Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 11/2006

01-11-2006 | Article

Genetic control of plasma lipid levels in a cross derived from normoglycaemic Brown Norway and spontaneously diabetic Goto–Kakizaki rats

Authors: K. Argoud, S. P. Wilder, M. A. McAteer, M. T. Bihoreau, F. Ouali, P. Y. Woon, R. H. Wallis, A. Ktorza, D. Gauguier

Published in: Diabetologia | Issue 11/2006

Login to get access

Abstract

Aims/hypothesis

Dyslipidaemia is a main component of the insulin resistance syndrome. The inbred Goto–Kakizaki (GK) rat is a model of spontaneous type 2 diabetes and insulin resistance, which has been used to identify diabetes-related susceptibility loci in genetic crosses. The objective of our study was to test the genetic control of lipid metabolism in the GK rat and investigate a possible relationship with known genetic loci regulating glucose homeostasis in this strain.

Materials and methods

Plasma concentration of triglycerides, phospholipids, total cholesterol, HDL, LDL and VLDL cholesterol were determined in a cohort of 151 hybrids of an F2 cross derived from GK and non-diabetic Brown Norway (BN) rats. Data from the genome-wide scan of the F2 hybrids were used to test for evidence of genetic linkage to the lipid quantitative traits.

Results

We identified statistically significant quantitative trait loci (QTLs) that control the level of plasma phospholipids and triglycerides (chromosome 1), LDL cholesterol (chromosome 3) and total and HDL cholesterol (chromosomes 1 and 5). These QTLs do not coincide with previously identified diabetes susceptibility loci in a similar cross. The significance of lipid QTLs mapped to chromosomes 1 and 5 is strongly influenced by sex.

Conclusion/interpretation

We established that several genetic loci control the quantitative variations of plasma lipid variables in a GK×BN cross. They appear to be distinct from known GK diabetes QTLs, indicating that lipid metabolism and traits directly relevant to glucose and insulin regulation are controlled by different gene variants in this strain combination.
Appendix
Available only for authorised users
Literature
1.
DeFronzo RA, Ferrannini E (1991) Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 14:173–194
2.
Kahn R, Buse J, Ferrannini E, Stern M (2005) The metabolic syndrome: time for a critical appraisal. Joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 48:1684–1699PubMedCrossRef
3.
4.
Stern MP (1995) Diabetes and cardiovascular disease. The “common soil” hypothesis. Diabetes 44:369–374PubMed
5.
Stern MP (2000) Strategies and prospects for finding insulin resistance genes. J Clin Invest 106:323–327PubMed
6.
7.
Portha B (2005) Programmed disorders of beta-cell development and function as one cause for type 2 diabetes? The GK rat paradigm. Diabetes Metab Res Rev 21:495–504PubMedCrossRef
8.
Gronholm T, Cheng ZJ, Palojoki E et al (2005) Vasopeptidase inhibition has beneficial cardiac effects in spontaneously diabetic Goto–Kakizaki rats. Eur J Pharmacol 519:267–276PubMedCrossRef
9.
O’Rourke CM, Davis JA, Saltiel AR, Cornicelli JA (1997) Metabolic effects of troglitazone in the Goto–Kakizaki rat, a non-obese and normolipidemic rodent model of non-insulin-dependent diabetes mellitus. Metabolism 46:192–198PubMedCrossRef
10.
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) Lessons from animal diabetes II. Libbey, London, pp 301–303
11.
Galli J, Li LS, Glaser A et al (1996) Genetic analysis of non-insulin dependent diabetes mellitus in the GK rat. Nat Genet 12:31–37PubMedCrossRef
12.
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 12:38–43PubMedCrossRef
13.
Wilder SP, Bihoreau MT, Argoud K, Watanabe TK, Lathrop M, Gauguier D (2004) Integration of the rat recombination and EST maps in the rat genomic sequence and comparative mapping analysis with the mouse genome. Genome Res 14:758–765PubMedCrossRef
14.
Bihoreau MT, Gauguier D, Kato N et al (1997) A linkage map of the rat genome derived from three F2 crosses. Genome Res 7:434–440PubMed
15.
Stam P (1995) Construction of integrated genetic linkage maps by means of a computer package: JoinMap. Plant J 5:739–744
16.
Ihaka R, Gentleman R (1996) R: A language for data analysis and graphics. J Comput Graph Statist 5:299–314CrossRef
17.
Ury HK (1976) A comparison of four procedures for multiple comparisons among means (pairwise contrasts) for arbitrary samples sizes. Technometrics 18:89–97CrossRef
18.
Doerge RW, Churchill GA (1996) Permutation tests for multiple loci affecting a quantitative character. Genetics 142:285–294PubMed
19.
Broman KW, Wu H, Sen S, Churchill GA (2003) R/qtl: QTL mapping in experimental crosses. Bioinformatics 19:889–890PubMedCrossRef
20.
Haley CS, Knott SA (1992) A simple regression method for mapping quantitative trait loci in line crosses using flanking markers. Heredity 69:315–324PubMed
21.
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 1:174–181PubMedCrossRef
22.
Boizel R, Benhamou PY, Lardy B, Laporte F, Foulon T, Halimi S (2000) Ratio of triacylglycerols to HDL cholesterol is an indicator of LDL particle size in patients with type 2 diabetes and normal HDL cholesterol levels. Diabetes Care 23:1679–1685PubMed
23.
Bottger A, van Lith HA, 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 98:856–862PubMedCrossRef
24.
Herrera VL, Didishvili T, Lopez LV, Myers RH, Ruiz-Opazo N (2004) Genome-wide scan identifies novel QTLs for cholesterol and LDL levels in F2[Dahl RxS]-intercross rats. Circ Res 94:446–452PubMedCrossRef
25.
Kato N, Tamada T, Nabika T et al (2000) Identification of quantitative trait loci for serum cholesterol levels in stroke-prone spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol 20:223–229PubMed
26.
Yamasaki Y, Watanabe TK, Okuno S et al (2000) Quantitative trait loci for lipid metabolism in the study of OLETF x (OLETF x Fischer 344) backcross rats. Clin Exp Pharmacol Physiol 27:881–886PubMedCrossRef
27.
Klimes I, Weston K, Kovacs P et al (2003) Mapping of genetic loci predisposing to hypertriglyceridaemia in the hereditary hypertriglyceridaemic rat: analysis of genetic association with related traits of the insulin resistance syndrome. Diabetologia 46:352–358PubMed
28.
Marion E, Kaisaki PJ, Pouillon V et al (2002) The gene INPPL1, encoding the lipid phosphatase SHIP2, is a candidate for type 2 diabetes in rat and man. Diabetes 51:2012–2017PubMed
29.
Yamane M, Jiao S, Kihara S et al (1995) Increased proportion of plasma apoB-48 to apoB-100 in non-insulin-dependent diabetic rats: contribution of enhanced apoB mRNA editing in the liver. J Lipid Res 36:1676–1685PubMed
30.
Oschry Y, Eisenberg S (1982) Rat plasma lipoproteins: re-evaluation of a lipoprotein system in an animal devoid of cholesteryl ester transfer activity. J Lipid Res 23:1099–1106PubMed
31.
Wang X, Paigen B (2005) Genetics of variation in HDL cholesterol in humans and mice. Circ Res 96:27–42PubMedCrossRef
32.
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 66:1237–1245PubMedCrossRef
33.
Elbein SX, Hasstedt SJ (2002) Quantitative trait linkage analysis of lipid-related traits in familial type 2 diabetes. Diabetes 51:528–535PubMed
34.
Weiss LA, Pan L, Abney M, Ober C (2006) The sex-specific genetic architecture of quantitative traits in humans. Nat Genet 30:218–222CrossRef
35.
Collins SC, Wallis RH, Wilder SP et al (2006) Mapping diabetes QTL in an intercross derived from a congenic strain of the Brown Norway and Goto–Kakizaki rats. Mamm Genome 17:538–547PubMedCrossRef
36.
37.
Watanabe TK, Suzuki M, Yamasaki Y et al (2005) Mutated G-protein-coupled receptor GPR10 is responsible for the hyperphagia/dyslipidaemia/obesity locus of Dmo1 in the OLETF rat. Clin Exp Pharmacol Physiol 32:355–366PubMedCrossRef
38.
Wallis RH, Wallace KJ, Collins SC et al (2004) 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. Diabetologia 47:1096–1106PubMedCrossRef
Metadata
Title
Genetic control of plasma lipid levels in a cross derived from normoglycaemic Brown Norway and spontaneously diabetic Goto–Kakizaki rats
Authors
K. Argoud
S. P. Wilder
M. A. McAteer
M. T. Bihoreau
F. Ouali
P. Y. Woon
R. H. Wallis
A. Ktorza
D. Gauguier
Publication date
01-11-2006
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 11/2006
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-006-0396-z

Other articles of this Issue 11/2006

Diabetologia 11/2006 Go to the issue

Letter- comment

Comment on: Evans JMM, Ogston SA, Emslie-Smith A, Morris AD (2006) Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia 49:930–936

Short Communication

Upregulation of adiponectin receptor 1 and 2 mRNA and protein in adipose tissue and adipocytes in insulin-resistant women with polycystic ovary syndrome

Article

Degeneration of the Golgi and neuronal loss in dorsal root ganglia in diabetic BioBreeding/Worcester rats

Letter

Comment on: Knol MJ, Twisk JWR, Beekman ATF, Heine RJ, Snoek FJ, Pouwer F. (2006) Depression as a risk factor for the onset of type 2 diabetes mellitus. A meta-analysis. Diabetologia; 49: 837–845

Article

Prevalent and incident depression in community-dwelling elderly persons with diabetes mellitus: results from the ZARADEMP project

Short Communication

The associations of birthweight, gestational age and childhood BMI with type 2 diabetes: findings from the Aberdeen Children of the 1950s cohort
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits