title: Islet structure and function in the GK rat.
abstract: Type 2 diabetes mellitus (T2D) arises when the endocrine pancreas fails to secrete sufficient insulin to cope with the metabolic demand because of beta-cell secretory dysfunction and/or decreased beta-cell mass. Defining the nature of the pancreatic islet defects present in T2D has been difficult, in part because human islets are inaccessible for direct study. This review is aimed to illustrate to what extent the Goto-Kakizaki rat, one of the best characterized animal models of spontaneous T2D, has proved to be a valuable tool offering sufficient commonalities to study this aspect. A comprehensive compendium of the multiple functional GK islet abnormalities so far identified is proposed in this perspective. The pathogenesis of defective beta-cell number and function in the GK model is also discussed. It is proposed that the development of T2D in the GK model results from the complex interaction of multiple events: (i) several susceptibility loci containing genes responsible for some diabetic traits (distinct loci encoding impairment of beta-cell metabolism and insulin exocytosis, but no quantitative trait locus for decreased beta-cell mass); (ii) gestational metabolic impairment inducing an epigenetic programming of the offspring pancreas (decreased beta-cell neogenesis and proliferation) transmitted over generations; and (iii) loss of beta-cell differentiation related to chronic exposure to hyperglycaemia/hyperlipidaemia, islet inflammation, islet oxidative stress, islet fibrosis and perturbed islet vasculature.
authors.affiliation: Laboratoire B2PE, Unité BFA, Université Paris-Diderot et CNRS EAC4413, F - 75205 Paris Cedex13, France. portha@univ-paris-diderot.fr
authors.forename: Bernard
authors.initials: B
authors.lastname: Portha
authors.forename: Grégory
authors.initials: G
authors.lastname: Lacraz
authors.forename: Audrey
authors.initials: A
authors.lastname: Chavey
authors.forename: Florence
authors.initials: F
authors.lastname: Figeac
authors.forename: Magali
authors.initials: M
authors.lastname: Fradet
authors.forename: Cécile
authors.initials: C
authors.lastname: Tourrel-Cuzin
authors.forename: Françoise
authors.initials: F
authors.lastname: Homo-Delarche
authors.forename: Marie-Héléne
authors.initials: MH
authors.lastname: Giroix
authors.forename: Danièle
authors.initials: D
authors.lastname: Bailbé
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Gangnerau
authors.forename: Jamileh
authors.initials: J
authors.lastname: Movassat
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002470:Cell Survival; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D004703:Endocrine System; D044127:Epigenesis, Genetic; D050417:Insulin-Secreting Cells / Q000166:cytology; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D018384:Oxidative Stress; D051381:Rats; D017382:Reactive Oxygen Species
chemical_list: D017382:Reactive Oxygen Species