| Summary: | 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 ([<sup>125</sup>I]Tyr<sup>A14</sup>)-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 ([<sup>125</sup>I]Tyr<sup>A14</sup>)insulin concentration approximately 5-fold (<i>p</i> < 0.001), demonstrating receptor dependency for plasma insulin clearance. Uptake by muscle (<i>p</i> < 0.01), liver (<i>p</i> < 0.05), and kidney (<i>p</i> < 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 (<i>p</i> = 0.056) while increasing renal clearance by >50% (<i>p</i> < 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.
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