Short-term Regulation of Insulin Receptor Affinity in Man

Abstract

We have studied the short term regulation of insulin receptors by serially measuring insulin binding to erythrocytes during 5 h of infusions of glucose and insulin. Two infusion protocols were employed: (1) Hyperinsulinemic study. Subjects were infused with insulin (80 mU/min) to induce sustained hyperinsulinemia, while euglycemia was approximated by infusion of glucose (8 mg/kg/min). (2) Hyperglycemic study. Subjects were infused with glucose (7 mg/kg/min) and a small amount of insulin (10 mU/min), while endogenous insulin secretion was inhibited with epinephrine and propranolol. Insulin binding to erythrocyte insulin receptors was measured serially during both of these infusion protocols for 5 h. The results demonstrated no change in insulin binding during the first 3 h of either infusion. However, by 5 h of either infusion, a striking 36% decrease in insulin binding, from 6.3 ± 0.5% to 4.0 ± 0.6%, was observed. Scatchard analysis and average affinity analysis of the binding data demonstrated that this decrease in insulin binding was entirely caused by a decrease in receptor affinity. Insulin binding to circulating monocytes was also measured, and comparable effects were observed. When cells were removed from the in vivo environment at 3 h and were incubated in vitro for a subsequent 2 h, decreased insulin binding developed during the incubation. Thus, this short term regulation of insulin receptor affinity occurred in vivo or in vitro, and cells that were programmed during the first 3 h of the infusion study could develop a decrease in insulin receptor affinity in vitro in the absence of plasma factors.

Increased Clearance and Degradation of [3H]Insulin in Streptozotocin Diabetic Rats

“…Similarly, muscle cells from experimentally hypoinsulinemic diabetic mice (4) and rats (5) display increased insulin binding. The observation in all three tissues is compatible with the widely accepted hypothesis of regulation of insulin receptors by ambient insulin concentration in vitro (6) and in vivo (7).…”

“…Blood samples (0.1 ml) were taken at times 1, 2,3, 5,6,7,8,10,15,20,25,30,35,40,45,50,55, and 60 min after injection. Total "4C-radioactivity and the concentration of intact [3H]insulin were then determined, the two isotopes being detected simultaneously in the scintillation counter.…”

Marked Increase in Insulin Sensitivity of Human Fat Cells 1 Hour after Glucose Ingestion

“…The recent observation (6) that human postglucose serum stimulates the insulin effect on rat adipocytes favors the latter hypothesis. It is unlikely that plasma glucose or insulin are such factors, because Insel and his colleagues (23) have shown that a 3-h infusion of insulin or glucose does not alter insulin receptor binding in man.…”

Insulin binding to erythrocytes in diabetic patients.

“…When competition data for the three groups were subjected to Scatchard analysis (Scatchard, 1949), plots were curvilinear and parallel to each other (Fig. 4) (Insel et al, 1980;Kobayashi et al, 1978). Scatchard analysis of the binding curves revealed that the change in insulin binding to erythrocytes was associated with an alteration in the insulin receptor concentration.…”