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Int. J. Mol. Sci. 2017, 18(12), 2602; https://doi.org/10.3390/ijms18122602

Rapid Non-Enzymatic Glycation of the Insulin Receptor under Hyperglycemic Conditions Inhibits Insulin Binding In Vitro: Implications for Insulin Resistance

Department of Physiology, Michigan State University, 567 Wilson Road, Room 2201, East Lansing, MI 48824, USA
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Received: 28 October 2017 / Revised: 20 November 2017 / Accepted: 28 November 2017 / Published: 2 December 2017
(This article belongs to the Special Issue Insulin and Insulin Receptor in Diseases)
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Abstract

The causes of insulin resistance are not well-understood in either type 1 or type 2 diabetes. Insulin (INS) is known to undergo rapid non-enzymatic covalent conjugation to glucose or other sugars (glycation). Because the insulin receptor (IR) has INS-like regions associated with both glucose and INS binding, we hypothesize that hyperglycemic conditions may rapidly glycate the IR, chronically interfering with INS binding. IR peptides were synthesized spanning IR- associated INS-binding regions. Glycation rates of peptides under hyperglycemic conditions were followed over six days using matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. INS conjugated to horse-radish peroxidase was used to determine INS binding to IR peptides in glycated and non-glycated forms. Several IR peptides were glycated up to 14% within days of exposure to 20–60 mM glucose. Rates of IR-peptide glycation were comparable to those of insulin. Glycation of four IR peptides significantly inhibits INS binding to them. Glycation of intact IR also decreases INS binding by about a third, although it was not possible to confirm the glycation sites on the intact IR. Glycation of the IR may therefore provide a mechanism by which INS resistance develops in diabetes. Demonstration of glycation of intact IR in vivo is needed. View Full-Text
Keywords: diabetic complications; hyperglycemia; insulin receptor; insulin resistance; glycosylation diabetic complications; hyperglycemia; insulin receptor; insulin resistance; glycosylation
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Rhinesmith, T.; Turkette, T.; Root-Bernstein, R. Rapid Non-Enzymatic Glycation of the Insulin Receptor under Hyperglycemic Conditions Inhibits Insulin Binding In Vitro: Implications for Insulin Resistance. Int. J. Mol. Sci. 2017, 18, 2602.

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