Hexosamines as mediators of nutrient sensing: relevance to obesity, insulin resistance, and diabetes

Publisher Website
Google Scholar
Abstract
High concentrations of glucose induce insulin resistance, impair insulin secretion, and affect hepatic glucose production in a manner that mirrors type 2 diabetes. High concentrations of hexosamines mimic many of these effects. This has led to the hypothesis that cells use hexosamine flux as a glucose-and satiety-sensing pathway. The hexosamine hypothesis for glucose sensing has been validated in several model systems. For example, with overexpression of the rate-limiting enzyme for hexosamine synthesis in transgenic mice, skeletal muscle becomes insulin resistant, the liver synthesizes excess fatty acid, and the β cells increase insulin secretion. Thus, excess hexosamine flux leads to a coordinated response whereby fuel is shunted toward long-term storage, mirroring the thrifty phenotype. However when these same adaptive changes occur chronically, they ultimately result in obesity, hyperlipidemia, β-cell failure, and type 2 diabetes. Recent work indicates that these effects may be the result of enzymatic O-linked glycosylation of proteins and that this glycosylation is regulated by the levels of the end-product of the hexosamine pathway, UDP-N-acetyl glucosamine. The results suggest a mechanism by which chronic overnutrition leads to the phenotype of type 2 diabetes.

This publication has 57 references indexed in Scilit: