TY - JOUR

T1 - Increased recovery rates of phosphocreatine and inorganic phosphate after isometric contraction in oxidative muscle fibres and elevated hepatic insulin resistance in homozygous carriers of the A-allele of FTO rs9939609

AU - Grunnet, Louise Groth

AU - Brøns, Charlotte

AU - Jacobsen, Stine

AU - Nilsson, Emma

AU - Astrup, Arne

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Poulsen, Pernille

AU - Quistorff, Bjørn

AU - Vaag, Allan

PY - 2009

Y1 - 2009

N2 - Objective. Recent studies identified the rs9939609 A-allele of the FTO (fat mass and obesity associated gene) to be associated with obesity and type 2 diabetes. We studied the role of the A-allele in the regulation of peripheral organ functions involved in the pathogenesis of obesity and type 2 diabetes. Methods. Forty-six young men underwent a hyperinsulinemic euglycemic clamp with excision of skeletal muscle biopsies, an intravenous glucose tolerance test, (31)phosphorous magnetic resonance spectroscopy and 24-hour whole body metabolism was measured in a respiratory chamber. Results. The FTO rs9939609 A-allele was associated with elevated fasting blood glucose and plasma insulin, hepatic insulin resistance and shorter recovery halftimes of phosphocreatine (PCr) and inorganic phosphate (Pi) after exercise in a primarily type I muscle. These relationships - except for fasting insulin - remained significant after correction for body fat percentage. The risk allele was not associated with fat distribution, peripheral insulin sensitivity, insulin secretion, 24-hour energy expenditure or glucose and fat oxidation. The FTO genotype did not influence the mRNA expression of FTO or a set of key nuclear or mitochondrially encoded genes in skeletal muscle during rest. Conclusion. Increased energy efficiency - and potentially increased mitochondrial coupling - as suggested by faster recovery rates of PCr and Pi in oxidative muscle fibres may contribute to the increased risk of obesity and type 2 diabetes in homozygous carriers of the FTO A-risk-allele. Hepatic insulin resistance may represent the key metabolic defect responsible for mild elevations of fasting blood glucose associated to the FTO phenotype.

AB - Objective. Recent studies identified the rs9939609 A-allele of the FTO (fat mass and obesity associated gene) to be associated with obesity and type 2 diabetes. We studied the role of the A-allele in the regulation of peripheral organ functions involved in the pathogenesis of obesity and type 2 diabetes. Methods. Forty-six young men underwent a hyperinsulinemic euglycemic clamp with excision of skeletal muscle biopsies, an intravenous glucose tolerance test, (31)phosphorous magnetic resonance spectroscopy and 24-hour whole body metabolism was measured in a respiratory chamber. Results. The FTO rs9939609 A-allele was associated with elevated fasting blood glucose and plasma insulin, hepatic insulin resistance and shorter recovery halftimes of phosphocreatine (PCr) and inorganic phosphate (Pi) after exercise in a primarily type I muscle. These relationships - except for fasting insulin - remained significant after correction for body fat percentage. The risk allele was not associated with fat distribution, peripheral insulin sensitivity, insulin secretion, 24-hour energy expenditure or glucose and fat oxidation. The FTO genotype did not influence the mRNA expression of FTO or a set of key nuclear or mitochondrially encoded genes in skeletal muscle during rest. Conclusion. Increased energy efficiency - and potentially increased mitochondrial coupling - as suggested by faster recovery rates of PCr and Pi in oxidative muscle fibres may contribute to the increased risk of obesity and type 2 diabetes in homozygous carriers of the FTO A-risk-allele. Hepatic insulin resistance may represent the key metabolic defect responsible for mild elevations of fasting blood glucose associated to the FTO phenotype.

U2 - 10.1210/jc.2008-1592

DO - 10.1210/jc.2008-1592

M3 - Journal article

C2 - 18984658

VL - 94

SP - 596

EP - 602

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 2

ER -