Naturally Occurring Glucokinase Mutations Are Associated with Defects in Posttranslational S-Nitrosylation

Ding, Shi-Ying; Tribble, Nicholas D.; Kraft, Catherine A.; Markwardt, Michele L.; Gloyn, Anna L.; Rizzo, Mark A.

doi:10.1210/me.2009-0138

Cited by 22 publications

(27 citation statements)

References 31 publications

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“…Previous studies have focused on the role of proteinprotein interaction by the GCK regulator (GCKR) or glucose on the regulation of GCK activity (44), whereas the control of cellular GCK activity or its expression at the posttranslational level, especially in ␤-cells, has not been previously considered. Recently, in pancreatic ␤-cells, insulin activates neuronaltype nitric-oxide synthase, which forms a complex with GCK on the surface of secretory granules, leading to S-nitrosylation of GCK following the dissociation of GCK from the surface of secretory granules (28). Furthermore, other studies have demonstrated that NO and endothelial nitric-oxide synthase generated by insulin-like growth factor-1 and insulin prevents serum starvation-induced RINm5F ␤-cell apoptosis (45).…”

Section: Discussionmentioning

confidence: 99%

“…These modifications could be also involved in pathophysiological processes such as inflammation, apoptosis, enzyme activity, and gene expression (27). A recent study demonstrated that insulin-induced neuronal nitric-oxide synthase leads to S-nitrosylation of GCK, which is involved in preventing the impaired glucose response and apoptosis of pancreatic ␤-cells (28). However, other studies have demonstrated that peroxynitrite generated by cytokines or endotoxins is also known to induce impaired glucose metabolism and apoptosis of pancreatic ␤-cells (29,30).…”

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confidence: 99%

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Chronic Ethanol Consumption-induced Pancreatic β-Cell Dysfunction and Apoptosis through Glucokinase Nitration and Its Down-regulation

Kim

Song

Lee

et al. 2010

Journal of Biological Chemistry

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Chronic ethanol consumption is known as an independent risk factor for type 2 diabetes, which is characterized by impaired glucose homeostasis and insulin resistance; however, there is a great deal of controversy concerning the relationships between alcohol consumption and the development of type 2 diabetes. We investigated the effects of chronic ethanol consumption on pancreatic ␤-cell dysfunction and whether generated peroxynitrite participates in the impaired glucose homeostasis. Here we show that chronic ethanol feeding decreases the ability of pancreatic ␤-cells to mediate insulin secretion and ATP production in coordination with the decrease of glucokinase, Glut2, and insulin expression. Specific blockade of ATF3 using siRNA or C-terminally deleted ATF3(⌬C) attenuated ethanol-induced pancreatic ␤-cell apoptosis or dysfunction and restored the down-regulation of glucokinase (GCK), insulin, and pancreatic duodenal homeobox-1 induced by ethanol. GCK inactivation and down-regulation were predominantly mediated by ethanol metabolism-generated peroxynitrite, which were suppressed by the peroxynitrite scavengers N ␥ -monomethyl-L-arginine, uric acid, and deferoxamine but not by the S-nitrosylation inhibitor DTT, indicating that tyrosine nitration is the predominant modification associated with GCK down-regulation and inactivation rather than S-nitrosylation of cysteine. Tyrosine nitration of GCK prevented its association with pBad, and GCK translocation into the mitochondria results in subsequent proteasomal degradation of GCK following ubiquitination. This study identified a novel and efficient pathway by which chronic ethanol consumption may induce GCK down-regulation and inactivation by inducing tyrosine nitration of GCK, resulting in pancreatic ␤-cell apoptosis and dysfunction. Peroxynitrite-induced ATF3 may also serve as a potent upstream regulator of GCK down-regulation and ␤-cell apoptosis.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Chronic Ethanol Consumption-induced Pancreatic β-Cell Dysfunction and Apoptosis through Glucokinase Nitration and Its Down-regulation

Kim

Song

Lee

et al. 2010

Journal of Biological Chemistry

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“…Tissue culture media and sera were also obtained from Invitrogen, with the exception of DMEM (Mediatech). Plasmid DNA encoding GCK reporter constructs are described elsewhere (17). Antifluorescent protein and anti-nitrosocysteine (SNO) antibodies were from Abcam (Cambridge, MA), and GCK antibodies were obtained from Santa Cruz Biotechnology (Santa Cruz, CA).…”

Section: Methodsmentioning

confidence: 99%

“…Activation is generally mediated through posttranslational S-nitrosylation of a specific cysteine residue on GCK (14). Diabetes-associated mutations in GCK also have been shown to affect post-translational regulation negatively in the absence of a direct effect on GCK activity in vitro (17), indicating that GCK S-nitrosylation may be a physiologically important control point for regulating glucose-stimulated insulin secretion. Therefore, regulation of GCK by GLP-1 is an attractive hypothesis not only because this mechanism may explain the insulinotropic effects of GLP-1 at normally subthreshold glucose concentrations, but also because it could provide additional insight into the mechanism through which naturally occurring gene mutations in GCK cause diabetes.…”

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confidence: 99%

Glucagon-like Peptide 1 Stimulates Post-translational Activation of Glucokinase in Pancreatic β Cells

Ding

Nkobena

Kraft

et al. 2011

Journal of Biological Chemistry

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Glucagon-like peptide 1 (GLP-1) potentiates glucose-stimulated insulin secretion from pancreatic ␤ cells, yet does not directly stimulate secretion. The mechanisms underlying this phenomenon are incompletely understood. Here, we report that GLP-1 augments glucose-dependent rises in NAD(P)H autofluorescence in both ␤TC3 insulinoma cells and islets in a manner consistent with post-translational activation of glucokinase (GCK). GLP-1 treatment increased GCK activity and enhanced GCK S-nitrosylation in ␤TC3 cells. A 2-fold increase in S-nitrosylated GCK was also observed in mouse islets. Furthermore, GLP-1 activated a FRET-based GCK reporter in living cells. Activation of this reporter was sensitive to inhibition of nitricoxide synthase (NOS), and incorporating the S-nitrosylationblocking V367M mutation into this sensor prevented activation by GLP-1. GLP-1 potentiation of the glucose-dependent increase in islet NAD(P)H autofluorescence was also sensitive to a NOS inhibitor, whereas NOS inhibition did not affect the response to glucose alone. Expression of the GCK(V367M) mutant also blocked GLP-1 potentiation of the NAD(P)H response to glucose in ␤TC3 cells, but did not significantly affect metabolism of glucose in the absence of GLP-1. Co-expression of WT or mutant GCK proteins with a sensor for insulin secretory granule fusion also revealed that blockade of post-translational GCK S-nitrosylation diminished the effects of GLP-1 on granule exocytosis by ϳ40% in ␤TC3 cells. These results suggest that post-translational activation of GCK is an important mechanism for mediating the insulinotropic effects of GLP-1. Glucagon-like peptide 1 (GLP-1)2 can potentiate glucosestimulated insulin secretion at glucose concentrations that are normally subthreshold, in the 3-5 mM range, but not at glucose concentrations less than that (1-3). In pancreatic ␤ cells, the glucose threshold for insulin secretion is strongly controlled by glucose metabolism and principally limited at the first metabolic step, which is conversion of glucose to glucose 6-phosphate (4). Glucokinase (GCK) activity largely controls the rate of secretion at this step in metabolism because of its weak glucose binding affinity. Half-maximal GCK activity occurs at ϳ8 mM (4, 5), and sufficient glucose metabolism to initiate secretion is observed at ϳ5 mM (6, 7). Therefore, changes in GCK activity are a likely control point for changes in threshold.Secretion at glucose levels that are normally subthreshold is possible if glucose-phosphorylating capacity is artificially modulated through overexpression of exogenous hexokinases (8) or GCK itself (9). Mathematical modeling of the effect of naturally occurring GCK mutations on secretion has also shown a tight relationship between GCK activity and the threshold for insulin secretion (10). Furthermore, mutations that enhance GCK activity reduce the glucose threshold for insulin secretion (11). Thus, there are similarities between the effects of enhancing GCK activity and the effects of incretin hormones on insulin secreti...

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“…Moreover, mutation of cysteine-371 to serine, which blocks S-nitrosylation of GK, caused GK to remain tightly bound to insulin secretory granules. On the other hand, naturally occurring, diabetes-associated point mutations in GK have been shown to negatively affect S-nitrosylation of GK (24). Thus, S-nitrosylation of GK by NOS1-derived NO is suggested to promote the dissociation of GK from insulin secretory granules, thereby facilitating insulin secretion.…”

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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Naturally Occurring Glucokinase Mutations Are Associated with Defects in Posttranslational S-Nitrosylation

Cited by 22 publications

References 31 publications

Chronic Ethanol Consumption-induced Pancreatic β-Cell Dysfunction and Apoptosis through Glucokinase Nitration and Its Down-regulation

Chronic Ethanol Consumption-induced Pancreatic β-Cell Dysfunction and Apoptosis through Glucokinase Nitration and Its Down-regulation

Glucagon-like Peptide 1 Stimulates Post-translational Activation of Glucokinase in Pancreatic β Cells

Dual Role of Nitric Oxide in Pancreatic β-Cells

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