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
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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.
|Journal||Journal of Clinical Endocrinology and Metabolism|
|Number of pages||7|
|Publication status||Published - 2009|