EXCEED THE SPACE PROVIDED. The objective of the proposed research is to elucidate the contribution of the cAMP phosphodiesterase, PDE7A, to the regulation of glucose homeostasis. Since cAMP antagonizes insulin action, cAMP phosphodiesterases can augment insulin signaling by reducing levels of cAMP pools relevant to insulin action. In particular, PDE3B augments insulin signaling in fat and liver. PDE3B, however, is not expressed in skeletal muscle. Our studies established PDE7A as a cAMP specific phosphodiesterase expressed to high levels in skeletal muscle as the particulate PDE7A2 splice variant. Our targeted disruption of the PDE7A gene in mice yielded PDE7KO mice with defects in glucose homeostasis - glucose intolerance and insulin resistance. PDE7KO mice, however, are not hyperinsulinemic and their insulin secretion in response to injected glucose is indistinguishable from that of wild type mice. Consistent with the abundant expression of PDE7A2 in skeletal muscle, and with the strong contribution of skeletal muscle to whole body glucose disposal, PDE7KO mice are impaired in insulin stimulated glucose uptake by skeletal muscle, but not by adipose tissue. Based on these observations, we hypothesize that a primary defect in PDE7KO mice is the disposal of glucose by skeletal muscle. The experimental program will examine in vivo defects of PDE7KO mice in glucose disposal, glucose and lipid metabolism, cAMP and insulin signaling, in skeletal muscle, and in liver and adipocytes. The contribution of pancreatic g-cells to PDE7KO phenotypes will also be assessed. Thus, the aim of the proposal is to at understand the cross talk between the insulin and the cAMP signaling pathways and mechanisms underlying diabetogenic, metabolic perturbations in glucose homeostasis. PERFORMANCE SITE ========================================Section End===========================================
| Han, Ping; Sonati, Pushpalatha; Rubin, Charles et al. (2006) PDE7A1, a cAMP-specific phosphodiesterase, inhibits cAMP-dependent protein kinase by a direct interaction with C. J Biol Chem 281:15050-7 |
