Locating the Site(s) of Insulin Resistance in Patients with Nonketotic Diabetes Mellitus

Insulin resistance and the ability of insulin to inhibit hepatic glucose production and to increase efficiency of glucose uptake were determined in 24 nonobese individuals: eight subjects with normal oral glucose tolerance, eight patients with chemical diabetes, and eight nonketotic patients with fasting hyperglycemia (> 150 mg. per cent). Insulin resistance was estimated by measuring the steady-state plasma glucose response to a continuous infusion of insulin, glucose, epinephrine, and propranolol. This approach permits us to inhibit endogenous insulin release, attain comparable steady-state plasma levels of exogenous insulin, and use the height of the steady-state plasma glucose response as a direct estimate of insulin resistance. The ability of insu lin to inhibit hepatic glucose production and to increase efficiency of glucose uptake was calculated from the results of two studies in which a continuous infusion of 3H-2-glucose was used to measure glucose turnover rate. The first study was performed after an overnight fast, under conditions of basal insulin levels, while the second was conducted during the infusion of insulin, glucose, epinephrine, and propranolol. Hepatic glucose production is equal to glucose turnover rate during the basal study and is equal to glucose turnover rate minus the infusion rate of cold glucose during the second study. Glucose uptake in both studies is equal to glucose turnover rate minus urinary glucose loss, and the efficiency of glucose uptake is calculated by dividing glucose uptake by the plasma glucose pool size. The mean (± S. E.) steady-state plasma glucose response wasll3 ± 9 mg. per cent in normal subjects, 205 ± 14 mg. per cent in chemical diabetics, and 346 ± 30 mg. per cent in patients with fasting hyperglycemia. Thus, insulin resistance exists in nonketotic diabetes, and the greater the degree of glucose intolerance, the greater the insulin resistance. The resistance to the insulin infusion in patients with chemical diabetes seemed to be mainly a function of the inability of insulin to increase efficiency of glucose uptake, since insulin did retain its ability to inhibit glucose production (although not to normal levels). In contrast, the infusion of insulin neither inhibited hepatic glucose production nor increased efficiency of glucose uptake in patients with fasting hyperglycemia. Thus, the insulin resistance that exists in patients with nonketotic diabetes cannot be considered to be a global phenomenon. Significant differences exist in the responsiveness of various tissues to the two general aspects of insulin's action on glucose homeostasis, and these differences provide a physiologic basis for the variations in degree of over-all insulin resistance that are present in the three groups of subjects.