Original Article Family History of Diabetes Links Impaired Substrate Switching and Reduced Mitochondrial Content in Skeletal Muscle Barbara Ukropcova, Olga Sereda, Lilian de Jonge, Iwona Bogacka, Tuong Nguyen, Hui Xie, George A. Bray, and Steven R. Smith Insulin resistance is associated with metabolic inflexibil- ity, 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 ob- jective 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 be- fore 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 ox- idation 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 contrib- uted 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 mus- cle mitochondrial mass cluster together in subjects with a family history of diabetes, supporting the role of an intrin- sic metabolic defect of skeletal muscle in the pathogenesis of insulin resistance. Diabetes 56:720 –727, 2007 A high-fat diet (HFD) is a risk factor for obesity and has been implicated in the development of insulin resistance (1). A short-term HFD, as well as a lipid infusion, causes insulin resis- tance (2– 4), reduces oxidative metabolism in skeletal muscle in rats (5), and downregulates genes of oxidative phosphorylation and mitochondrial biogenesis, such as peroxisome proliferator–activated  coactivator-1 (PGC- 1) (6). Moreover, oxidative phosphorylation and PGC-1 gene expression are decreased in insulin resistance (7,8). Taken together, these findings point to HFD, reduced oxidative capacity, and lipotoxicity in the pathophysiology of insulin resistance (9,10). Substantial interindividual variability exists in the change of fat oxidation during adaptation to a HFD (11). Impaired fat oxidation during adaptation to a HFD is observed in restrained eaters (12), postobese (13) and obese (14) individuals, and in individuals with a family history of obesity (15), pointing toward a possible genetic basis for reduced fat oxidation (1). Impaired substrate switching in response to insulin (metabolic inflexibility) and dietary stimuli (attenuated adaptation to a HFD) are hypothesized to contribute to obesity and insulin resis- tance (1,16). Metabolic inflexibility, as defined by Kelley and Man- darino (17), represents impaired substrate switching in skeletal muscle in insulin resistance. Healthy lean individ- uals who are flexible rely on lipids as a main source of fuel under fasting conditions and readily switch to carbohy- drate oxidation in response to insulin infusion (18). On the contrary, the inflexible muscle of an insulin-resistant indi- vidual is characterized by lower fasting lipid utilization and lacks the ability to switch to carbohydrate oxidation in the insulin-stimulated state (18). Substrate competition in skeletal muscle and its role in systemic fatty acid utiliza- tion has been explored by a number of investigators (18,19). Mitochondrial oxidative enzyme activity is reduced in skeletal muscle in obesity and insulin resistance (20). Bruce et al. (21) found that skeletal muscle oxidative capacity was a better predictor of insulin sensitivity than intramyocellular lipids. A higher fasting respiratory quo- tient (RQ), indicating decreased fat oxidation, is a predic- tor of weight gain (22). We showed that dynamic changes in fat oxidation in primary human muscle cells exposed to increased concentrations of fatty acid or glucose in vitro were closely related to metabolic flexibility, insulin sensi- tivity, and other clinical phenotypes of young, healthy donors in vivo (23), suggesting the importance of intrinsic, genetically, or epigenetically determined characteristics of fat oxidation for the flexible, insulin-sensitive phenotype. Decreased mitochondrial ATP synthesis in the offspring of patients with type 2 diabetes (24) supports the hypothesis that genetic factors control the reduced mitochondrial oxidative phosphorylation of insulin-resistant individuals. Type 2 diabetes is largely a genetic disorder with a strong environmental influence (25). The concordance for type 2 diabetes in siblings is very high (26), and offspring From the Pennington Biomedical Research Center, Baton Rouge, Louisiana. Address correspondence and reprint requests to Steven R. Smith, Penning- ton Biomedical Research Center, 6400 Perkins Rd., Baton Rouge, LA 70808. E-mail: smithsr@pbrc.edu. Received for publication 18 April 2006 and accepted in revised form 23 November 2006. B.U. is currently affiliated with the Diabetes Laboratory and DIABGENE Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-0521. FFA, free fatty acid; mtDNA, mitochondrial DNA; HFD, high-fat diet; RQ, respiratory quotient. DOI: 10.2337/db06-0521 © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 720 DIABETES, VOL. 56, MARCH 2007 Downloaded from http://diabetesjournals.org/diabetes/article-pdf/56/3/720/663664/zdb00307000720.pdf by guest on 31 January 2024