Tuesday, November 13, 2012

Hexosamine biosynthesis pathway

The rate limiting enzyme of hexosamine synthesis (glutamine: fructose 6-phosphate amidotransferase, GFAT is overactive in diabetes and hyperglycemia; this leads to overproduction of UDP-N acetyl glucosamine and other nucleotide hexosamines which are the major substrates for glycosylation of proteins including many cytoplasmic and nuclear proteins (transcription factors) on their serine or threonine residue. Thus this pathway mediates effect of glucose on expression of several gene and thus participates if glucotoxicity or glucose induced insulin resistance. Hexosamine pathway is a cellular sensor of energy availability or glucose availability.

It is able to modify the expression of nuclear-encoded mitochondrial genes involved in oxidative phosphorylation in muscle and fat and expression of leptin in adipocytes. Defects in glycolysis and glycogenesis shunt glucose through this pathway leading to insulin resistance, reduced insulin secretion. This causes glucotoxicity. The features of which are reduced GLUT4 translocation, reduced glycogen synthase activity, increased hepatic glucose output, reduced beta cell glucokinase activity (reducing insulin secretion as a result of impaired beta cell glycolysis which provide ATP for insulin secretion). 

Glycosylation of proteins due to activation of hexosamine pathway, like glycosylation of endothelial nitric oxide synthase, PKA, PKC can contribute to endothelial dysfunction.
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