[Transmitted beta-cell dysfunction as a cause for type 2-diabetes].
The pathways that control insulin release and regulate pancreatic beta-cell mass are crucial on the development of type 2 diabetes mellitus. Maturity-onset diabetes of the young comprises a number of single-gene disorders affecting beta-cell development and/or function. A genetic basis for the more common forms of type 2 diabetes which affect adults in developed as well as many developing countries is less clear cut. It is also characterized by abnormal beta-cell function. Appropriate inbred rodent models are an essential tool for the identification of genes and environmental factors that increase the risk of type 2 diabetes. The informations available from studies in the Goto-Kakizaki (GK) rat are here reviewed in such a perspective. This model was obtained by selective breeding of individuals with mild glucose intolerance from a non-diabetic Wistar rat colony. Heritability of defective beta-mass and beta-cell function in GK model is proposed to reflect the complex interactions of three pathogenic players: (1) three independent loci containing genes causating impaired insulin secretion; (2) gestational metabolic (hyperglycaemic) impairment inducing a programming of endocrine pancreas (decreased beta-cell mass) which is transmitted to the next generation; (3) secondary (acquired) loss of beta-cell differentiation due to chronic exposure to hyperglycaemia (glucotoxicity). A better understanding of the mechanisms involved in the failure of beta-cell function in the GK model will lead to identification of new therapeutic targets for both the prevention and treatment of type 2 diabetes.
Portha
Bernard
B
Groupe Régulations métaboliques et diabètes, Laboratoire de Physiopathologie de la Nutrition, Cnrs UMR 7059, Université Paris 7-Denis Diderot, 2, place Jussieu, 75251 Paris Cedex 05, France. portha@paris7.jussieu.fr
D000328:Adult; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology*; D004195:Disease Models, Animal; D005941:Glucokinase / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000503:physiopathology*; D010766:Phosphorylation; D051381:Rats; D011919:Rats, Inbred Strains
D007328:Insulin; D005941:Glucokinase; D005947:Glucose