PATHOGENESIS OF THE INSULIN-RESISTANCE SYNDROME (SYNDROME-X)

1. Insulin resistance is an early and major feature in the development of non-insulin-dependent diabetes mellitus (NIDDM), but it is also as sociated with hyperlipidaemia, hypertension, obesity and cardiovascula r disease, the so-called 'insulin-resistance syndrome' (Syndrome X). 2 . There is a strong genetic determination of NIDDM and insulin resista nce, but the environmental factors of calorie excess, reduced activity and obesity also make a major contribution. 3. Central (abdominal) ob esity is much more strongly associated with insulin resistance than is overall obesity. From twin studies, there appears to be specific gene tic determinants of central abdominal fat, independent of overall obes ity. 4. Calorie restriction and weight loss improve insulin sensitivit y in overweight humans. Isocaloric alteration of macronutrients substa ntially affects insulin sensitivity in rats but not, at least in the s hort-term, in humans. 5. Exercise training improves insulin sensitivit y via increased oxidative enzymes, glucose transporters (GLUT(4)) and capillarity in muscle as well as by reducing abdominal fat. 6. Metform in has been the only available drug that has been used clinically to s ignificantly improve insulin sensitivity, but the new 'glitazones' (th iazolidinediones) have a more specific effect via altered Lipid metabo lism.