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Linkage analysis previously identified a hyperglycemic quantitative trait locus (QTL), Nidd 2/of, on rat Chromosome 14 in crosses utilizing OLETF (Otsuka Long Evans Tokushima Fatty) rat, a model for type 2 diabetes. A separate QTL study mapped an obesity QTL, Obs5, to the same chromosomal region. A congenic strain placing ca. 38 cM OLETF-derived segments containing both Nidd2/of and Obs5 on the F344 background was shown to possess mild diabetic and obese phenotypes, suggesting the presence of mutations affecting the glucose metabolism and fat accumulation. In order to localize the loci more precisely, we generated a series of deletion-subcongenic strains in which OLETF-segments were shortened from either ends. We found that there are at least two hyperglycemic QTLs within the Nidd2/of locus. We predict that they are localized towards both ends of the Nidd2/of region. In contrast, Obs5 QTL was further narrowed down to a single region of ca. 10 cM fragment.

Left atrial (LA) function is associated with left ventricular (LV) diastolic filling and cardiac output response to exercise. But the relation between LA function and exercise performance has not been adequately evaluated. The aim of this study was to investigate the relation between LA function and exercise capacity in dilated cardiomyopathy (DCM) with cardiopulmonary exercise testing. Forty-four patients with a left ventricular end-diastolic dimension (LVDd) > or = 60 mm and an ejection fraction (EF) < or = 40%, and in normal sinus rhythm were included in this study. Patients were divided into group 1 and group 2 according to their exercise peak oxygen uptake (VO2) (group 1: peak VO2 >14 mL/kg/min, group 2: peak VO2 < or = 14 mL/ kg/min). LA function indices were defined as follows: LA end-systolic diameter (LASd), end-diastolic diameter (LADd), LA systolic volume (LASV), LA diastolic volume (LADV), LA ejection volume (LAEV), and LA ejection fraction (LAEF). LASd, LADd, LASV, and LADV were significantly increased in group 2 (P < 0.001, P < 0.001, P < 0.05, P < 0.005). Group 1 had significantly higher LAEF (P < 0.001 ) and LVEF (P < 0.05). Group 2 had significantly shorter exercise duration, and decreased anaerobic threshold levels and minute ventilation volumes (P < 0.001, P < 0.001, P < 0.005 ). There was a positive correlation between peak VO2 and LVEF (r = 0.46, P = 0.002), and LAEF (r = 0.61, P < 0.001), peak A wave velocity (r = 0.39, P = 0.009), E wave deceleration time (r = 0.56, P < 0.001), and isovolumic relaxation time (IVRT) (r = 0.35, P = 0.04). There was a negative correlation between peak VO2 and LASd (r = -0.53, P < 0.001) LADd (r = -0.59, P < 0.001), LASVI (r = -0.34, P = 0.027), LADVI (r = -0.37, P = 0.001), and the E/A ratio (r = -0.41, P = 0.006), Decreased LAEF and increased LA sizes were associated with decreased peak VO2. The results clearly demonstrate that LA functions at rest are related to exercise performance in patients with heart failure.

Leptin is produced by adipose tissue and acts as a feedback signal to the hypothalamus controlling energy homeostasis, by reducing food consumption and increasing energy expenditure. Because serum leptin levels are highly correlated with body fat mass, they can be used as an index to predict obesity-related diseases. However, the identity of genetic factors that influence the obesity and the obesity-related metabolic disorders remains largely unknown. In this study, we performed a whole-genome scan search, using 382 F2 intercross progeny between the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model for obese type 2 diabetes in human, and F344 rat, in order to identify loci responsible for the regulation of leptin and other obesity-related plasma substances. We have identified two quantitative trait loci (QTLs) contributing to serum leptin levels. These two loci, designated Olep1 [Chromosome (Chr) 2] and Olep2 (Chr 6), were homologous to those of human genome regions containing several potential candidate genes for obesity. These are fatty acid-binding protein 2 (FABP2), FABP4, and FABP5 for Olep1, and proopiomelanocortin (POMC) and glucose regulatory protein (GCKR) for Olep2.

The rat strain Otsuka Long-Evans Tokushima Fatty (OLETF) is an animal model for type 2 diabetes mellitus. Nidd8/of has been identified as one of 14 quantitative trait loci (QTLs) involved in the diabetes by a whole genome search in 160 F2 progenies obtained by mating the OLETF and F344 rats. Comparative mapping between human and rat indicated that the Nidd8/of genomic region, near D9rat21 on rat chromosome 9, contains the calpain10 (Capn10) gene, which is putative type 2 diabetes-susceptibility gene in humans. In this study, we found no difference in Capn10 mRNA expression in the heart, liver, skeletal muscle and pancreas between OLETF and F344 rats at 5 and 10 weeks of age. However, we found a single nucleotide polymorphism (SNP) (A/A genotype in OLETF and G/G genotype in F344 and LETO rats) at the base 583 downstream from the translation start site in the rat Capn10 cDNA sequence. This SNP was deduced to substitute serine (OLETF) for glycine (F344 and LETO) at the 195 amino acid residue within the protease domain of rat Capn10. Because serine is generally not interchangeable with glycine in respect of the protein structure and function, it was deduced that the A/A genotype in OLETF is not a 'safe' mutation. This non-conservative amino acid substitution might be associated with susceptibility to type 2 diabetes in OLETF rats.

A genomic region between D1Wox8 and D1Rat90 on rat chromosome 1 was previously shown to be linked to intramuscular fat accumulation by quantitative trait locus (QTL) analysis using a F2 population derived from the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, which exhibits an increase in the levels of intramuscular fat content in Musculus longissimus, and the F344 rat. There exist two regions showing major and minor lod peaks for linkage to intramuscular fat accumulation, in the chromosomal region. We constructed a congenic strain introgressing the OLETF allele on the minor but not the major lod peak region in the F344 rat strain. The congenic strain had higher levels of intramuscular fat content in Musculus longissimus than the inbred partner F344 rat, thereby proving the existence of a QTL, designated Imfm (for Intramuscular fat-minor), responsible for the intramuscular fat accumulation in the congenic region of the minor lod peak region of about 10 cM. The F344.OLETF-Imfm congenic strain might provide a refined tool for the analysis of the gene causing intramuscular fat accumulation.

The Otuska Long-Evans Tokushima Fatty (OLETF) rat is one of the well-characterized animal models for the study of type 2 diabetes. Our previous QTL mapping identified 11 loci responsible for non-insulin-dependent diabetes mellitus (NIDDM) susceptibility in the OLETF rat. Here we generated a series of congenic animals by individually introgressing all 11 OLETF-derived NIDDM loci into a normoglycemic F344 background. Subsequent oral glucose tolerance test revealed that the congenic strains for Nidd1/of, Nidd2/of, Nidd3/of Nidd4/of, Nidd7/of, and Nidd10/of showed significantly higher levels of blood glucose in comparison with parental host strain F344. Furthermore, simultaneously made heterozygote animals for Nidd1/of and Nidd2/of did not increase blood glucose levels, indicating that these loci are recessively inherited as predicted by the QTL analysis. Congenic strains for the other five loci-Nidd5/of, Nidd6/of, Nidd8/of, Nidd9/of, and Nidd11/of-were apparently normoglycemic, presumably owing to heterosis or because the effect of these loci may not be detected unless interactions with other OLETF genes exist. We believe that these congenic strains should provide useful agents for decomposing complex diabetic traits and for positional cloning.

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese type 2 diabetes. We showed that the OLETF rat exhibits higher levels of intramuscular fat content in Musculus longissimus as compared to the Fischer-344 (F344) rat. Our investigation was designed to identify quantitative trait loci (QTLs) contributing to the increased levels of intramuscular fat content by performing a whole-genome search using 108 F2 intercross obtained by mating the OLETF and the F344 rats. We identified one QTL responsible for intramuscular fat accumulation on rat chromosome 1 with a maximum lod score of 3.4, which accounts for 5% of the total variance. As expected, the OLETF allele corresponds to the increased levels of intramuscular fat content.

A number of studies have indicated that cholecystokinin type A receptor (CCK-AR) plays a crucial role in postnatal pancreatic proliferation and blood glucose regulation through stimulating insulin secretion. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat has been shown to possess poor pancreatic proliferation (PPP) capability after pancreatectomy (Px). Here we have constructed a congenic strain which introgressed an OLETF-derived 18.5 cM genomic fragment identified in our previous quantitative trait locus (QTL) analysis as a locus responsible for PPP into normoglycemic F344 genetic background The introgressed region includes CCK-AR null mutation. After Px, the congenic rat showed weak pancreatic proliferation equivalent to that of the OLETF rat. Furthermore, post-surgery non-fasting blood glucose levels for the congenic rats are significantly higher in comparison with the F344 rats. At 28 days after Px, the congenic rats also showed lower blood insulin levels than the F344 rats. These results further provide the genetic evidence that 1) CCK-AR is essential for pancreatic regeneration; 2) impaired pancreatic proliferation mediates the development of hyperglycemia.

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese type 2 diabetes in human. Obesity is essential for the onset of type 2 diabetes in this rat. Our present investigation was designed to identify quantitative trait loci (QTLs) contributing to obesity by performing a whole-genome search using 214 F(2) intercross progeny between OLETF and F344 rats. We have identified six QTLs responsible for adiposity indices of fat pads on rat chromosomes 2 (Obs1 for mesenteric fat), 4 (Obs2 for retroperitoneal fat), 8 (Obs3 for mesenteric fat), 9 (Obs4 for retroperitoneal fat), and 14 (Obs5 and Obs6 for retroperitoneal fat), demonstrating that the adiposity indices of individual fat pads were under the control of different genes. As expected, the OLETF allele corresponds to increased adiposity indices for all QTLs, except for Obs3, in which the F344 allele leads to an increase in the index., (Copyright 2000 Academic Press.)

We have developed a new surgical technique, 'total en bloc spondylectomy' (TES), to treat a solitary metastasis in the thoracic or lumbar vertebra. This operation is designed as a local cure for the metastatic site and involves the radical resection of the affected vertebra with a wide margin. The spondylectomy consists of two steps: en bloc laminectomy with posterior spinal instruments for stabilisation (first step) and en bloc corporectomy and replacement using a vertebral prosthesis (second step). TES makes it possible to remove the affected vertebra extracompartmentally with its tumour barrier and accomplishes circumferential decompression of the spinal cord. Before clinical practice, we constructed experimental models using cats to examine spinal cord blood flow (SCBF) after ligation of the nerve roots and circumspinal decompression. The changes of SCBF were negligible, so it was proved that TES on one vertebra has little effect on spinal cord circulation. This method was used in 24 patients. Fourteen of the 18 patients with neurological deficits improved remarkably, and the 23 evaluable cases experienced pain relief. Impending paralysis was prevented in all six patients by this surgical intervention. There has been no recurrence of the local tumour after surgery. After a median follow up period of 14.1 months, 12 patients have survived. These data suggest that TES may have a significant clinical value in the treatment of spinal metastasis.