Receptor and postreceptor insulin resistance induced by in vivo hyperinsulinemia

We examined the effects of inducing hyperinsulinemia in vivo in rats on the insulin receptors of, and the glucose oxidation by their adipocytes. Hyperinsulinemia was induced over a 2-week period by injecting NPH insulin subcutaneously. This was given in doses that were gradually increased to a final dose of 6 units/day. Profound hypoglycemia was avoided by providing supplemental sucrose to both the insulin-treated and control rats. The insulin concentration was eight times greater in the insulin-treated rats. However, they were not grossly obese and their adipocytes were not enlarged. The adipocytes of the hyperinsulinemic rats had a 25% lower maximal insulin binding capacity and were resistant to the effects of insulin on glucose oxidation. We felt that the hyperinsulinemia was sufficient so that, despite their somewhat lower insulin binding capacity, these adipocytes would not bind less insulin in vivo than would adipocytes from control rats. Hence, we postulated that, this massive hyperinsulinemia not only down regulated the insulin receptor, but also led to a postreceptor resistance. This notion was supported by two lines of in vitro data. First, even at maximally effective medium concentrations of insulin, the maximum rate of glucose oxidation by the adipocytes from hyperinsulinemic rats reached a plateau which was less than that reached by cells from controls. Second, when this in vitro glucose oxidation was related not merely to the medium insulin concentration, but to the amount of insulin bound to adipocytes, the response of the hyperinsulinemic rats' cells was always lower than control.(ABSTRACT TRUNCATED AT 250 WORDS)