Volume 1 number 1 Summer 2003
Special issue for the abstracts of the 7th Pan Arab Conference on Diabetes
PACD7 , 25 – 28 March 2003 Cairo

Abstract Number : 75
Insulin resistance: from impairment of insulin-mediatedglucose metabolism to cardiovascular risk

Stefano Del Prato – Department of Endocrinology and Metabolism, Section of Diabetes and Metabolic Diseases - University of Pisa, 
Italy

The concept of insulin resistance became apparent as soon as the method for determination of plasma insulin levels was made available. It was indeed evident that glucose homeostasis could be maintained at the expense of different levels of circulating insulin, i.e. some individuals require little insulin while others need much larger amount of insulin to ensure euglycemia. Typically, insulin resistance occurs in-patients with type 2 diabetes, where it is believed to play a main pathogenetic role. However, it was soon realized that insulin resistance was not spedific to diabetes but it could be found in many other conditions (obesity, hypertension, dyslipidemia, etc.) as well as in otherwise “normal” individuals. Insulin resistance is a common denominator of the Metabolic Syndrome, a cluster of entangled abnormalities including hyperinsulinemia, central obesity, glucose intolerance and diabetes, high triglyceride and low HDL-cholesterol levels, increased prothrombotic and antifibrinolytic factors, and hypertension. People with the Metabolic Syndrome have greater risk for cardiovascular disease. Recent work has shown that insulin resistance is an independent risk factor for cardiovascular mortality in Caucasians as well as in Mexican-Americans with or without diabetes mellitus. In spite of the many biological effects of insulin, the term “insulin resistance” indicates impaired ability of insulin to promote glucose utilisation in skeletal muscle, adipose tissue, and liver. In the presence of normal beta-cell function, hyperinsulinemia ensues in the attempt to compensate for concomitant insulin resistance. At the cellular level, excess insulin may trigger several pathways involved in atherogenesis. A crucial role of the concomitance of insulin resistance and hyperinsulinemia is likely to be played at the endothelial level. A strong correlation exists between insulin action and vascular reactivity. The IRS/PI3K pathway is common in endothelial and skeletal muscle cells. Insulin resistance is associated with impairment in this pathway accounting for reduced glucose utilisation in skeletal muscle and reduced nitric oxide generation, increased MMP 2 and 9, and apoptosis in endothelial cells. Concomitant hyperinsulinemia can, therefore, result in over-activation of the normally sensitive MAPK pathway. This will be responsible, in endothelial cells, for cell proliferation, increased PA1-1 synthesis, endothelin receptor, increased sensitivity to angiotensin-II and prostaglandin effects, and adhesion molecules transcription. The latter is mediated by the activation of Nuclear Factor-kB, also triggered in the presence of insulin resistance. This activation may account for the correlation observed between circulating levels of acute-phase proteins and insulin action, a more recent component of the Syndrome. In conclusion, insulin resistance and compensatory hyperinsulinemia are likely to play a major role in the pathogenesis of the Metabolic Syndrome, a common condition in the western societies and a growing problem in the developing Countries. 

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