Islet structure and function in the GK rat.
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.
Portha
Bernard
B
Laboratoire B2PE, Unité BFA, Université Paris-Diderot et CNRS EAC4413, F - 75205 Paris Cedex13, France. portha@univ-paris-diderot.fr
Lacraz
Grégory
G
Chavey
Audrey
A
Figeac
Florence
F
Fradet
Magali
M
Tourrel-Cuzin
Cécile
C
Homo-Delarche
Françoise
F
Giroix
Marie-Héléne
MH
Bailbé
Danièle
D
Gangnerau
Marie-Noëlle
MN
Movassat
Jamileh
J
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
D017382:Reactive Oxygen Species