AZUMA, KOICHIRO, FUMINORI KATSUKAWA, SHUJI OGUCHI, MITSURU MURATA, HAJIME YAMAZAKI, AKIRA SHIMADA, AND TAKAO SARUTA. Correlation between serum resistin level and adiposity in obese individuals. Obes Res. 2003;11: 997-1001. Objective: Resistin is associated with insulin resistance in mice and may play a similar role in humans. The aim of our study was to examine the relationship of serum resistin level to body composition, insulin resistance, and related obesity phenotypes in humans. Research Methods and Procedures: Sixty-four young (age 32 Ϯ 10 years), obese (BMI 32.9 Ϯ 5.6), nondiabetic subjects taking no medication, and 15 lean (BMI 21.1 Ϯ 1.3) volunteers were studied cross-sectionally. Thirty-five of the subjects were also reevaluated after 1.5 years on a weight reduction program entailing dieting and exercise; changes of serum resistin were compared with changes of BMI, body composition, fat distribution, and several indices of insulin sensitivity derived from plasma glucose and serum insulin levels measured during 75-g oral glucose tolerance test. Results: In a cross-sectional analysis, serum resistin was significantly higher in obese subjects than in lean volunteers (24.58 Ϯ 12.93 ng/mL; n ϭ 64 vs. 12.83 Ϯ 8.30 ng/mL; n ϭ 15; p Ͻ 0.01), and there was a correlation between resistin level and BMI, when the two groups were combined ( ϭ 0.35, p Ͻ 0.01). Although cross-sectional analysis in obese subjects revealed no correlation between serum resistin and parameters related to adiposity or insulin resistance, longitudinal analysis revealed change in serum resistin to be positively correlated with changes in BMI, body fat, fat mass, visceral fat area, and mean glucose and insulin ( ϭ 0.39, 0.40, 0.44, 0.50, 0.40, and 0.50; p ϭ 0.02, 0.03, 0.02, Ͻ0.01, 0.02, and Ͻ0.01, respectively). Discussion: Resistin appears to be related to human adiposity and to be a possible candidate factor in human insulin resistance.

OBJECTIVE-Reduced mitochondrial capacity in skeletal muscle occurs in type 2 diabetic patients and in those at increased risk for this disorder, but the extent to which mitochondrial dysfunction in type 2 diabetic patients is remediable by physical activity and weight loss intervention is uncertain. We sought to address whether an intervention of daily moderate-intensity exercise combined with moderate weight loss can increase skeletal muscle mitochondrial content in type 2 diabetic patients and to address the relationship with amelioration of insulin resistance and hyperglycemia.RESEARCH DESIGN AND METHODS-Muscle biopsies were obtained before and after a 4-month intervention to assess mitochondrial morphology, mitochondrial DNA content, and mitochondrial enzyme activities. Glucose control, body composition, aerobic fitness, and insulin sensitivity were measured.RESULTS-In response to a weight loss of 7.1 Ϯ 0.8% and a 12 Ϯ 1.6% improvement in VO 2max (P Ͻ 0.05), insulin sensitivity improved by 59 Ϯ 21% (P Ͻ 0.05). There were significant increases in skeletal muscle mitochondrial density (by 67 Ϯ 17%, P Ͻ 0.01), cardiolipin content (55 Ϯ 17%, P Ͻ 0.01), and mitochondrial oxidation enzymes. Energy expenditure during physical activity correlated with the degree of improvement in insulin sensitivity (r ϭ 0.84, P Ͻ 0.01), and, in turn, improvement in mitochondrial content was a strong correlate of interventioninduced improvement in A1C and fasting plasma glucose.CONCLUSIONS-Intensive short-term lifestyle modifications can restore mitochondrial content and functional capacity in skeletal muscle in type 2 diabetic patients. The improvement in the oxidative capacity of skeletal muscle may be a key component mediating salutary effects of lifestyle interventions on hyperglycemia and insulin resistance. Diabetes 56:2142-2147, 2007

Ritov VB, Menshikova EV, Azuma K, Wood R, Toledo FG, Goodpaster BH, Ruderman NB, Kelley DE. Deficiency of electron transport chain in human skeletal muscle mitochondria in type 2 diabetes mellitus and obesity. Am J Physiol Endocrinol Metab 298: E49 -E58, 2010. First published November 3, 2009 doi:10.1152/ajpendo.00317.2009.-Insulin resistance in skeletal muscle in obesity and T2DM is associated with reduced muscle oxidative capacity, reduced expression in nuclear genes responsible for oxidative metabolism, and reduced activity of mitochondrial electron transport chain. The presented study was undertaken to analyze mitochondrial content and mitochondrial enzyme profile in skeletal muscle of sedentary lean individuals and to compare that with our previous data on obese or obese T2DM group. Frozen skeletal muscle biopsies obtained from lean volunteers were used to estimate cardiolipin content, mtDNA (markers of mitochondrial mass), NADH oxidase activity of mitochondrial electron transport chain (ETC), and activity of citrate synthase and ␤-hydroxyacyl-CoA dehydrogenase (␤-HAD), key enzymes of TCA cycle and ␤-oxidation pathway, respectively. Frozen biopsies collected from obese or T2DM individuals in our previous studies were used to estimate activity of ␤-HAD. The obtained data were complemented by data from our previous studies and statistically analyzed to compare mitochondrial content and mitochondrial enzyme profile in lean, obese, or T2DM cohort. The total activity of NADH oxidase was reduced significantly in obese or T2DM subjects. The cardiolipin content for lean or obese group was similar, and although for T2DM group cardiolipin showed a tendency to decline, it was statistically insignificant. The total activity of citrate synthase for lean and T2DM group was similar; however, it was increased significantly in the obese group. Activity of ␤-HAD and mtDNA content was similar for all three groups. We conclude that the total activity of NADH oxidase in biopsy for lean group is significantly higher than corresponding activity for obese or T2DM cohort. The specific activity of NADH oxidase (per mg cardiolipin) and NADH oxidase/citrate synthase and NADH oxidase/ ␤-HAD ratios are reduced two-to threefold in both T2DM and obesity. insulin resistance; ␤-oxidation; cardiolipin; reduced nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide ratio; trichloroacetic acid cycle TYPE 2 DIABETES MELLITUS (T2DM) is characterized by insulin resistance in skeletal muscle that can be a result of combining a genetic predisposition with obesity and sedentary lifestyle (12,34,44). Insulin resistance in skeletal muscle in obesity or T2DM is associated with reduced muscle oxidative capacity (53, 60) and with reduced expression in a cluster of nuclear genes responsible for oxidative metabolism [peroxisome proliferator-activated receptor-␥ coactivator-1␣ (PGC-1␣) and genes activated by PGC-1␣] (17, 30, 33, 38). In our previous study, we found a significant reduction in the total activity of mitochondrial electron transpo...

OBJECTIVE-In obesity and type 2 diabetes, exercise combined with weight loss increases skeletal muscle mitochondrial capacity. It remains unclear whether mitochondrial capacity increases because of weight loss, improvements in insulin resistance, or physical training. In this study, we examined the effects of an intervention of weight loss induced by diet and compared these with those of a similar intervention of weight loss by diet with exercise. Both are known to improve insulin resistance, and we tested the hypothesis that physical activity, rather than improved insulin resistance, is required to increase mitochondrial capacity of muscle. RESEARCH DESIGN AND METHODS-Sixteen sedentaryoverweight/obese volunteers were randomized to a 16-week intervention of diet (n ϭ 7) or diet plus exercise (n ϭ 9). Insulin sensitivity was measured using euglycemic clamps. Mitochondria were examined in muscle biopsies before and after intervention. We measured mitochondrial content and size by electron microscopy, electron transport chain (ETC) activity, cardiolipin content, and mitochondrial DNA content. Intramyocellular content of lipid (IMCL) and fiber-type distribution were determined by histology. RESULTS-The diet-only and diet plus exercise groups achieved similar weight loss (10.8 and 9.2%, respectively); only the diet plus exercise group improved aerobic capacity. Insulin sensitivity improved similarly in both groups. Mitochondrial content and ETC activity increased following the diet plus exercise intervention but remained unchanged following the diet-only intervention, and mitochondrial size decreased with weight loss despite improvement in insulin resistance. IMCL decreased in the diet-only but not in the diet plus exercise intervention.CONCLUSIONS-Despite similar effects to improve insulin resistance, these interventions had differential effects on mitochondria. Clinically significant weight loss in the absence of increased physical activity ameliorates insulin resistance and IMCL but does not increase muscle mitochondrial capacity in obesity. Diabetes 57:987-994, 2008

OBJECTIVE-Compared with nondiabetic subjects, type 2 diabetic subjects are metabolically inflexible with impaired fasting fat oxidation and impaired carbohydrate oxidation during a hyperinsulinemic clamp. We hypothesized that impaired insulinstimulated glucose oxidation is a consequence of the lower cellular glucose uptake rate in type 2 diabetes. Therefore, we compared metabolic flexibility to glucose adjusted for glucose disposal rate in nondiabetic versus type 2 diabetic subjects and in the latter group after 1 year of lifestyle intervention (the Look AHEAD [Action For Health in Diabetes] trial).RESEARCH DESIGN AND METHODS-Macronutrient oxidation rates under fasting and hyperinsulinemic conditions (clamp at 80 mU/m 2 per min), body composition (dual-energy X-ray absorptiometry), and relevant hormonal/metabolic blood variables were assessed in 59 type 2 diabetic and 42 nondiabetic individuals matched for obesity, sex, and race. Measures were repeated in diabetic participants after weight loss.RESULTS-Metabolic flexibility to glucose (change in respiratory quotient [RQ]) was mainly related to insulin-stimulated glucose disposal rate (R 2 ϭ 0.46, P Ͻ 0.0001) with an additional 3% of variance accounted for by plasma free fatty acid concentration at the end of the clamp (P ϭ 0.03). The impaired metabolic flexibility to glucose observed in type 2 diabetic versus nondiabetic subjects (⌬RQ 0.06 Ϯ 0.01 vs. 0.10 Ϯ 0.01, respectively, P Ͻ 0.0001) was no longer observed after adjusting for glucose disposal rate (P ϭ 0.19). Additionally, the increase in metabolic flexibility to glucose after weight loss was accounted for by the concomitant increase in insulin-stimulated glucose disposal rate.CONCLUSIONS-This study suggests that metabolic inflexibility to glucose in type 2 diabetic subjects is mostly related to defective glucose transport. Diabetes 57:841-845, 2008 M etabolic flexibility is the capacity of the body to match fuel oxidation to fuel availability. It is typically assessed by the increase in respiratory quotient (RQ) from fasting to glucose/ insulin-stimulated conditions (1). 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).Insulin-resistant and type 2 diabetic subjects have shown both higher fasting RQ (2,5,6) and blunted increase in RQ during a hyperinsulinemic clamp compared with insulin-sensitive subjects (2,7). Structural and functional mitochondrial impairments in obesity and type 2 diabetes are proposed to be a cause of insulin resistance and metabolic inflexibility (8,9).During a euglycemic-hyperinsulinemic clamp, the metabolic flexibility to glucose should be lower in type 2 diabetic versus nondiabetic subjects, since cellular glucose uptake rate and therefore free cellular glucose available for oxidation is reduced. Such phenomenon is analogous to the thermic effect of a meal, which is proporti...