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 euglycemichyperinsulinemic 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. 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 resistance (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 resistance (1,16).Metabolic inflexibility, as defined by Kelley and Mandarino (17), represents impaired substrate switching in skeletal muscle in insulin resistance. Healthy lean individuals who are flexible rely on lipids as a main source of fuel under fasting conditions and readily switch to carbohydrate oxidation in response to insulin infusion (18). On the contrary, the inflexible muscle of an insulin-resistant individual is characterized by lower fasting ...

Metabolic Flexibility in Response to Glucose Is Not Impaired in People With Type 2 Diabetes After Controlling for Glucose Disposal Rate

“…During the overnight transition from the fed to the fasting state, metabolic inflexibility can also be evident by a higher fasting RQ (2). Finally, the lower capacity to adapt fat oxidation to a fat overload is another feature of metabolic inflexibility (3,4).…”

SIRT3 Regulates Mitochondrial Protein Acetylation and Intermediary Metabolism

“…Mitochondrial dysfunction appears to play a particularly important role in the pathogenesis of the metabolic syndrome-a group of metabolic abnormalities characterized by central obesity, dyslipidemia, high blood pressure, and increased fasting glucose. A number of abnormalities in mitochondria have been identified in patients and animal models with the metabolic syndrome, including reduced mitochondrial mass (Kelley et al 2002), altered mitochondrial morphology (Civitarese et al 2010), reduced fatty-acid oxidation (Zhang et al 2007), lower oxidative phosphorylation (Petersen et al 2005;Befroy et al 2007), and increased reactive oxygen species (ROS) (Patti et al 2003;Petersen et al 2004;Civitarese et al 2006;Ukropcova et al 2007). Various posttranslational modifications fine-tune the activities of metabolic enzymes, and acetylation is increasingly recognized as an important posttranslational modification for a number of key metabolic pathways.…”

Fat oxidation at rest predicts peak fat oxidation during exercise and metabolic phenotype in overweight men

“…A low fat oxidation at rest has previously been described as a predictor for weight gain [12][13][14] and might be involved in the development of insulin resistance. 15,16 In this study we investigated peak fat oxidation during exercise in moderately overweight, sedentary, but otherwise healthy subjects, who were selected for either a high or a low fat oxidation under resting and fasting conditions. We chose to study relatively young subjects (age 20-40 years) to avoid the influence of the secondary complications of obesity on the parameters studied.…”