Résumés
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.
Summary
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.
Parties annexes
Références
- 1. Kahn SE. The importance of β-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab 2001; 86; 4047-8.
- 2. Maechler P, Wolheim CB. Mitochondrial function in normal and diabetic β-cells. Nature 2001; 414; 807-12.
- 3. Neel JV. Diabetes mellitus; a «thrifty»genotype rendered detrimental by «progress»? Am J Hum Genet 1962; 14; 353-62.
- 4. Goto Y, Kakizaki M, Masaki N. Spontaneous diabetes produced by selective breeding of normal Wistar rats. Proc Jpn Acad 1975; 51; 80-5.
- 5. Portha B, Giroix MH, Serradas P, et al. β-cell function and viability in the spontaneously diabetic GK rat. Information from the GK/Par colony. Diabetes 2001; 50; 89-93.
- 6. Jonas JC, Sharma A, Hasenkamp W, et al. Chronic hyperglycemia triggers loss of pancreatic β cell differentiation in an animal model of diabetes. J Biol Chem 1999; 274; 14112-21.
- 7. Barker DJ. The fetal origins of diseases of old age. Eur J Clin Nutr 1992; 46; S3-S6.
- 8. Patel MS, Srinivasan M. metabolic programming; causes and consequences. J Biol Chem 2002; 277; 1629-32.
- 9. Blondeau B, Garofano A, Czernichow P, Bréant B. Age-dependent inability of the endocrine pancreas to adapt to pregnancy; a long-term consequence of perinatal malnutrition in the rat. Endocrinology 1999; 140; 4208-13.
- 10. Bertin E, Gangnerau MN, Bellon G, Bailbé D, Arbelot De Vacqueur A, Portha B. Development of β-cell mass in fetuses of rats deprived of protein and/or energy in last trimester of pregnancy. Am J Physiol 2002; 283; R623-R630.
- 11. Bihoreau MT, Ktorza A, Kinebanyan MF, Picon L. Impaired glucose homeostasis in adult rats from hyperglycemic mothers. Diabetes 1986; 35; 979-84.
- 12. Kwong WY, Wild AE, Roberts P, Willis AC, Fleming TP. Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension. Development 2000; 127; 4195-202.
- 13. Gauguier D, Bihoreau MT, Ktorza A, Berthault MF, Picon L. Inheritance of diabetes mellitus as consequence of gestational hyperglycemia in rats. Diabetes 1990; 39; 734-9.
- 14. Waterland RA, Garza C. Potential mechanisms of metabolic imprinting that lead to chronic disease. Am J Clin Nutr 1999; 69; 179-97.
- 15. Kierszenbaum AL. Genomic imprinting and epigenetic reprogramming; unearthing the garden of forking paths. Mol Reprod Dev 2002; 63; 269-72.
- 16. Jacob RA. Folate, DNA methylation, and gene expression; factors of nature and nurture. Am J Clin Nutr 2000; 72; 903-4.
- 17. Gauguier D, Froguel P, Parent V, et al. Chromosomal mapping of genetic loci associated with non-insulin dependent diabetes in the GK rat. Nat Genet 1996; 12; 38-43.