Modulation of skeletal muscle insulin signaling with chronic caloric restriction in cynomolgus monkeys

Abstract

Objective: Caloric 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 caloric restriction over a 4 year period.

Research Design: After baseline, 32 male adult cynomolgus monkeys (Macaca fascicularis) were randomized to an Ad libitum diet (AL) or to 30% CR. Dietary intake, body weight and insulin sensitivity were obtained at routine intervals over 4 years. At end of study, hyperinsulinemic-euglycemic clamps were performed and skeletal muscle (vastus lateralis) obtained in the basal and insulin stimulated states for insulin receptor signaling and gene expression profiling.

Results: CR significantly increased whole-body insulin mediated glucose disposal compared to AL and increased insulin receptor signaling, i.e. IRS-1 and 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, IRS-2, were not increased with caloric restriction 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.

Conclusion: CR 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.