Abstract
BB rats develop type 1 diabetes and WOKW rats facets of the metabolic syndrome. Both strains are common the RT1u haplotype of major histocompatibility complex (MHC) which is essential for type 1 diabetes development in BB rats (Iddm1). However, BB rats need an additional gene (lymphopenia, Iddm2, Gimap5) to develop type 1 diabetes. Because WOKW lacks Iddm2 and does not develop hyperglycemia a congenic WOKW rat strain was generated recombining the region of chromosome 4 with Iddm2 onto the genetic background of WOKW rats (WOKW.4BB). These newly established rats and their parental WOKW rats were genetically and phenotypically characterized. Congenic WOKW.4BB rats showed a lymphopenic phenotype. The sequences of the highly polymorphic exon 2 of RT1-Bb class II gene in WOKW, BB/OK, WOKW.4BB and LEW.1W rats were comparable and clearly showed the RT1u haplotype. In addition, there were significant differences in metabolic traits between WOKW.4BB and parental WOKW. Although congenic WOKW.4BB rats were homozygous for Iddm1 and Iddm2 of the BB/OK rat none of WOKW.4BB rats developed hyperglycemia. This observation may be attributed to the idea that either WOKW.4BB rats need a third Iddm gene of BB/OK rats to develop hyperglycemia or WOKW background gene/s protect/s them for hyperglycemia.
Key words
type 1 diabetes - metabolic syndrome - congenics - hyperglycemia - MHC class II gene
References
-
1
Kovacs P, Voigt B, Berg S. et al .
WOK.1W rats: A potential animal model of the insulin resistance syndrome.
Ann NY Acad Sci.
1997;
827
94-100
-
2
van den Brandt J, Kovacs P, Klöting I.
Features of the metabolic syndrome in the spontaneously hypertriglyceridemic Wistar Ottawa Karlsburg W (RT1u haplotype) rat.
Metabolism.
2000;
49
1140-1144
-
3
van den Brandt J, Kovacs P, Klöting I.
Metabolic features in disease-resistant as well as in hypertensive SHR and newly established obese Wistar Ottawa Karlsburg inbred rats.
Int J Obesity.
2000;
24
1618-1622
-
4
van den Brandt J, Kovacs P, Klöting I.
Metabolic syndrome and ageing in Wistar Ottawa Karlsburg W rats.
Int J Obesity.
2002;
26
1-4
-
5
Klöting N, Blüher M, Klöting I.
The polygenetically inherited metabolic syndrome of WOKW rats is associated with insulin resistance and altered gene expression in adipose tissue.
Diabetes Metab Res Rev.
2006;
22
146-154
-
6
Klöting I, Kovacs P, van den Brandt J.
Sex-specific and sex-independent quantitative trait loci for facets of the metabolic syndrome in WOKW rats.
Biochem Biophys Res Commun.
2001;
284
150-156
-
7
Kovacs P, van den Brandt J, Klöting I.
Genetic dissection of the syndrome X in the rat.
Biochem Biophys Res Commun.
2000;
269
600-605
-
8
Klöting I, Vogt L.
BB/O(ttawa)K(arlsburg) rats: Features of a subline of diabetes-prone BB rats.
Diabetes Res.
1991;
18
79-87
-
9
Klöting I, Voigt B, Vogt L.
Molecular analysis of diabetes-prone BB rat sublines and derivatives of their common ancestor as a tool to search for candidate loci causing different phenotypes in BB rats.
Diabetes Res.
1995;
29
65-71
-
10
Hornum L, Romer J, Markholst H.
The diabetes-prone BB rat carries a frameshift mutation in Ian4, a positional candidate of Iddm1.
Diabetes.
2002;
51
1972-1979
-
11
MacMurray AJ, Moralejo DH, Kwitek AE. et al .
Lymphopenia in the BB rat model of type 1 diabetes is due to a mutation in a novel immune-associated nucleotide (Ian)-related gene.
Genome Res.
2002;
12
1029-1039
-
12
Rutledge EA, Fuller JM, Van Yserloo B. et al .
Sequence Variation and Expression of the Gimap Gene Family in the BB Rat.
Exp Diabetes Res.
2009;
2009:835650. Epub 2009 May 3
-
13
Klöting I, Kovacs P, Kuttler B.
Phenotypic consequences after restoration of lymphopenia in the diabetes-prone BB/OK rat.
Biochem Biophys Res Commun.
1997;
239
106-110
-
14
Klöting N, Follak N, Klöting I.
Diabetes per se and metabolic state influence gene expression in tissue-dependent manner of BB/OK rats.
Diabet Metab Res Rev.
2005;
21
281-287
-
15
Klöting N, Klöting I.
Genetic variation in the multifunctional transcription factor Yy1 and type 1 diabetes mellitus in the BB rat.
Mol Genet Metab.
2004;
82
255-259
-
16
Kuttler B, Volk HD, Kauert C. et al .
Phenotyping of lymphocytes following transplantation of allogeneic rat pancreatic islets into streptozotocin-diabetic recipients.
Exp Clin Endocrinol.
1990;
95
64-69
-
17
Kuttler B, Lehmann M, Lacha J. et al .
Anti-CD4 therapy induces a donor-specific, organ-unspecific tolerance in allogeneic kidney graft recipients.
Transplant Proc.
1994;
26
728-729
-
18
Klöting I, Kovacs P, van den Brandt J.
Congenic BB.SHR (D4Mit6-Npy-Spr) rats: a new aid to dissect the genetics of obesity.
Obes Res.
2002;
10
1074-1077
-
19
Klöting N, Wilke B, Klöting I.
Phenotypic and genetic analysis of subcongenic BB.SHR rat lines shorten the region on chromosome 4 bearing gene(s) for underlying facets of the metabolic syndrome.
Physiol Genomics.
2004;
18
325-330
-
20
Klöting N, Wilke B, Klöting I.
Alleles on rat chromosome 4 (D4Got41-Fabp1/Tacr1) regulate subphenotypes of obesity.
Obes Res.
2005;
13
589-595
-
21
Kovács P, van den Brandt J, Bonné ACM. et al .
Congenic BB.SHR rat provided evidence for effects of a chromosome 4-segment (D4Mit6-Npy ∼1 cM) on total serum and lipoprotein lipid concentration and composition after feeding a high-fat, high-cholesterol diet.
Metabolism.
2001;
50
458-462
Correspondence
I. Klöting
Department of Laboratory
Animal Science
Medical Faculty
University of Greifswald
D-17495 Karlsburg
Germany
Telefon: +49/3834/86 19 261
Fax: +49/3834/86 19 111
eMail: kloeting@uni-greifswald.de
