Nature Genetics
12, 38 - 43 (1996)
doi:10.1038/ng0196-38
Chromosomal mapping of genetic loci associated with non-insulin dependent diabetes in the GK ratDominique Gauguier1, 2, 5, Philippe Froguel2, 3, Véronique Parent1, Catherine Bernard4, Marie-Thérèse Bihoreau1, Bernard Portha4, Michael R. James1, Luc Penicaud4, Mark Lathrop1, 2
& Alain Ktorza4
1The Wellcome Trust Centre for Human Genetics, Windmill Road, Headington, Oxford OX3 7BN, UK.
2INSERM U358,St Louis Hospital, 12 rue de la Grange aux Belles, 75010 Paris, France.
3CNRS EP 10, Institute Pasteur of Lille, 59019 Lille, France.
4Laboratory of Physiopathology of Nutrition, CNRS URA307, University of Paris 7-Denis Diderot, 2 place Jussieu, 75005 Paris, France.
5Correspondence should be addressed to D.G. Goto-Kakizaki (GK) rats are a well characterized model for non-insulin dependent diabetes mellitus (NIDDM). We have used a combination of physiological and genetic studies to identify quantitative trait loci (QTLs) responsible for the control of glucose homeostasis and insulin secretion in a F2 cohort bred from spontaneously diabetic GK rats. The genetic dissection of NIDDM allowed us to map up to six independently segregating loci predisposing to hyperglycaemia, glucose intolerance or altered insulin secretion, and a seventh locus implicated in body weight. QTLs implicated in glucose tolerance and adiposity map to the same region of rat chromosome 1, and may indicate the influence of a single locus. Our study demonstrates that distinct combinations of genetic loci are responsible for different physiological characteristics associated with the diabetic phenotype in the GK rat, and it constitutes an important step for directing the search for the genetic factors involved in human NIDDM.
REFERENCES
- Taylor, A. Aetiology of non-insulin dependent diabetes. Br. Med. Bull. 45, 73−91 (1989).
- Barnett, A.H., Eff, C., Leslie, R.D.G. & DA Diabetes in identical twins: A study of 200 pairs. Diabetobgia 20, 87−93 (1981).
- Newman, B. et al. Concordance for type 2 (non-insulin-dependent) diabetes mellitus in male twins. Diabetologia 30, 763−768 (1987).
- Taylor, S.I. et al. Molecular genetics of insulin resistant diabetes mellitus. J. Clin. Endocr. Metab. 73, 1158−1163 (1991).
- Ballinger, S.C. et al. Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletion. Nature Genet. 1, 11−15 (1992).
- Froguel, P. et al. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin dependent diabetes mellitus. Nature 356 162−164 (1992).
- Steiner, D.F. et al. Lessons learned from molecular biology of insulin-gene mutations. Diabetes Care 13 600−609 (1990).
- King, H. Aetiology of non-insulin dependent diabetes mellitus. Baillière's Clin. Endocrinol. Metab. 2, 291−305 (1988).
- Rich, S.S. Mapping genes in diabetes Genetic epidemiological perspective. Diabetes 39, 1315−1319 (1990).
- Dubay, C. et al. Genetic determinants of diastolic and pulse pressure map to different loci in Lyon hypertensive rats. Nature. Genet. 3, 354−357 (1993).
- Goto, Y., Suzuki, K.Y., Sasaki, M., Ono, T. & Abe, S. GK rat as a model of non-obese, non-insulin-dependent diabetes. Selective breeding over 35 generations. In Lessons From Animal Diabetes II. (eds Shafrir, E. & Renold, A.E.) 490−492 (Libbey, J. London, 1988).
- Portha, B. et al.
 cell insensitivity to glucose in the GK rat, a spontaneous non obese model for type II (non insulin-dependent) diabetes. Diabetes 40, 486−491 (1991).
- Gauguier, D. et al. Higher maternal than paternal inheritance of diabetes in the GK rat. Diabetes 43, 220−224 (1994).
- 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).
- Wallum, B.J., Kahn, S.E., McCulloch, O.K. & Porte, D. Jr., Insulin secretion in the normal and diabetic human. In International Textbook of Diabetes Mellitus. (eds Albert!, K.G.G.M., De Fronzo, R.A., Keen, H. & Zimmer, P.) 285−301 (Wiley, New York, 1992).
- Cook, D.L. & Taborsky, G.J., B-cell function and insulin secretion. In International Textbook of Diabetes Mellitus. (eds Alberti, K.G.G.M., De Fronzo, R.A., Keen, H. & Zimmer, R) 89−109 (Wiley, New York, 1992).
- Paterson, A.H. et al. Resolution of quantitative traits into Mendelian factors by using a complete linkage map of restriction fragment length polymorphisms. Nature 335, 721−726 (1988).
- Jacob, H. et al. Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell 67, 213−224 (1991).
- Andersson, L. et al. Genetic mapping of quantitative trait loci for growth and fatness in pigs. Science 263, 1771−1774 (1994).
- Hilbert, R. et al. Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats. Nature 353, 521−529 (1991).
- Serikawa, T. et al. Rat gene mapping using PCR-analyzed microsatellites. Genetics 131, 701−721 (1992).
- Ghosh, S. et al. Polygenic control of autoimmune diabetes in non-obese diabetic mice. Nature Genet. 4, 404−409 (1993).
- Daughaday, W.H. & R Insulin-like growth factor I and II Peptide, messenger ribonucleic acid and gene structure, serum, and tissue concentrations. Endocr. Rev. 10, 68−91 (1989).
- Rosen, K.M., Wentworth, B.M., Rosenthal, N. & Villa-Komanoff, L., Specific, temporally regulated expression of the insulin-like growth factors and their binding proteins in normal human lymphocytes. Endocrinol. 133, 168−172 (1993).
- Glaser, B. et al. Familial hyperinsulinism maps to chromosome 11 p14−15.1, 30 cM centromeric to the insulin gene. Nature Genet 7, 185−188 (1994).
- Thomas, P.M. et al. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 268, 426−429 (1995).
- Deng, Y. & Rapp, J.P. Cosegregation of blood pressure with angiotensin converting enzyme and atrial natriuretic peptide receptor genes using Dahl salt-sensitive rats. Nature Genet. 1, 267−272 (1992).
- Lindpaintner, K., Hilbert, P., Inagami, T. & Iwai, N. Molecular genetics of the SA gene: cosegregation with hypertension and mapping to rat chromosome 1. J. Hypertension 1, 19−23 (1993).
- Samani, N.J. et al. A gene differentially expressed in the kidney of the spontaneously hypertensive rat cosegregates with increased blood pressure. J. Clin. Invest. 92, 1099−1103 (1993).
- West, D.B., Goudey-Lefevre, J., York, B., Truett, G.E. Dietary obesity linked to genetic loci on chromosomes 9 and 15 in a polygenic mouse model. J. din. Invest. 94, 1410−1416 (1994).
- Jacob, H. et al. Genetic dissection of autoimmune type I diabetes in the BB rat. Nature Genet. 2, 56−60 (1992).
- Sheik, S.R. et al. Release of NPY in pig pancreas: dual parasympathetic and sympathetic regulation. AD.J. Physiol. 255 G46−G54 (1988).
- Leibowitz, S.F. Brain neuropeptide Y: an integrator of endocrine, metabolic, and behavioral processes. Brain Res. Bull. 27 333−337 (1991).
- Akabayashi, A., Wahlestedt, C., Alexander, J.T. & Leibowitz, S.F. Specific inhibition of endogenous neuropeptide Y synthesis in arcuate nucleus by antisense oligonucleotides suppresses feeding behavior and insulin secretion. Mol. Brain. Res. 21, 55−61 (1994).
- Goto, Y., Kukizaki, M. & Masaki, N. Spontaneous diabetes produced by selective breeding of normal Wistar rats. Proc. Japan Acad. 51, 80−85 (1975).
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