Effects of type‐selective phosphodiesterase inhibitors on glucose‐induced insulin secretion and islet phosphodiesterase activity

Shafiee-Nick, Reza; Pyne, Nigel J.; Furman, Brian L.

doi:10.1111/j.1476-5381.1995.tb16641.x

Cited by 46 publications

(63 citation statements)

References 31 publications

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“…The anti-insulin monoclonal antibody was from Sigma. The anti-IGF-1 receptor and anti-insulin receptor antibodies were from Santa Cruz Biotechnology; both antibodies were raised against the N-terminal unique sequences (amino acids [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] of the corresponding receptor. IGF-1 was from Becton Dickinson or GIBCO͞BRL.…”

Section: Methodsmentioning

confidence: 99%

“…13). Interestingly though, only the specific pharmacological inhibitors for PDE3 will actually potentiate insulin secretion (12,14). These data suggest a possible functional importance for a PDE3 isozyme in the regulation of insulin secretion from pancreatic islets.…”

mentioning

confidence: 92%

“…Many insulin secretagogues that utilize cAMP as a second messenger will potentiate glucose-stimulated insulin secretion (1,8,9), and agents that elevate cAMP, such as nonspecific phosphodiesterase (PDE) inhibitors (e.g., isobutylmethylxanthine and theophylline), are potent insulin secretagogues (10)(11)(12). Several recent studies have suggested the presence of both PDE3 and PDE4 activities within pancreatic islets (for a review about various types of PDEs, see ref.…”

mentioning

confidence: 99%

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Attenuation of insulin secretion by insulin-like growth factor 1 is mediated through activation of phosphodiesterase 3B

Zhao

Teague

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

138

115

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Both insulin and insulin-like growth factor 1 (IGF-1) are known to reduce glucose-dependent insulin secretion from the ␤ cells of pancreatic islets. In this paper we show that the mechanism by which IGF-1 mediates this effect is in large part through activation of a specific cyclic nucleotide phosphodiesterase, phosphodiesterase 3B (PDE3B). More specifically, in both isolated pancreatic islets and insulin-secreting HIT-T15 cells, IGF-1 inhibits insulin secretion that has been increased by glucose and glucagonlike peptide 1 (GLP-1). Moreover, IGF-1 decreases cAMP levels in parallel to the reduction of insulin secretion. Insulin secretion stimulated by cAMP analogs that activate protein kinase A and also are substrates for PDE3B is also inhibited by IGF-1. However, IGF-1 does not inhibit insulin secretion stimulated by nonhydrolyzable cAMP analogs. In addition, selective inhibitors of PDE3B completely block the ability of IGF-1 to inhibit insulin secretion. Finally, PDE3B activity measured in vitro after immunoprecipitation from cells treated with IGF-1 is higher than the activity from control cells. Taken together with the fact that pancreatic ␤ cells express little or no insulin receptor but large amounts of IGF-1 receptor, these data strongly suggest a new regulatory feedback loop model for the control of insulin secretion. In this model, increased insulin secretion in vivo will stimulate IGF-1 synthesis by the liver, and the secreted IGF-1 in turn feedback inhibits insulin secretion from the ␤ cells through an IGF-1 receptormediated pathway. This pathway is likely to be particularly important when levels of both glucose and secretagogues such as GLP-1 are elevated.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 92%

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confidence: 99%

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Attenuation of insulin secretion by insulin-like growth factor 1 is mediated through activation of phosphodiesterase 3B

Zhao

Teague

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

138

115

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“…There are 11 different families of PDEs representing 21 different gene products (Bender and Beavo, 2006;Conti, 2000). Use of specific pharmacological inhibitors of certain isoforms of PDE has inferred the presence of PDEs 3 and 4 and calcium sensitive PDEs in β cells (Parker et al, 1995;Shafiee-Nick et al, 1995;Sugden and Ashcroft, 1981). Inhibition of PDE3B in particular has demonstrated the firmest evidence for a PDE being implicated in inhibiting insulin secretion.…”

Section: Stimulation Of Camp Productionmentioning

confidence: 99%

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

576

465

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Glucagon-like peptide-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past twenty years culminating in a naturally occurring GLP-1 receptor agonist, exendin-4, now being used to treat type 2 diabetes. GLP-1 engages a specific G-protein coupled receptor that is present in tissues other than the pancreas (brain, kidney, lung, heart, major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1 receptor activation, adenylyl cyclase is activated and cAMP generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in type 2 diabetic patients treated with exendin-4. This review we will focus on the effects resulting from GLP-1 receptor activation in islets of Langerhans

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“…Three isoenzymes of phosphodiesterase might be involved in the degradation of cGMP, namely phosphodiesterases I, II and V. Zaprinast is considered a selective inhibitor of cGMP type V phosphodiesterase [13]. Therefore zaprinast should cause the elevation of cGMP by inhibiting endogenous cGMP phosphodiesterase activity [13].…”

Section: Introductionmentioning

confidence: 99%

Evidence for altered sensitivity of the nitric oxide/cGMP signalling cascade in insulin-resistant skeletal muscle

Young

Leighton

1998

Biochemical Journal

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Nitric oxide activates guanylate cyclase to form cGMP, comprising a signalling system that is believed to be a distinct mechanism for increasing glucose transport and metabolism in skeletal muscle. The effects of a selective cGMP phosphodiesterase inhibitor, zaprinast, on basal glucose utilization was investigated in incubated rat soleus muscle preparations isolated from both insulin-sensitive (lean Zucker; Fa/?) and insulin-resistant (obese Zucker; fa/fa) rats. Zaprinast at 27 μM significantly increased cGMP levels in incubated soleus muscle isolated from lean, but not obese, Zucker rats. Muscles were incubated with 14C-labelled glucose and various concentrations of zaprinast (3, 27 and 243 μM). Zaprinast (at 27 and 243 μM) significantly increased rates of net and 14C-labelled lactate release and of glycogen synthesis in lean Zucker rat soleus muscle; glucose oxidation was also increased by 27 μM zaprinast. In addition, regardless of concentration, the phosphodiesterase inhibitor failed to increase any aspect of 14C-labelled glucose utilization in soleus muscles isolated from obese Zucker rats. The maximal activity of nitric oxide synthase (NOS) was significantly decreased in insulin-resistant obese Zucker muscles. Thus the lack of effect of zaprinast in insulin-resistant skeletal muscle is consistent with decreased NOS activity. To test whether there is a defect in insulin-resistant skeletal muscle for endogenous activation of guanylate cyclase, soleus muscles were isolated from both insulin-sensitive and insulin-resistant Zucker rats and incubated with various concentrations of the NO donor sodium nitroprusside (SNP; 0.1, 1, 5 and 15 mM). SNP significantly increased rates of net and 14C-labelled lactate release, as well as glucose oxidation in muscles isolated from both insulin-sensitive and insulin-resistant rats. A decreased response to SNP was observed in the dose-dependent generation of cGMP within isolated soleus muscles from insulin-resistant rats. A possible link between impaired NO/cGMP signalling and abnormal glucose utilization by skeletal muscle is discussed.

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Effects of type‐selective phosphodiesterase inhibitors on glucose‐induced insulin secretion and islet phosphodiesterase activity

Cited by 46 publications

References 31 publications

Attenuation of insulin secretion by insulin-like growth factor 1 is mediated through activation of phosphodiesterase 3B

Attenuation of insulin secretion by insulin-like growth factor 1 is mediated through activation of phosphodiesterase 3B

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Evidence for altered sensitivity of the nitric oxide/cGMP signalling cascade in insulin-resistant skeletal muscle

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