G6PD Deficiency Is Crucial for Insulin Signaling Activation in Skeletal Muscle.
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ABSTRACT:
SUBMITTER: Jiang A
PROVIDER: S-EPMC9267066 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveCaloric restriction (CR) has been shown to retard aging processes, extend maximal life span, and consistently increase insulin action in experimental animals. The mechanism by which CR enhances insulin action, specifically in higher species, is not precisely known. We sought to examine insulin receptor signaling and transcriptional alterations in skeletal muscle of nonhuman primates subjected to CR over a 4-year period.Research design and methodsAt baseline, 32 male adult cynomolgus monkeys (Macaca fascicularis) were randomized to an ad libitum (AL) diet or to 30% CR. Dietary intake, body weight, and insulin sensitivity were obtained at routine intervals over 4 years. At the end of the study, hyperinsulinemic-euglycemic clamps were performed and skeletal muscle (vastus lateralis) was obtained in the basal and insulin-stimulated states for insulin receptor signaling and gene expression profiling.ResultsCR significantly increased whole-body insulin-mediated glucose disposal compared with AL diet and increased insulin receptor signaling, i.e., insulin receptor substrate (IRS)-1, insulin receptor phosphorylation, and IRS-associated PI 3-kinase activity in skeletal muscle (P < 0.01, P < 0.01, and P < 0.01, respectively). Gene expression for insulin signaling proteins, i.e., IRS-1 and IRS-2, were not increased with CR, although a significant increase in protein abundance was noted. Components of the ubiquitin-proteasome system, i.e., 20S and 19S proteasome subunit abundance and 20S proteasome activity, were significantly decreased by CR.ConclusionsCR increases insulin sensitivity on a whole-body level and enhances insulin receptor signaling in this higher species. CR in cynomolgus monkeys may alter insulin signaling in vivo by modulating protein content of insulin receptor signaling proteins.
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Project description:In type 2 diabetes (T2D), both muscle and liver are severely resistant to insulin action. Muscle insulin resistance accounts for more than 80% of the impairment in total body glucose disposal in T2D patients and is often characterized by an impaired insulin signaling. Mitsugumin 53 (MG53), a muscle-specific TRIM family protein initially identified as a key regulator of cell membrane repair machinery has been suggested to be a critical regulator of muscle insulin signaling pathway by acting as ubiquitin E3 ligase targeting both the insulin receptor and insulin receptor substrate 1 (IRS1). Here, we show using in vitro and in vivo approaches that MG53 is not a critical regulator of insulin signaling and glucose homeostasis. First, MG53 expression is not consistently regulated in skeletal muscle from various preclinical models of insulin resistance. Second, MG53 gene knock-down in muscle cells does not lead to impaired insulin response as measured by Akt phosphorylation on Serine 473 and glucose uptake. Third, recombinant human MG53 does not alter insulin response in both differentiated C2C12 and human skeletal muscle cells. Fourth, ectopic expression of MG53 in HEK293 cells lacking endogenous MG53 expression fails to alter insulin response as measured by Akt phosphorylation. Finally, both male and female mg53 -/- mice were not resistant to high fat induced obesity and glucose intolerance compared to wild-type mice. Taken together, these results strongly suggest that MG53 is not a critical regulator of insulin signaling pathway in skeletal muscle.
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