Mechanisms of Insulin-Induced Insulin-Receptor Downregulation: Decrease of Receptor Biosynthesis and mRNA Levels

Abstract

The influence of insulin on the downregulation of its receptor was studied in AR42J cultured pancreatic acinar cells, a cell line that has been demonstrated to be metabolically responsive to insulin. Downregulation induced by insulin was time and dose dependent. After a 20-h incubation with 1 microM insulin, Scatchard analysis revealed approximately 80% loss of insulin receptors. Studies of receptor half-life indicated that treatment with insulin accelerated the degradation of both the alpha- and beta-subunits of the insulin receptor by 30-60%. In addition, biosynthetic-labeling studies indicated that insulin inhibited the biosynthesis of the insulin-receptor precursor by greater than 30%. This decreased biosynthesis of the precursor was associated with decreased production of mature receptor subunits. Poly(A)+ RNA was extracted from control cells and cells treated for 24 h with 100 nM insulin. Slot blots and Northern transfers revealed that insulin induced an approximately 50% decrease in insulin-receptor mRNA levels. Therefore, these studies indicate that insulin may diminish the concentration of its receptors in target cells by at least two mechanisms: acceleration of receptor degradation and inhibition of receptor biosynthesis at the level of mRNA.

Subpressor Dose of L-NAME Unmasks Hypertensive Effect of Chronic Hyperinsulinemia

“…This is a consistent finding in our experiments 10,12,14 -16 and could be explained, in part, by insulininduced insulin receptor downregulation. 23 Thus, our results confirmed our hypothesis that a nonhypertensive dose of L-NAME may unmask a hypertensive effect of insulin. However, our measurements of NO metabolites in plasma and urine did not support the hypothesis of insulin blunting its own effect by activating the NO system.…”

Muscle insulin receptor concentrations in obese patients post bariatric surgery: relationship to hyperinsulinemia

“…Downregulation of IR number by insulin has been demonstrated in vitro with several cell types. 6,7,25 The downregulation can be attributed to both the accelerated degradation of IR-bound insulin and reduction of IR mRNA levels. 6 Analysis of the correlation between IR number and plasma insulin levels in this study revealed a biphasic relationship.…”

“…6,7,25 The downregulation can be attributed to both the accelerated degradation of IR-bound insulin and reduction of IR mRNA levels. 6 Analysis of the correlation between IR number and plasma insulin levels in this study revealed a biphasic relationship. When our patients' fasting plasma insulin levels were less than 20 mU/ml, we observed a strong correlation between IR number and fasting plasma insulin.…”

“…[1][2][3] These events in the IR are followed by tyrosine phosphorylation and activation of downstream signaling molecules. 4,5 In vitro evidence from numerous studies in cultured cell systems 6,7 indicate that hyperinsulinemia downregulates IR content. In vivo, skeletal muscle from obese subjects demonstrates impaired insulin action at the earliest steps of IR signaling.…”

Insulin Receptor

“…Acini prepared from diabetic mice showed an increased number of insulin receptors compared to normal mice and addition of insulin to 24 hour cultured acini decreased insulin binding (36). Using pancreatic AR42J cells, insulin decreased the biosynthesis of insulin receptors in part by decreasing IR mRNA levels (37,38). The binding of insulin was also affected by CCK and other secretagogues (39).…”