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



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.



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.



We have identified a novel, previously unrecognized role for G6PDH in the regulation of skeletal muscle glucose metabolism.
Cellular and Molecular Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia. Electronic address: robert.lee-young@monash.edu.
Robert S
RS
Lee-Young
Diabetes & Metabolism Division, Garvan Institute of Medical Research, NSW, Australia.
Nolan J
NJ
Hoffman
Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Melbourne, VIC, Australia.
Kate T
KT
Murphy
Cellular and Molecular Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia.
Darren C
DC
Henstridge
Diabetes & Metabolism Division, Garvan Institute of Medical Research, NSW, Australia.
Dorit
D
Samocha-Bonet
Metabolic and Vascular Physiology Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia.
Andrew L
AL
Siebel
Cellular and Molecular Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia.
Peter
P
Iliades
Cellular and Molecular Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia.
Borivoj
B
Zivanovic
Institute for Sports, Exercise and Active Living, Victoria University, Footscray, VIC, Australia.
Yet H
YH
Hong
Muscle Research and Therapeutics Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia.
Timothy D
TD
Colgan
Cellular and Molecular Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia.
Michael J
MJ
Kraakman
School of Exercise and Nutrition Sciences, Deakin University, Burwood, VIC, Australia.
Clinton R
CR
Bruce
Muscle Research and Therapeutics Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia.
Paul
P
Gregorevic
Institute for Sports, Exercise and Active Living, Victoria University, Footscray, VIC, Australia.
Glenn K
GK
McConell
Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Melbourne, VIC, Australia.
Gordon S
GS
Lynch
Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, VIC, Australia.
Grant R
GR
Drummond
Metabolic and Vascular Physiology Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia.
Bronwyn A
BA
Kingwell
Diabetes & Metabolism Division, Garvan Institute of Medical Research, NSW, Australia.
Jerry R
JR
Greenfield
Cellular and Molecular Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia; Diabetes & Metabolism Division, Garvan Institute of Medical Research, NSW, Australia. Electronic address: m.febbraio@garvan.org.au.
Mark A
MA
Febbraio
D000818:Animals; D005947:Glucose / Q000378:metabolism*; D019298:Glucose-6-Phosphate; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism*; D006801:Humans; D007328:Insulin; D007333:Insulin Resistance; D051379:Mice; D018485:Muscle Fibers, Skeletal; D018482:Muscle, Skeletal / Q000378:metabolism*; D009569:Nitric Oxide
D007328:Insulin; D009569:Nitric Oxide; D019298:Glucose-6-Phosphate; D005954:Glucosephosphate Dehydrogenase; D005947:Glucose
Enzyme activity; Glucose metabolism; Insulin sensitivity