title: Independent and combined effects of acute physiological hyperglycaemia and hyperinsulinaemia on metabolic gene expression in human skeletal muscle.
abstract: Physiological hyperglycaemia and hyperinsulinaemia are strong modulators of gene expression, which underpins some of their well-known effects on insulin action and energy metabolism. The aim of the present study was to examine whether acute in vivo exposure of healthy humans to hyperinsulinaemia and hyperglycaemia have independent or additive effects on expression of key metabolic genes in skeletal muscle. On three randomized occasions, seven young subjects underwent a 4 h (i) hyperinsulinaemic (50 m-units·m⁻²·min⁻¹) hyperglycaemic (10 mmol/l) clamp (HIHG), (ii) hyperglycaemic (10 mmol/l) euinsulinaemic (5 m-units·m⁻²·min⁻¹) clamp (LIHG) and (iii) hyperinsulinaemic (50 m-units·m⁻²·min⁻¹) euglycaemic (4.5 mmol/l) clamp (HING). Muscle biopsies were obtained before and after each clamp for the determination of expression of genes involved in energy metabolism, and phosphorylation of key insulin signalling proteins. Hyperinsulinaemia and hyperglycaemia exerted independent effects with similar direction of modulation on PI3KR1 (phosphatidylinositol 3-kinase, regulatory 1), LXRα (liver X receptor α), PDK4 (pyruvate dehydrogenase kinase 4) and FOXO1 (forkhead box O1A) and produced an additive effect on PI3KR1, the gene that encodes the p85α subunit of PI3K in human skeletal muscle. Acute hyperglycaemia itself altered the expression of genes involved in fatty acid transport and oxidation [fatty acid transporter (CD36), LCAD (long-chain acyl-CoA dehydrogenase) and FOXO1], and lipogenesis [LXRα, ChREBP (carbohydrate-responseelement-binding protein), ABCA1 (ATP-binding cassette transporter A1) and G6PD (glucose-6-phosphate dehydrogenase). Surperimposing hyperinsulinaemia on hyperglycaemia modulated a number of genes involved in insulin signalling, glucose metabolism and intracellular lipid accumulation and exerted an additive effect on PI3KR1. These may be early molecular events that precede the development of glucolipotoxicity and insulin resistance normally associated with more prolonged periods of hyperglycaemia and hyperinsulinaemia.
authors: School of Biomedical Sciences, Nottingham University Medical School, Queens Medical Centre, Nottingham NG7 2UH, UK. Kostas.Tsintzas@nottingham.ac.uk
authors: Kostas
authors: K
authors: Tsintzas
authors: Luke
authors: L
authors: Norton
authors: Kamal
authors: K
authors: Chokkalingam
authors: Nusrat
authors: N
authors: Nizamani
authors: Scott
authors: S
authors: Cooper
authors: Francis
authors: F
authors: Stephens
authors: Rudolf
authors: R
authors: Billeter
authors: Andrew
authors: A
authors: Bennett
mesh_terms: D000328:Adult; D001706:Biopsy; D001786:Blood Glucose; D004734:Energy Metabolism / Q000235:genetics*; D015870:Gene Expression; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; D007328:Insulin; D005947:Glucose