title: Programmed disorders of beta-cell development and function as one cause for type 2 diabetes? The GK rat paradigm.
abstract: Now that the reduction in beta-mass has been clearly established in humans with type 2 diabetes mellitus (T2DM) 1-4, the debate focuses on the possible mechanisms responsible for decreased beta-cell number and impaired beta-cell function and their multifactorial etiology. Appropriate inbred rodent models are essential tools for identification of genes and environmental factors that increase the risk of abnormal beta-cell function and of T2DM. The information available in the Goto-Kakizaki (GK) rat, one of the best characterized animal models of spontaneous T2DM, are reviewed in such a perspective. We propose that the defective beta-cell mass and function in the GK model reflect the complex interactions of three pathogenic players: (1) several independent loci containing genes causing impaired insulin secretion; (2) gestational metabolic impairment inducing a programming of endocrine pancreas (decreased beta-cell neogenesis) which is transmitted to the next generation; and (3) secondary (acquired) loss of beta-cell differentiation due to chronic exposure to hyperglycemia (glucotoxicity). An important message is that the 'heritable' determinants of T2DM are not simply dependant on genetic factors, but probably involve transgenerational epigenetic responses.
authors.affiliation: Lab. Physiopathologie de la Nutrition, Université Paris 7/D. Diderot, Paris Cedex, France. portha@paris7.jussieu.fr
authors.forename: Bernard
authors.initials: B
authors.lastname: Portha
mesh_terms: D000328:Adult; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000473:pathology / Q000502:physiology*; D008297:Male; D011236:Prediabetic State / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar