ERRgamma and Pancreatic beta-cell function. Mus musculus breed:C57Bl/6

Estrogen-related receptor γ (ERRγ) signaling increases during the neonatal to adult transition in pancreatic islet β-cells. We show that β-cell-specific ERRγ-deficient (βERRγKO) mice exhibit glucose intolerance with reduced glucose-stimulated insulin secretion (GSIS) and βERRγKO islets have defective GSIS function accompanied by changes in genes that regulate ATP biosynthesis, oxidative phosphorylation, and the electron transport chain. ERRγ overexpression enhances genes involved in mitochondrial metabolism, resulting in transformation of β-like-cells into metabolically functional β-cells that can ameliorate STZ-induced hyperglycemia in NOD-SCID mice. These results suggest that ERRγ signaling is essential for the metabolic maturation of β-like-cells and thus represents a novel therapeutic target in the treatment of diabetes.