Relationship between in Vivo Insulin Resistance and Decreased Insulin Receptors in Obese Man*

We have studied the relationship between in vivo insulin sensitivity and in vitro insulin binding to adipocytes in obese and nonobese subjects. Insulin binding studies demonstrated a 40% (P > 0.01) decrease in the number of receptor sites per cell in adipocytes from the obese patients. Insulin sensitivity was assessed by a previously defined technique in which insulin and glucose are constantly administered while endogenous insulin secretion is inhibited by an infusion of epinephrine (6 μg/min) and propranolol (0.08 mg/min). Using this technique, the resulting steady state plasma glucose (SSPG) levels provide a measure of overall in vivo insulin sensitivity. The dose-response relationship between the steady state plasma insulin concentration and glucose disposal was determined by performing three separate infusions on each subject in which the glucose infusion rate was kept constant while the rate of insulin infusion was serially increased in each study. Compared to the normal subjects, the dose-response curves for the obese subjects were markedly shifted to the right. Thus, for any given submaximal plasma insulin level the SSPG level was always greater in the obese patients. However, at the maximal insulin level, the SSPG levels in the obese subjects were reduced to the normal range. Therefore, although the obese patients were insulin resistant at submaximal insulin levels, this insulin resistance could be overcome at higher insulin levels, and this is the predicted functional consequence of a decrease in the number of cellular insulin receptors. In conclusion, 1) obese subjects demonstrate decreased in vivo insulin sensitivity and decreased adipocyte insulin receptors; 2) the in vivo dose-response relationship between plasma insulin and glucose disposal is shifted to the right in obesity; and 3) these data are most consistent with the concept that decreased target tissue insulin receptors are the predominant cause of the overall in vivo insulin resistance in obesity. (J Clin Endocrinol Metab48: 487,1979)