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

Abstract

ObjectiveThe 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.MethodsMultiple 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.ResultsWe 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.ConclusionsWe have identified a novel, previously unrecognized role for G6PDH in the regulation of skeletal muscle glucose metabolism.

TIGAR Attenuates High Glucose-Induced Neuronal Apoptosis via an Autophagy Pathway

“…The increased production of NO enhanced S-nitrosation of ATG4 and impaired autophagosome biogenesis, and finally leads to neurotoxicity. An inverse association between the activity of G6PD and muscle-specific nNOS was observed in skeletal muscle cells (Lee-Young et al, 2016). Moreover, overexpression of G6PD displayed remarkable resistance against NO-mediated apoptosis in PC12 cells (García-Nogales et al, 2003).…”

Resistance training regulates gene expression of molecules associated with intramyocellular lipids, glucose signaling and fiber size in old rats

“…In fact, endurance training induced greater glycogen concentration, which was associated with elevated protein abundance of GLUT-4, Hk-2 and glycogen synthase in older people 43 . In this context, glucose-6-phosphate dehydrogenase (G6PDH) was recently associated with glucose uptake 44 , although this enzyme has been poorly studied in skeletal muscle 20 . Whereas aging did not affect G6PDH mRNA levels in this study, its activity and protein content was reduced in the gastrocnemius of aged rodents 45 .…”

The Role of Metabolic Remodeling in Macrophage Polarization and Its Effect on Skeletal Muscle Regeneration

“…In addition, a major contributor to the insulin-resistance onset might be an altered and pro-oxidant cellular redox state, which decreases NADPH levels that, in turn, activate glucose-6-phosphate dehydrogenase (G6PDH), which is crucial for NADPH maintenance. G6PDH activity is elevated in adipose tissue and its over-expression causes insulin resistance (176). In such a context, the anti-inflammatory and antioxidant effects of M2 polarization might also help in reducing G6PDH expression.…”