POITOUT25_03_2013 ANNONCE

CPER Cardio-diabète
Diabète : du syndrome métabolique aux complications vasculaires
Conférences
Lundi 25 mars 2013 – 11h00
Amphi A
Faculté de Médecine – Pôle recherche
Place de Verdun - Lille
(métro ligne 1 CHR Oscar Lambret)
Vincent Poitout, DVM, PhD
Montreal Diabetes Research Center, Canada
à l’invitation des Pr. Philippe Froguel, François Pattou, Bart Staels
The pancreatic beta-cell response to metabolic stress
Simultaneously elevated levels of circulating glucose and fatty acids have been postulated to contribute to the
deterioration of pancreatic beta-cell function during the course of type 2 diabetes, a phenomenon often referred to
as glucolipotoxicity.
In vitro, exposure of isolated rat islets to chronically elevated levels of glucose and fatty acids impairs glucoseinduced insulin secretion, inhibits insulin gene expression and, under some circumstances, leads to beta-cell death
by apoptosis. Previous studies in our laboratory have shown that the decrease in insulin gene expression in response
to elevated fatty acids and glucose in isolated rodent islets occurs at the transcriptional level; is due to nuclear
exclusion of the transcription factor pancreas-duodenum homeobox-1 (PDX-1) and reduced expression of the
transcription factor MafA. Glucolipotoxicity at the insulin gene in this model is mediated by de novo synthesis of
ceramide and, at least in part, inhibition of expression of the enzyme PAS kinase.
In normal Wistar rats, cyclical and alternate infusions of glucose and Intralipid lead to an early decrease in insulin
gene expression accompanied by relocalization of PDX-1 to the perinuclear compartment, confirming that the
molecular mechanisms of glucolipotoxicity identified in isolated islets are also operative in vivo. Further, combined
and continuous infusions of glucose and Intralipid in 6-month old Wistar rats lead to a coordinated impairment of
second-phase glucose-induced insulin secretion, proinsulin biosynthesis, and insulin gene expression. Surprisingly,
this is accompanied by a marked increase in beta-cell proliferation and mass.
These findings led us to conclude that the beta-cell response to metabolic stress in vivo involves a compensatory
increase in beta-cell mass which is, however, insufficient to adequately compensate for insulin resistance and is
associated with beta-cell dysfunction, characterized by an early impairment of insulin gene expression.
Comité de suivi et de coordination - Prs. Philippe Froguel, François Pattou, Bart Staels ;
Contacts : [email protected] et [email protected] - Tél. 03.20.97.42.16