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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Transition Award (R00)
Project #
4R00DK085142-03
Application #
8310339
Study Section
Special Emphasis Panel (NSS)
Program Officer
Margolis, Ronald N
Project Start
2011-09-01
Project End
2014-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
3
Fiscal Year
2011
Total Cost
$249,000
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Cao, Jia; Peng, Jinghua; An, Hongying et al. (2017) Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity. Nat Commun 8:131
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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