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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

Steno Diabetes Center (L.G.G., C.B., S.J., E.N., T.H., O.P., P.P., A.V.), DK-2820 Gentofte, Denmark; Department of International Health (L.G.G.), The University of Copenhagen, DK-2200 Copenhagen, Denmark; Department of Human Nutrition (C.B., A.A.), The Faculty of Life Sciences, The University of Copenhagen, DK-1870 Frederiksberg, Denmark; and Department of Medical Biochemistry and Genetics (B.Q.), Panum Institute, The University of Copenhagen, DK-2200 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Louise G. Grunnet, Steno Diabetes Center, Niels Steensens vej 2, 2820 Gentofte, Denmark. E-mail: loug{at}steno.dk.

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.

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.