In vitro inhibition of insulin-degrading enzyme by long-chain fatty acids and their coenzyme A thioesters

Frederick G Hamel, Jennifer L. Upward, Robert G Bennett

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Insulin-degrading enzyme is responsible for initiating insulin degradation in cells, but little is known about the factors controlling its activity. Because obesity and high levels of free fatty acids decrease insulin clearance, we examined the effect of some common free fatty acids and their acyl-coenzyme A thioesters on insulin-degrading enzyme partially purified from the livers of male Sprague Dawley rats. Octanoic acid (C8:0) had no effect on activity. Long-chain free fatty acids (C16-C20) inhibited between 50% and 90% of the insulin degradation with ICso values in the range of 10-50 μM. In general, the corresponding acyl-coenzyme A thioesters had lower IC50 values and were slightly more efficacious. 125I-insulin cross-linking studies showed free fatty acids did not inhibit hormone binding to insulin-degrading enzyme. Kinetic analysis showed a noncompetitive type of inhibition. Furthermore, fatty acids eliminated the ability of insulin to inhibit the proteasome. These results suggest that when intracellular long-chain fatty acid concentrations are elevated, they may act directly on insulin-degrading enzyme to decrease insulin metabolism and alter insulin action in intact cells. This mechanism may contribute to the hyperinsulinemia and insulin resistance seen with elevated fatty acids and obesity.

Original languageEnglish (US)
Pages (from-to)2404-2408
Number of pages5
JournalEndocrinology
Volume144
Issue number6
DOIs
StatePublished - Jun 1 2003

Fingerprint

Insulysin
Coenzyme A
Fatty Acids
Insulin
Nonesterified Fatty Acids
Acyl Coenzyme A
Obesity
Hyperinsulinism
Proteasome Endopeptidase Complex
In Vitro Techniques
Inhibitory Concentration 50
Sprague Dawley Rats
Insulin Resistance
Hormones
Liver

ASJC Scopus subject areas

  • Endocrinology

Cite this

In vitro inhibition of insulin-degrading enzyme by long-chain fatty acids and their coenzyme A thioesters. / Hamel, Frederick G; Upward, Jennifer L.; Bennett, Robert G.

In: Endocrinology, Vol. 144, No. 6, 01.06.2003, p. 2404-2408.

Research output: Contribution to journalArticle

@article{976b9295594d4745aea23e1c81d6cd98,
title = "In vitro inhibition of insulin-degrading enzyme by long-chain fatty acids and their coenzyme A thioesters",
abstract = "Insulin-degrading enzyme is responsible for initiating insulin degradation in cells, but little is known about the factors controlling its activity. Because obesity and high levels of free fatty acids decrease insulin clearance, we examined the effect of some common free fatty acids and their acyl-coenzyme A thioesters on insulin-degrading enzyme partially purified from the livers of male Sprague Dawley rats. Octanoic acid (C8:0) had no effect on activity. Long-chain free fatty acids (C16-C20) inhibited between 50{\%} and 90{\%} of the insulin degradation with ICso values in the range of 10-50 μM. In general, the corresponding acyl-coenzyme A thioesters had lower IC50 values and were slightly more efficacious. 125I-insulin cross-linking studies showed free fatty acids did not inhibit hormone binding to insulin-degrading enzyme. Kinetic analysis showed a noncompetitive type of inhibition. Furthermore, fatty acids eliminated the ability of insulin to inhibit the proteasome. These results suggest that when intracellular long-chain fatty acid concentrations are elevated, they may act directly on insulin-degrading enzyme to decrease insulin metabolism and alter insulin action in intact cells. This mechanism may contribute to the hyperinsulinemia and insulin resistance seen with elevated fatty acids and obesity.",
author = "Hamel, {Frederick G} and Upward, {Jennifer L.} and Bennett, {Robert G}",
year = "2003",
month = "6",
day = "1",
doi = "10.1210/en.2002-0007",
language = "English (US)",
volume = "144",
pages = "2404--2408",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "6",

}

TY - JOUR

T1 - In vitro inhibition of insulin-degrading enzyme by long-chain fatty acids and their coenzyme A thioesters

AU - Hamel, Frederick G

AU - Upward, Jennifer L.

AU - Bennett, Robert G

PY - 2003/6/1

Y1 - 2003/6/1

N2 - Insulin-degrading enzyme is responsible for initiating insulin degradation in cells, but little is known about the factors controlling its activity. Because obesity and high levels of free fatty acids decrease insulin clearance, we examined the effect of some common free fatty acids and their acyl-coenzyme A thioesters on insulin-degrading enzyme partially purified from the livers of male Sprague Dawley rats. Octanoic acid (C8:0) had no effect on activity. Long-chain free fatty acids (C16-C20) inhibited between 50% and 90% of the insulin degradation with ICso values in the range of 10-50 μM. In general, the corresponding acyl-coenzyme A thioesters had lower IC50 values and were slightly more efficacious. 125I-insulin cross-linking studies showed free fatty acids did not inhibit hormone binding to insulin-degrading enzyme. Kinetic analysis showed a noncompetitive type of inhibition. Furthermore, fatty acids eliminated the ability of insulin to inhibit the proteasome. These results suggest that when intracellular long-chain fatty acid concentrations are elevated, they may act directly on insulin-degrading enzyme to decrease insulin metabolism and alter insulin action in intact cells. This mechanism may contribute to the hyperinsulinemia and insulin resistance seen with elevated fatty acids and obesity.

AB - Insulin-degrading enzyme is responsible for initiating insulin degradation in cells, but little is known about the factors controlling its activity. Because obesity and high levels of free fatty acids decrease insulin clearance, we examined the effect of some common free fatty acids and their acyl-coenzyme A thioesters on insulin-degrading enzyme partially purified from the livers of male Sprague Dawley rats. Octanoic acid (C8:0) had no effect on activity. Long-chain free fatty acids (C16-C20) inhibited between 50% and 90% of the insulin degradation with ICso values in the range of 10-50 μM. In general, the corresponding acyl-coenzyme A thioesters had lower IC50 values and were slightly more efficacious. 125I-insulin cross-linking studies showed free fatty acids did not inhibit hormone binding to insulin-degrading enzyme. Kinetic analysis showed a noncompetitive type of inhibition. Furthermore, fatty acids eliminated the ability of insulin to inhibit the proteasome. These results suggest that when intracellular long-chain fatty acid concentrations are elevated, they may act directly on insulin-degrading enzyme to decrease insulin metabolism and alter insulin action in intact cells. This mechanism may contribute to the hyperinsulinemia and insulin resistance seen with elevated fatty acids and obesity.

UR - http://www.scopus.com/inward/record.url?scp=0037900150&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037900150&partnerID=8YFLogxK

U2 - 10.1210/en.2002-0007

DO - 10.1210/en.2002-0007

M3 - Article

C2 - 12746301

AN - SCOPUS:0037900150

VL - 144

SP - 2404

EP - 2408

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 6

ER -