The overall objective of this proposal is to elucidate the molecular mechanisms by which elevated levels of glucose and fatty acids adversely affect the pancreatic ?-cell, a phenomenon referred to as glucolipodysfunction. The underlying hypothesis, based on our previous findings and preliminary data, proposes that early stages of glucolipodysfunction involve two complementary mechanisms: 1- Inhibition of expression of the enzyme Per Arnt Sim kinase (PASK) which results in diminished expression and activity of the transcription factors pancreatic-duodenal homeobox-1 (Pdx-1) and mammalian homologue of avian MafA/l-Maf (MafA), leading to decreased insulin expression via alterations of the histone code and a closed chromatin conformation;and 2- Nutrient-induced ?-cell proliferation driven by elevated circulating levels of fibroblast growth factor 21 (FGF21) activating FoxM1 signaling and leading to a dysfunctional ?-cell mass.
In specific Aim 1 we will determine how inhibition of PASK expression impairs insulin gene expression in glucolipodysfunction. Our working hypothesis is that PASK phosphorylates, and thereby inactivates, glycogen synthase kinase (GSK) 3? which alleviates proteasomal degradation of Pdx-1 and MafA. Using rodent genetic models we propose to further delineate the functional relationship between PASK and GSK3 ? and its consequences on Pdx-1 and MafA expression and function under conditions of glucolipodysfunction.
In specific Aim 2 we will characterize the modifications of the histone code and DNA methylation profile at the Pdx-1, MafA, and insulin promoters associated with glucolipodysfunction. Our working hypothesis is that Pdx-1 deficiency in glucolipodysfunction results in defective recruitment of the histone methyltransferase Set7/9 and alterations of the histone methylation profile at the insulin, Pdx-1, and MafA promoters. Using ex vivo and in vivo models we propose to identify the epigenetic modifications responsible for the initiation of glucolipodysfunction.
In specific Aim 3 we will ascertain how insulin resistance induces ? -cell proliferation in glucolipodysfunction. Our working hypothesis is that insulin resistance in response to nutrient excess in 6-mo-old rats is associated with a rise in circulating factors, FGF21 being a likely candidate, which stimulate FoxM1- mediated ?-cell proliferation. Using in vivo models we propose to identify the mechanisms whereby insulin resistance promotes ?-cell growth under conditions of nutrient excess. We expect that the studies described in this application will reveal the molecular signature of glucolipodysfunction in the pancreatic ?-cell. We anticipate that these findings will serve as a basis to design novel therapeutic approaches to prevent the deterioration of ?-cell function in T2D.
Pancreatic ?-cell function inexorably declines during the course of type 2 diabetes mellitus. This deterioration is due, at least in part, to the metabolic perturbations associated with diabetes, chiefly chronic hyperglycemia and dyslipidemia, which themselves have detrimental effects on ?-cell function. By discovering the molecular mechanisms by which chronic excess of nutrients impair insulin production from the ?-cell we hope to identify potential therapeutic targets to curtail the degradation of glucose homeostasis in type 2 diabetes.
|Kilic, Gamze; Alvarez-Mercado, Ana I; Zarrouki, Bader et al. (2014) The islet estrogen receptor-? is induced by hyperglycemia and protects against oxidative stress-induced insulin-deficient diabetes. PLoS One 9:e87941|
|Zarrouki, Bader; Benterki, Isma; Fontes, Ghislaine et al. (2014) Epidermal growth factor receptor signaling promotes pancreatic *-cell proliferation in response to nutrient excess in rats through mTOR and FOXM1. Diabetes 63:982-93|
|d'Assignies, Gaspard; Fontés, Ghislaine; Kauffmann, Claude et al. (2013) Early detection of liver steatosis by magnetic resonance imaging in rats infused with glucose and intralipid solutions and correlation to insulin levels. Metabolism 62:1850-7|
|Sabatini, Paul V; Krentz, Nicole A J; Zarrouki, Bader et al. (2013) Npas4 is a novel activity-regulated cytoprotective factor in pancreatic *-cells. Diabetes 62:2808-20|
|Fergusson, Grace; Ethier, Mélanie; Zarrouki, Bader et al. (2013) A model of chronic nutrient infusion in the rat. J Vis Exp :|
|Semache, Meriem; Zarrouki, Bader; Fontes, Ghislaine et al. (2013) Per-Arnt-Sim kinase regulates pancreatic duodenal homeobox-1 protein stability via phosphorylation of glycogen synthase kinase 3* in pancreatic *-cells. J Biol Chem 288:24825-33|
|Poitout, V (2013) Lipotoxicity impairs incretin signalling. Diabetologia 56:231-3|
|Amyot, Julie; Benterki, Isma; Fontes, Ghislaine et al. (2011) Binding of activating transcription factor 6 to the A5/Core of the rat insulin II gene promoter does not mediate its transcriptional repression. J Mol Endocrinol 47:273-83|
|Semplici, Francesca; Vaxillaire, Martine; Fogarty, Sarah et al. (2011) Human mutation within Per-Arnt-Sim (PAS) domain-containing protein kinase (PASK) causes basal insulin hypersecretion. J Biol Chem 286:44005-14|
|Fontes, G; Zarrouki, B; Hagman, D K et al. (2010) Glucolipotoxicity age-dependently impairs beta cell function in rats despite a marked increase in beta cell mass. Diabetologia 53:2369-79|
Showing the most recent 10 out of 27 publications