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.
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.
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|An, Hongying; He, Ling (2016) Current understanding of metformin effect on the control of hyperglycemia in diabetes. J Endocrinol 228:R97-106|
|He, Ling; Chang, Evan; Peng, Jinghua et al. (2016) Activation of the cAMP-PKA pathway Antagonizes Metformin Suppression of Hepatic Glucose Production. J Biol Chem 291:10562-70|
|Meng, Shumei; Cao, Jia; He, Qiyi et al. (2015) Metformin activates AMP-activated protein kinase by promoting formation of the ??? heterotrimeric complex. J Biol Chem 290:3793-802|
|He, Ling; Wondisford, Fredric E (2015) Metformin action: concentrations matter. Cell Metab 21:159-62|
|Wondisford, Anne R; Xiong, Lishou; Chang, Evan et al. (2014) Control of Foxo1 gene expression by co-activator P300. J Biol Chem 289:4326-33|
|He, Ling; Meng, Shumei; Germain-Lee, Emily L et al. (2014) Potential biomarker of metformin action. J Endocrinol 221:363-9|
|Cao, Jia; Meng, Shumei; Chang, Evan et al. (2014) Low concentrations of metformin suppress glucose production in hepatocytes through AMP-activated protein kinase (AMPK). J Biol Chem 289:20435-46|
|Mei, Shuang; Yang, Xuefeng; Guo, Huailan et al. (2014) A small amount of dietary carbohydrate can promote the HFD-induced insulin resistance to a maximal level. PLoS One 9:e100875|
|He, Ling; Cao, Jia; Meng, Shumei et al. (2013) Activation of basal gluconeogenesis by coactivator p300 maintains hepatic glycogen storage. Mol Endocrinol 27:1322-32|
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