New animal models reveal that coenzyme Q2 (Coq2) and placenta-specific 8 (Plac8) are candidate genes for the onset of type 2 diabetes associated with obesity in rats.

Obesity is a major risk factor for the onset of type 2 diabetes; however, little is known about the gene(s) involved. Therefore, we developed new animal models of obesity to search for diabetogenic genes associated with obesity. We generated double congenic rat strains with a hyperglycaemic quantitative trait locus (QTL) derived from the Otsuka Long-Evans Tokushima Fatty rat and a fa/fa (Lepr-/-) locus derived from the Zucker Fatty rat; phenotypic analysis for plasma glucose and insulin levels and RNA and protein levels were determined using reverse transcription quantitative PCR and Western blotting analyses, respectively. The double congenic strain F344-fa-nidd2 (Lepr-/- and Nidd2/of) exhibited significantly higher glucose levels and significantly lower hypoglycaemic response to insulin than the obese control strain F344-fa (Lepr-/-). These phenotypes were clearly observed in the obese strains but not in the lean strains. These results indicate that the Nidd2/of locus harbours a diabetogenic gene associated with obesity. We measured the expression of 60 genes in the Nidd2/of QTL region between the strains and found that the mRNA expression levels of five genes were significantly different between the strains under the condition of obesity. However, three of the five genes were differentially expressed in both obese and lean rats, indicating that these genes are not specific for the condition of obesity. Conversely, the other two genes, coenzyme Q2 (Coq2) and placenta-specific 8 (Plac8), were differentially expressed only in the obese rats, suggesting that these two genes are candidates for the onset of type 2 diabetes associated with obesity in rats.

Modifications of azoxymethane-induced carcinogenesis and 90-day oral toxicities of 2-tetradecylcyclobutanone as a radiolytic product of stearic acid in F344 rats.

A 90-day oral toxicity test in rats was performed to evaluate the toxicity of 2-tetradecylcyclobutanone (2-tDCB), a unique radiolytic product of stearic acid. Six-week-old male and female F344 rats (n=15/group) were given 2-tDCB at concentrations of 0, 12, 60 and 300 ppm in a powder diet for 13 weeks. Slight dose-dependent increases in serum total protein and albumin in male rats were found, but these changes were not considered to be a toxic effect. The fasting, but not non-fasting, blood glucose levels of the male rats in the 300 ppm group and female rats in the 60 and 300 ppm groups were lower than those of the controls. Gas chromatography-mass spectrometry analysis showed dose-dependent accumulation of 2-tDCB in adipose tissue, notably in males. Next, we performed an azoxymethane (AOM)-induced two-stage carcinogenesis study. After injection of 6-week-old male F344 rats (n=30/group) once a week for 3 weeks, the animals received 2-tDCB at concentrations of 0, 10, 50 and 250 ppm in a powder diet for 25 weeks. The incidences of colon tumors for the 2-tDCB dosages were 34%, 45%, 40% and 37%, respectively, and were not statistically significant. These data suggest that 2-tDCB shows no toxic or tumor-modifying effects under the present conditions, and that the no-observed-adverse-effect level for 2-tDCB is 300 ppm in both sexes, equivalent to 15.5 mg/kg b.w./day in males and 16.5 mg/kg b.w./day in females.

Molecular mechanisms of apoptosis induction by 2-dodecylcyclobutanone, a radiolytic product of palmitic acid, in human lymphoma U937 cells.

The irradiation of fat-containing food forms 2-dodecylcyclobutanone (2-DCB) from palmitic acid (PA). In this study, we investigated whether 2-DCB and PA induce apoptosis in human lymphoma U937 cells. We found that cell viability decreased by 2-DCB and apoptosis was induced by 2-DCB and PA. 2-DCB and PA significantly enhanced the formation of intracellular reactive oxygen species (ROS). Apoptosis induced by 2-DCB and PA was strongly prevented by an antioxidant, N-acetyl-L: -cysteine. The treatment with 2-DCB and PA resulted in the loss of mitochondrial membrane potential, and Fas, caspase-8 and caspase-3 activation. Pretreatment with a pan-caspase inhibitor (z-VAD) significantly inhibited apoptosis induced by 2-DCB and PA. Moreover, 2-DCB and PA also induced Bax up-regulation, the reduction in Bcl-2 expression level, Bid cleavage and the release of cytochrome c from the mitochondria to the cytosol. In addition, an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) was observed after the treatment with 2-DCB and PA. Our results indicated that intracellular ROS generation, the modulation of the Fas-mitochondrion-caspase-dependent pathway and the increase in [Ca(2+)](i) involved in apoptosis are induced by 2-DCB and PA in U937 cells.

Alterations in activity and energy expenditure contribute to lean phenotype in Fischer 344 rats lacking the cholecystokinin-1 receptor gene.

CCK is hypothesized to inhibit meal size by acting at CCK1 receptors (CCK1R) on vagal afferent neurons that innervate the gastrointestinal tract and project to the hindbrain. Earlier studies have shown that obese Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which carry a spontaneous null mutation of the CCK1R, are hyperphagic and obese. Recent findings show that rats with CCK1R-null gene on a Fischer 344 background (Cck1r(-/-)) are lean and normophagic. In this study, the metabolic phenotype of this rat strain was further characterized. As expected, the CCK1R antagonist, devazepide, failed to stimulate food intake in the Cck1r(-/-) rats. Both Cck1r(+/+) and Cck1r(-/-) rats became diet-induced obese (DIO) when maintained on a high-fat diet relative to chow-fed controls. Cck1r(-/-) rats consumed larger meals than controls during the dark cycle and smaller meals during the light cycle. These effects were accompanied by increased food intake, total spontaneous activity, and energy expenditure during the dark cycle and an apparent reduction in respiratory quotient during the light cycle. To assess whether enhanced responsiveness to anorexigenic factors may contribute to the lean phenotype, we examined the effects of melanotan II (MTII) on food intake and body weight. We found an enhanced effect of MTII in Cck1r(-/-) rats to suppress food intake and body weight following both central and peripheral administration. These results suggest that the lean phenotype is potentially driven by increases in total spontaneous activity and energy expenditure.

Nanostructure of a poly(acrylic acid) brush and its transition in the amphiphilic diblock copolymer monolayer on the water surface.

The nanostructure and its transition of in a poly(acrylic acid) (PAA) brush in the water surface monolayers of poly(hydrogenated isoprene)-b-poly(acrylic acid) with different block lengths and block ratios were investigated by X-ray reflectivity as a function of surface pressure (brush density) and salt concentration in the subphase. The PAA brush showed the same behavior after salt addition as did the poly(methacrylic acid) (PMAA) brush, which was investigated previously. The brush chains expanded and then shrunk after passing the maximum with increasing added salt concentration. This behavior could be explained by the change in electric charges on the PAA brush chains as was observed on the PMAA brush. The PAA brush chains showed a critical brush density, where there was a transition between the carpet layer only and carpet + brush layer structures, as did the PMAA and poly(styrene sulfonic acid) (PSS) brushes. The critical brush density was about 0.4 chains nm(-2), which was higher than that of the PSS brush, a strong acid brush, and was close to that of the PMAA brush, a weak acid brush. However, the critical brush density of the PAA brush was independent of the hydrophilic chain length whereas that of the PMAA brush decreased with increasing PMAA chain length. In addition, the PAA brush had a thicker carpet layer than the PSS and PMAA brushes. Hence, the mechanism of PAA brush formation was predicted to be different from that of not only the PSS brush (strong acid brush) but also the PMAA brush.

OLETF allele of hyperglycemic QTL Nidd3/of is dominant.

The OLETF rat is a well-established model for the study of type 2 diabetes associated with obesity and has been shown to possess multiple hyperglycemic alleles in its genome. Here we focused on and carefully characterized one of the previously reported congenic strains, F.O-Nidd3/of that carries the OLETF allele of the Nidd3/of locus (also known as Niddm21 in the Rat Genome Database) in the normoglycemic F344 genetic background. A prominent finding was that the F1 progeny between the congenic and the F344 stain, whose genotype is heterozygote at the Nidd3/of locus, showed mild hyperglycemia equal to the parental congenic rat, suggesting that the OLETF allele is dominant. To our knowledge, this is the first study in which a diabetic QTL has been directly demonstrated to be dominant by using congenic strains.

Proteomic analysis of a diabetic congenic rat identified age-dependent alteration of an acidic protein.

Proteomic analysis was performed in an attempt to identify a gene responsible for the expression of type 2 diabetes using a congenic rat, F.O-Nidd2/of, which possesses a single hyperglycemic QTL locus derived from the diabetic OLETF (Otsuka Long-Evans Tokushima Fatty) rat. Since the genetic difference between the congenic and its host strain, the F344 rat, is limited to the introgressed segment of 38 cM or ca. 2% of the rat whole genome, any discordant protein spots on two dimensional polyacrylamid gel electrophoresis (2D PAGE) will be considered strong candidate genes of this locus. Here we analyzed ca. one thousand protein spots in three different tissue types, liver, muscle and pancreas at 10, 20 and 30 weeks of age, we found that an acidic protein of 55 kD in muscle tissue shifts towards acidic end in an age dependent fashion in the congenic strain. However, the shift was not observed in the control rat, which is intriguing because the timing of the shift corresponds to the age at which hyperglycemia begins in the congenic. Future biochemical analysis should aid in elucidating the molecular mechanisms of glucose metabolism.

10-Hydroxy-2-decenoic acid, a natural product, improves hyperglycemia and insulin resistance in obese/diabetic KK-Ay mice, but does not prevent obesity.

10-Hydroxy-2-decenoic acid (10H2DA) is a fatty acid found in royal jelly (RJ). In healthy mice, it activates 5'-AMP-activated protein kinase (AMPK) and increases glucose transporter 4 (GLUT4) translocation. Therefore, we examined whether 10H2DA has a potential therapeutic effect against type 2 diabetes in obese/diabetic KK-Ay mice. 10H2DA (3 mg/kg body weight) was administered to female KK-Ay mice for 4 weeks by oral gavage. Phenotypes for body weight, plasma glucose by oral glucose tolerance test and insulin levels were measured. mRNA and protein levels were determined using qRT-PCR and Western blot analyses, respectively. Long-term administration of 10H2DA significantly improved hyperglycemia and insulin resistance in KK-Ay mice, but did not prevent obesity. 10H2DA increased the expression of phosphorylated AMPK (pAMPK) protein in skeletal muscles; however, this expression did not correlate with increased GLUT4 translocation. Furthermore, 10H2DA neither enhanced the expression of adiponectin receptor mRNA nor activated the insulin signaling cascade, such as GSK-3ß phosphorylation, in the liver. We found that 10H2DA-treated mice had a significant increase in the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Pgc-1α) mRNA in skeletal muscles compared with non-treated group (P=0.0024). These findings suggest that 10H2DA is involved in the improvement of type 2 diabetes, at least in part via activation of Pgc-1α expression, but does not prevent obesity.

Royal jelly improves hyperglycemia in obese/diabetic KK-Ay mice.

The study examined whether royal jelly (RJ) can prevent obesity and ameliorate hyperglycemia in type 2 diabetes. This study utilized obese/diabetic KK-Ay mice. RJ (10 mg/kg) was administered by oral gavage. Body weight, plasma glucose and insulin levels were measured. mRNA and protein levels were determined using quantitative reverse transcription polymerase chain reaction and western blotting, respectively. Four weeks of RJ administration improved hyperglycemia and partially suppressed body weight gain, although the latter effect did not reach statistical significance. In addition, RJ administration did not improve insulin resistance. RJ administration suppressed the mRNA expression of glucose-6-phosphatase (G6Pase), a key enzyme of gluconeogenesis, in the liver. Simultaneously, RJ administration induced adiponectin (AdipoQ) expression in abdominal fat, adiponectin receptor-1 (AdipoR1) expression in the liver and phosphorylated AMP-activated protein kinase (pAMPK) expression, which suppressed G6Pase levels in the livers of KK-Ay mice. pAMPK levels were also increased in skeletal muscle, but glucose transporter-4 (Glut4) translocation was not increased in the RJ supplementation group. The improvement in hyperglycemia due to long-term RJ administration may be because of the suppression of G6Pase expression through the upregulation of AdipoQ and AdipoR1 mRNA and pAMPK protein expressions.

Plekhs1 and Prdx3 are candidate genes responsible for mild hyperglycemia associated with obesity in a new animal model of F344-fa-nidd6 rat.

Type 2 diabetes is a polygenic disease and characterized by hyperglycemia and insulin resistance, and it is strongly associated with obesity. However, the mechanism by which obesity contributes to onset of type 2 diabetes is not well understood. We generated rat strains with a hyperglycemic quantitative trait locus (QTL) derived from the Otsuka Long-Evans Tokushima Fatty rat and a fa/fa (Lepr-/-) locus derived from the Zucker Fatty rat. Phenotypes for plasma glucose, and insulin levels were measured, and RNA and protein levels were determined using reverse transcription quantitative PCR and Western blot analyses, respectively. Compared with the obese control strain F344-fa (Lepr-/-), plasma glucose levels of the obese F344-fa-nidd6 (Lepr-/- and Nidd6/of) significantly increased, and plasma insulin levels significantly decreased. These phenotypes were not observed in the lean strains, suggesting that the Nidd6/of locus harbors a diabetogenic gene associated with obesity. We measured the expression of 41 genes in the Nidd6/of QTL region of each strain and found that the mRNA expression levels of the two genes significantly differed between the obese strains. The two genes, pleckstrin homology domain-containing, family S member 1 (Plechs1) and peroxiredoxin III (Prdx3), were differentially expressed only in the obese rats, suggesting that these two genes are involved in the mild elevation of blood glucose levels and insulin resistance in obesity.

Fine mapping of the hyperglycemic and obesity QTL by congenic strains suggests multiple loci on rat chromosome 14.

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.

[Successfully resected advanced gastric carcinoma after combined chemotherapy of TS-1 plus CDDP--a case report].

A 66-year-old man complained of epigastralgia and a close examination was done. A type 3 gastric carcinoma was found. The tumor invading the pancreas and swelling lymphnodes around the stomach were confirmed according to abdominal CT. We considered it difficult to resect the tumor completely, and so we used combined chemotherapy of TS-1 plus CDDP. TS-1 was taken at 120 mg/day for 28 days followed by 14 days rest. CDDP was injected at 140 mg on day 8. Because the tumor in the stomach changed to scar and swelling lymphnodes diminished after two courses of therapy, total gastrectomy was done. After operation, combined chemotherapy of LV and 5-FU resulted in no recurrence to date. Although combined chemotherapy of TS-1 plus CDDP is effective for advanced gastric carcinoma, the number of days TS-1 is taken and the duration of the preoperative chemotherapy must be investigated in forthcoming study.

Use of Drosophila as an evaluation method reveals imp as a candidate gene for type 2 diabetes in rat locus Niddm22.

Type 2 diabetes (T2D) is one of the most common human diseases. QTL analysis of the diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats has identified numerous hyperglycemic loci. However, molecular characterization and/or gene identification largely remains to be elucidated due mostly to the weak genetic variances contributed by each locus. Here we utilized Drosophila melanogaster as a secondary model organism for functional evaluation of the candidate gene. We demonstrate that the tissue specific knockdown of a homologue of igf2bp2 RNA binding protein leads to increased sugar levels similar to that found in the OLETF rat. In the mutant, the expression of two of the insulin-like peptides encoded in the fly genome, dilp2 and dilp3, were found to be downregulated. Consistent with previous reports of dilp mutants, the imp mutant flies exhibited an extension of life span; in contrast, starvation tolerance was reduced. These results further reinforce the possibility that imp is involved in sugar metabolism by modulating insulin expression.

Expression of G1 phase-related cell cycle molecules in naturally developing hepatocellular carcinoma of Long-Evans Cinnamon rats.

It has been shown that a variety of cell cycle-related proteins play important roles in the process of carcinogenesis including hepatocarcinogenesis. In the present study, we evaluated mRNA and protein expression of G1 phase-related cell cycle molecules in the process of hepatocarcinogenesis, using Long-Evans Cinnamon (LEC) rats, an animal model of hepatocellular carcinoma (HCC). The expression of cyclin D1, cyclin-dependent kinase 4 (Cdk4) and Cdk6 was measured quantitatively by real-time polymerase chain reaction. Cyclin D1 mRNA expression was increased significantly in chronic hepatitis liver compared with normal liver, and then decreased in HCC and the surrounding precancerous liver of LEC rats. Levels of Cdk4 mRNA were increased significantly in HCC compared to precancerous and chronic hepatitis livers. In contrast, mRNA levels of Cdk6 did not change significantly during hepatocarcinogenesis. We also evaluated the protein levels of these G1 phase-related cell cycle molecules by Western blot analyses and confirmed similar results. Total amounts of retinoblastoma protein (pRb) in the liver did not change significantly in the process of hepatocarcinogenesis in LEC rats. However, levels of phosphorylated pRb were increased markedly in the process of hepatocarcinogenesis, and the highest in HCC compared to precancerous, chronic hepatitis and normal livers. These results indicate that cyclin D1 may be involved in the regeneration of hepatocytes rather than hepatocarcinogenesis, while Cdk4 but not Cdk6 may play an important role in the development of HCC.

Long-term consequences of Kawasaki disease among first-year junior high school students.

OBJECTIVE: To determine whether height, weight, and electrocardiographic (ECG) abnormalities differ at the age of 13 years between adolescents with and without Kawasaki disease (KD) (also known as mucocutaneous lymph node syndrome). DESIGN: A population-based cohort study. SETTING: School community and public health service. METHODS: Data from the nationwide surveys of KD in Japan were linked with those of junior high school cardiac screening in Tochigi Prefecture between April 1, 1986, and June 30, 1998 (except data for 1988 and 1994). Using this database, students with KD and students without KD in the first year of junior high school were compared. MAIN OUTCOME MEASURES: Height, weight, and ECG abnormalities. RESULTS: Eight hundred sixty students (486 adolescent boys and 374 adolescent girls) with KD and 308 729 students (158 193 adolescent boys and 150 536 adolescent girls) without KD were located. There was no difference in average height and weight between the students with and without KD (using the P values for a t test of the means). The proportion of abnormal ECG findings was 10% and 3% among those with and without KD, respectively. CONCLUSION: Even at age 13 years, the proportion of abnormal ECG findings was about 3 times higher among adolescents with KD (using a chi(2) test of the difference in 2 binomial proportions).

A congenic strain (F344.OLETF-Imfm) displays the existence of intramuscular fat accumulation QTL on rat chromosome 1.

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.

Detection of a quantitative trait locus for intramuscular fat accumulation using the OLETF rat.

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.

Single diabetic QTL derived from OLETF rat is a sufficient agent for severe diabetic phenotype in combination with leptin-signaling deficiency.

Obesity has been considered one of the leading causative agents for diseases such as type 2 diabetes, stroke, and heart attack. Due to their complex etiology, establishing a useful animal model is increasingly crucial for better molecular understanding of how obesity influences on disease development. OLETF rat is a spontaneous model of type 2 diabetes. We mapped 14 hyperglycemia QTLs in the genome of the OLETF rat and subsequently generated a panel of congenic strains each possessing OB-R mutation in F344 genetic background. Here we show that one of the loci, Nidd2/of, is highly responsive to obesity. When leptin receptor mutation is introgressed into the Nidd2/of congenic strain, the rat showed hyperglycemia equivalent to that of the parental OLETF rat. This suggests that the Nidd2/of locus has a strong genetic interaction with leptin signaling pathway. Furthermore, when another hyperglycemia QTL Nidd1/of is additionally combined, the strain developed overt diabetes. A single QTL dissected out in spontaneous model normally exerts only mild effect on the quantitative trait, which makes it difficult to clone the gene. Our new model may help not only to identify the causative gene but also to investigate how obesity interacts with a QTL to regulate diabetic traits.

Genetic dissection of complex genetic factor involved in NIDDM of OLETF rat.

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese-type, noninsulin-dependent diabetes mellitus (NIDDM) in humans. NIDDM in this rat model was shown to be regulated by multiple genes. We have identified 14 quantitative trait loci (QTLs) responsible for NIDDM (Nidd1-14/of) on chromosomes 1, 5, 7, 8, 9, 11, 12, 14, 16, and 17 by a whole genome search in 160 F2 progenies obtained by mating the OLETF and the F344 rats. Among these loci, two QTLs, Nidd1 and 2/of, were declared significant loci at a genome-wide level. Nidd3, 8, 9, and 13/of exhibited heterosis: heterozygotes showing significantly higher glucose levels than OLETF or F344 homozygotes. We also found evidence for interaction (epistasis) between Nidd1/of and Nidd2/of, between Nidd1/of and Nidd10/of, between Nidd2/of and Nidd8/of, and between Nidd2/of and Nidd14/of. Furthermore, Nidd6 and 11/of showed linkage with body weight, and Nidd1, 2, 8, 9, 10, and 12/of had an interaction with body weight. These indicated that NIDDM in the OLETF would have a higher degree of genetic complexity. We suggest several interesting candidate genes located in rat genomic regions for Nidd1-14/of or the syntenic regions in human genome.

Genetic interaction between hyperglycemic QTLs is manifested under a high calorie diet in OLETF-derived congenic rats.

The condition of hyperglycemia results from multiple genetic and environmental factors. In recent years much progress has been made with regards to the search for candidate genes involved in the expression of various common diseases including type 2 diabetes. However less is known about the specific genetic and environmental connections that are important for the development of the disease. In the present study, we used hyperglycemic congenic rats to address this issue. When given a normal diet, two hyperglycemic QTLs (quantitative trait locus), Nidd2/of and Nidd10/of, showed mild obesity and/or increased blood glucose in the oral glucose tolerance test. In a double congenic strain possessing both loci, these indices were not significantly different from those of either single congenic strain. In contrast, the double congenic strain fed a high-calorie diet showed significantly greater body weight than the single congenic strains or normoglycemic control rats. Although postprandial glucose levels of the double congenic rat were not further aggravated even on the high fat diet, it was notable that the postprandial insulin levels were drastically elevated. From these results, we constructed a novel model animal especially for the study of prediabetic hyperinsulemia, in which two QTLs and an additional dietary condition are involved. This may help to shed light on the genetic basis and gene-to-diet interaction during the early stage of type 2 diabetes.