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.
Original languageEnglish
JournalJournal of Clinical Endocrinology and Metabolism
Issue number2
Pages (from-to)596-602
Number of pages7
Publication statusPublished - 2009

ID: 10000856