Dataset Information

Glucose-6-phosphate dehydrogenase contributes to the regulation of glucose uptake in skeletal muscle.

ABSTRACT:

Objective

The development of skeletal muscle insulin resistance is an early physiological defect, yet the intracellular mechanisms accounting for this metabolic defect remained unresolved. Here, we have examined the role of glucose-6-phosphate dehydrogenase (G6PDH) activity in the pathogenesis of insulin resistance in skeletal muscle.

Methods

Multiple mouse disease states exhibiting insulin resistance and glucose intolerance, as well as obese humans defined as insulin-sensitive, insulin-resistant, or pre-diabetic, were examined.

Results

We identified increased glucose-6-phosphate dehydrogenase (G6PDH) activity as a common intracellular adaptation that occurs in parallel with the induction of insulin resistance in skeletal muscle and is present across animal and human disease states with an underlying pathology of insulin resistance and glucose intolerance. We observed an inverse association between G6PDH activity and nitric oxide synthase (NOS) activity and show that increasing NOS activity via the skeletal muscle specific neuronal (n)NOS? partially suppresses G6PDH activity in skeletal muscle cells. Furthermore, attenuation of G6PDH activity in skeletal muscle cells via (a) increased nNOS?/NOS activity, (b) pharmacological G6PDH inhibition, or (c) genetic G6PDH inhibition increases insulin-independent glucose uptake.

Conclusions

We have identified a novel, previously unrecognized role for G6PDH in the regulation of skeletal muscle glucose metabolism.

SUBMITTER: Lee-Young RS

PROVIDER: S-EPMC5081409 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Publications

Glucose-6-phosphate dehydrogenase contributes to the regulation of glucose uptake in skeletal muscle.

Lee-Young Robert S RS Hoffman Nolan J NJ Murphy Kate T KT Henstridge Darren C DC Samocha-Bonet Dorit D Siebel Andrew L AL Iliades Peter P Zivanovic Borivoj B Hong Yet H YH Colgan Timothy D TD Kraakman Michael J MJ Bruce Clinton R CR Gregorevic Paul P McConell Glenn K GK Lynch Gordon S GS Drummond Grant R GR Kingwell Bronwyn A BA Greenfield Jerry R JR Febbraio Mark A MA

Molecular metabolism 20160909 11

<h4>Objective</h4>The development of skeletal muscle insulin resistance is an early physiological defect, yet the intracellular mechanisms accounting for this metabolic defect remained unresolved. Here, we have examined the role of glucose-6-phosphate dehydrogenase (G6PDH) activity in the pathogenesis of insulin resistance in skeletal muscle.<h4>Methods</h4>Multiple mouse disease states exhibiting insulin resistance and glucose intolerance, as well as obese humans defined as insulin-sensitive, i ...[more]

PMID: 27818934

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Project description:BACKGROUND: Retinoid X receptor (RXR) ? is a nuclear receptor-type transcription factor expressed mostly in skeletal muscle, and regulated by nutritional conditions. Previously, we established transgenic mice overexpressing RXR? in skeletal muscle (RXR? mice), which showed lower blood glucose than the control mice. Here we investigated their glucose metabolism. METHODOLOGY/PRINCIPAL FINDINGS: RXR? mice were subjected to glucose and insulin tolerance tests, and glucose transporter expression levels, hyperinsulinemic-euglycemic clamp and glucose uptake were analyzed. Microarray and bioinformatics analyses were done. The glucose tolerance test revealed higher glucose disposal in RXR? mice than in control mice, but insulin tolerance test revealed no difference in the insulin-induced hypoglycemic response. In the hyperinsulinemic-euglycemic clamp study, the basal glucose disposal rate was higher in RXR? mice than in control mice, indicating an insulin-independent increase in glucose uptake. There was no difference in the rate of glucose infusion needed to maintain euglycemia (glucose infusion rate) between the RXR? and control mice, which is consistent with the result of the insulin tolerance test. Skeletal muscle from RXR? mice showed increased Glut1 expression, with increased glucose uptake, in an insulin-independent manner. Moreover, we performed in vivo luciferase reporter analysis using Glut1 promoter (Glut1-Luc). Combination of RXR? and PPAR? resulted in an increase in Glut1-Luc activity in skeletal muscle in vivo. Microarray data showed that RXR? overexpression increased a diverse set of genes, including glucose metabolism genes, whose promoter contained putative PPAR-binding motifs. CONCLUSIONS/SIGNIFICANCE: Systemic glucose metabolism was increased in transgenic mice overexpressing RXR?. The enhanced glucose tolerance in RXR? mice may be mediated at least in part by increased Glut1 in skeletal muscle. These results show the importance of skeletal muscle gene regulation in systemic glucose metabolism. Increasing RXR? expression may be a novel therapeutic strategy against type 2 diabetes.

Project description:Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in the pentose phosphate pathway and a major source of nicotinamide adenine dinucleotide phosphate reduced (NADPH), which regulates numerous enzymatic (including glutathione reductase and NADPH oxidase that, respectively, generates reduced glutathione and reactive oxygen species) reactions involved in various cellular actions, yet its physiological function is seldom investigated. We, however, recently showed that inhibiting G6PD causes precontracted coronary artery (CA) to relax in an endothelium-derived relaxing factor- and second messenger-independent manner. Here we assessed the role of G6PD in regulating CA contractility. Treating bovine CAs for 20 min with potassium chloride (KCl; 30 mM), amphotericin B (50 μM), or U46619 (100 nM) significantly (p < 0.05) increased both G6PD activity and glucose flux through the pentose phosphate pathway. The effect was Ca(2+) independent, and there was a corresponding increase in protein kinase C (PKC) activity. Activation of G6PD by KCl was blocked by the PKCδ inhibitor rottlerin (10 μM) or by knocking down PKCδ expression using siRNA. Phorbol 12, 13-dibutyrate (10 μM), a PKC activator, significantly increased G6PD phosphorylation and activity, whereas single (S210A, T266A) and double (S210A/T266A) mutations at sites flanking the G6PD active site significantly inhibited phosphorylation, shifted the isoelectric point, and reduced enzyme activity. Knocking down G6PD decreased NADPH and reactive oxygen species generation, and reduced KCl-evoked increases in [Ca(2+)](i) and myosin light chain phosphorylation, thereby reducing CA contractility. Similarly, aortas from G6PD-deficient mice developed less KCl/phorbol 12, 13-dibutyrate-evoked force than those from their wild-type littermates. Conversely, overexpression of G6PD augmented KCl-evoked increases in [Ca(2+)](i), thereby augmenting CA contraction. Our findings demonstrate that G6PD activity and NADPH is increased in activated CA in a PKCδ-dependent manner and that G6PD modulates Ca(2+) entry and CA contractions evoked by membrane depolarization.

Dataset Information

Glucose-6-phosphate dehydrogenase contributes to the regulation of glucose uptake in skeletal muscle.

Objective

Methods

Results

Conclusions

Publications

Glucose-6-phosphate dehydrogenase contributes to the regulation of glucose uptake in skeletal muscle.

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