Rapid Non-Enzymatic Glycation of the Insulin Receptor under Hyperglycemic Conditions Inhibits Insulin Binding In Vitro: Implications for Insulin Resistance
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...
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doaj-6559414918324b4188a73b098fe8197b2020-11-24T20:45:32ZengMDPI AGInternational Journal of Molecular Sciences1422-00672017-12-011812260210.3390/ijms18122602ijms18122602Rapid Non-Enzymatic Glycation of the Insulin Receptor under Hyperglycemic Conditions Inhibits Insulin Binding In Vitro: Implications for Insulin ResistanceTyler Rhinesmith0Thomas Turkette1Robert Root-Bernstein2Department of Physiology, Michigan State University, 567 Wilson Road, Room 2201, East Lansing, MI 48824, USADepartment of Physiology, Michigan State University, 567 Wilson Road, Room 2201, East Lansing, MI 48824, USADepartment of Physiology, Michigan State University, 567 Wilson Road, Room 2201, East Lansing, MI 48824, USAThe 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.https://www.mdpi.com/1422-0067/18/12/2602diabetic complicationshyperglycemiainsulin receptorinsulin resistanceglycosylation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tyler Rhinesmith Thomas Turkette Robert Root-Bernstein |
spellingShingle |
Tyler Rhinesmith Thomas Turkette Robert Root-Bernstein Rapid Non-Enzymatic Glycation of the Insulin Receptor under Hyperglycemic Conditions Inhibits Insulin Binding In Vitro: Implications for Insulin Resistance International Journal of Molecular Sciences diabetic complications hyperglycemia insulin receptor insulin resistance glycosylation |
author_facet |
Tyler Rhinesmith Thomas Turkette Robert Root-Bernstein |
author_sort |
Tyler Rhinesmith |
title |
Rapid Non-Enzymatic Glycation of the Insulin Receptor under Hyperglycemic Conditions Inhibits Insulin Binding In Vitro: Implications for Insulin Resistance |
title_short |
Rapid Non-Enzymatic Glycation of the Insulin Receptor under Hyperglycemic Conditions Inhibits Insulin Binding In Vitro: Implications for Insulin Resistance |
title_full |
Rapid Non-Enzymatic Glycation of the Insulin Receptor under Hyperglycemic Conditions Inhibits Insulin Binding In Vitro: Implications for Insulin Resistance |
title_fullStr |
Rapid Non-Enzymatic Glycation of the Insulin Receptor under Hyperglycemic Conditions Inhibits Insulin Binding In Vitro: Implications for Insulin Resistance |
title_full_unstemmed |
Rapid Non-Enzymatic Glycation of the Insulin Receptor under Hyperglycemic Conditions Inhibits Insulin Binding In Vitro: Implications for Insulin Resistance |
title_sort |
rapid non-enzymatic glycation of the insulin receptor under hyperglycemic conditions inhibits insulin binding in vitro: implications for insulin resistance |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2017-12-01 |
description |
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. |
topic |
diabetic complications hyperglycemia insulin receptor insulin resistance glycosylation |
url |
https://www.mdpi.com/1422-0067/18/12/2602 |
work_keys_str_mv |
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