Elsevier

Molecular Metabolism

Volume 5, Issue 11, November 2016, Pages 1083-1091
Molecular Metabolism

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

https://doi.org/10.1016/j.molmet.2016.09.002Get rights and content
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open access

Highlights

  • Defective skeletal muscle G6PDH activity in multiple insulin resistant animal models.

  • Demonstration of defective skeletal muscle G6PDH activity in pre-diabetic individuals.

  • Identification of nNOSμ as a regulator of G6PDH activity in skeletal muscle.

  • G6PDH activity modulates insulin-independent 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)NOSμ partially suppresses G6PDH activity in skeletal muscle cells. Furthermore, attenuation of G6PDH activity in skeletal muscle cells via (a) increased nNOSμ/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.

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Keywords

Glucose metabolism
Enzyme activity
Insulin sensitivity

Cited by (0)

9

Current address: Centre for Exercise and Nutrition, Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, Australia.

10

Current address: School of Biosciences, The University of Melbourne, Melbourne, VIC, Australia.