Acción de la insulina en el músculo esquelético de la rata wistar efecto del envejecimiento, la restricción calórica y la leptina en la rata wistar

Resumen

Nowadays the number of patients suffering of obesity and diabetes type II is increasing far beyond the predictions of the WHO. It has been long demonstrated that ageing associates with insulin resistance in humans and rodents, and the WHO considers ageing as one of the risk factors associated with the type II diabetes and obesity epidemics. The Wistar rat has emerged as an appropriate experimental model to study the development of insulin resistance in the absence of marked changes in glucose homeostasis so that alterations in insulin action of primary character can be established. During the last two decades, our research group has studied the development of insulin resistance in the Wistar rat and established that insulin resistance develops first on the adipose tissue and the hypothalamus in association with a large increase in visceral adiposity. At advanced age rats develop overall insulin resistance together with central leptin resistance and hyperleptinemia. Following previous studies in isolated adipocytes that showed that both, central and peripheral leptin action inhibit insulin signaling and insulin action on fat tissue, in this work we have further explored whether leptin could also contribute to the development and maintenance of insulin resistance in skeletal muscle during aging. In order to do that we analyzed in vivo early insulin signaling, as well as ex vivo insulin stimulation of glucose transport, in oxidative and glycolytic skeletal muscles from 3-, 8-, and 24-month old rats. In addition, similar studies were performed in muscles from 8- and 24-month old animals after three months of moderate caloric restriction, in order to separate the effects of ageing from those of increased adiposity. Our data in this work indicate that ageing associates with a decreased insulin signaling in oxidative and glycolytic muscles. Oxidative muscles show lower insulin signaling at early aging (8-month old animals) whereas glycolytic fibres develop insulin resistance at a later stage. As previously shown, caloric restriction improves insulin sensitivity in skeletal muscle and is more efficacious in younger that in older animals. Our work also shows that leptin stimulates directly skeletal muscle and that this action decreases along ageing. Interestingly, both in vivo leptin infusion and ex vivo leptin pretreatment of muscles strips results in a decreased capacity of insulin to stimulate insuling signaling and glucose uptake in muscle. Part of the leptin effect on insulin stimulation of glucose transporte seems to be due to its ability to inhibit p38 phosphorylation. Nevertheless, further studies are needed to elucidate how leptin blocks insulin receptor phosphorylation in response to insulin. We propose that leptin elicits two different effects on insulin action, one due to its signaling through the hypothalamus and the central nervous system, which results in the sensitization of muscle to insulin action, and the other one mediated by its direct interaction with muscle leptin receptors that blocks insulin signaling and insulin action. We postulate that this direct action of high doses of leptin plays likely an important role in the development and/or maintenance of insulin resistance during aging.