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In Vitro Inhibition of Insulin-Degrading Enzyme by Long-Chain Fatty Acids and Their Coenzyme A Thioesters -- Hamel et al. 144 (6): 2404 -- Endocrinology Anglais Degradinggorgeousunclothedteachers Lv Modules Php Name Duyurular Degrading Gorgeous Unclothed Teachers

Anglais Degradinggorgeousunclothedteachers Lv Modules Php Name Duyurular Degrading Gorgeous Unclothed Teachers

In Vitro Inhibition of Insulin-Degrading Enzyme by Long-Chain Fatty Acids and Their Coenzyme A Thioesters

Research Service (F.G.H., J.L.U., R.G.B.), Department of Veterans Affairs Medical Center, Omaha, Nebraska 68105; and Departments of Internal Medicine (F.G.H., R.G.B.) and Pharmacology (F.G.H.), University of Nebraska Medical Center, Omaha, Nebraska 68198

Address all correspondence and requests for reprints to: Frederick G. Hamel, Ph.D., Department of Veterans Affairs Medical Center, 4101 Woolworth Avenue, Omaha, Nebraska 68105. E-mail: fghamel{}unmc.edu.

	Abstract

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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 IC₅₀ 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.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
OBESITY AND ELEVATED levels of free fatty acids (FFAs) are associated with insulin resistance and the development of type 2 diabetes mellitus. One consequence of these conditions is a decrease in insulin processing. Hepatic insulin clearance is reduced in overfed rats and negatively correlated with hepatic triglyceride content (1). Similar results were found with bovine cells (2). Severely obese humans also demonstrate decreased insulin clearance, which is significantly improved with weight loss (3). It is not just high tissue lipid content that is responsible for this effect; addition of FFAs to rat liver perfusate acutely decreased hepatic insulin removal by up to 40% (4). In vivo experiments in dogs have also shown that elevated circulating FFAs decrease peripheral insulin clearance and hepatic insulin extraction (5). In vitro experiments with FFAs and isolated hepatocytes have shown a decrease in insulin binding and degradation (6, 7, 8). These studies showed no effect of FFAs on partially purified insulin receptors and support the idea that receptor turnover and insulin processing were affected. Because insulin-degrading enzyme is the enzyme primarily responsible for initiating insulin degradation in endosomes (9), this is an obvious possible target ^{z In Vitro Inhibition of Insulin-Degrading Enzyme by Long-Chain Fatty Acids and Their Coenzyme A Thioesters -- Hamel et al. 144 (6): 2404 -- Endocrinology Anglais Degradinggorgeousunclothedteachers Lv Modules Php Name Duyurular Degrading Gorgeous Unclothed Teachersj f Degrading Unclothed s In Vitro Inhibition of Insulin-Degrading Enzyme by Long-Chain Fatty Acids and Their Coenzyme A Thioesters -- Hamel et al. 144 (6): 2404 -- Endocrinology Anglais Degradinggorgeousunclothedteachers Lv Modules Php Name Duyurular Degrading Gorgeous Unclothed Teachersz Gorgeous Degrading}