Central regulation of insulin sensitivity

Insulin rapidly lowers blood glucose levels via inhibition of endogenous glucose production and stimulation of glucose uptake. The mechanisms by which insulin modulates hepatic glucose production involve either activation of insulin signaling in hepatocytes (direct efects) or activation of insulin receptors in extra-hepatic sites (indirect effects), which in turn leads to inhibition of glucose production via neural and/or humoral mediators. The direct effects can be further divided into acute insulin action leading to rapid decrease in glucose production and chronic insulin action modulating the gene expression of rate-limiting enzymes within the biochemical pathways leading to glucose production. Short-term effects of insulin on hepatic glucose fluxes may be divided into three major components: (a) direct effects on the liver, mostly leading to rapid inhibition of glycogenolysis;1,2 (b) indirect effects mediated via peripheral actions of insulin, mostly modulating lipolysis;3-6 (c) indirect effects mediated via activation of hypothalamic insulin signaling.7,8 Furthermore, insulin exerts potent long-term effects on liver gene expression and function.9. These more chronic actions of insulin can in turn markedly affect the acute responses to an increase in circulating insulin levels.10,11.