Nitric Oxide Does Not Initiate but Potentiates Glucose-Induced Insulin Secretion in Pancreatic Beta-Cells

Ding, Yan; Rana, R. S.

doi:10.1006/bbrc.1998.9536

Cited by 23 publications

(28 citation statements)

References 26 publications

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“…Our demonstration of a stimulatory effect of NO on insulin release is in agreement with previously published reports (5,(13)(14)(15)21,22); however, a number of studies argue against a stimulatory role for NO (6,9,16 -18,23-27). Since we used the intracellular NO donor HA to simulate physiological endogenous NO production (and demonstrated this production using Daf2) and because we used a ␤-cell line, we produced an experimental model in which we were able to observe the effect of NO produced within the ␤-cell acting on the ␤-cell.…”

Section: Discussionsupporting

confidence: 93%

“…The ability of glucose to stimulate endogenous NO generation likely stems from its ability to increase cellular levels of the NOS co-substrate NADPH (48) and Ca 2ϩ , effects that are likely to increase cNOS activity (2). This finding is in agreement with studies using indirect measurement of NO (via nitrate conversion to nitrite and the Griess reaction) (5,14). Considering that applied NO exerted an insulinotropic effect, it is tempting to speculate that the observed glucose-stimulated NO production may be involved in normal physiological glucose-stimulated insulin secretion.…”

Section: Discussionsupporting

confidence: 75%

“…NOS inhibition has been reported to produce an inhibitory effect (5,(13)(14)(15), a stimulatory effect (6,9,16 -18), and no effect at all (19,20) on insulin release. Similarly, exogenously applied NO has been reported to exert a stimulatory (5,13,14,21,22) and an inhibitory effect (6,18,(23)(24)(25)(26)(27) on insulin release. These discrepant data may be the result of variations in the specifics of the experimental conditions, including differences in the agents used (e.g., NOS substrate, NOS inhibitors, NO donors), the concentration of these agents, whether other stimulatory pathways were activated concurrently (e.g., with glucose), the experimental model used (e.g., ␤-cell line, islets, pancreas), and the species.…”

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confidence: 99%

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Exogenous Nitric Oxide and Endogenous Glucose-Stimulated β-Cell Nitric Oxide Augment Insulin Release

et al. 2002

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The role nitric oxide (NO) plays in physiological insulin secretion has been controversial. Here we present evidence that exogenous NO stimulates insulin secretion, and that endogenous NO production occurs and is involved in the regulation of insulin release. Radioimmunoassay measurement of insulin release and a dynamic assay of exocytosis using the dye FM1-43 demonstrated that three different NO donors-hydroxylamine (HA), sodium nitroprusside, and 3-morpholinosydnonimine (SIN-1)-each stimulated a marked increase in insulin secretion from INS-1 cells. Pharmacological manipulation of the guanylate cyclase/guanosine 3,5-cyclic monophosphate pathway indicated that this pathway was involved in mediating the effect of the intracellular NO donor, HA, which was used to simulate endogenous NO production. This effect was further characterized as involving membrane depolarization and intracellular T he endogenous synthesis of nitric oxide (NO) from L-arginine (L-arg) has been shown to play a critical role in a wide variety of physiological functions including neurotransmission, vascular tone, platelet aggregation, immunological reactions, penile erection, and endocrine and exocrine function (1). Cellular NO is synthesized by a family of NO synthase (NOS) enzymes, comprised of constitutively expressed, Ca 2ϩ / calmodulin-dependent neuronal NOS (nNOS) and endothelial NOS (eNOS), and a Ca 2ϩ /calmodulin-independent inducibly expressed NOS (iNOS) (2).Pancreatic ␤-cells are able to express the iNOS enzyme in response to inflammatory stimuli, leading to high cytotoxic levels of NO production, which appear to be involved in ␤-cell damage, dysfunction, and death and the pathogenesis of type 1 diabetes (3,4). The presence of a constitutive NOS (cNOS) enzyme in ␤-cells is substantiated by considerable evidence, including biochemical, histochemical, immunohistochemical, immunofluorescence, RT-PCR, and protein immunoblot analyses (5-11). Given that the amino acid NO precursor L-arg has long been known to stimulate insulin release (12), it has been postulated that a low level of NO produced from the ␤-cell cNOS isoform functions in the regulation of insulin release. However, several reports in which cNOS activity was manipulated or exogenous NO was applied have yielded seemingly conflicting results. NOS inhibition has been reported to produce an inhibitory effect (5,13-15), a stimulatory effect (6,9,16 -18), and no effect at all (19,20) on insulin release. Similarly, exogenously applied NO has been reported to exert a stimulatory (5,13,14,21,22) and an inhibitory effect (6,18,23-27) on insulin release. These discrepant data may be the result of variations in the specifics of the experimental conditions, including differences in the agents used (e.g., NOS substrate, NOS inhibitors, NO donors), the concentration of these agents, whether other stimulatory pathways were activated concurrently (e.g., with glucose), the experimental model used (e.g., ␤-cell line, islets, pancreas), and the species. These critical differences may result in d...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 75%

mentioning

confidence: 99%

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Exogenous Nitric Oxide and Endogenous Glucose-Stimulated β-Cell Nitric Oxide Augment Insulin Release

et al. 2002

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“…Conversely, NOS inhibitors were shown to increase l-arginine-or glucose-induced insulin secretion from isolated islets of mice (15) and rats (16). Moreover, controversial data have also been presented that aqueous NO solution or some NO donors stimulated (17,18) or inhibited (15,19) insulin secretion. We have provided evidence for concentration-dependent dual effects of NO on insulin secretion, which could explain at least partly the discrepancies (20).…”

Section: Dual Effects Of No On Insulin Secretionmentioning

confidence: 99%

Dual Role of Nitric Oxide in Pancreatic β-Cells

Kaneko

Ishikawa

2013

J Pharmacol Sci

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Abstract. An involvement of inducible nitric oxide (NO) synthase (NOS) in pancreatic b-cell degeneration during the process of type 1 diabetes has been well discussed. Recently, there is growing evidence for pivotal roles of constitutive NOS (cNOS) in b-cells; the presence of NOS1 and NOS3 in pancreatic b-cells and the effects of low-concentration NO, which is assumed to be derived from cNOS, on b-cell functions have been reported. However, the roles of cNOS-derived NO in b-cells are still under debate. One of the reasons seems to be that NO has multiple biological activities, which are dependent on its concentration. In b-cells, NO has been shown to exert positive and negative regulation of insulin secretion and anti-and pro-apoptotic activities, which is likely to be dependent on concentrations. In this review article, we will describe the current understanding of the roles of NO in pancreatic b-cells, especially focusing on cNOS-derived NO and its differential roles depending on concentrations.

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“…28,29 However, some studies suggest that NO stimulates insulin production and cell viability. [30][31][32][33] This would suggest that the role of NO in islet cell biology may be concentration-dependent. Furthermore, conventional NO donors do not provide the islet cells with other bioactive cues that promote cell viability and functionality.…”

mentioning

confidence: 99%

Enhanced MIN-6 beta cell survival and function on a nitric oxide-releasing peptide amphiphile nanomatrix

Lim¹,

Andukuri²,

Vines³

et al. 2014

IJN

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Innovative biomaterial strategies are required to improve islet cell retention, viability, and functionality, and thereby obtain clinically successful outcomes from pancreatic islet cell transplantation. To address this need, we have developed a peptide amphiphile-based nanomatrix that incorporates multifunctional bioactive cues and sustained release of nitric oxide. The goal of this study was to evaluate the effect of this peptide amphiphile nanomatrix on the viability and functionality of MIN-6 islet cells. Additionally, this study provides insight into the role of nitric oxide in islet cell biology, given that conventional nitric oxide donors are unable to release nitric oxide in a controlled, sustained manner, leading to ambiguous results. It was hypothesized that controlled nitric oxide release in synergy with multifunctional bioactive cues would promote islet cell viability and functionality. Nitric oxide-releasing peptide amphiphile nanomatrices within the range of 16.25 μmol to 130 μmol were used to analyze MIN-6 cell behavior. Both 32.5 μmol and 65 μmol peptide amphiphiles showed improved MIN-6 functionality in response to glucose over a 7-day time period, and the elevated functionality was correlated with both PDX-1 and insulin gene expression. Our results demonstrate that nitric oxide has a beneficial effect on MIN-6 cells in a concentration-dependent manner.

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Nitric Oxide Does Not Initiate but Potentiates Glucose-Induced Insulin Secretion in Pancreatic Beta-Cells

Cited by 23 publications

References 26 publications

Exogenous Nitric Oxide and Endogenous Glucose-Stimulated β-Cell Nitric Oxide Augment Insulin Release

Exogenous Nitric Oxide and Endogenous Glucose-Stimulated β-Cell Nitric Oxide Augment Insulin Release

Dual Role of Nitric Oxide in Pancreatic β-Cells

Enhanced MIN-6 beta cell survival and function on a nitric oxide-releasing peptide amphiphile nanomatrix

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