Gene expression in humans with diabetes and prediabetes: what have we learned about diabetes pathophysiology?

Type 2 diabetes mellitus is characterized by insulin resistance and pancreatic beta-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.

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 gamma 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.

Nuclear respiratory factor and peroxisome proliferator activated receptor gamma 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.