The Insulin Receptor Mediates Insulin's Early Plasma Clearance by Liver, Muscle, and Kidney.

Rick I Meijer,Eugene J Barrett

doi:10.3390/biomedicines9010037

Abstract

The role of the insulin receptor in mediating tissue-specific insulin clearance in vivo has not been reported. Using physiologic insulin doses, we measured the initial clearance rate (first 5 min) of intravenously injected ([125I]TyrA14)-insulin by muscle, liver, and kidney in healthy rats in the presence and absence of the insulin receptor blocker S961. We also tested whether 4 weeks of high-fat diet (HFD) affected the initial rate of insulin clearance. Pre-treatment with S961 for 60 min prior to administering labeled insulin raised plasma ([125I]TyrA14)insulin concentration approximately 5-fold (p < 0.001), demonstrating receptor dependency for plasma insulin clearance. Uptake by muscle (p < 0.01), liver (p < 0.05), and kidney (p < 0.001) were each inhibited by receptor blockade, undoubtedly contributing to the reduced plasma clearance. The initial plasma insulin clearance was not significantly affected by HFD, nor was muscle-specific clearance. However, HFD modestly decreased liver clearance (p = 0.056) while increasing renal clearance by >50% (p < 0.01), suggesting a significant role for renal insulin clearance in limiting the hyperinsulinemia that accompanies HFD. We conclude that the insulin receptor is a major mediator of initial insulin clearance from plasma and for its clearance by liver, kidney, and muscle. HFD feeding increases renal insulin clearance to limit systemic hyperinsulinemia.

Highlights

Insulin activates signaling networks in many tissues by binding to the insulin receptor (IR) [1]
We conclude that the insulin receptor is a major mediator of initial insulin clearance from plasma and for its clearance by liver, kidney, and muscle
We recently reported that S961, inhibits ([125 I]Tyr A14 )insulin’s initial brain clearance [5] by blocking insulin uptake by the brain microvascular endothelial cell [6], implicating vascular

Summary

Introduction

Insulin activates signaling networks in many tissues by binding to the insulin receptor (IR) [1]. Insulin’s action in the liver increases IR endocytosis and insulin clearance [2]. Muscle, adipose, brain, and other tissues clear insulin [3,4]. The IR’s role in systemic insulin clearance at these other sites has not been defined. We recently reported that S961 (a specific IR blocker), inhibits ([125 I]Tyr A14 )insulin’s initial brain clearance [5] by blocking insulin uptake by the brain microvascular endothelial cell [6], implicating vascular. We used S961 (which blocks IR, not IGF-1R or hybrid receptors) to test IR’s role in whole-body (plasma) and tissue-specific (skeletal muscle, liver, and kidney) insulin clearance in rats. We tested the effect of 4 weeks of high-fat diet (HFD) feeding on systemic and tissue-specific insulin clearance

Methods

Results

Discussion

Conclusion