Increased hexosamine pathway flux and high fat feeding are not additive in
inducing insulin resistance: evidence for a shared pathway.
Authors Cooksey RC, McClain DA
Submitted By Richard McIndoe on 2/22/2012
Status Published
Journal Amino acids
Year 2011
Date Published 3/1/2011
Volume : Pages 40 : 841 - 846
PubMed Reference 20658157
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 of the principal end product of the hexosamine pathway, UDP-N-acetyl
glucosamine. Serum leptin levels, which are modulated both by feeding and
hexosamine flux, also show no additivity in their stimulation by GFA
overexpression and high fat feeding. These data are consistent with a shared
nutrient sensing pathway for high fat and carbohydrate fluxes and a common
pathway by which glucose and lipids induce insulin resistance.