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.
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, 31phosphorous 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.


CONCLUSIONS
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.
Grunnet
Louise G
LG
Steno Diabetes Center, Niels Steensens vej 2, 2820 Gentofte, Denmark. loug@steno.dk
Brøns
Charlotte
C
Jacobsen
Stine
S
Nilsson
Emma
E
Astrup
Arne
A
Hansen
Torben
T
Pedersen
Oluf
O
Poulsen
Pernille
P
Quistorff
Bjørn
B
Vaag
Allan
A
D000328:Adult; D000483:Alleles; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D001786:Blood Glucose / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology; D007537:Isometric Contraction / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D008931:Mitochondria, Muscle / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology; D010085:Oxidative Phosphorylation; D010710:Phosphates / Q000378:metabolism*; D010725:Phosphocreatine / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology; D055815:Young Adult
D001786:Blood Glucose; D007328:Insulin; D010710:Phosphates; D011506:Proteins; D010725:Phosphocreatine; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human