title: Family history of diabetes links impaired substrate switching and reduced mitochondrial content in skeletal muscle.
abstract: Insulin resistance is associated with metabolic inflexibility, impaired switching of substrate oxidation from fatty acids to glucose in response to insulin. Impaired switching to fat oxidation in response to a high-fat diet (HFD) is hypothesized to contribute to insulin resistance. The objective of this study was to test the hypothesis that defects in substrate switching in response to insulin and a HFD are linked to reduced mitochondrial biogenesis and occur before the development of diabetes. Metabolic flexibility was measured in young sedentary men with (n = 16) or without (n = 34) a family history of diabetes by euglycemic-hyperinsulinemic clamp. Flexibility correlated with fat oxidation measured in a respiratory chamber after a 3-day HFD. Muscle mitochondrial content was higher in flexible subjects with high fat oxidation after a HFD and contributed 49% of the variance. Subjects with a family history of diabetes were inflexible and had reduced HFD-induced fat oxidation and muscle mitochondrial content but did not differ in the amount of body or visceral fat. Metabolic inflexibility, lower adaptation to a HFD, and reduced muscle mitochondrial mass cluster together in subjects with a family history of diabetes, supporting the role of an intrinsic metabolic defect of skeletal muscle in the pathogenesis of insulin resistance.
authors.affiliation: Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ukropcova
authors.forename: Olga
authors.initials: O
authors.lastname: Sereda
authors.forename: Lilian
authors.initials: L
authors.lastname: de Jonge
authors.forename: Iwona
authors.initials: I
authors.lastname: Bogacka
authors.forename: Tuong
authors.initials: T
authors.lastname: Nguyen
authors.forename: Hui
authors.initials: H
authors.lastname: Xie
authors.forename: George A
authors.initials: GA
authors.lastname: Bray
authors.forename: Steven R
authors.initials: SR
authors.lastname: Smith
mesh_terms: D000293:Adolescent; D000328:Adult; D001823:Body Composition; D004272:DNA, Mitochondrial / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D004032:Diet; D004040:Dietary Carbohydrates / Q000378:metabolism*; D004041:Dietary Fats / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D008931:Mitochondria, Muscle / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology*
chemical_list: D004272:DNA, Mitochondrial; D004040:Dietary Carbohydrates; D004041:Dietary Fats