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Article
Nature Genetics  12, 31 - 37 (1996)
doi:10.1038/ng0196-31

Genetic analysis of non-insulin dependent diabetes mellitus in the GK rat

Joakim Galli1, Luo-Sheng Li1, Anna Glaser1, Claes-Göran Östenson1, Hong Jiao1, Hossein Fakhrai-Rad1, Howard J. Jacob2, Eric S. Lander3, 4 & Holger Luthman1, 5

  1Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Hospital, L602, S−17176 Stockholm, Sweden.

  2Cardiovascular Research Center, Massachusetts General Hospital, Charkstown Massachusetts 02129, USA.

  3Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.

  4Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

  5Correspondence should be addressed to H.L.

Non-insulin dependent diabetes mellitus (NIDDM) is a major public health problem, but its aetiology remains poorly understood. We have performed a comprehensive study of the genetic basis of diabetes in the Goto-Kakizaki (GK) rat, the most widely used animal model of non-obese NIDDM. The genetic dissection of NIDDM using this model has allowed us to map three independent loci involved in the disease. In addition, we identify a major factor affecting body weight, but not glucose tolerance, on chromosome 7 and map a further 10 regions that are suggestive for linkage. We conclude that NIDDM is polygenic and fasting hyperglycaemia and postprandial hyperglycaemia clearly have distinct genetic bases.

REFERENCES
  1. WHO Tech. Rep. Ser. In Prevention of Diabetes Mellitus. Vol. 844 (WHO, Geneva, 1994).
  2. Bennett, P.H. Epidemiology of diabetes mellitus. In Diabetes Mellitus. Theory and Practice. (eds Rifkin, H. & Porte, J.D.) 357−377 (Elsevier, New York,1990).
  3. Goto, Y., Kakizaki, M. & Masaki, N. Spontaneous diabetes produced by selective breeding of normal Wistar rats. Proc. Japan. Acad. 51, 80−85 (1975).
  4. Suzuki, K.-I., Goto, Y. & Toyota, T. Spontaneously diabetic GK (Goto-Kakizaki) rats. In Lessons from Animal Diabetes. (ed. Shafrir, E.) 107−116 (Smith-Gordon, London, 1992).
  5. Portha, B. et al. beta-cell insensitivity to glucose in the GK rat, a spontaneous nonobese model for type II diabetes. Diabetes. 40, 486−491 (1991).
  6. Bisbis, S. et al. Insulin resistance in the GK rat: decreased receptor number but normal kinase activity in liver. Am. J. Physiol. 265, E807−E813 (1993).
  7. Ostenson, C.-G. et al. Abnormal insulin secretion and glucose metabolism in pancreatic islets from the spontaneously diabetic GK rat. Diabetologia. 36, 3−8 (1993).
  8. Abdel-Halim, S.M. et al. Impact of diabetic inheritance on glucose tolerance and insulin secretion in spontaneously diabetic GK-Wistar rats. Diabetes 43, 281−288 (1994).
  9. Gauguier, D. et al. Higher maternal than paternal inheritance of diabetes in GK rats. Diabetes 43, 220−224 (1994).
  10. Hughes, S.J., Suzuki, K. & Goto, Y. The role of islet secretory function in the development of diabetes in the GK Wistar rat. Diabetologia 37, 863−870 (1994).
  11. Villar-Palasi, C. & Farese, R.V. Impaired skeletal muscle glycogen synthase activation by insulin in the Goto-Kakizaki (GK) rat. Diabetologia 37, 885−888 (1994).
  12. S., Wright The genetics of quantitative variability. In Evolution and the Genetics of Populations. Genetics and Biometric Foundations. 373−420 (University of Chicago Press, Chicago, 1968).
  13. Lander, E.S. & Botstein, D. Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics 121, 185−199 (1989).
  14. Martin, A.O., Simpson, J.L., Ober, C. & Freinkel, N. Frequency of diabetes mellitus in mothers of probands with gestational diabetes: possible predisposition to gestational diabetes. Am. J. Obstet Gynec. 151, 471−475 (1985).
  15. Dorner, G., Plagemann, A. & Reinagel, H. Familial diabetes aggregation in type I diabetics: gestational diabetes an apparent risk factor for increased diabetes susceptibility in the offspring. Exp. Clin. Endocrinol. 89, 84−90 (1987).
  16. Harlan, L.C., Harian, W.R., Landis, J.R. & Goldstein, N.G. Factors associated with glucose tolerance in adults in the United States. Am. J. Epidemiol. 126, 674−684 (1987).
  17. Alcolado, J.C. & Alcolado, R. Importance of maternal history of non-insulin dependent diabetes patients. Br. Med. J. 302, 1178−1180 (1991).
  18. Mitchell, B.D. et al. Differences in the prevalence of diabetes and impaired glucose tolerance according to maternal or paternal history of diabetes. Diabefes Care. 16, 1262−1267 (1993).
  19. Thomas, F., Balkau, B., Vauzelle-Kervroedan, F., Papoz, L. & The CODIAB-INSERM-Zeneca Study Group. Maternal effect and familial aggregation in NIDDM. The CODIAB Study. Diabetes. 43, 63−67 (1994).
  20. Mitchell, B.D., Kammerer, C.M., Reinhart, L.J., Stern, M.R. & MacCluer, J.W. Is there an excess in maternal transmission of NIDDM? Diabetologia. 38, 314−317 (1995).
  21. Jacob, H.J. et al. A genetic linkage map of the laboratory rat, Rattus norvegicus. Nature Genet. 9, 63−69 (1995).
  22. Lander, E.S. & Schork, N.J. Genetic dissection of complex traits. Science. 265, 2037−2048 (1994).
  23. Mitrakou, A. et al. Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. New Engl. J. Med. 326, 22−29 (1992).
  24. Lillioja, S. et al. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. New Engl. J. Med. 318, 1217−1225 (1988).
  25. Rossetti, L., Giaccari, A.& DeFronzo, R.A. Glucose toxicity. Diabetes Care. 13, 610−630 (1990).
  26. Walker, M.D.T., Boulet, A.M & Rutter, W.J. Cell-specific expression controlled by the 5'-flanking region of insulin and chymotrypsin genes. Nature 306, 557−561 (1983).
  27. Alperet, S., Hanahan, D. & Teitelman, G. Hybrid insulin genes reveal a developmental lineage for pancreatic endocrine cells and imply a relationship with neurons. Cell 53, 295−308 (1988).
  28. Karisson, O., Edlund, T., Moss, J.B., Rutter, W.J. & Walker, M.D. A mutational analysis of the insulin gene transcription control region: expression in beta cells is dependent on two related sequences within the enhancer. Proc. Natl. Acad. Sci. USA 84, 8819−8823 (1987).
  29. German, M.S. & Wang, J. The insulin gene contains multiple transcriptional elements that respond to glucose. Molec. Cell. Biol. 14, 4067−4075 (1994).
  30. Jacob, H.J. et al. Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell 67, 213−224 (1992).
  31. Lakshmikumaran, M.S., D'Ambrosio, E., Laimins, L.A., Lin, D.T & Furano, A.V. Long interspersed repeated DNA (LINE) causes polymorphism at the rat insulin 1 locus. Molec. Cell. Biol. 5, 2197−2203 (1985).
  32. Wedell, A., Ritzen, E.M., Haglund-Stengler, B. & Luthman, H. Steroid 21-hydroxylase deficiency: three new mutated alleles and establishment of phenotype-genotype relationships of common mutations. Proc. Natl. Acad. Sci. USA. 89, 7232−7236 (1992).
  33. Chomczynski, P. & Sacchi, N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Analyt. Biochem. 162, 156−159 (1987).
  34. Norgren, S., Zierath, J., Wedell, A.H., Wallberg-Henriksson, H. & Luthman, H. Regulation of human insulin receptor RNA splicing in vivo. Proc. Natl. Acad. Sci. USA. 91, 1465−1469 (1994).
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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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