The incidence of obesity is increasing, and as a result other diseases associated with obesity such as diabetes and cardiovascular disease continue to pose major clinical problems. This co-morbidity has been linked to insulin resistance, a condition proposed to be caused by hyperlipidemia and a consequent failure of insulin responsiveness. Considerable attention has been paid to the development of insulin sensitizers and in particular molecules that are able to modify the release or activity of (pre)adipocyte-derived mediators such as leptin, adiponectin and resistin. Endothelin-1 (ET-1) is a 21 amino acid peptide demonstrated to possess vasoconstrictor, positive inotropic, mitogenic, and metabolic properties. In numerous disease states, including congestive heart failure, obesity, and diabetes, elevated levels of ET-1 have been reported and are thought to contribute to the pathology of the disease. Considering the link between these diseases, ET-1 deserves attention with respect to its role in insulin resistance and the control of adipocyte function. Previous clinical studies have demonstrated that ET-1 induces a state of insulin resistance. This phenomenon has also been investigated in cell-based systems and it has been shown that ET-1 prevents insulin-stimulated glucose uptake by adipocytes through the activation of ETA receptors. This was suggested to involve decreased tyrosine phosphorylation of insulin receptor substrates such as IRS-1. More recently, researchers at Auburn University have demonstrated that ET-1 decreases basal and insulin-stimulated resistin secretion by 3T3 adipocytes. This therefore suggests that increases in ET-1 levels observed during conditions such as obesity alter not only the glucose handling properties of adipocytes but also the endocrine function of these cells. ET-1 may therefore, like triglyceride, underlie the link between obesity and diabetes, supporting the use of ETA receptor antagonists in the treatment of diabetes. This concept is supported by studies showing that ETA receptor antagonism markedly reduced hyperglycemia and restored plasma glucose clearance rates towards normal in an animal model of diabetes.

Entry date October, 2002

Adapted from Zhong et al, Biochem Biophys Res Commun 2002 Aug 16;296(2):383-7

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