(A) PGC-1α expression and activity have been shown to be increased in the liver and pancreatic β cell in several animal models of diabetes mellitus. Conversely, gene expression profiling indicates that PGC-1α expression is diminished in skeletal muscle of type 1 and 2 diabetic humans along with reduced expression of genes involved in oxidative phosphorylation (OXPHOS). This tissue-specific pattern of dysregulated PGC-1α activity is predicted to potentially contribute to systemic insulin resistance, glucose intolerance, and insulin deficiency. (B) The generalized PGC-1α–deficient mouse is relatively protected against diet-induced insulin resistance and glucose intolerance despite impairments in skeletal muscle OXPHOS capacity. Improved insulin sensitivity may stem from diminished hepatic glucose production, a principal constituent of whole-body glucose homeostasis. However, the relative contribution of individual organ systems to the systemic insulin-sensitive phenotype requires further investigation.