Gene expression in humans with diabetes and prediabetes: what have we learned about diabetes pathophysiology?Patti, Mary-ElizabethCurrent Opinion in Clinical Nutrition & Metabolic Care: July 2004 - Volume 7 - Issue 4 - pp 383-390 Genes and nutrition Abstract Author Information Purpose of review: Type 2 diabetes mellitus is characterized by insulin resistance and pancreatic β-cell dysfunction. In high-risk individuals, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, and glycogen synthesis, and the accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and diabetes mellitus has been identified in humans. However, recent analyses of gene expression patterns in muscle tissue from metabolically characterized humans have highlighted new genes and pathways potentially important in the pathogenesis of diabetes mellitus. This review will summarize these data and highlight the potential importance of oxidative metabolism in diabetes pathophysiology. Recent findings: Genomic analysis of skeletal muscle samples from patients with diabetes mellitus has revealed the reduced expression of genes encoding key enzymes in oxidative metabolism and mitochondrial function. Moreover, the same pattern of gene expression is also observed in insulin resistant ‘prediabetic’ individuals with normal glucose tolerance. Many of the genes dysregulated in both diabetes and ‘prediabetes’ are regulated by the transcription factor nuclear respiratory factor-1 and the peroxisome proliferator-activated receptor γ co-activator 1. These data suggest a potential role for both genetic and environmental factors to modify the risk of diabetes by modifying the expression or activity of these transcriptional regulators. Summary: Nuclear respiratory factor and peroxisome proliferator activated receptor γ co-activator-1-dependent oxidative metabolic pathways may play a central, and potentially primary, role in the pathogenesis of type 2 diabetes. Additional studies will be required to identify upstream genetic and environmental determinants of this expression phenotype. Joslin Diabetes Center, Boston, Massachusetts, USA; and Harvard Medical School, Boston, Massachusetts, USA Correspondence to Mary-Elizabeth Patti, Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215, USA Tel: +1 617 735 1966; fax: +1 617 735 1970; e-mail: firstname.lastname@example.org Abbreviations NRF: nuclear respiratory factor PPAR: peroxisome proliferator-activated receptor PGC-1: PPARγ co-activator 1 © 2004 Lippincott Williams & Wilkins, Inc.