Insulin resistance is so common in noninsulin dependent diabetes mellitus (NIDDM) that it has been proposed as the syndrome's most important pathogenetic element. Yet most insulin-resistant persons are euglycemic, by virtue of an adaptative increase in insulin secretion. It remains to be seen whether diabetics become extraordinarily insulin resistant in response to aging, adiposity and other factors, or whether they have subnormal islet adaptation to any increase in insulin requirement. I propose first to develop valid methods of quantitating insulin sensitivity and then to analyze the relative importance of exaggerated insulin resistance and inadequate islet adaptation in diabetic hyperglycemia. R. N. Bergman has developed a minimal model of insulin action which allows parameters of insulin action to be estimated from an intravenous glucose tolerance test (IVGTT). From these parameters is derived an index of sensitivity to insulin (S1). I propose to perform glucose clamp studies to test the validity of the minimal model in man. If it proves valid, I will determine the validity of IVGTT estimations of S1 by comparing them to clamp studies in normal and diabetic subjects. Using the most efficient measures of insulin sensitivity that prove valid, I will then evaluate what determines how much hyperglycemia results from short-term dexamethasone treatment in man. Factors tested will be islet glucose sensitivity (as measured by potentiation slope), the adaptation of islet glucose sensitivity during steroid treatment, and the dexamethasone-induced decline in S1. These tests will also be performed in NIDD and in steroid-sensitive relatives of NIDD, to find the basis of their abnormally hyperglycemic response to steroids. The data will also give the relation of untreated fasting glycemia to S1 and potentiation slope in a cross-section of persons, allowing an estimate of the contributions of insulin resistance and islet dysfunction to the hyperglycemia of individuals. This may help predict the effect of various treatments on glucose level in specific diabetics. These studies may lead to clinically useful methods of detecting those constitutionally prone to NIDDM. Particularly if the IVGTT method proves valid, they may also provide an approach to analyzing the natural history of the development of diabetic hyperglycemia.