Anomalies programmées de la sécrétion d’insuline dans le diabète de type 2 : le paradigme du rat GK

Transmitted β-cell dysfunction as a cause for type 2-diabetes

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

Résumé

La perte de fonction β-cellulaire joue un rôle central dans la physiopathologie des diabètes de type 2. Alors que dans les formes rares de la maladie, les MODY (maturity onset diabetes of the young), son étiologie est simple, monogénique et décryptée, dans les formes courantes de diabète de type 2, elle est certainement beaucoup plus complexe et demeure mystérieuse. Cet article établit le bilan des données actuellement disponibles relatives au déterminisme de l’atteinte β-cellulaire dans un modèle animal approprié, le rat GK, spontanément porteur d’un diabète de type 2.

Abstract

The pathways that control insulin release and regulate pancreatic β-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 β-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 β-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 β-mass and β-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 β-cell mass) which is transmitted to the next generation; (3) secondary (acquired) loss of β-cell differentiation due to chronic exposure to hyperglycaemia (glucotoxicity). A better understanding of the mechanisms involved in the failure of β-cell function in the GK model will lead to identification of new therapeutic targets for both the prevention and treatment of type 2 diabetes.