Nitric oxide is not involved in the initiation of insulin secretion from rat islets of Langerhans

Jones, Peter M.; Persaud, Shanta J.; Bjaaland, T.; Pearson, Jeremy D.; Howell, S. L.

doi:10.1007/bf02221676

Cited by 78 publications

(57 citation statements)

References 30 publications

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“…the fi cell physiological stimulus, with respect to the conflicting reports as to the ability of glucose to induce NO formation (Jones et al, 1992;Schmidt et al, 1992) our data agree with an activation of the constitutive form of NO synthase by glucose. However, unlike the stimulating effect on insulin secretion previously proposed, our results bring evidence for an inhibitory effect; addition of L-NAME at increasing concentrations, when performed prior to and during high glucose, progressively converted the biphasic pattern of fi cell response into a greater monophasic one, whereas D-NAME was without effect.…”

Section: Discussionsupporting

confidence: 83%

Alterations of insulin response to different β cell secretagogues and pancreatic vascular resistance induced by N^ω‐nitro‐L‐arginine methyl ester

Gross

Roye

Manteghetti

et al. 1995

British J Pharmacology

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1 We studied a possible interplay of pancreatic NO synthase activity on insulin secretion induced by different P cell secretagogues and also onf pancreatic vascular bed resistance. 2 This study was performed in the isolated perfused pancreas of the rat. Blockade of NO synthase was achieved with N"-nitro-L-arginine methyl estr (L-NAME); the specificity of the antagonist was checked by using its D-enantiomer as well as by substitutive treatments with sodium nitroprusside (SNP) as a NO donor in studies of glucose-induced insulin secretion. 3 Arginine (5 mM) induced a monophasic -insulin response which was, in the presence of L-NAME at equimolar concentration, very strongly potentiated and converted into a 13 times higher biphasic one. D-NAME (5 mM) was only able to induce a 3 times higher response, but provoked a similar vasoconstrictor effect. 4 The small biphasic insulin secretion induced by L-leucine (5 mM) was also strongly enhanced, by 8 times, in the presence of L-NAME (5 mm) vs 2 times in the presence of D-NAME (5 mM). 5 f cell responses to KCl (5 mM) and tolbutamide (0.185 mM) were only slightly increased by L-NAME (5 mM) to values not far from the sum of the effects of L-NAME and of the two drugs alone. D-NAME (5 mM) was totally ineffective on the actions of both secretagogues. 6 L-NAME, infused 15 min before and during a rise in glucose concentration from 5 to 11 mm, was able in the low millimolar range (0.1-0.5 mM) to blunt the classical biphasic pattern of fi cell response to glucose and, at 5 mm, to convert it into a significantly greater monophasic one. In contrast, D-NAME (5 mM) was unable to induce similar effects. 7 SNP alone at 3 JAM was ineffective but at 30 JM substantially reduced the second phase of insulin response to glucose; however, at both concentrations the NO donor partly reversed alterations in insulin secretion caused by L-NAME (5 mM) and restored a biphasic pattern of insulin response. At a high (300 juM) concentration, SNP drastically reduced the second phase of f cell response, but in the presence of L-NAME, provoked a significantly greater biphasic response.8 When L-NAME was infused only for the 15 min before high glucose, an exaggerated first phase of P cell response was followed by an abortive second one. SNP, at a low concentration (30 nM), given simultaneously with L-NAME, restored a biphasic pattern and prevented the vasoconstrictor effect induced by the inhibitor. 9 L-NAME, when infused only during high glucose, markedly enhanced the second phase of insulin response which could be significantly reduced by SNP (3 aM). The NO donor induced a dilator effect significantly greater in L-NAME-treated pancreata than in non-treated ones. 10 In conclusion our data bring evidence that NO synthase activity exerts an inhibitory control on pancreatic f cell response to various nutrient secretagogues and may, at least partly, be implicated in the generation of the biphasic pattern of insulin response to glucose.

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Section: Discussionsupporting

confidence: 83%

Alterations of insulin response to different β cell secretagogues and pancreatic vascular resistance induced by N^ω‐nitro‐L‐arginine methyl ester

Gross

Roye

Manteghetti

et al. 1995

British J Pharmacology

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“…The results of the present study are in agreement with in vitro and in vivo studies in animals showing that although NO is a mediator of glucose-induced cGMP production in islets, the resulting increase in cGMP is not correlated with insulin secretion (31). Moreover, Pueyo et al (19) have shown that the administration of N-nitro-L-arginine methyl ester in vivo markedly diminished NO-dependent cGMP production without affecting insulin secretion .…”

Section: Euglycemic-hyperinsulinemic Clampsupporting

confidence: 91%

Long-Term Oral l-Arginine Administration Improves Peripheral and Hepatic Insulin Sensitivity in Type 2 Diabetic Patients

Piatti¹,

Monti²,

Valsecchi³

et al. 2001

Diabetes Care

184

119

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OBJECTIVE -The aim of this study was to evaluate whether long-term administration of L-arginine acting through a normalization of NO/cyclic-guanosine-3Ј,5Ј-cyclic monophosphate (cGMP) pathway was able to ameliorate peripheral and hepatic insulin sensitivity in 12 lean type 2 diabetic patients. RESEARCH DESIGN AND METHODS-A double-blind study was performed for 3 months. In the first month, patients were treated with their usual diet. Then they were randomly allocated into two groups. In group 1, patients were treated with diet plus placebo (orally three times per day) for 2 months. In group 2 patients were treated for 1 month with diet plus placebo (orally, three times per day) and then for 1 month with diet plus L-arginine (3 g three times per day). At the end of the first and the second month of therapy, patients underwent a euglycemichyperinsulinemic clamp combined with [6, H 2 ]glucose infusion. A total of 10 normal subjects underwent the same test as control subjects.RESULTS -In group 1, no changes in basal cGMP levels, systolic blood pressure, forearm blood flow, glucose disposal, and endogenous glucose production were observed throughout. In group 2, L-arginine normalized basal cGMP levels and significantly increased forearm blood flow by 36% and glucose disposal during the clamp by 34%, whereas it decreased systolic blood pressure and endogenous glucose production by 14 and 29%, respectively. However, compared with normal subjects, L-arginine treatment was not able to completely overcome the defect in glucose disposal.CONCLUSIONS -L-Arginine treatment significantly improves but does not completely normalize peripheral and hepatic insulin sensitivity in type 2 diabetic patients. Diabetes Care 24:875-880, 2001C ontradictory results have been found concerning the influence of insulin on nitric oxide (NO), a potent molecule with vasodilatory function. Baron et al. (1,2) showed that insulinmediated vasodilation is largely dependent on the action of insulin on NO release, whereas Petrie et al. (3) have shown that endothelial NO synthesis and insulin sensitivity are positively correlated in healthy individuals. In addition, in obese patients and patients with type 2 diabetes, the insulin-mediated vasodilatory response seems blunted (4). However, Yki-Jarvinen et al. (5) were unable to find any correlation between insulin action and increment in blood flow in normal and obese subjects, although all agree that methacoline-induced vasodilation is impaired in insulin-resistant subjects.L-Arginine is a precursor for NO, and both in vitro and in vivo studies have demonstrated that L-arginine can augment vascular dilation under certain conditions (6). Experimental studies in cholesterol-fed rabbits have shown that dietary supplementation with L-arginine causes attenuation of endothelial dysfunction with increased NO activity, resulting in reduced platelet activation (7), monocyte adhesion (8), and a marked reduction in aortic and coronary atherosclerosis (9). Moreover, in young hypercholesterolemic adults, the administr...

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“…Although increases in cyclic GMP have been linked with decreases in insulin secretion [44,45], the role of this nucleotide in the islet beta cell remains unclear [46,47]. More recent studies suggest that cyclic GMP could mediate the effects of low concentrations of nitric oxide in augmenting glucose-induced Ca 2+ oscillations and insulin secretion in rat-isolated beta cells [48,49,50].…”

Section: Cyclic Gmpmentioning

confidence: 99%

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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Nitric oxide is not involved in the initiation of insulin secretion from rat islets of Langerhans

Cited by 78 publications

References 30 publications

Alterations of insulin response to different β cell secretagogues and pancreatic vascular resistance induced by N^ω‐nitro‐L‐arginine methyl ester

Alterations of insulin response to different β cell secretagogues and pancreatic vascular resistance induced by N^ω‐nitro‐L‐arginine methyl ester

Long-Term Oral l-Arginine Administration Improves Peripheral and Hepatic Insulin Sensitivity in Type 2 Diabetic Patients

Cyclic nucleotide phosphodiesterases in pancreatic islets

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Nitric oxide is not involved in the initiation of insulin secretion from rat islets of Langerhans

Cited by 78 publications

References 30 publications

Alterations of insulin response to different β cell secretagogues and pancreatic vascular resistance induced by Nω‐nitro‐L‐arginine methyl ester

Alterations of insulin response to different β cell secretagogues and pancreatic vascular resistance induced by Nω‐nitro‐L‐arginine methyl ester

Long-Term Oral l-Arginine Administration Improves Peripheral and Hepatic Insulin Sensitivity in Type 2 Diabetic Patients

Cyclic nucleotide phosphodiesterases in pancreatic islets

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Alterations of insulin response to different β cell secretagogues and pancreatic vascular resistance induced by N^ω‐nitro‐L‐arginine methyl ester

Alterations of insulin response to different β cell secretagogues and pancreatic vascular resistance induced by N^ω‐nitro‐L‐arginine methyl ester