title: Differential hexosamine biosynthetic pathway gene expression with type 2 diabetes.
abstract: The hexosamine biosynthetic pathway (HBP) culminates in the attachment ofO-linked β-N-acetylglucosamine (O-GlcNAc) onto serine/threonine residues of target proteins. The HBP is regulated by several modulators, i.e.O-linked β-N-acetylglucosaminyl transferase (OGT) and β-N-acetylglucosaminidase (OGA) catalyze the addition and removal ofO-GlcNAc moieties, respectively; while flux is controlled by the rate-limiting enzyme glutamine:fructose-6-phosphate amidotransferase (GFPT), transcribed by two genes,GFPT1andGFPT2. Since increased HBP flux is glucose-responsive and linked to insulin resistance/type 2 diabetes onset, we hypothesized that diabetic individuals exhibit differential expression of HBP regulatory genes. Volunteers (n = 60; n = 20 Mixed Ancestry, n = 40 Caucasian) were recruited from Stellenbosch and Paarl (Western Cape, South Africa) and classified as control, pre- or diabetic according to fasting plasma glucose and HbA1c levels, respectively. RNA was purified from leukocytes isolated from collected blood samples andOGT,OGA,GFPT1andGFPT2expressions determined by quantitative real-time PCR. The data reveal lowerOGAexpression in diabetic individuals (P< 0.01), while pre- and diabetic subjects displayed attenuatedOGTexpression vs. controls (P< 0.01 andP< 0.001, respectively). Moreover,GFPT2expression decreased in pre- and diabetic Caucasians vs. controls (P< 0.05 andP< 0.01, respectively). We also found ethnic differences, i.e. Mixed Ancestry individuals exhibited a 2.4-fold increase inGFPT2expression vs. Caucasians, despite diagnosis (P< 0.01). Gene expression of HBP regulators differs between diabetic and non-diabetic individuals, together with distinct ethnic-specific gene profiles. Thus differential HBP gene regulation may offer diagnostic utility and provide candidate susceptibility genes for different ethnic groupings.
authors.affiliation: Cardio-Metabolic Research Group (CMRG), Department of Physiological Sciences, Stellenbosch University, Stellenbosch 7600, South Africa.
authors.forename: Megan
authors.initials: M
authors.lastname: Coomer
authors.affiliation: Cardio-Metabolic Research Group (CMRG), Department of Physiological Sciences, Stellenbosch University, Stellenbosch 7600, South Africa.
authors.forename: M Faadiel
authors.initials: MF
authors.lastname: Essop
keywords: Fasting blood glucose; GFPT, glutamine:fructose-6-phosphate amidotransferase; Gene expression; HBP, hexosamine biosynthetic pathway; Hexosamine biosynthetic pathway; Leukocytes; O-GlcNAc, O-linked β-N-acetylglucosamine; OGA, β-N-acetylglucosaminidase; OGT, O-linked β-N-acetylglucosaminyl transferase; Pre- and overt diabetes