Unacylated ghrelin restores insulin and autophagic signaling in skeletal muscle of diabetic mice

Abstract

Impairment of insulin signaling in skeletal muscle detrimentally affects insulin-stimulated disposal of glucose. Restoration of insulin signaling in skeletal muscle is important as muscle is one of the major sites for disposal of blood glucose. Recently, unacylated ghrelin (UnAG) has received attention in diabetic research due to its favorable actions on improving glucose tolerance, glycemic control, and insulin sensitivity. The investigation of UnAG has entered phase Ib clinical trial in type 2 diabetes and phase II clinical trial in hyperphagia in Prader-Willi syndrome. Nonetheless, the precise mechanisms responsible for the anti-diabetic actions of UnAG remain incompletely understood. In this study, we examined the effects of UnAG on restoring the impaired insulin signaling in skeletal muscle of db/db diabetic mice. Our results demonstrated that UnAG effectively restored the impaired insulin signaling in diabetic muscle. UnAG decreased insulin receptor substrate (IRS) phosphorylation, increased protein kinase B (Akt) phosphorylation, and, hence, suppressed mTOR signaling. Consequently, UnAG enhanced Glut4 localization and increased PDH activity in the diabetic skeletal muscle. Intriguingly, our data indicated that UnAG normalized the suppressed autophagic signaling in diabetic muscle. In conclusion, our findings illustrated that UnAG restored the impaired insulin and autophagic signaling in skeletal muscle of diabetic mice, which are valuable to understand the underlying mechanisms of the anti-diabetic action of UnAG at peripheral skeletal muscle level.

Safety, tolerability, pharmacokinetics and pharmacodynamics of AZP‐531, a first‐in‐class analogue of unacylated ghrelin, in healthy and overweight/obese subjects and subjects with type 2 diabetes

“…No significant changes in insulin levels were observed after AZP‐531 administration in overweight/obese subjects, while glucose concentrations improved, consistent with the insulin‐sensitizing mechanism of action extensively documented for UAG in experimental animals . In a clinical study, improved insulin sensitivity, as assessed by measurement of the M index during a hyperinsulinaemic–euglycaemic clamp, was observed in overweight patients with T2D who were infused with UAG for 2.5 h .…”

“… shows that UAG lowers reactive oxygen species (ROS) generation and inflammation in muscle while enhancing insulin signalling and insulin‐stimulated glucose uptake, thereby preventing hyperglycaemia and insulin resistance in models of high‐fat‐diet‐induced obesity. It is noteworthy that the protective effects of UAG from oxidative stress and inflammation have been previously reported for a variety of cells including pancreatic β cells , endothelial cells , cardiomyocytes and muscle cells , and have been observed for AZP‐531 as well.…”

“…Tam et al. showed that UAG is able to restore the impaired insulin signalling and to normalize the suppressed autophagic signalling in skeletal muscle of diabetic mice in conjunction with decreased fasting glucose levels and body weight. The work of Cappellari et al.…”

Ghrelin stimulates fatty acid oxidation and inhibits lipolysis in isolated muscle from male rats

“…) and protein (Tam et al. ). In male humans, the acute administration of AG decreases both basal and insulin‐stimulated whole‐body glucose clearance (Vestergaard et al.…”

Current Evidence for a Role of Neuropeptides in the Regulation of Autophagy

“…This effect parallels the upregulation of mTOR pathway which likely acts in an AMPK-suppressed and p38-MAPK-activated manner [65]. In contrast, ghrelin stimulated insulin levels in skeletal muscles of diabetic mice, thus restoring the suppressed mTOR-dependent autophagy [66]. Accordingly, in human ovarian epithelial carcinoma cells, ghrelin inhibited mTOR, enhanced LC3-II levels, and, consequently, induced apoptosis [67].…”