Increased hexosamine pathway flux and high fat feeding are not additive in inducing insulin resistance: evidence for a shared pathway.

Amino Acids
Robert C Cooksey, Donald A McClain

Abstract

Excess fatty acids and carbohydrates have both been implicated in the pathogenesis of type 2 diabetes, and both can reproduce essential features of the disease including insulin resistance and beta cell failure. It has been proposed that both nutrients may regulate metabolism through a common fuel sensing mechanism, namely hexosamine synthesis. We have previously shown that transgenic overexpression of the rate-limiting enzyme for hexosamine synthesis, glutamine:fructose-6-phosphate amidotransferase (GFA), targeted to muscle and fat, leads to insulin resistance mediated by increased O-linked glycosylation of nuclear and cytosolic proteins. We report here that hexosamine-induced insulin resistance is not additive with that induced by high fat feeding. In control mice fed a high fat diet, glucose disposal rates during euglycemic hyperinsulinemia were decreased by 37% (p < 0.02) compared to mice on a low fat diet. Transgenic mice overexpressing GFA and fed a low fat diet exhibited a 51% decrease in glucose disposal compared to controls on a low fat diet (p < 0.001), but no further decrease was evident in the transgenic mice fed a high fat diet. Decreased glucose disposal rates were mirrored by increases in skeletal muscle levels o...Continue Reading

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Citations

Oct 12, 2012·Current Hypertension Reports·Adam R WendeE Dale Abel
Apr 13, 2012·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Ruth B S Harris, John W Apolzan
Jan 15, 2013·Molecular Endocrinology·Brent A PenqueJeffrey S Elmendorf
Sep 30, 2015·Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology·Kai ZhangHuixia Yang
Feb 27, 2013·Indian Dermatology Online Journal·Uwe WollinaAndreas Nowak

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