Aims/hypothesis. We carried out global transcript profiling to identify differentially expressed skeletal muscle genes in insulin resistance, a major risk factor for Type II (non-insulin-dependent) diabetes mellitus. This approach also complemented the ongoing genomic linkage analyses to identify genes linked to insulin resistance and diabetes in Pima Indians. Methods. We compared gene expression profiles of skeletal muscle tissues from 18 insulin-sensitive versus 17 insulin-resistant equally obese, non-diabetic Pima Indians using oligonucleotide arrays consisting of about 40,600 transcripts of known genes and expressed sequence tags, and analysed the results with the Wilcoxon rank sum test. We verified the mRNA expression of ten differentially (best-ranked) and ten similarly (worst-ranked) genes using quantitative Real Time PCR.Results. There were 185 differentially expressed transcripts by the rank sum test. The differential expressions of two out of the ten best-ranked genes were confirmed and the similar expressions of all ten worstranked genes were reproduced. Conclusion/interpretation. Of the 185 differentially expressed transcripts, 20 per cent were true positives and some could generate new hypotheses about the aetiology or pathophysiology of insulin resistance. Furthermore, differentially expressed genes in chromosomal regions with linkage to diabetes and insulin resistance serve as new diabetes susceptibility genes. [Diabetologia (2002[Diabetologia ( ) 45:1584[Diabetologia ( -1593

Uncoupling protein 5 (UCP5) or brain mitochondrial carrier protein-1 (BMCP1) enhances mitochondrial proton leak in vitro and its hepatic and brain expression profiles are modulated by diet and cold exposure in mice. Alternative splicing generates three isoforms: a long form (UCP5L), a short form (UCP5S), and a short form with a 31 amino acid insert (UCP5SI). We investigated the relationship between skeletal muscle UCP5 expression and in vivo energy metabolism in 36 non-diabetic Pima Indians. We determined the expression levels of total UCP5 (UCP5T), and the isoforms UCP5L, UCP5S, and UCP5SI (66.8, 32.5, and 0.8% of UCP5T, respectively). None correlated with body weight or percent body fat. The transcript level of UCP5SI, but not the others, was positively correlated with resting metabolic rate (r=0.38, P=0.02, adjusted for age, sex, fat mass, and fat-free mass) and lipid oxidation rate (adjusted for age, sex, and percent body fat) during a euglycemic clamp with infusion of insulin at a physiologic concentration (r=0.42, P=0.01).

Aims/hypothesis. Whole body insulin resistance results largely from impaired insulin-stimulated glucose disposal into skeletal muscle. We carried out muscle gene expression profiling to identify differentially expressed genes associated with insulin resistance. Methods. Skeletal muscle total RNA samples from six pairs of non-diabetic insulin-resistant and insulin-sensitive Pima Indians matched for percent body fat were analyzed by DDPCR with 90 primer combinations. The mRNA expression concentrations of selected 13 known genes and four expressed sequences tags were measured by quantitative real-time RT-PCR in 50 nondiabetic Pima subjects. Results. From over 6500 displayed DDPCR cDNA bands, 36 of the most differentially expressed cDNAs were identified, revealing 29 unique sequences: 16 known genes, 10 expressed sequences tags and three unknown transcripts. Multiple regression analyses indicated that whole body insulin-mediated glucose disposal rates of the subjects, independent of age, sex, and percent body fat, were negatively correlated with mRNA concentrations of an EST (DD23; r=−0.38, p=0.007), ATP1A2 (r=−0.27, p=0.05), MAP2K4 (r= −0.34, p=0.02), and PRPSAP1 (r=−0.37, p=0.008). Transcript concentrations of DD23 (r=0.27, p=0.05) and MTND4 (r=−0.29, p=0.05) were correlated with plasma insulin concentration, independent of age, sex, and percent body fat. Conclusion/interpretation. Altered expression concentrations of these genes might be causes or consequences of insulin resistance, and these genes serve as candidate susceptibility genes for insulin resistance. [Diabetologia (2003[Diabetologia ( ) 46:1567[Diabetologia ( -1575