of both PDE1C and PDE3 augmented glucose-dependent insulin secretion. The PDE1C of ␤TC3 cells is a novel isozyme possessing a K m of 0.47 M for cAMP and 0.25 M for cGMP. The PDE1C isozyme of ␤TC3 cells is sensitive to 8-methoxymethyl isobutylmethylxanthine and zaprinast (IC 50 ‫؍‬ 7.5 and 4.5 M, respectively) and resistant to vinpocetine (IC 50 > 100 M). Increased responsiveness of PDE1C activity to calcium/calmodulin is evident upon exposure of cells to glucose. Enhanced cAMP degradation by PDE1C, due to increases in its responsiveness to calcium/calmodulin and in intracellular calcium, constitutes a glucose-dependent feedback mechanism for the control of insulin secretion.

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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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The effect of selective phosphodiesterase inhibitors on plasma insulin concentrations and insulin secretion in vitro in the rat

Cited by 24 publications

References 23 publications

Cyclic nucleotide phosphodiesterases in pancreatic islets

Cyclic nucleotide phosphodiesterases in pancreatic islets

The Calcium/Calmodulin-dependent Phosphodiesterase PDE1C Down-regulates Glucose-induced Insulin Secretion

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

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