Substitution of Dmo1 with normal alleles results in decreased manifestation of diabetes in OLETF rats.
OBJECTIVE
Dmo1 (Diabetes Mellitus OLETF type I) is a major quantitative trait locus for dyslipidaemia, obesity and diabetes phenotypes in the Otsuka Long Evans Tokushima Fatty (OLETF) rat strain. To evaluate possible metabolic and pathological improvements generated by correction of the Dmo1 genetic pathway, we produced congenic lines, in which both OLETF Dmo1 alleles are replaced by the F344-derived genome.


METHODS
Congenic animals were produced by introgressing F344-derived Dmo1 alleles into the OLETF rat. Congenic animals of the fourth generation (BC4) were intercrossed to obtain F1 animals (BC4:F1). Animals of the next generation, BC4:F2, were used for this study. We used 23 BC4:F2 males harbouring homozygous replacement of the OLETF Dmo1 region with the F344-derived genome. Seven animals with OLETF-derived Dmo1 alleles were used as controls.


RESULTS
Dmo1-F344/F344 congenic rats showed significant decreases in body weight, abdominal fat weight, serum triacylglycerols, total cholesterol, food consumption and blood glucose after glucose loading (13%, 39%, 45%, 27%, 18% and 27% respectively; p < 0.05) compared with Dmo1-OLETF/OLETF animals. Furthermore, histopathological analysis of the kidney showed that mesangial sclerosis, hyalin deposits and deposition of PAS-positive substance were significantly lower in Dmo1-F344/F344 animals (p < 0.05).


CONCLUSIONS
Improvements in metabolic parameters and histopathological scores show that correction of the Dmo1 genetic pathway in the diabetic and mildly obese OLETF rat strain produces wide-ranging therapeutic effects. Thus, this pathway might represent a new drug target also applicable to humans.
Okuno
S
S
Otsuka GEN Research Institute, Otsuka Pharmaceutical Co. Ltd, Kawauchi-cho, Tokushima, Japan.
Kondo
M
M
Yamasaki
Y
Y
Miyao
H
H
Ono
T
T
Iwanaga
T
T
Omori
K
K
Okano
M
M
Suzuki
M
M
Momota
H
H
Hishigaki
H
H
Hayashi
I
I
Goto
Y
Y
Shinomiya
H
H
Harada
Y
Y
Hirashima
T
T
Kanemoto
N
N
Asai
T
T
Wakitani
S
S
Takagi
T
T
Nakamura
Y
Y
Tanigami
A
A
Watanabe
T K
TK
D000818:Animals; D020296:Animals, Congenic; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics; D006943:Hyperglycemia / Q000378:metabolism; D006949:Hyperlipidemias / Q000378:metabolism; D007668:Kidney / Q000648:ultrastructure; D008099:Liver / Q000648:ultrastructure; D008297:Male; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D011916:Rats, Inbred F344; D020334:Rats, Inbred OLETF