Is insulin resistance the principal cause of type 2 diabetes

The data presented from these recent studies raise serious doubt concerning the commonly held view that insulin resistance is the principal cause of type 2 diabetes: first of all they provide evidence that insulin resistance may not be the primary genetic factor for type 2 diabetes; secondly, they demonstrate that at least under certain circumstances insulin resistance is not essential for diabetes to occur, and then finally, they indicate that insulin resistance may not be the predominant factor determining the degree of hyperglycaemia. Although these studies suggest that the role of insulin resistance relative to that of beta-cell dysfunction in the pathogenesis of type 2 diabetes has been generally overestimated, one should not be left with the impression that insulin resistance is not important. It is certainly an important factor in determining the degree of hyperglycaemia or glucose intolerance present at a given level of beta-cell function. The improvement in glycaemic control after weight loss which lessens insulin resistance or after the administration of pharmacologic agents that improve insulin sensitivity clearly argue that insulin resistance is important in this regard. In addition to influencing the severity of glucose intolerance, insulin resistance is probably also important in determining the time of onset of diabetes. It may do this simply by altering the balance between the body's demand for insulin and the ability of the pancreas to provide insulin. It might adversely affect beta-cell function in addition to increasing the demand for insulin. This concept is schematically represented in figure 3. It is well established that beta-cell function normally deteriorates as a function of age [41]. Although the prevalence of type 2 diabetes increases as a function of age, this by itself obviously does not result in diabetes in the great majority of people. In such individuals their insulin sensitivity is sufficient to maintain the balance between the supply and demand for insulin above the threshold for developing diabetes. Theoretically one may postulate three other situations originating with a genetic beta-cell defect: some people may start off life with normal beta-cell function but experience a genetically determined accelerated deterioration; some people may start off life with reduced beta-cell function (e.g. less beta-cell s); still others may start off with reduced beta-cell function and have an accelerated rate of deterioration. In each of the above situations, at any given level of beta-cell function, the degree of insulin resistance present would alter the threshold for developing impaired glucose tolerance and ultimately type 2 diabetes; in other words, the greater the insulin resistance, the lower the threshold, the earlier the onset and the more severe the diabetes will be. It follows therefore that efforts to diminish insulin resistance and to preserve beta-cell function should both be beneficial. Weight loss and increased physical activity, both of which reduceinsulin resistance, have been shown to prevent progression of people with impaired glucose tolerance to diabetes. Whether this is simply due to shifting the balance between insulin requirements and insulin availability or whether it also involves an improvement in beta-cell function and/or prevention of its deterioration remains to be clarified. Furthermore, it is not known whether pharmacologic agents which improve insulin sensitivity have similar effects.