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, (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)