The Distinct Role of CBP and p300 in Regulating Hepatic Glucose Production

糖尿病在世界范围内变得越来越普遍，新诊断的成年人的数量几乎 在1980年到2005年之间增长了三倍。2型糖尿病患者的空腹高血糖是由以下原因引起的： 胰岛素抵抗和胰高血糖素水平升高，导致不可抑制的肝葡萄糖产生。 我们已经证明，抗糖尿病药物二甲双胍和胰岛素都磷酸化了转录辅基， 激活剂CBP通过PKC在丝氨酸436处，导致肝葡萄糖产生的抑制。一个相关 辅激活因子p300缺乏该磷酸化位点，也是调节葡萄糖的重要介质 生产我们在这个K99/R 00奖项中提出了3个目标，以进一步了解转录调控， 通过p300/CBP类共激活剂的肝硬化发生。在目标1中，我们将表征胰岛素 p300突变小鼠禁食和进食状态下的信号传导和促凋亡酶基因表达谱 其中PKC磷酸化位点已经重建。在目标2中，我们将鉴定蛋白质 磷酸酶介导CBP在Ser 436处的胰高血糖素去磷酸化。在目标3中，我们将定义 CREB-p300/CBP-TORC 2复合物中的每种共激活剂在增强胚胎发生中的作用， CBP和p300相互乙酰化在介导肝脏葡萄糖产生中重要性目标1中的研究 目标2和目标3将在独立的R 00阶段完成。的 本研究旨在探讨胰岛素和胰高血糖素在控制肝硬化中的作用， 葡萄糖生产，将是关键的发展，有效的新模式，在治疗糖尿病 糖尿病。

Diabetes mellitus is becoming more prevalent worldwide, with the number of newly diagnosed adults nearly tripling between 1980 and 2005 in the US. Fasting hyperglycemia in type 2 diabetes mellitus is caused by insulin 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 related co-activator, p300, lacking this phosphorylation site, is also am important mediator in regulation glucose production. We propose 3 aims in this K99/R00 award to further understand transcriptional regulation of hepatic gluconeogenesis by the p300/CBP class of co-activators. In Aim 1, we will characterize the insulin signaling and gluconeogenic enzyme gene expression profile in the fasted and fed states in p300 mutant mice where the PKC¿/¿ phosphorylation site has been reconstituted. In Aim 2, we wil identify the protein phosphatase mediating glucagon dephosphorylation of CBP at Ser436. In Aim 3, we wil define the role of each co-activator in the CREB-p300/CBP-TORC2 complex in augmenting gluconeogenesis and the importance of inter-acetylation of CBP and p300 in mediating hepatic glucose production. The studies in Aim 1 will be finished in mentored K99 phase, while Aims 2 and 3 will be finished in the independent R00 phase. The mechanistic studies in this proposal, which explore the actions of insulin and glucagon in controlling hepatic glucose production, will be critical for the development of effective new modalities in the treatment of diabetes mellitus.