During feeding and in the post-prandial state, elevated blood glucose levels promptly increase the secretion of insulin and decrease the secretion of glucagon, leading to the suppression of glucose release and storage of glucose as glycogen in the liver. In the post-absorptive state and during early fasting, hepatic glycogenolysis is activated to maintain euglycemia. In contrast, gluconeogenesis plays a dominant role in maintaining blood glucose levels during prolonged fasting after glycogen stores are depleted. Contrary to this model, studies in humans have shown that gluconeogenesis is not completely suppressed even in the presence of excess insulin. These data suggest that a component of hepatic gluconeogenesis may be normally unregulated, and it is estimated that as much as 40-70% of newly synthesized glycogen is formed via the gluconeogenic pathway. We suggest that p300 normally drives basal gluconeogenesis and glycogen synthesis because depletion of hepatic p300 leads to reduced glycogen content and relative hypoglycemia. In contrast, high-fat diet (HFD) feeding markedly and promptly increases p300 protein levels. Given that inappropriate hepatic gluconeogenesis is a major cause of hyperglycemia in obese and diabetic patients, the early induction of p300 by HFD feeding may be responsible for elevated hepatic gluconeogenesis. Understanding the mechanism of early p300 induction by HFD feeding will prove invaluable for understanding basic mechanisms underlying unregulated hepatic glucose production in T2DM. We therefore propose three specific aim to address these questions: 1) To define the interaction between FOXO1 and p300 in regulation of hepatic glucose production (HGP);2) To determine the effect of p300 on hepatic glycogen synthesis through gluconeogenesis and glycogenesis;and 3) To define the mechanism of early induction of p300 protein in the liver of mice fed a HFD and compare to p300 expression in a chronic obesity mouse model (ob/ob).

Public Health Relevance

Elevated hepatic glucose production is a major cause of hyperglycemia in obese and diabetic patients. This proposal seeks to define the mechanism(s) underlying the cause of elevated hepatic glucose production leading to hyperglycemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK063349-09A1
Application #
8639131
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Margolis, Ronald N
Project Start
2002-09-30
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
9
Fiscal Year
2014
Total Cost
$352,350
Indirect Cost
$134,850
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
He, Ling; Meng, Shumei; Germain-Lee, Emily L et al. (2014) Potential biomarker of metformin action. J Endocrinol 221:363-9
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
Wondisford, Fredric E (2011) A new medical therapy for Cushing disease? J Clin Invest 121:4621-3
Song, Woo-Jin; Shah, Rohan; Hussain, Mehboob A (2009) The use of animal models to study stem cell therapies for diabetes mellitus. ILAR J 51:74-81
He, Ling; Sabet, Amin; Djedjos, Stephen et al. (2009) Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 137:635-46
Hussain, Mehboob A; Porras, Delia L; Rowe, Matthew H et al. (2006) Increased pancreatic beta-cell proliferation mediated by CREB binding protein gene activation. Mol Cell Biol 26:7747-59
Zhou, Xiao Yan; Shibusawa, Nobuyuki; Naik, Karuna et al. (2004) Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein. Nat Med 10:633-7