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OBJECTIVE--Type 2 diabetes has become a global epidemic, and Asian Indians have a higher susceptibility to diabetes than Europeans. We investigated whether Indians had any metabolic differences compared with Northern European Americans that may render them more susceptible to diabetes. RESEARCH DESIGN AND METHODS--We studied 13 diabetic Indians, 13 nondiabetic Indians, and 13 nondiabetic Northern European Americans who were matched for age, BMI, and sex. The primary comparisons were insulin sensitivity by hyper-insulinemic-euglycemic clamp and skeletal muscle mitochondrial capacity for Oxidative phosphorylation (OXPHOS) by measuring mitochondrial DNA copy number (mtDNA), OXPHOS gene transcripts, citrate synthase activity, and maximal mitochondrial ATP production rate (MAPR). Other factors that may cause insulin resistance were also measured. RESULTS--The glucose infusion rates required to maintain identical glucose levels during the similar insulin infusion rates were substantially lower in diabetic Indians than in the nondiabetic participants (P < 0.001), and they were lower in nondiabetic Indians than in nondiabetic Northern European Americans (P < 0.002). mtDNA (P < 0.02), OXPHOS gene transcripts (P < 0.01), citrate synthase, and MAPR (P < 0.03) were higher in Indians irrespective of their diabetic status. Intramuscular triglyceride, C-reactive protein, interleukin-6, and tumor necrosis factor-α concentrations were higher, whereas adiponectin concentrations were lower in diabetic Indians. CONCLUSIONS--Despite being more insulin resistant, diabetic Indians had similar muscle OXPHOS capacity as nondiabetic Indians, demonstrating that diabetes per se does not cause mitochondrial dysfunction. Indians irrespective of their diabetic status had higher OXPHOS capacity than Northern European Americans, although Indians were substantially more insulin resistant, indicating a dissociation between mitochondrial dysfunction and insulin resistance. Diabetes 57:1166-1175, 2008 [ABSTRACT FROM AUTHOR]

Asian Indians are highly susceptible to Type 2 Diabetes (T2D) and constitute the largest diabetic population in the world. The underlying etiology for this increased susceptibility for T2D among Asian Indians remains to be defined. To determine whether Asian Indians are more insulin resistant and whether their insulin resistance is associated with any differences in muscle gene transcript levels, we studied 13 non-diabetic (fasting glucose < 100 mg/dl) Asian Indians (Age=47.2±2.4 y, BMI=23.8±0.5 kg/m²) and 13 gender-matched Americans of North European origin (European Americans; Age=46.6±2.2 y, BMI=24.5±0.8 kg/m2). Insulin sensitivity was measured by hyperinsulinemic (1.5 mU/kg FFM/min) euglycemic clamp. To maintain identical plasma glucose levels, Asian Indians required a substantially lower glucose infusion rate than European American controls (42.3 ± 4.0 vs. 68.3 ± 4.2 µmol/Kg FFM/min,p<0.001). Percutaneous needle biopsy samples were collected for gene array analysis. Total RNA was extracted from snap frozen muscle biopsy samples, amplified, labeled with fluorescent probe, fragmented and hybridized to the U133 Pins 2.0 Affymetrix genechip and GCRMA software was used to analyze microarray data. Out of about 47,000 transcripts surveyed, 58 genes transcript levels were altered (52 increased and 6 decreased) in Asian Indians compared to European Americans. Examples are as follows: Lipid metabolism: Fatty acid binding protein 7 (↑3.7); Glucose metabolism: GAPDH (↑1.03), Lactate dehydrogenase A (↑1.3); Chaperone: heat shock proteins 70 (↓0.65); and Energy metabolism: NADH1 (↑1.07), ATP synthase (↑1.1), Cytochrome C oxidase Va (↑1.20), Cytochrome C oxidase VLLc (↑1.1). In conclusion, nondiabetic Asian Indians are significantly more insulin resistant and have altered skeletal muscle gene transcript levels involving multiple metabolic pathways including mitochondrial bioenergetics. The results indicate potential mechanisms for higher susceptibility of Asian Indians to become diabetic. [ABSTRACT FROM AUTHOR]