GLUCOSE AND FREE FATTY-ACID METABOLISM IN HUMAN OBESITY - RELATIONSHIPS TO INSULIN-RESISTANCE

Human obesity is associated with several alterations in lipid and gluc ose metabolism traditionally explained by substrate competition betwee n free fatty acids (FFAs) and glucose (Randle cycle), which causes ins ulin resistance, compensated by beta-cell hypersecretion. In this scen ario, central distribution of fat is the hallmark of a more serious su btype of obesity, More recently, several studies have partially elucid ated the cellular mechanisms underlying the insulin resistance of obes ity, Recent findings have also demonstrated that excessive amounts of FFAs may alter beta-cell function and impair muscle glucose metabolism through mechanisms and effecters not included in the Randle cycle (li potoxicity). Furthermore, tumor necrosis factor-alpha, leptin, beta(3) -adrenergic receptor, and plasma membrane glycoprotein PC-1 may play m ajor roles in insulin resistance and fat metabolism in obesity, Finall y recent evidence suggests that FFAs may also be detrimental to endoth elial function, thereby connecting, from a pathophysiological viewpoin t, the prediabetic and prehypertensive alterations of obesity.