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Diabetologia

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01-06-2004 | Article

Enhanced insulin secretion and cholesterol metabolism in congenic strains of the spontaneously diabetic (Type 2) Goto Kakizaki rat are controlled by independent genetic loci in rat chromosome 8

Authors: R. H. Wallis, K. J. Wallace, S. C. Collins, M. McAteer, K. Argoud, M. T. Bihoreau, P. J. Kaisaki, D. Gauguier

Published in: Diabetologia | Issue 6/2004

Abstract

Aims/hypothesis

Genetic investigations in the spontaneously diabetic (Type 2) Goto Kakizaki (GK) rat have identified quantitative trait loci (QTL) for diabetes-related phenotypes. The aims of this study were to refine the chromosomal mapping of a QTL (Nidd/gk5) identified in chromosome 8 of the GK rat and to define a pathophysiological profile of GK gene variants underlying the QTL effects in congenics.

Methods

Genetic linkage analysis was carried out with chromosome 8 markers genotyped in a GKxBN F2 intercross previously used to map diabetes QTL. Two congenic strains were designed to contain GK haplotypes in the region of Nidd/gk5 transferred onto a Brown Norway (BN) genetic background, and a broad spectrum of diabetes phenotypes were characterised in the animals.

Results

Results from QTL mapping suggest that variations in glucose-stimulated insulin secretion in vivo, and in body weight are controlled by different chromosome 8 loci (LOD3.53; p=0.0004 and LOD4.19; p=0.00007, respectively). Extensive physiological screening in male and female congenics at 12 and 24 weeks revealed the existence of GK variants at the locus Nidd/gk5, independently responsible for significantly enhanced insulin secretion and increased levels of plasma triglycerides, phospholipids and HDL, LDL and total cholesterol. Sequence polymorphisms detected between the BN and GK strains in genes encoding ApoAI, AIV, CIII and Lipc do not account for these effects.

Conclusions/interpretation

We refined the localisation of the QTL Nidd/gk5 and its pathophysiological characteristics in congenic strains derived for the locus. These congenic strains provide novel models for testing the contribution of a subset of GK alleles on diabetes phenotypes and for identifying diabetes susceptibility genes.

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Hanson RL, Knowler WC (2003) Quantitative trait linkage studies of diabetes-related traits. Curr Diab Rep 3:176–183PubMed

Horikawa Y, Oda N, Cox NJ et al. (2000) Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 26:163–175PubMed

Goto Y, Suzuki KI, Sasaki M, Ono T, Abe S (1988) GK rat as a model of nonobese, noninsulin-dependent diabetes. Selective breeding over 35 generations. In: Shafrir E, Renold AE (eds) Frontiers in diabetes research. Lessons from animal diabetes II. Libbey, London, pp 301–303

Portha B, Serradas P, Bailbe D, Suzuki KI, Goto Y, Giroix MH (1991) β cell insensitivity to glucose in the GK rat, a spontaneous non obese model for type II (non insulin-dependent) diabetes. Diabetes 40:486–491PubMed

Galli J, Li LS, Glaser A et al. (1996) Genetic analysis of non insulin dependent diabetes mellitus in the GK rat. Nat Genet 12:31–37PubMed

Gauguier D, Froguel P, Parent V et al. (1996) Chromosomal mapping of genetic loci associated with non-insulin dependent diabetes in the GK rat. Nat Genet 12:38–43PubMed

Gauguier D, Samani NJ (2002) Approaches to the analysis of complex quantitative phenotypes and marker map construction based on the analysis of rat models of hypertension. In: Camp N, Cox A (eds) Quantitative trait loci, methods and protocols. Humana Press, Totowa, pp 225–251

Nadeau JH, Singer JB, Matin A, Lander ES (2000) Analysing complex genetic traits with chromosome substitution strains. Nat Genet 24:221–225CrossRefPubMed

Rogner UC, Avner P (2003) Congenic mice: cutting tools for complex immune disorders. Nat Rev Immunol 3:243–52CrossRefPubMed

10.

Cowley AW Jr (2003) Genomics and homeostasis. Am J Physiol Regul Integr Comp Physiol 284:R611–R627PubMed

11.

Bihoreau MT, Sebag-Montefiore L, Godfrey RF et al. (2001) A high resolution consensus linkage map of the rat integrating radiation hybrid and genetic maps. Genomics 75:57–69CrossRefPubMed

12.

Collins SC, Wallis RH, Wallace K, Bihoreau MT, Gauguier D (2003) Marker Assisted Congenic Screening (MACS): a database tool for the efficient production and characterisation of congenic lines. Mamm Genome 14:350–356CrossRefPubMed

13.

Watanabe TK, Bihoreau M-T, McCarthy LC et al. (1999) A radiation hybrid map of the rat genome containing 5,255 markers. Nat Genet 22:27–36PubMed

14.

Mu JL, Naggert JK, Svenson KL et al. (1999) Quantitative trait loci analysis for the differences in susceptibility to atherosclerosis and diabetes between inbred mouse strains C57BL/6J and C57BLKS/J. J Lipid Res 40:1328–1335PubMed

15.

Doerge RW, Churchill GA (1996) Permutation tests for multiple loci affecting a quantitative character. Genetics 142:285–294PubMed

16.

Lander ES, Green P, Abrahamson J et al. (1987) MAPMAKER: an interactive computer package for constructing primary genetic linkage maps of experimental and natural populations. Genomics 1:174–181PubMed

17.

Ogino T, Wei S, Wei K et al. (2000) Genetic evidence for obesity loci involved in the regulation of body fat distribution in obese type 2 diabetes rat, OLETF. Genomics 70:19–25CrossRefPubMed

18.

Okuno S, Watanabe TK, Ono T et al. (1999) Genetic determinants of plasma triacylglycerol levels in (OLETF x BN) x OLETF backcross rats. Genomics 62:350–355CrossRefPubMed

19.

Bottger A, Lith HA van, Kren V et al. (1996) Quantitative trait loci influencing cholesterol and phospholipid phenotypes map to chromosomes that contain genes regulating blood pressure in the spontaneously hypertensive rat. J Clin Invest 98:856–862PubMed

20.

Rapp JP (2000) Genetic analysis of inherited hypertension in the rat. Physiol Rev 80:135–172PubMed

21.

Reaven GM (2002) Multiple CHD risk factors in type 2 diabetes: beyond hyperglycaemia. Diabetes Obes Metab 4:S13–S18CrossRefPubMed

22.

Cohen JC, Wang Z, Grundy SM, Stoesz MR, Guerra R (1994) Variations at the hepatic lipase and apolipoprotein AI/CIII/AIV loci is a major cause of genetically determined variation in plasma HDL cholesterol levels. J Clin Invest 94:2377–2384

23.

West DB, Goudey-Lefevre J, York B, Truett GE (1994) Dietary obesity linked to genetic loci on chromosomes 9 and 15 in a polygenic mouse model. J Clin Invest 94:1410–1416

24.

Mehrabian M, Castellani LW, Wen PZ et al. (2000) Genetic control of HDL levels and composition in an interspecific mouse cross (CAST/Ei x C57BL/6J). J Lipid Res 41:1935–1946

25.

Wang X, Paigen B (2002) Quantitative trait loci and candidate genes regulating HDL cholesterol. A murine chromosome map. Arterioscler Thromb Vasc Biol 22:1390–1401CrossRefPubMed

26.

Almasy L, Hixson JE, Rainwater DL et al. (1999) Human pedigree-based quantitative-trait-locus mapping: localization of two genes influencing HDL-cholesterol metabolism. Am J Hum Genet 64:1686–1693

27.

Duggirala R, Blangero J, Almasy L et al. (2000) A major susceptibility locus influencing plasma triglyceride concentrations is located on chromosome 15q in Mexican Americans. Am J Hum Genet 66:1237–1245CrossRefPubMed

28.

Cox NJ, Frigge M, Nicolae DL et al. (1999) Loci on chromosomes 2 (NIDDM1) and 15 interact to increase susceptibility to diabetes in Mexican Americans. Nat Genet 21:213–215CrossRefPubMed

29.

Pajukanta P, Terwilliger JD, Perola M et al. (1999) Genomewide scan for familial combined hyperlipidemia genes in finnish families, suggesting multiple susceptibility loci influencing triglyceride, cholesterol, and apolipoprotein B levels. Am J Hum Genet 64:1453–1463

30.

Kort EN, Ballinger DG, Ding W et al. (2000) Evidence of linkage of familial hypoalphalipoproteinemia to a novel locus on chromosome 11q23. Am J Hum Genet 66:1845–1856PubMed

Title: Enhanced insulin secretion and cholesterol metabolism in congenic strains of the spontaneously diabetic (Type 2) Goto Kakizaki rat are controlled by independent genetic loci in rat chromosome 8
Authors: R. H. Wallis
K. J. Wallace
S. C. Collins
M. McAteer
K. Argoud
M. T. Bihoreau
P. J. Kaisaki
D. Gauguier
Publication date: 01-06-2004
Publisher: Springer-Verlag
Published in: Diabetologia / Issue 6/2004
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-004-1416-5

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Enhanced insulin secretion and cholesterol metabolism in congenic strains of the spontaneously diabetic (Type 2) Goto Kakizaki rat are controlled by independent genetic loci in rat chromosome 8

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

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