Mechanisms of the Fasting-Induced Increase in Insulin Binding to Rat Adipocytes

Abstract

A B S T R A C T Fasting leads to an increase in the ability ofadipocytes to bind insulin, and this was accounted for by an increase in the affinity ofthe receptors for insulin without any change in the number of receptors per cell. Binding affinity can increase because of a decrease in the dissociation rate constant (kd), an increase in the association rate constant (ka), or both. Kinetic studies demonstrated that fasting leads to a striking decrease in the rate at which insulin dissociates from its receptor, and the near two-fold prolongation of the time at which 50% of the bound 125I-insulin dissociates (28±4 vs. 50±5 min) correlated quite well with the two-fold increase in binding affinity. On the other hand, the rate at which insulin associates with its receptor was essentially unchanged. Negatively cooperative interactions between receptors were readily demonstrated in cells from control and fasting animals, and the magnitude and sensitivity ofthis effect was the same in both groups of cells. It seemed likely that during fasting a change in the concentration of some substrate or hormone could lead to these effects on insulin binding. However, in vitro attempts to recreate the substrate and hormonal changes which occur in fasting produced no evidence to support this idea. In conclusion: (a) fasting leads to an increase in the ability ofadipocytes to bind insulin because of an increase in binding affinity; (b) this increase in the affinity ofthe receptor for insulin was primarily accounted for by a decrease in the rate at which insulin dissociates from its receptors; and (c) fasting did not appreciably alter the negatively cooperative interactions displayed by adipocyte insulin receptors.

Increased affinity of insulin receptor on hepatocytes from streptozotocin-induced diabetic rats.

“…4-b). This is similar to the findings in normal rats by Olefsky et al (1978). In our present studies, the Scatchard analysis gave a more concave curve in STZ rats than in normal rats.…”

“…We have also reported that not only the num- (Olefsky et al, 1978) . These facts suggest that Scatchard analysis cannot be used in some conditions, and that it is important to re-evaluate the results obtained by Scatchard analysis in intact cells with method which are not affected by internalization.…”

“…Previous studies have shown that the affinity of insulin receptor is altered in a number of situations, such as acute glucose ingestion (Muggeo et al, 1977), hypoglycemia (Bar et al, 1977), acidosis (De Meyts et al, 1976), fasting (Bar et al, 1976;DeFronzo et al, 1977;Olefsky et al, 1978) and streptozotocin (STZ)-induced insulin deficiency (Kobayashi et al, 1979). We have also reported that not only the num- (Olefsky et al, 1978) .…”

Counterregulation of insulin by leptin as key component of autonomic regulation of body weight

“…Considering first the peripheral tissues, it is well established that insulin sensitivity increases with body fat and body mass losses, and insulin resistance increases with body fat and body mass gains. Tissues such as the liver, muscle and the WAT display direct autoregulatory increases in numbers of spare receptors, hormone-receptor binding [223] , and enzyme sensitivity to nutrients as they are depleted of storage molecules and structural proteins. After glycogendepleting exercise, activity of glycogen synthase increases in proportion to the magnitude of glycogen depletion which leads to a faster rate of glycogen resynthesis during recovery from exercise [224,225] .…”

“…After glycogendepleting exercise, activity of glycogen synthase increases in proportion to the magnitude of glycogen depletion which leads to a faster rate of glycogen resynthesis during recovery from exercise [224,225] . As they are depleted of storage nutrients, liver, muscle, and WAT develop direct and autoregulatory increases in sensitivities to the anabolic actions of insulin [191,223,[225][226][227] and catabolic actions of catecholamines [228] some of which are induced by counterregulatory actions of leptin [190][191][192][193] . Changes in hormone sensitivities and responses are greater to more rapid rather than to gradual or prolonged reductions in…”