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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]