Yoshihisa Hiromine

Prevention and Treatment of Obesity, Insulin Resistance, and Diabetes by Bile Acid–Binding Resin

Bile acid–binding resins, such as cholestyramine and colestimide, have been clinically used as cholesterol-lowering agents. These agents bind bile acids in the intestine and reduce enterohepatic circulation of bile acids, leading to accelerated conversion of cholesterol to bile acids. A significant improvement in glycemic control was reported in patients with type 2 diabetes whose hyperlipidemia was treated with bile acid–binding resins. To confirm the effect of such drugs on glucose metabolism and to investigate the underlying mechanisms, an animal model of type 2 diabetes was given a high-fat diet with and without colestimide. Diet-induced obesity and fatty liver were markedly ameliorated by colestimide without decreasing the food intake. Hyperglycemia, insulin resistance, and insulin response to glucose, as well as dyslipidemia, were markedly and significantly ameliorated by the treatment. Gene expression of the liver indicated reduced expression of small heterodimer partner, a pleiotropic regulator of diverse metabolic pathways, as well as genes for both fatty acid synthesis and gluconeogenesis, by treatment with colestimide. This study provides a molecular basis for a link between bile acids and glucose metabolism and suggests the bile acid metabolism pathway as a novel therapeutic target for the treatment of obesity, insulin resistance, and type 2 diabetes.

Low programmed cell death‐1 (PD‐1) expression in peripheral CD4+ T cells in Japanese patients with autoimmune type 1 diabetes

Programmed cell death‐1 (PD‐1) is a co‐stimulatory molecule that inhibits T cell proliferation. We aimed to clarify PD‐1 expression in CD4+ T cells and the association between PD‐1 expression and the 7785C/T polymorphism of PDCD1, with a focus on the two subtypes of type 1 diabetes, type 1A diabetes (T1AD) and fulminant type 1 diabetes (FT1D), in the Japanese population. We examined 22 patients with T1AD, 15 with FT1D, 19 with type 2 diabetes (T2D) and 29 healthy control (HC) subjects. Fluorescence‐activated cell sorting (FACS) and real‐time PCR were utilized to analyse PD‐1 expression quantitatively. Genotyping of 7785C/T in PDCD1 was performed using the TaqMan method in a total of 63 subjects (21 with T1AD, 15 with FT1D and 27 HC). FACS revealed a significant reduction in PD‐1 expression in CD4+ T cells in patients with T1AD (mean: 4·2 vs. 6·0% in FT1D, P = 0·0450; vs. 5·8% in T2D, P = 0·0098; vs. 6·0% in HC, P = 0·0018). PD‐1 mRNA expression in CD4+ T cells was also significantly lower in patients with T1AD than in the HC subjects. Of the 63 subjects, PD‐1 expression was significantly lower in individuals with the 7785C/C genotype than in those with the C/T and T/T genotypes (mean: 4·1 vs. 5·9%, P = 0·0016). Our results indicate that lower PD‐1 expression in CD4+ T‐cells might contribute to the development of T1AD through T cell activation.

Clinical and genetic characteristics of patients with autoimmune thyroid disease with anti-islet autoimmunity

In contrast to the large number of studies on autoimmunity against the thyroid gland in patients with type 1 diabetes mellitus, little is known about the anti-islet autoimmune status in patients with autoimmune thyroid diseases (AITDs). We therefore studied the anti-islet autoimmune status in patients with AITD and the clinical and genetic characteristics of AITD patients with anti-islet autoimmunity. The positivity and titer of glutamic acid decarboxylase antibody (GAD Ab) were studied in 866 Japanese patients with AITD (546 with Graves disease and 320 with Hashimoto thyroiditis), 221 patients with thyroid disease of nonautoimmune origin, and 282 control subjects. The clinical characteristics and genotypes of HLA-DRB1, DQB1, and CTLA4 were compared between AITD patients with and without GAD Ab. The prevalence of GAD Ab was significantly higher in AITD patients than in control subjects (5.8% vs 2.1%, P = .01), particularly in Graves disease (7.1% vs 2.1%, P = .0019). The prevalence of diabetes mellitus was significantly higher in AITD patients with GAD Ab than in those without (40.0% vs 10.1%, P < .0001), particularly in those with a high titer of GAD Ab (high vs low titer: 64% vs 16%, P = .001) and also in those positive for insulinoma-associated antigen 2 (IA-2) Ab (IA-2 positive vs negative: 75.0% vs 31.3%, P = .016). The AITD patients with GAD Ab were characterized by younger age at onset of diabetes, lower body mass index, higher hemoglobin A(1c) level, and higher frequency of insulin therapy than those without GAD Ab. The frequency of the DRB1*0405-DQB1*0401 haplotype was significantly higher in AITD patients with GAD Ab than in those without GAD Ab and control subjects. A single nucleotide polymorphism (rs3087243) of CTLA4 was significantly associated with AITD, but not with positivity of GAD Ab. These results indicate that patients with AITD, and in particular Graves disease, are prone to develop β-cell autoimmunity and insulin-requiring diabetes, particularly those with a high titer of GAD Ab and/or positive for both GAD and IA-2 Ab. Glutamic acid decarboxylase Ab positivity in AITD patients was associated with HLA, conferring susceptibility to type 1 diabetes mellitus.

Genetic Basis of Type 1 Diabetes: Similarities and Differences between East and West

Type 1 diabetes is a multifactorial disease caused by a complex interaction of genetic and environmental factors. The genetic factors involved consist of multiple susceptibility genes, at least five of which, HLA, INS, CTLA4, PTPN22 and IL2RA/CD25, have been shown to be associated with type 1 diabetes in Caucasian (Western) populations, as has recently been confirmed by genome-wide association studies. It has been proposed, however, that the contribution of these genes to type 1 diabetes susceptibility may be different in Asian (Eastern) populations. HLA and INS genes are consistently associated with type 1 diabetes in both Caucasian and Asian populations, but apparent differences in disease-associated alleles and haplotypes are observed between Japanese and Caucasian subjects. The association of CTLA4 with type 1 diabetes is concentrated in a subset of patients with autoimmune thyroid disease (AITD) in both Japanese and Caucasian populations, while the association of PTPN22 with type 1 diabetes in Japanese and most Asian populations is not as clear as in Caucasians. IL2RA/CD25 genes seem to be similarly distributed in type 1 diabetes patients in the two populations, whereas genetic heterogeneity may exist regarding SUMO4, with an association of the M55V variant with type 1 diabetes observed in Asians, but not in Caucasians. Genome-wide association studies (GWA) are largely outstanding for Asian populations but they are now underway in Japan. This review reports on the discovered similarities and differences in susceptibility genes for type 1 diabetes between East and West and discusses the most recent observations made by the involved investigators.

Insulin Transactivator MafA Regulates Intrathymic Expression of Insulin and Affects Susceptibility to Type 1 Diabetes

OBJECTIVE Tissue-specific self-antigens are ectopically expressed within the thymus and play an important role in the induction of central tolerance. Insulin is expressed in both pancreatic islets and the thymus and is considered to be the primary antigen for type 1 diabetes. Here, we report the role of the insulin transactivator MafA in the expression of insulin in the thymus and susceptibility to type 1 diabetes. RESEARCH DESIGN AND METHODS The expression profiles of transcriptional factors (Pdx1, NeuroD, Mafa, and Aire) in pancreatic islets and the thymus were examined in nonobese diabetic (NOD) and control mice. Thymic Ins2 expression and serum autoantibodies were examined in Mafa knockout mice. Luciferase reporter assay was performed for newly identified polymorphisms of mouse Mafa and human MAFA. A case-control study was applied for human MAFA polymorphisms. RESULTS Mafa, Ins2, and Aire expression was detected in the thymus. Mafa expression was lower in NOD thymus than in the control and was correlated with Ins2 expression. Targeted disruption of MafA reduced thymic Ins2 expression and induced autoantibodies against pancreatic islets. Functional polymorphisms of MafA were newly identified in NOD mice and humans, and polymorphisms of human MAFA were associated with susceptibility to type 1 diabetes but not to autoimmune thyroid disease. CONCLUSIONS These data indicate that functional polymorphisms of MafA are associated with reduced expression of insulin in the thymus and susceptibility to type 1 diabetes in the NOD mouse as well as human type 1 diabetes.

Association of SUMO4, as a Candidate Gene for IDDM5, with Susceptibility to Type 1 Diabetes in Asian Populations

Abstract:  Recent study demonstrated that M55V variant in SUMO4 at IDDM5 was associated with susceptibility to type 1 diabetes. Subsequent studies, however, showed inconsistency in the association. To clarify the population‐wide effect on the association of SUMO4 with type 1 diabetes, we have performed meta‐analysis including our own data in Asian populations, which confirmed a highly significant association in Asian populations (summary odds ratio [OR]: 1.29, P= 7.0 × 10−6), but indicated significant heterogeneity in the genetic effect of the SUMO4 gene on type 1 diabetes among diverse ethnic groups. These observations indicated the association of SUMO4 with type 1 diabetes in Asian populations.

Direct evidence for susceptibility genes for type 2 diabetes on mouse chromosomes 11 and 14

Aims/hypothesisDiabetogenic loci for type 2 diabetes have been mapped to mouse chromosome (Chr) 11 and 14 in the Nagoya–Shibata–Yasuda (NSY) mouse, an animal model of type 2 diabetes. We aimed to obtain direct evidence of these genes on each chromosome and to clarify their function and interaction in conferring susceptibility to type 2 diabetes.MethodsWe established three consomic strains homozygous for diabetogenic NSY-Chr11, NSY-Chr14 or both on the control C3H background (C3H-11NSY, C3H-14NSY and C3H-11NSY14NSY, respectively), and monitored diabetes-related phenotypes longitudinally. The glucokinase gene was sequenced as a positional candidate gene on Chr11.ResultsC3H-11NSY mice showed hyperglycaemia associated with impaired insulin secretion and age-dependent insulin resistance without obesity. C3H-14NSY mice exhibited hyperglycaemia mainly due to insulin resistance, with a slight increase in percentage body fat. C3H-11NSY14NSY double consomic mice showed marked hyperglycaemia and obesity, which was not observed in single consomic strains. Sequences of the glucokinase gene were allelically variant between NSY and C3H mice.Conclusions/interpretationThese data provide direct evidence that Chr11 and Chr14 harbour major susceptibility genes for type 2 diabetes. These two chromosomes interact to cause more severe hyperglycaemia and obesity, which was not observed with the presence of either single chromosome, indicating different modes of gene–gene interaction depending on the phenotype. Marked changes in the phenotypes retained in the consomic strains will facilitate fine mapping and the identification of the responsible genes and their interaction with each other, other genes and environmental factors.

The Gene for Human IL‐21 and Genetic Susceptibility to Type 1 Diabetes in the Japanese

Abstract:  Type 1 diabetes is under polygenic control both in humans and the NOD mouse. Recently a possible role of IL‐21 in the pathogenesis of type 1 diabetes was demonstrated in the NOD mouse. Furthermore, the murine IL‐21 gene is mapped to the Idd3 interval, making the human IL‐21 gene (IL21) a functional as well as positional candidate for susceptibility. We therefore screened sequence variants of IL21 and studied the association with type 1 diabetes. Preliminary data showed no association of IL21 polymorphisms with the disease, suggesting that IL21 plays little role in susceptibility to type 1 diabetes in Japanese.

Organ Specificity in Autoimmune Diseases: Thyroid and Islet Autoimmunity in Alopecia Areata

CONTEXT Multiple autoimmune diseases, such as autoimmunity against the thyroid gland and pancreatic islets, are often observed in a single patient. Although alopecia areata (AA) is one of the most frequent organ-specific autoimmune diseases, the association of AA with other autoimmune diseases and the genetic basis of the association remain to be analyzed. OBJECTIVE The aim of this study was to clarify the similarities and differences in HLA and clinical characteristics of thyroid and islet autoimmunity in patients with AA. PARTICIPANTS A total of 126 patients with AA were newly recruited. Anti-islet and antithyroid autoantibodies were tested, and genotypes of HLA genes were determined. RESULTS Among the autoimmune diseases associated with AA, autoimmune thyroid disease was most frequent (10.0%), followed by vitiligo (2.7%) and rheumatoid arthritis (0.9%) but not type 1 diabetes (0.0%). The prevalence of thyroid-related autoantibodies in patients with AA was significantly higher than that in controls (TSH receptor antibody [TRAb]: 42.7% vs 1.2%, P = 1.6 × 10(-46); thyroid peroxidase antibody: 29.1% vs 11.6%; P = 1.7 × 10(-6)), whereas the prevalence of islet-related autoantibodies was comparable between patients with AA and control subjects. The frequency of DRB1*15:01-DQB1*06:02, a protective haplotype for type 1 diabetes, was significantly higher in TRAb-positive (12.8%, P = .0028, corrected P value [Pc] = .02) but not TRAb-negative (7.1%, not significant) patients with AA than in control subjects (4.5%). The frequency of DRB1*04:05-DQB1*04:01, a susceptible haplotype for type 1 diabetes, was significantly lower in patients with AA (TRAb-positive: 8.5%; TRAb-negative: 11.9%) than in those with type 1 diabetes (29.5%, Pc < .0003 and Pc < .0008, respectively). CONCLUSION AA was associated with thyroid autoimmunity but not islet autoimmunity, which correlated with class II HLA haplotypes susceptible or resistant to each autoimmune disease.

Molecular scanning of the gene for thioredoxin, an antioxidative and antiapoptotic protein, and genetic susceptibility to type 1 diabetes.

Oxidative stress has been implicated in the destruction of β cells in type 1 diabetes (T1D). Thioredoxin has been shown to protect cells from oxidative stress and apoptosis. In this study, we screened for sequence variants of the human thioredoxin gene (TXN), and studied the association of the variants in persons with T1D in Japanese. The frequency of the A allele of the G/A SNP in the 3′ flanking region was highest in T1D (8.4%), followed by type 2 diabetes (6.8%), and the lowest in the controls (5.9%), suggesting the contribution of TXN polymorphism to susceptibility to T1D.