Animal models have provided important information for the genetics and pathophysiology of diabetes. Here we have established a novel, nonobese rat strain with spontaneous diabetes, Long-Evans Agouti (LEA) rat derived from Long-Evans (LE) strain. The incidence of diabetes in the males was 10% at 6 months of age and 86% at 14 months, while none of the females developed diabetes. The blood glucose level in LEA male rats was between 200 and 300 mg/dl at 120 min according to OGTT. The glucose intolerance in correspondence with the impairment of insulin secretion was observed in male rats, which was the main cause of diabetes in LEA rats. Histological examination revealed that the reduction of β-cell mass was caused by progressive fibrosis in pancreatic islets in age-dependent manner. The intracytoplasmic hyaline droplet accumulation and the disappearance of tubular epithelial cell layer associated with thickening of basement membrane were evident in renal proximal tubules. The body mass index and glycaemic response to exogenous insulin were comparable to those of control rats. The unique characteristics of LEA rat are a great advantage not only to analyze the progression of diabetes, but also to disclose the genes involved in type 2 diabetes mellitus.

this study investigated the correlation of four single nucleotide polymorphisms (Snps) in Apolipoprotein M (ApoM) with the risk of type 2 diabetes mellitus (T2DM) and effects of the interactions of this gene and obesity. The effects of SNP and obesity interaction on T2DM was examined by generalized multifactor dimensionality reduction (GMDR) combined with the logistic regression model. T2DM patient-control haplotype was analyzed in silico using the haplotype analysis algorithm SHesis. The rs805296-C allele or 724-del allele indicted high risk of T2DM. The incidence of T2DM in individuals with rs805296-C allele polymorphism (TC + cc) was higher than those without (tt), adjusted oR (95%CI) = 1.29 (1.10-1.66) (p < 0.001). Moreover, the individuals with 724-delallele have a higher risk of T2DM compared to those with 724-ins variants, adjusted OR (95%CI) = 1.66 (1.40-2.06), p < 0.001. GMDR analysis suggested that the interaction model composed of the two factors, rs805296 and obesity, was the best model with statistical significance (P value from sign test [P sign ]=0.0107). The T2DM risk in obese individuals having TC or CC genotype was higher than non-obese individuals with tt genotype (oR = 2.38, 95% CI = 1.58-3.53). Haplotype analysis suggests that rs805297-C and rs9404941-C alleles haplotype indicate high risk of T2DM, OR (95%CI) = 1.62 (1.29-2.16), p < 0.001. Our results suggested that rs805296 and 724-del minor allele of ApoM gene, interaction of rs805296 and obesity, rs805297-C and rs9404941-C alleles haplotype were indicators of high T2DM risk. Among adults in China, the estimated overall prevalence ofdiabetes was 10.9%, and that for prediabetes was 35.7%. Thus, the prevalence of type 2 diabetes mellitus (T2DM) in China is the highest in the world 1 , and the number of patients with T2DM will be about 438 million in 2030 2,3. Unfortunately, the incidence of T2DM will continue to increase in the next decades in many countries, including China, due to longevity of human life and obesity 4. The development and progression of T2DM are believed to be closely correlated with the interaction of multiple susceptibility genes and gene interactions with the environment 5-7. Human apolipoprotein M gene is structurally conserved across species and located at the human chromosome 6p21.33 8,9. ApoM is reported to be highly expressed in liver and kidneys, but weakly expressed in other human tissues 10. Previous studies reported associations between ApoM gene variations and human diseases, including CAD and T2DM; however, these observations remain controversial 11-15. In Chinese populations, Xu et al. 11 showed the ApoM rs9404941 (T-855C) polymorphism predicts a high incidence of CAD. Furthermore, ApoM rs805296 (T-778C) polymorphism was closely related with the incidence of either type 1 or type 2 diabetes 12,13. However, the association of Apo Mgene polymorphism in rs805296 (T-778C) and the risk of T2DM was found in another independent study based on Southern Chinese population 14. Emerging evidence showed that genetic and ...

Mottled Tohoku (Atp7a(Mo-Tohm) or Mo(Tohm)) is an X-linked mutation with mottled pigmentation in heterozygous (Mo(Tohm)/+) females and is embryonic lethal at E11 in hemizygous (Mo(Tohm)/Y) males. Copper levels were low in the brain and high in the intestine of Mo(Tohm) mice. Two congenic strains with ICR or C57BL/6 (B6) background were produced for genetic and phenotypic analyses and revealed that Mo(Tohm)/+ females with ICR background survived until adulthood, while most with B6 background died within 2 days after birth. The Mo(Tohm)/Y males with both backgrounds died at around E11. Massive hemorrhage was shown in the yolk sac cavity with irregular attachment between the mesoderm and the endothelial cells of blood vessels in the embryos at E10.5, suggesting that this irregular attachment causes embryonic lethality. The Mo(Tohm) mutant had a 1440-bp deletion between intron 22 and exon 23 of the Atp7a gene. Mo(Tohm)/Y males with the wild-type Atp7a cDNA transgene were rescued from embryonic lethality, confirming that the Mo(Tohm) mutant is caused by the defect in the Atp7a gene. This mutant mouse is the most severe model of human Menkes disease in mottled mice established to date and one of the useful models for understanding the gene function of Menkes disease.

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