Insulin-regulated mitochondrial gene expression is associated with glucoseflux in human skeletal muscle

To identify abnormally expressed genes contributing to muscle insulin resis tance in type 2 diabetes, we screened the mRNA populations from normal and diabetic human skeletal muscle using cDNA differential display and isolated abnormally expressed cDNA clones of mitochondrial-encoded NADH dehydrogena se 1 (ND1), cytochrome oxidase 1, tRNA(leu), and displacement loop. We then measured mRNA expression err these mitochondrial genes using a relative qu antitative polymerase chain reaction method in biopsies taken before and af ter an insulin clamp in 12 monozygotic twin pairs discordant for type 2 dia betes and 12 matched control subjects and in muscle biopsies taken after an insulin clamp from 13 subjects with type 2 diabetes, 15 subjects with impa ired glucose tolerance, and 14 subjects with normal glucose tolerance. Insu lin infusion increased mRNA expression of ND1 from 1.02 +/- 0.04 to 2.55 +/ - 0.30 relative units (P < 0.001) and of cytochrome oxidase 1 from 0.80 +/- 0.01 to 1.24 +/- 0.10 relative units (P < 0.001), The ND1 response to insu lin correlated with glucose uptake (r = 0.46, P = 0.002). Although the rate of insulin-mediated glucose uptake was decreased in the diabetic versus th e nondiabetic twins (5.2 +/- 0.7 vs. 8.5 +/- 0.8 mg.kg(-1) fat-free mass.mi n(-1), P < 0.01), insulin-stimulated ND1 expression was not significantly d ifferent between them (2.4 +/- 0.5 vs, 2.7 +/- 0.5 relative units). Neither was there any significant intrapair correlation of ND1 expression between the monozygotic twins (r = -0.15, NS). We conclude that insulin upregulates mitochondrial-encoded gene expression in skeletal muscle. Given the positi ve correlation between ND1 expression and glucose uptake and the lack of in trapair correlation between monozygotic twins, mitochondrial gene expressio n may represent an adaptation to intracellular glucose Bwr rather than an i nherited trait.