Increased Recovery Rates of Phosphocreatine and Inorganic Phosphate after Isometric Contraction in Oxidative Muscle Fibers and Elevated Hepatic Insulin Resistance in Homozygous Carriers of the A-allele of FTO rs9939609

被引:28
作者
Grunnet, Louise G. [1 ,2 ]
Brons, Charlotte [1 ,3 ]
Jacobsen, Stine [1 ]
Nilsson, Emma [1 ]
Astrup, Arne [3 ]
Hansen, Torben [1 ]
Pedersen, Oluf [1 ]
Poulsen, Pernille [1 ]
Quistorff, Bjorn [4 ]
Vaag, Allan [1 ]
机构
[1] Steno Diabet Ctr, DK-2820 Gentofte, Denmark
[2] Univ Copenhagen, Dept Int Hlth, DK-2200 Copenhagen, Denmark
[3] Univ Copenhagen, Fac Life Sci, Dept Human Nutr, DK-1870 Frederiksberg, Denmark
[4] Univ Copenhagen, Panum Inst, Dept Med Biochem & Genet, DK-2200 Copenhagen, Denmark
关键词
LOW-BIRTH-WEIGHT; ENERGY-EXPENDITURE; PHYSICAL-ACTIVITY; SKELETAL-MUSCLE; ADULT OBESITY; GENE; ASSOCIATION; HUMANS; CHILDHOOD; VARIANTS;
D O I
10.1210/jc.2008-1592
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective: Recent studies identified the rs9939609 A-allele of the FTO ( fat mass and obesity associated) gene as being 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 iv glucose tolerance test, (31)phosphorous magnetic resonance spectroscopy, and 24-h 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 half-times of phosphocreatine and inorganic phosphate 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-h 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 phosphocreatine and inorganic phosphate in oxidative muscle fibers 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 with the FTO phenotype. (J Clin Endocrinol Metab 94: 596-602, 2009)
引用
收藏
页码:596 / 602
页数:7
相关论文
共 34 条
[11]   Mitochondrial uncoupling as a target in the treatment of obesity [J].
Costford, Sheila ;
Gowing, Adrienne ;
Harper, Mary-Ellen .
CURRENT OPINION IN CLINICAL NUTRITION AND METABOLIC CARE, 2007, 10 (06) :671-678
[12]   Insulin-resistant muscle is exercise resistant: evidence for reduced response of nuclear-encoded mitochondrial genes to exercise [J].
De Filippis, Elena ;
Alvarez, Guy ;
Berria, Rachele ;
Cusi, Kenneth ;
Everman, Sarah ;
Meyer, Christian ;
Mandarino, Lawrence J. .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 2008, 294 (03) :E607-E614
[13]  
DEL PS, 1993, J CLIN INVEST, V91, P484
[14]   Variation in FTO contributes to childhood obesity and severe adult obesity [J].
Dina, Christian ;
Meyre, David ;
Gallina, Sophie ;
Durand, Emmanuelle ;
Koerner, Antje ;
Jacobson, Peter ;
Carlsson, Lena M. S. ;
Kiess, Wieland ;
Vatin, Vincent ;
Lecoeur, Cecile ;
Delplanque, Jerome ;
Vaillant, Emmanuel ;
Pattou, Francois ;
Ruiz, Juan ;
Weill, Jacques ;
Levy-Marchal, Claire ;
Horber, Fritz ;
Potoczna, Natascha ;
Hercberg, Serge ;
Le Stunff, Catherine ;
Bougneres, Pierre ;
Kovacs, Peter ;
Marre, Michel ;
Balkau, Beverley ;
Cauchi, Stephane ;
Chevre, Jean-Claude ;
Froguel, Philippe .
NATURE GENETICS, 2007, 39 (06) :724-726
[15]   Genetic variants of FTO influence adiposity, insulin sensitivity, leptin levels, and resting metabolic rate in the Quebec Family Study [J].
Do, Ron ;
Bailey, Swneke D. ;
Desbiens, Katia ;
Belisle, Alexandre ;
Montpetit, Alexandre ;
Bouchard, Claude ;
Perusse, Louis ;
Vohl, Marie-Claude ;
Engert, James C. .
DIABETES, 2008, 57 (04) :1147-1150
[16]   Mitochondrial uncoupling proteins - What is their physiological role? [J].
Echtay, Karim S. .
FREE RADICAL BIOLOGY AND MEDICINE, 2007, 43 (10) :1351-1371
[17]  
Elia M, 1992, World Rev Nutr Diet, V70, P68
[18]   Genome-wide association studies provide new insights into type 2 diabetes aetiology [J].
Frayling, Timothy M. .
NATURE REVIEWS GENETICS, 2007, 8 (09) :657-662
[19]   A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity [J].
Frayling, Timothy M. ;
Timpson, Nicholas J. ;
Weedon, Michael N. ;
Zeggini, Eleftheria ;
Freathy, Rachel M. ;
Lindgren, Cecilia M. ;
Perry, John R. B. ;
Elliott, Katherine S. ;
Lango, Hana ;
Rayner, Nigel W. ;
Shields, Beverley ;
Harries, Lorna W. ;
Barrett, Jeffrey C. ;
Ellard, Sian ;
Groves, Christopher J. ;
Knight, Bridget ;
Patch, Ann-Marie ;
Ness, Andrew R. ;
Ebrahim, Shah ;
Lawlor, Debbie A. ;
Ring, Susan M. ;
Ben-Shlomo, Yoav ;
Jarvelin, Marjo-Riitta ;
Sovio, Ulla ;
Bennett, Amanda J. ;
Melzer, David ;
Ferrucci, Luigi ;
Loos, Ruth J. F. ;
Barroso, Ines ;
Wareham, Nicholas J. ;
Karpe, Fredrik ;
Owen, Katharine R. ;
Cardon, Lon R. ;
Walker, Mark ;
Hitman, Graham A. ;
Palmer, Colin N. A. ;
Doney, Alex S. F. ;
Morris, Andrew D. ;
Smith, George Davey ;
Hattersley, Andrew T. ;
McCarthy, Mark I. .
SCIENCE, 2007, 316 (5826) :889-894
[20]   The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase [J].
Gerken, Thomas ;
Girard, Christophe A. ;
Tung, Yi-Chun Loraine ;
Webby, Celia J. ;
Saudek, Vladimir ;
Hewitson, Kirsty S. ;
Yeo, Giles S. H. ;
McDonough, Michael A. ;
Cunliffe, Sharon ;
McNeill, Luke A. ;
Galvanovskis, Juris ;
Rorsman, Patrik ;
Robins, Peter ;
Prieur, Xavier ;
Coll, Anthony P. ;
Ma, Marcella ;
Jovanovic, Zorica ;
Farooqi, I. Sadaf ;
Sedgwick, Barbara ;
Barroso, Ines ;
Lindahl, Tomas ;
Ponting, Chris P. ;
Ashcroft, Frances M. ;
O'Rahilly, Stephen ;
Schofield, Christopher J. .
SCIENCE, 2007, 318 (5855) :1469-1472