A role for N-acetylglucosamine as a nutrient sensor and mediator of insulin resistance.
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.
Wells
L
L
Department of Biological Chemistry, Johns Hopkins School of Medicine, 517 Woods Basic Science Building, 725 N. Wolfe Street, Baltimore, Maryland 21205, USA.
Vosseller
K
K
Hart
G W
GW
D000117:Acetylglucosamine / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005544:Forecasting; D005947:Glucose / Q000378:metabolism; D006031:Glycosylation; D006595:Hexosamines / Q000096:biosynthesis; D006801:Humans; D006943:Hyperglycemia; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008954:Models, Biological; D015398:Signal Transduction
D006595:Hexosamines; D007328:Insulin; D005947:Glucose; D000117:Acetylglucosamine