Diabetes mellitus is becoming more prevalent worldwide, with the number of newly diagnosed adults nearlytripling between 1980 and 2005 in the US. Fasting hyperglycemia in type 2 diabetes mellitus is caused byinsulin resistance and elevated glucagon levels, which result in non-suppressible hepatic glucose production.We have shown that both the anti-diabetic agent metformin and insulin phosphorylate the transcriptional co-activator CBP at serine 436 via PKC / , leading to the suppression of hepatic glucose production. A relatedco-activator, p300, lacking this phosphorylation site, is also am important mediator in regulation glucoseproduction. We propose 3 aims in this K99/R00 award to further understand transcriptional regulation ofhepatic gluconeogenesis by the p300/CBP class of co-activators.
In Aim 1, we will characterize the insulinsignaling and gluconeogenic enzyme gene expression profile in the fasted and fed states in p300 mutant micewhere the PKC / phosphorylation site has been reconstituted.
In Aim 2, we wil identify the proteinphosphatase mediating glucagon dephosphorylation of CBP at Ser436.
In Aim 3, we wil define the role ofeach co-activator in the CREB-p300/CBP-TORC2 complex in augmenting gluconeogenesis and theimportance of inter-acetylation of CBP and p300 in mediating hepatic glucose production. The studies in Aim 1will be finished in mentored K99 phase, while Aims 2 and 3 will be finished in the independent R00 phase. Themechanistic studies in this proposal, which explore the actions of insulin and glucagon in controlling hepaticglucose production, will be critical for the development of effective new modalities in the treatment of diabetesmellitus.
in this proposal, we will attempt to define the roles of p300 in gluconeogenesis;identify the protein phosphatase mediated glucagon dephosphorylation of CBP;determine the acetylation of CBP and p300 in regulating glucose production in the liver. We hope to provide mechanistic understanding for the development of hyperglycemia found in patients with type 2 diabetes mellitus.
