Ameliorative Effect Of Pioglitazone, An Insulin Sensitizer, On Insulin Resistance And Its Mechanism

Diabetes mellitus has been widely recognized as a major health problem affecting many people's life around the world. Type 2 diabetes is the most common form of diabetes, affecting more than 150 million people and about 10-20% of adults in many developed countries suffer from the disease. The development of type 2 diabetes requires the presence of two fundamental defects: insulin resistance and impaired insulin secretion. Insulin resistance, characterized by reduced responsiveness the normal circulating insulin in target tissues, is now considered as a fundamental aspect of etiology of type 2 daibetes and also link to a wide array of other pathophysiologic sequelae including impaired glucose tolerance (IGT), obesity, hypertension, hyperlipidemia and atherosclerosis. How IR contributes to all these disorders and how the different disorders related with each other? Exploring the molecular mechanism of IR and searching for potent insulin sensitizer has appeared to be an essential and important problem.Thiazolidinediones are a class of compounds that appear to enhance insulin action without directly stimulating β-cell to secrete insulin. However, troglitazone, the first thiazolidinedione derivate on-market, had been forbidden in US and Europe for its severe hepatotoxicity, though proved effective in improving peripheral glucose utilization, reducing hepatic glucose production and ameliorating IR. So exploring the mechanism of this class of agent, developing more effective and safety agent is very necessary.This study was undertaken to determine whether Pioglitazone, a member of the TZD, could prevent the development of insulin resistance and the related abnormalities produced by various ways. First, hyperinsulinemic-euglycemic glucose clamp technique was established, by which insulin sensitivity was evaluated in 3 different animal models. Then, we studied the characteristics of...