Involvement of microsomal triglyceride transfer protein in nonalcoholic steatohepatitis in novel spontaneous mouse model.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is currently recognized as a global health issue and encompasses a wide spectrum of entities, ranging from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). The lack of a spontaneous animal model of NASH, however, has hampered basic research in this field. METHODS: We examined the hepatic lesions in the inbred Fatty Liver Shionogi (FLS) mouse, which exhibits type 2 diabetes, and investigated the molecular mechanism leading to NAFLD/NASH. Using vector-mediated hepatic expression of microsomal triglyceride transfer protein (MTP), a key molecule for very low density lipoprotein (VLDL) assembly and export, its contribution to the hepatic lesions as well as to glucose intolerance was examined. RESULTS: The FLS mouse, maintained on normal chow, exhibited excessive hepatic triglyceride (TG) accumulation due to impaired VLDL secretion, and subsequently hepatic lesions comparable to NASH, with increased expression of inflammatory molecules as well as insulin resistance. Gene expression and Western blot analyses demonstrated reduced hepatic expression of MTP in the FLS mouse. Hepatic induction of MTP resulted in a reduction in hepatic TG accumulation, improvement of VLDL export, and amelioration of NASH-like lesions, as well as glucose intolerance. CONCLUSIONS: These data suggest that the FLS mouse could serve as a spontaneous model of NASH with insulin resistance, and that reduced MTP is involved in the development of NASH, pointing towards MTP as a critical target for the prevention and treatment of NASH.

A novel mouse model for type 2 diabetes and non-alcoholic fatty liver disease: spontaneous amelioration of diabetes by augmented beta cell mass.

Given the potential for beta-cells to increase their mass, glucose intolerance might be ameliorated by a compensatory increase in beta-cell mass. However, it remains uncertain whether such amelioration is feasible in vivo. In this study, we investigated glucose tolerance, islet morphology, and islet gene expression of Fatty Liver Shionogi (FLS) mice, a model for non-alcoholic fatty liver disease (NAFLD). Relative to control mice, FLS mice showed an age-dependent increase in glucose intolerance up to the age of 24 weeks, leading to the development of diabetes. After this time, glucose tolerance ameliorated spontaneously and diabetes resolved by 48 week of age, associated with marked hyperinsulinemia. Islets of the FLS mice demonstrated a marked increase in beta-cell mass with an increase in beta-cell numbers. Islet gene expression analysis in FLS mice demonstrated no changes in gene expression of glucokinase or insulin receptor substrate 2. These data demonstrated that the 24-week-old FLS mouse is a model for type 2 diabetes with NAFLD and that the 48-week-old FLS mouse exhibits spontaneous amelioration of type 2 diabetes associated with augmented beta-cell number/mass.

Trinucleotide repeats of programmed cell death-1 gene are associated with susceptibility to type 1 diabetes mellitus.

Multiple genes are involved in conferring susceptibility to autoimmune type 1 diabetes mellitus. The immunoreceptor programmed cell death-1 (PDCD-1), an inhibitory costimulatory molecule regulating peripheral tolerance, is reported to play an important role in the development of type 1 diabetes mellitus, making the human PDCD-1 gene, PDCD1, a candidate for disease susceptibility. The aim of this study was to clarify the contribution of PDCD1 to genetic susceptibility to type 1 diabetes mellitus in humans. To screen for sequence variants, we sequenced all 5 exons and exon-intron junctions of PDCD1 in Japanese subjects, 16 with type 1 diabetes mellitus and 16 without the disease. Some of the sequence variations identified were genotyped in larger samples (n = 275) with and without type 1 diabetes mellitus by polymerase chain reaction restriction fragment length polymorphism method or a fluorescence-based method. The distributions of polymorphisms were compared between patients with type 1 diabetes mellitus and healthy controls by contingency table analysis and Pearson chi(2) test. In this study, we found 16 sequence variants, including a TGC repeating variant in the 3' untranslated region. We found this variant to be associated with the development of type 1 diabetes mellitus. These data suggest the contribution of PDCD1 and its gene product to the development of type 1 diabetes mellitus.

Present state of diabetes management in the elderly, Japan.

A recent dramatic increase in elderly patients with diabetes mellitus has made the proper management of the disease in this population more important. Here, we discuss the present status of diabetes management in the elderly in Japan. As a characteristic feature of elderly persons, body weight reduction is difficult, because of the profound adaptive reduction in resting energy expenditure under calorie restriction in the elderly. However, hyperglycemia increases the risk for diabetic complications, except proliferative retinopathy, similarly in elderly and non-elderly. Of note, there is marked clinical heterogeneity in this generation in the following aspects: duration, complication status (past aspect), insulin secretion, insulin sensitivity, familial support and physical exercise/activity (present aspect), as well as the expected lifespan (future aspect). This heterogeneity among the elderly should render diabetes treatment diverse, and in fact, one of the largest surveys in Japan demonstrated significant diversity in diabetes management in the elderly. In Japan, thus, the present management of diabetes in the elderly is considerably diverse, reflecting the clinical heterogeneity among elderly patients with diabetes. Further clinical evidence is awaited for the establishment of proper and safe management of diabetes in the elderly.

Molecular scanning of interleukin-21 gene and genetic susceptibility to type 1 diabetes.

A recent study in the nonobese diabetic (NOD) mouse demonstrated the involvement of interleukin (IL)-21 in the pathogenesis of type 1 diabetes. A strong susceptibility locus, Idd3, has also been mapped to the interval containing the murine gene for IL-21 (Il21), making Il21 and the human orthologue IL21 a functional and positional candidate gene for type 1 diabetes. To investigate the contribution of the human genes for IL-21 and its receptor (IL-21R) to susceptibility to type 1 diabetes, we re-sequenced IL21 to identify novel sequence variants, searched for informative variants of IL21R, and studied the association of these variants with the disease. Two polymorphisms, a single nucleotide polymorphism (SNP) and a mononucleotide repeat polymorphism, were identified for IL21, and an allele of the mononucleotide repeat polymorphism was positively associated with the disease. Two novel microsatellite polymorphisms of IL21R were identified, one of which was associated with the disease. Scoring of individuals according to the status of these alleles showed a significant trend for high scores for susceptibility in diabetes patients, suggesting the contribution of IL21 and IL21R to disease susceptibility in an additive manner. These data suggest a contribution of IL21 and IL21R to genetic susceptibility to type 1 diabetes and possible involvement of IL-21 and its receptor system in the disease pathogenesis.

Association of small ubiquitin-like modifier 4 (SUMO4) variant, located in IDDM5 locus, with type 2 diabetes in the Japanese population.

CONTEXT: Despite distinct differences in the pathogenesis, epidemiological data have indicated familial clustering of type 1 and type 2 diabetes, suggesting a common genetic basis between these two types of diabetes. Few shared susceptibility genes, however, have been reported to date. OBJECTIVE: Small ubiquitin-like modifier 4 (SUMO4) has been identified as a candidate gene for the IDDM5 locus and suggested to have possible involvement in immune responses, such as autoimmunity and inflammation. Recent reports demonstrated that a polymorphism with an amino acid substitution (Met55Val) in SUMO4 was associated with type 1 diabetes in Asian populations, although no association was reproduced in subjects of Caucasian descent. The present study aimed to clarify the contribution of SUMO4 to type 2 diabetes susceptibility in the Japanese population. SUBJECTS: The 753 subjects included 355 cases and 398 control subjects. METHODS: The SUMO4 Met55Val (rs237025) and 001Msp (rs577001) polymorphisms were genotyped. RESULTS: Strong linkage disequilibrium (D': 1.0 in each pair of single-nucleotide polymorphisms) across the MAP3K7IP2/SUMO4 region was shown in the Japanese population. The frequency of genotypes with the G allele of the SUMO4 Met55Val polymorphism was significantly higher in patients with type 2 diabetes [odds ratio, 1.46; 95% confidence interval (CI), 1.08-1.93; P = 0.01, chi(2) test]. The association was concentrated in patients without insulin therapy (odds ratio, 1.56; 95% CI, 1.13-2.15; P = 0.0072), but not in those with insulin (odds ratio, 1.24; 95% CI, 0.81-1.89; not significant). CONCLUSIONS: These data, together with previous reports, suggest the contribution of the SUMO4 Met55Val polymorphism to both type 1 and type 2 diabetes susceptibility in the Japanese population.