Orphan Receptor Small Heterodimer Partner Is an Important Mediator of Glucose Homeostasis

The orphan receptor small heterodimer partner (SHP; NROB2) is a transcriptional repressor that inhibits nuclear receptor signaling in diverse metabolic pathways. Here, we report that SHP−/− mice exhibited hypoinsulinemia with age, which was associated with increased peripheral insulin sensitivity and increased response of isolated islets to glucose stimulation, yet maintain normal levels of blood glucose. Deficiency in SHP function resulted in up-regulation of glucose transporter 4 mRNA and glucose uptake in muscles, and overexpression of SHP in C2C12 cells inhibited both basal and peroxisomal proliferator-activated receptor γ (PPARγ) coactivator-1α-stimulated glucose transporter 4 expression and glucose uptake. SHP−/− hepatocytes showed markedly decreased basal glucose production in cultures, and SHP−/− livers had increased glycogen stores and were more sensitive to insulin inhibition of glucose output, which were concomitant with decreased expression for PPARγ1, fatty acid translocase, glucose-6-phospha...