A role for N -acetylglucosamine as a nutrient sensor and mediator of insulin resistance

Abstract

The ability to regulate energy balance at both the cellular and whole body level is an essential process of life. As western society has shifted to a higher caloric diet and more sedentary lifestyle, the incidence of type 2 diabetes (non-insulin-dependent diabetes mellitus) has increased to epidemic proportions. Thus, type 2 diabetes has been described as a disease of 'chronic overnutrition'. There are abundant data to support the relationship between nutrient availability and insulin action. However, there have been multiple hypotheses and debates as to the mechanism by which nutrient availability modulates insulin signaling and how excess nutrients lead to insulin resistance. One well-established pathway for nutrient sensing is the hexosamine biosynthetic pathway (HSP), which produces the acetylated aminosugar nucleotide uridine 5'-diphospho-N-acetylglucosamine (UDP-Glc-NAc) as its end product. Since UDP-GlcNAc is the donor substrate for modification of nucleocytoplasmic proteins at serine and threonine residues with N-acetylglucosamine (O-GlcNAc), the possibility of this posttranslational modification serving as the nutrient sensor has been proposed. We have recently directly tested this model in adipocytes by examining the effect of elevated levels of O-GlcNAc on insulin-stimulated glucose uptake. In this review, we summarize the existing work that implicates the HSP and O-GlcNAc modification as nutrient sensors and regulators of insulin signaling.

Regulation of Insulin Receptor Substrate 1 (IRS-1)/AKT Kinase-mediated Insulin Signaling by O-Linked β-N-Acetylglucosamine in 3T3-L1 Adipocytes

“…A growing number of publications are beginning to elucidate the role that O-GlcNAc plays in the cellular function of Type II diabetes (13,22,24,(53)(54)(55)(56)(57)(58) …”

Lipid-deprived diet perturbs O-glycosylation of secretory proteins in rat mammary epithelial cells

“…Worth noting is the fact that a role for N-acetylglucosamine as a nutrient sensor and mediator of insulin resistance has been proposed (for review see Wells et al, 2003;Zachara and Hart, 2004). On the other hand, these molecules serve as the donor sugar nucleotides for glycosylation reactions, N-acetylgalactosamine being usually the first sugar added to serine or threonine during secretory protein O-glycosylation.…”

Caenorhabditis elegans ortholog of a diabetes susceptibility locus: oga-1 ( O -GlcNAcase) knockout impacts O -GlcNAc cycling, metabolism, and dauer

“…We recently showed that the hexosamine-signaling pathway influences insulin-like signaling in C. elegans (25, 26) and mice (17). In man, the hexosamine-signaling pathway has been implicated in both diabetes mellitus and neurodegeneration (1,2,17,27). One of the striking features of type 2 diabetes mellitus is insulin resistance.…”