A potential role for skeletal muscle caveolin-1 as an insulin sensitivity modulator in ageing-dependent non-obese type 2 diabetes: studies in a new mouse model

Abstract

Aims/hypothesis Type 2 diabetes mellitus is a common agedependent disease. We discovered that male offspring of non-diabetic C57BL/6 and DBA/2 mice, called JYD mice, develop type 2 diabetes when they grow old. JYD mice show characteristics of insulin resistance, hyperglycaemia and hyperinsulinaemia in old age without obesity. We postulated that the mechanism of age-dependent type 2 diabetes in this model relates to caveolin-1 status in skeletal muscle, which appears to regulate insulin sensitivity in the mice. Methods We compared insulin sensitivity in aged C57BL/6 and JYD mice using glucose and insulin tolerance tests and 18 Ffluorodeoxyglucose positron emission tomography. We also determined insulin signalling molecules and caveolin proteins using western blotting, and altered caveolin-1 levels in skeletal muscle of C57BL/6 and JYD mice using viral vector systems, to examine the effect of this on insulin sensitivity. Results In 30-week-old C57BL/6 and JYD mice, the basal levels of IRS-1, Akt and peroxisome proliferator-activated receptor-γ decreased, as did insulin-stimulated phosphorylation of Akt and insulin receptor β. However, caveolin-1 was only increased about twofold in 30-week-old JYD mice as compared with 3-week-old mice, whereas an eightfold increase was seen in C57BL/6 mice. Downregulation of caveolin-1 production in C57BL/6 mice caused severe impairment of glucose and insulin tolerance. Upregulation of caveolin-1 in aged diabetic JYD mice significantly improved insulin sensitivity with a concomitant increase of glucose uptake in the skeletal muscle. Conclusions/interpretation The level of skeletal muscle caveolin-1 is correlated with the progression of age-dependent type 2 diabetes in JYD mice.

Modulation of Insulin Sensitivity and Caveolin-1 Expression by Orchidectomy in a Nonobese Type 2 Diabetes Animal Model

“…We previously found that male, but not female, JYD mice developed type 2 diabetes in old age, and that reduced levels of caveolin-1 were correlated with the development of diabetes in male mice (18). In the present study, we investi-…”

“…JYD F1 mice were obtained from mating female C57BL/6 and male DBA/2 mice, as previously described (18). Mice were given free access to food and water, except when noted otherwise, and were kept on a cycle of 12-h light/12-h dark at 23°C and 65% humidity.…”

Dexamethasone downregulates caveolin-1 causing muscle atrophy via inhibited insulin signaling

“…Although the mechanisms of signaldependent regulation in the caveolae remain unclear, our results indicate that IRa and IRS1 are positively regulated by CAV1 in muscle cells. Consistent with these results, an increase in Cav1 expression in skeletal muscle improves insulin sensitivity (Cohen et al 2004, Oh et al 2008. Conversely, Cav1-null mice displayed skeletal muscle abnormalities due to tubular aggregate formation (Schubert et al 2007) and exercise intolerance (Razani et al 2001), demonstrating that insulin/IGF signaling depends on the level of Cav1 expression in muscle.…”

“…In humans, CAV1 mutations cause generalized lipodystrophy, insulin resistance, and hypertriglyceridemia (Gazzerro et al 2010). Moreover, we have demonstrated that the level of CAV1 in skeletal muscle is related to insulin sensitivity in vitro and in vivo (Oh et al 2008), indicating that CAV1 may regulate insulin signaling. Notably, Cav1-deficient mice have a lean phenotype (Razani et al 2002).…”

“…The adenoviral vectors and infective recombinant adenovirus expressing Cav1 used in this study have been described previously (Oh et al 2008). In brief, infective recombinant adenovirus was made using the AdEasy system.…”