The etiology and pathogenesis of non-insulin-dependent diabetes.

Although environmental factors are important triggers of non-insulin-dependent diabetes mellitus (NIDDM), heredity plays a major role in the pathogenesis of the disease. Insulin resistance manifested as impaired activation of glycogen synthase and thereby storage of glucose as glycogen in skeletal muscle is demonstrable early on in NIDDM relatives, suggesting that NIDDM could be an inherited muscle disease. On the other hand, insulin deficiency is almost unequivocally present before manifest diabetes develops. An intensive search for candidate genes for NIDDM has been initiated; so far it has not been possible to ascribe NIDDM to any alterations in the human genome. Given the heterogenous nature of NIDDM, its age-dependent penetrance and strong influence of environmental factors, it may not be fruitful to use NIDDM as an end-point in genetic linkage or association studies. It is more likely that DNA defects result in either insulin resistance or insulin deficiency, which in turn, can both lead to NIDDM. In accordance with the thrifty gene hypothesis, the insulin resistance gene has protected individuals during long periods of starving by storing energy as fat rather than as glycogen in muscle. The abundance of food in Western society has made this once protective gene a deleterious one, suggesting that these individuals are not equipped with the metabolic machinery to handle overeating.