Identification of two nickel ion-induced genes, NCI16 and PcGST1, in Paramecium caudatum.

Here, we describe the isolation of two nickel-induced genes in Paramecium caudatum, NCI16 and PcGST1, by subtractive hybridization. NCI16 encoded a predicted four-transmembrane domain protein (∼16 kDa) of unknown function, and PcGST1 encoded glutathione S-transferase (GST; ∼25 kDa) with GST and glutathione peroxidase (GPx) activities. Exposing cells to cobalt chloride also caused the moderate upregulation of NCI16 and PcGST1 mRNAs. Both nickel sulfate and cobalt chloride dose dependently induced NCI16 and PcGST1 mRNAs, but with different profiles. Nickel treatment caused a continuous increase in PcGST1 and NCI16 mRNA levels for up to 3 and 6 days, respectively, and a notable increase in H2O2 concentrations in P. caudatum. NCI16 expression was significantly enhanced by incubating cells with H2O2, implying that NCI16 induction in the presence of nickel ions is caused by reactive oxygen species (ROS). On the other hand, PcGST1 was highly induced by the antioxidant tert-butylhydroquinone (tBHQ) but not by H2O2, suggesting that different mechanisms mediate the induction of NCI16 and PcGST1. We introduced a luciferase reporter vector with an ∼0.42-kb putative PcGST1 promoter into cells and then exposed the transformants to nickel sulfate. This resulted in significant luciferase upregulation, indicating that the putative PcGST1 promoter contains a nickel-responsive element. Our nickel-inducible system also may be applicable to the efficient expression of proteins that are toxic to host cells or require temporal control.

Mediobasal hypothalamic PTEN modulates hepatic insulin resistance independently of food intake in rats.

Phosphatase and tensin homolog (PTEN) dephosphorylates phosphatidylinositol (PI) 3,4,5-triphosphate and antagonizes PI 3-kinase. Insulin acts in the mediobasal hypothalamus (MBH) to not only suppress food intake and weight gain but also improve glucose metabolism via PI 3-kinase activation. Thus, the blocking of hypothalamic PTEN is a potential target for treating obesity as well as diabetes. However, genetic modification of PTEN in specific neuronal populations in the MBH yielded complex results, and no postnatal intervention for hypothalamic PTEN has been reported yet. To elucidate how postnatal modification of hypothalamic PTEN influences food intake as well as glucose metabolism, we bidirectionally altered PTEN activity in the MBH of rats by adenoviral gene delivery. Inhibition of MBH PTEN activity reduced food intake and weight gain, whereas constitutive activation of PTEN tended to induce the opposite effects. Interestingly, the effects of MBH PTEN intervention on food intake and body weight were blunted by high-fat feeding. However, MBH PTEN blockade improved hepatic insulin sensitivity even under high-fat-fed conditions. On the other hand, constitutive activation of MBH PTEN induced hepatic insulin resistance. Hepatic Akt phosphorylation and the G6Pase expression level were modulated bidirectionally by MBH PTEN intervention. These results demonstrate that PTEN in the MBH regulates hepatic insulin sensitivity independently of the effects on food intake and weight gain. Therefore, hypothalamic PTEN is a promising target for treating insulin resistance even in states of overnutrition.

New diagnostic criteria (2023) for slowly progressive type 1 diabetes (SPIDDM): Report from Committee on Type 1 Diabetes in Japan Diabetes Society (English version).

The diagnostic criteria for slowly progressive type 1 diabetes (slowly progressive insulin-dependent diabetes mellitus; SPIDDM) have been revised by the Committee on Type 1 Diabetes of the Japan Diabetes Society. All of the following three criteria must be met for "a definitive diagnosis of SPIDDM": (1) presence of anti-islet autoantibodies at some point in time during the disease course; (2) absence of ketosis or ketoacidosis at the diagnosis of diabetes with no requirement of insulin treatment to correct hyperglycemia immediately after diagnosis in principle; and (3) gradual decrease of insulin secretion over time, with insulin treatment required at more than 3 months after diagnosis, and presence of severe endogenous insulin deficiency (fasting serum C-peptide immunoreactivity < 0.6 ng/mL) at the last observed point in time. When a patient fulfills the only (1) and (2), but not (3), he/she is diagnosed with "SPIDDM (probable)" because the diabetes is non-insulin-dependent state.

New diagnostic criteria (2023) for slowly progressive type 1 diabetes (SPIDDM): Report from Committee on Type 1 Diabetes of the Japan Diabetes Society (English version).

The diagnostic criteria for slowly progressive type 1 diabetes (slowly progressive insulin-dependent diabetes mellitus; SPIDDM) have been revised by the Committee on Type 1 Diabetes of the Japan Diabetes Society. All of the following three criteria must be met for 'a definitive diagnosis of SPIDDM': (1) presence of anti-islet autoantibodies at some point in time during the disease course; (2) absence of ketosis or ketoacidosis at the diagnosis of diabetes with no requirement for insulin treatment to correct hyperglycemia immediately after diagnosis in principle; and (3) gradual decrease of insulin secretion over time, with insulin treatment required at more than 3 months after diagnosis, and the presence of severe endogenous insulin deficiency (fasting serum C-peptide immunoreactivity <0.6 ng/mL) at the last observed point in time. When a patient fulfills only (1) and (2), but not (3), he/she is diagnosed with 'SPIDDM (probable)' because the diabetes is non-insulin-dependent type.

Prediction of future insulin-deficiency in glutamic acid decarboxylase autoantibody enzyme-linked immunosorbent assay-positive patients with slowly-progressive type 1 diabetes.

AIMS/INTRODUCTION: This study aimed to identify risk factors that contribute to the progression of slowly-progressive type 1 diabetes by evaluating the positive predictive value (PPV) of factors associated with the progression to an insulin-dependent state. MATERIALS AND METHODS: We selected 60 slowly-progressive type 1 diabetes patients who tested positive for glutamic acid decarboxylase autoantibodies (GADA) at diagnosis from the Japanese Type 1 Diabetes Database Study. GADA levels in these patients were concurrently measured using both radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) techniques. RESULTS: Compared with the non-progressor group (fasting C-peptide [F-CPR] levels maintained ≥0.6 ng/mL), the progressor group showed a younger age at diagnosis, lower body mass index (BMI), lower F-CPR levels and a higher prevalence of insulinoma-associated antigen-2 autoantibodies (IA-2A). The PPV of RIA-GADA increased from 56.3 to 70.0% in the high titer group (≥10 U/mL), and further increased to 76.9, 84.2, 81.0 and 75.0% when combined with specific thresholds for age at diagnosis <47 years, BMI <22.6 kg/m2, F-CPR <1.41 ng/mL and IA-2A positivity, respectively. In contrast, the PPV of ELISA-GADA (71.8%) remained the same at 73.1% in the high titer group (≥180 U/mL), but increased to 81.8, 82.4 and 79.0% when evaluated in conjunction with age at diagnosis, BMI and F-CPR level, respectively. CONCLUSIONS: Our findings show that, unlike RIA-GADA, ELISA-GADA shows no association between GADA titers and the risk of progression to an insulin-dependent state. The PPV improves when age at diagnosis, BMI and F-CPR levels are considered in combination.

A low-frequency GLIS3 variant associated with resistance to Japanese type 1 diabetes.

The role of low-frequency variants in type 1 diabetes (T1D) susceptibility still remains to be clarified. In the present study, we analyzed low-frequency variants of the T1D candidate genes in Japanese. We first screened for protein-changing variants of 24 T1D candidate genes in 96 T1D patients and 96 control subjects, and then the association with T1D was tested in 706 T1D patients and 863 control subjects recruited from the collaborating institutions in Japan. In total, 56 protein-changing variants were discovered; among them, 34 were low-frequency variants (allele frequency < 5%). The association analysis of the low-frequency variants revealed that only the A908V variant of GLIS3 was strongly associated with resistance to T1D (Haldane's odds ratio = 0.046, p = 8.21 × 10(-4), and pc=2.22 × 10(-2)). GLIS3 is a zinc finger transcription factor that is highly expressed in pancreatic beta cells, and regulates beta cell development and insulin gene expression. GLIS3 mRNA is also moderately expressed in the human thymus. The precise mechanism responsible for the association is unclear at present, but the A908V variant may affect autoimmunity to the GLIS3 protein itself; the 908V containing epitope may induce central or peripheral tolerance more efficiently than that of 908A.

Clostridium butyricum MIYAIRI 588 improves high-fat diet-induced non-alcoholic fatty liver disease in rats.

BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD) has become a common liver disease, as its prevalence has increased markedly in recent decades. The aim of the present study was to examine the improving effect of Clostridium butyricum MIYAIRI 588 (CBM588), a probiotic in clinical use for antibiotic-associated diarrhea, against high-fat diet (HFD)-induced fatty liver in rats. METHODS: After feeding HFD or HFD coated with CBM588 (HFD-CBM) for 12 weeks, we evaluated the hepatic mRNA levels related to lipid metabolism, and then assessed the hepatic protein levels of several transcription factors regulating these lipogenic gene expressions. RESULTS: The HFD-CBM group had decreased accumulation of lipid droplets in the liver compared with the HFD group. The HFD-CBM group had significantly decreased diacylglycerol acyltransferase (DGAT) 2 mRNA in the liver compared with the HFD group, whereas DGAT1 mRNA did not change between the HFD group and the HFD-CBM group. Moreover, the HFD-CBM group had significantly increased hepatic mRNA regulating cholesterol catabolism enzymes and excretion transporters. Correspondingly, the HFD-CBM588 groups had increased hepatic protein levels of peroxisome proliferator-activated receptor α/γ and liver X receptor α compared with the HFD group. The HFD-CBM group had accelerated excretion of total bile acid and non-esterified fatty acid in the feces. CONCLUSIONS: CBM588 intake may have novel potential for improving NAFLD.

VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death.

Amyotrophic lateral sclerosis (ALS) is an incurable degenerative disorder of motoneurons. We recently reported that reduced expression of Vegfa causes ALS-like motoneuron degeneration in Vegfa(delta/delta) mice. In a meta-analysis of over 900 individuals from Sweden and over 1,000 individuals from Belgium and England, we now report that subjects homozygous with respect to the haplotypes -2,578A/-1,154A/-634G or -2,578A/-1,154G/-634G in the VEGF promoter/leader sequence had a 1.8 times greater risk of ALS (P = 0.00004). These 'at-risk' haplotypes lowered circulating VEGF levels in vivo and reduced VEGF gene transcription, IRES-mediated VEGF expression and translation of a novel large-VEGF isoform (L-VEGF) in vivo. Moreover, SOD1(G93A) mice crossbred with Vegfa(delta/delta) mice died earlier due to more severe motoneuron degeneration. Vegfa(delta/delta) mice were unusually susceptible to persistent paralysis after spinal cord ischemia, and treatment with Vegfa protected mice against ischemic motoneuron death. These findings indicate that VEGF is a modifier of motoneuron degeneration in human ALS and unveil a therapeutic potential of Vegfa for stressed motoneurons in mice.

Graft failure after allogeneic islet transplantation in a patient with type 1 diabetes and a high anti-glutamic acid decarboxylase antibody titer.

Pancreatic islet transplantation is a ß-cell replacement therapy for people with insulin-deficient diabetes who have difficulty in glycemic control and suffer from frequent severe hypoglycemia. However, the number of islet transplantations carried out is still limited in Asia. We report a case of allogeneic islet transplantation in a 45-year-old Japanese man with type 1 diabetes. Although the islet transplantation was successfully carried out, graft loss was observed on the 18th day. Immunosuppressants were used in accordance with the protocol, and donor-specific anti-human leukocyte antigen antibodies were not detected. Autoimmunity relapse was also not observed. However, the patient had a high titer of anti-glutamic acid decarboxylase antibody from before the islet transplantation, and autoimmunity might thus have affected the ß-cells in the transplanted islet. The evidence is still scarce to reach conclusions, and further data accumulation is required to enable proper patient selection before islet transplantation.

Comparing the clinical significance and antigen specificity of insulinoma-associated antigen-2 autoantibodies between radioimmunoassay and enzyme-linked immunosorbent assay in Japanese patients with type 1 diabetes.

AIMS/INTRODUCTION: This study aimed to investigate the clinical significance and antigen specificity of autoantibodies to insulinoma-associated antigen-2 (IA-2A) by radioimmunoassay (RIA; IA-2A-RIA) and enzyme-linked immunosorbent assay (ELISA; IA-2A-ELISA) in Japanese patients with type 1 diabetes. MATERIALS AND METHODS: A total of 338 type 1 diabetic patients were enrolled, including 38 fulminant type 1 diabetes, 168 acute-onset type 1 diabetes and 137 slowly-progressive type 1 diabetes (SPIDDM). The concordance, correlation of autoantibody titer, and the relationship between IA-2A and progression to the insulin-deficient state were examined. Also, competitive assay was used to examine the antigen specificity. RESULTS: The prevalence of IA-2A-ELISA was 4-5% lower than that of IA-2A-RIA in both the acute-onset type 1 diabetes and SPIDDM, but the diagnostic sensitivities of both subtypes, when measured in combination with glutamic acid decarboxylase autoantibody, were comparable. The diagnosis of type 1 diabetes using either the RIA or ELISA methods showed substantial agreement with the exponential correlation of autoantibody titers detected by RIA and ELISA. Among the SPIDDM patients, the fasting C-peptide for IA-2A-positive cases by ELISA, but not the RIA method, was significantly lower than in the negative cases (P < 0.05). Furthermore, IA-2A-ELISA proved superior to the RIA method in predicting the progression to insulin deficiency in SPIDDM. Competitive analysis showed that even sera with discrepant results by RIA and ELISA have IA-2-specific autoantibodies. CONCLUSION: These results suggest that IA-2A-ELISA is a reliable marker not only for the diagnosis of type 1 diabetes, but also for the prediction of future insulin dependency; that is, detection of IA-2A-ELISA helps identify a subtype of SPIDDM patients who would likely progress onto insulin-deficient state.

Bivalent GAD autoantibody ELISA improves clinical utility and risk prediction for adult autoimmune diabetes.

AIM/INTRODUCTION: To investigate the differences in the clinical significance and glutamic acid decarboxylase autoantibody (GADA) affinity between RIA (RIA-GADA) and ELISA (ELISA-GADA) in patients with type 1 diabetes. METHODS: A total of 415 patients with type 1 diabetes were enrolled, including 199 acute-onset type 1 diabetes, 168 slowly progressive type 1 diabetes (SPIDDM), and 48 fulminant type 1 diabetes. GADA affinity was measured by a competitive binding experiment using unlabeled recombinant human GAD65 protein, and the diagnostic performance of both assays and the relationship between GADA affinity and the decline of fasting C-peptide (F-CPR) were examined. RESULTS: While the ELISA-GADA displayed a higher sensitivity than the RIA method in diagnosing type 1 diabetes in acute-onset patients, about 40% of SPIDDM patients with low-titer RIA-GADA were determined as negative by the ELISA method. Patients with type 1 diabetes with RIA-GADA alone had an older age of onset, less diabetic ketoacidosis, a higher BMI, and a higher F-CPR compared with patients positive for both RIA-GADA and ELISA-GADA. Additionally, 36% of RIA-GADA-positive patients had low-affinity GADA (<1010 L/mol), which was significantly higher than in the ELISA-GADA-positive patients (4%, P < 0.0001). Furthermore, over a 3 year monitoring period, F-CPR levels decreased in ELISA-GADA-positive SPIDDM, whereas it was maintained in patients with RIA-GADA alone, regardless of GADA affinity. CONCLUSIONS: These results suggest that bivalent ELISA for GADA is superior to the RIA method in diagnosing type 1 diabetes. Moreover, the diagnostic superiority of the ELISA-GADA made possible the concurrent identification of SPIDDM patients at high-risk of early progression, and allowed for more accurate clinical diagnosis and management.

Hypoglycemic effects of colestimide on type 2 diabetic patients with obesity.

Recent studies have shown colestimide, a bile acid-binding resin, to also exert a glucose-lowering effect via amelioration of insulin resistance. To evaluate the effects of colestimide on glucose metabolism and to elucidate the underlying mechanism, we conducted a 6-month, open-label pilot study on 43 type 2 diabetic patients with obesity (BMI ≥ 25). The subjects were randomized to either treatment with colestimide 4g/day (T group, n=23) or continuation of their current therapy (C group, n=20). In the T group patients, mean HbA1c and fasting glucose improved markedly (from 7.71 ± 0.32% to 6.97 ± 0.20%; from 147.4 ± 7.3mg/dL to 127.0 ± 5.0mg/dL, respectively), while obesity-related parameters, i.e. body weight, waist circumference, and visceral fat and subcutaneous fat as determined by umbilical slice abdominal CT, showed no significant changes. Fractionation analyses of serum bile acids revealed significantly increased cholic acids (CA) and decreased chenodeoxycholic acids (CDCA) in the T group patients. However, no correlation was observed between these changes and ΔHbA1c. According to logistic regression analysis, baseline HbA1c was the only variable predicting the decrease of HbA1c (>0.5%) among sex, age, BMI, total cholesterol, ΔCA and ΔCDCA. The index of insulin resistance, i.e. HOMA-R, did not improve, and the index of ß cell function, i.e. HOMA-ß, actually increased significantly. These results suggests that, in obese patients with type 2 diabetes, the mechanism underlying improved glycemic control with colestimide treatment involves enhanced ß cell activity rather than improved insulin resistance.

Japanese Type 1 Diabetes Database Study (TIDE-J): rationale and study design.

Type 1 diabetes (T1D) is classified into three subtypes: acute-onset, slowly progressive, and fulminant T1D, according to the heterogeneity of clinical course in Japan. Although several cross-sectional databases of T1D have been reported, prospective longitudinal databases to investigate clinical outcomes are lacking in our country. Therefore, we herein construct multi-center prospective longitudinal database of the three subtypes of T1D, accompanied with genetic information and biobanking, which is named Japanese Type 1 Diabetes Database Study (TIDE-J). Inclusion criteria of this study are as follows: (1) the duration of T1D was less than 5 years, (2) the patients had one or more islet-related autoantibodies and/or fasting serum C-peptide levels were less than 1.0 ng/mL, (3) the patients could clearly understand the study consent in writing. In the TIDE-J, clinical data, including glycemic control, endogenous insulin secretion, islet-related autoantibodies, diabetic complications, and treatment, are collected annually using electric data collection system, which is named REDCap. Furthermore, HLA genotypes of each participant were analyzed at entry and the blood samples were stored for assessing exploratory markers and further genetic analysis annually. The TIDE-J certainly helps in revealing distinct clinical course of each T1D subtype. Moreover, this database may help in identifying novel markers for diagnosing each subtype of T1D and predicting clinical outcomes (including pancreatic beta cell function and disease severity) in patients.

Associations of cigarette smoking but not serum fatty acids with age-related macular degeneration in a Japanese population.

PURPOSE: To assess modifiable environmental risk factors and protective factors for age-related macular degeneration (AMD) in a native Japanese population. DESIGN: A case-control study. PARTICIPANTS: We included 422 case-control samples composed of 279 consecutive AMD cases and 143 controls. METHODS: Information regarding systemic conditions and lifestyle were documented in each subject by standardized questionnaire including age, gender, smoking history, body mass index (BMI), and history of cardiovascular disease, hypertension, and diabetes. Serum fatty acids profiles were analyzed by gas chromatography performed on blood samples taken from each study participant. Logistic regression and multiple comparison analyses were utilized in this study. MAIN OUTCOME MEASURES: Population-specific information assessing systemic conditions, lifestyle, and serum fatty acid profiles. RESULTS: Among environmental factors analyzed cigarette smoking showed the most significant association with development of all AMD (P<0.00001; odds ratio [OR], 4.06; 95% confidence interval [CI], 2.22-7.43), typical neovascular AMD (P<0.0001, OR, 4.59; 95% CI, 2.29-9.18), and polypoidal choroidal vasculopathy (P<0.001; OR, 4.87; 95% CI, 1.96-12.1). Hypertension and BMI showed a mild association with AMD. Although male prevalence was significantly higher in all case groups than in controls with conventional Scheffe correction, there was no association of gender with AMD development when logistic regression analysis was used to adjust for cigarette smoking. There was no difference in fatty acid profiles, except for a mild association of eicosapentaenoic acid concentration in the all AMD group. CONCLUSIONS: In the Japanese population studied, cigarette smoking influenced the risk of AMD but fractionated serum fatty acid levels did not. Although prior reports indicate a male predominance in Japanese patients with AMD, this study demonstrates that cigarette smoking accounts for this confounding bias. In addition, our population-specific data do not demonstrate significant differences in serum fatty acid composition, including ω-3 and ω-6 long chain polyunsaturated fatty acids, in Japanese patients with and without AMD. These results are consistent with the high proportion of smokers in aged Japanese men and the high fish oil intake in this population. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Complement factor H and high-temperature requirement A-1 genotypes and treatment response of age-related macular degeneration.

PURPOSE: To determine whether there is an association between complement factor H (CFH), high-temperature requirement A-1 (HTRA1), vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor (PEDF) genotypes and response to treatment with photodynamic therapy (PDT) for age-related macular degeneration (AMD) in a Japanese population. DESIGN: Prospective, case-control study. PARTICIPANTS: One hundred ten patients with exudative AMD treated by verteporfin PDT were recruited prospectively at the Department of Ophthalmology, Saitama Medical University Hospital, Saitama, Japan. METHODS: The patients were genotyped for 4 single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996, rs2274700) in the CFH gene, a rs11200638-SNP in the HTRA1 gene, 3 SNPs (rs699947, rs1570360, rs2010963) in the VEGF gene, and 4 SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the PEDF gene using a TaqMan assay. MAIN OUTCOME MEASURES: The treatment outcomes and genotypes of CFH, HTRA1, VEGF, and PEDF polymorphisms. RESULTS: Best-corrected visual acuity 1 year after PDT was significantly increased in patients with the HTRA1-rs11200638 GG genotype as compared with patients with the GA or AA genotypes (P = 2.9 × 10⁻², 7.0 × 10⁻4, respectively). The rate of recurrence in the 12-month period after PDT was also associated with HTRA1-rs11200638 genotype (P = 3.12 × 10⁻²). Patients with the AA genotype of HTRA1-rs11200638 had an approximately 6-fold greater risk of the recurrence than patients with the GG genotype (P = 5.58 × 10⁻³). Significant differences were demonstrated in the mean time interval from the initial treatment to the time of recurrence for the genotypes of CFH-rs1410996/-rs2274700 (P = 8.50 × 10⁻³). CONCLUSIONS: The HTRA1-rs11200638 and CFH-rs1410996/-rs2274700 variants were associated with response to PDT in this study population. These variants may be used for genetic biomarkers to estimate visual outcomes and recurrences in the response to PDT with significant predictive power.

Analysis of the HLA and non-HLA susceptibility loci in Japanese type 1 diabetes.

BACKGROUND: We previously reported the associations of human leukocyte antigen (HLA) (DRB1 and DQB1), INS, CTLA4, IL2RA, ERBB3 and CLEC16A with Japanese type 1 diabetes (T1D). In this study, we jointly analysed these loci in addition to IFIH1 and IL7R. METHODS: A maximum of 790 T1D patients and 953 control subjects were analysed. HLA was determined by sequencing-based typing. Seven non-HLA single nucleotide polymorphisms were genotyped using TaqMan assay. RESULTS: HLA DRB1*0405, DRB1*0901 and DRB1*0802-DQB1*0302 haplotypes were positively associated with T1D, while the DRB1*15 haplotypes were negatively associated. Non-HLA single nucleotide polymorphisms, INS, IL2RA, ERBB3, CLEC16A and IL7R were associated with T1D. By a prediction model using the HLA loci alone (HLA model) or the non-HLA loci alone (non-HLA model), it was revealed that the cumulative effect of the non-HLA model was much weaker than that of the HLA model (average increase in odds ratio: 1.17 versus 3.14). Furthermore, the area under the receiver operating characteristic curve of the non-HLA model was also much smaller than that of the HLA model (0.65 versus 0.81, p<10(-11)). Finally, a patient-only analysis revealed the susceptible HLA haplotypes and the risk allele of INS to be negatively associated with slower onset of the disease. In addition, the DRB1*0901 haplotype and the risk alleles of ERBB3, CLEC16A and CTLA4 were positively associated with the co-occurrence of thyroid autoimmunity. CONCLUSIONS: Although several non-HLA susceptibility genes in Japanese were confirmed trans-racially and appear to contribute to the heterogeneity of the clinical phenotypes, the cumulative effect on the ability to predict the development of T1D was weak.

Phenotype and genotype characteristics of age-related macular degeneration in a Japanese population.

PURPOSE: To describe phenotype and genotype characteristics of age-related macular degeneration (AMD) in Japanese patients. DESIGN: A case-control study. PARTICIPANTS: A total of 550 case-control samples composed of 408 consecutive AMD cases and 142 controls. METHODS: Clinical information assessing age, gender, affected eyes, fundus features, and fluorescein/indocyanine green angiograms were systematically evaluated. Four single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996, rs2274700) in the complement factor H (CFH) gene, 1 SNP (rs11200638) in the high-temperature requirement factor A1 (HTRA1) gene, 3 SNPs (rs699947, rs1570360, rs2010963) in the vascular endothelial growth factor (VEGF) gene, and 4 SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the pigment epithelium-derived factor (PEDF) gene were assessed using TaqMan technology. MAIN OUTCOME MEASURES: The clinical phenotype information and genotypes of CFH, HTRA1, VEGF, and PEDF polymorphisms. RESULTS: Of Japanese patients with neovascular AMD (nAMD), 219 (58.7%) had typical nAMD and 154 (41.3%) had polypoidal choroidal vasculopathy (PCV). The frequency of bilateral exudative involvement was similar between typical nAMD (15.5%) and PCV (13.6%) (P = 0.613). Significant soft drusen were observed in the fellow eyes of 88 (47.6%) of 185 patients with unilateral typical nAMD and in 25 (18.8%) of 133 patients with unilateral PCV (P = 1.24x10(-7)). A serous pigment epithelium detachment was seen in 55 (25.1%) of 219 patients with typical nAMD and in 64 (41.6%) of 154 patients with PCV. A significant association was noted in CFH-rs800292, CFH-rs1410996, CFH-rs2274700, and HTRA1-rs11200638 with AMD development (P = 2.36x10(-5), 7.18x10(-5), 7.18x10(-5), 2.70x10(-7), respectively; population attributable risk = 57.3%, 57.8%, 57.8%, and 58.9%, respectively). We estimated the highest-risk group to have an approximately 70-fold greater risk of nAMD compared with the lowest-risk group when analyzing a combination of 4 SNPs in the CFH and HTRA1 genes. CONCLUSIONS: The Japanese AMD phenotype is characterized by a higher frequency of PCV, male predominance, and lower frequency of bilateral presentation compared with Caucasian AMD. Genotype analyses demonstrate a significant population attributable risk for SNPs in the CFH and HTRA1 genes and demonstrate joint effects for both genes. Gene variants in both CFH and HTRA1 contribute significantly to the AMD phenotype in a Japanese population.

Pancreas transplantation for type 1 diabetes in Japan: past, present and future prospects.

In Japan, the first pancreas transplantation was performed in 1984 from a brain-dead donor; subsequently, however, the concept of brain death became a social issue. Thereafter, the "Organ Transplant Act", which enables brain-dead transplantation, was enacted in 1997, and then revised in 2010 so that donation after brain death became possible only with the consent of the family. Under the recipient selection and registration system developed after the enactment of the "Organ Transplant Act", more than 400 pancreas transplants have been carried out at facilities certified for brain-dead pancreas transplantation in Japan. Of the 410 total cadaveric pancreas transplants performed by the end of 2019, the patient survival and pancreatic and kidney graft survival rates were considered to be comparable to those in the United States and Europe despite the high frequency of marginal donors. Minimally invasive allogenic islet transplantation came to be covered by national health insurance in 2020 following good outcomes of a recent trial. Furthermore, to overcome the serious donor shortage in Japan, development of xenogeneic islet transplantation and regenerative medicine using stem cells is in progress, with xenotransplantation using porcine islets appearing particularly promising.

Association of type 1 diabetes with two Loci on 12q13 and 16p13 and the influence coexisting thyroid autoimmunity in Japanese.

CONTEXT: Recent genome-wide association studies have identified several novel type 1 diabetes (T1D) loci in white populations. OBJECTIVE: In line with recent findings, we conducted a replication study of two loci on chromosome 12p13 and 16p13 and assessed their potential associations with thyroid autoimmunity in a Japanese population. SUBJECTS AND METHODS: Two single-nucleotide polymorphisms (SNPs), rs2292399 in ERBB3 on 12q13 and rs2903692 in CLEC16A (or KIAA0350) on 16p13, were analyzed in Japanese subjects consisting of 735 T1D patients, 330 patients with autoimmune thyroid disease (AITD), and 621 control subjects. RESULTS: According to a case-control study and logistic regression adjusting for sex and age, we observed that these SNPs in ERBB3 and CLEC16A were both significantly associated with T1D, with the risk alleles being consistent with those in white populations [adjusting odds ratio by multiplicative model: 1.37 (1.13-1.67), P = 0.001; and 1.28 (1.02-1.60), P = 0.030, respectively]. In both SNPs, the association was suggested to be stronger in T1D complicated with AITD (Graves' disease, Hashimoto's thyroiditis, or thyroid autoantibodies). Furthermore, a joint analysis, with the INS and CTLA4 SNPs, revealed that CTLA4 rs3087243, ERBB3 rs2292399, and CLEC16A rs2903692, but not INS rs689, were significant risk factors for the cooccurrence of AITD in Japanese T1D. CONCLUSION: We confirmed two loci on 12q13 and 16p13 that were identified by the independent genome-wide association studies in white populations, thus suggesting that these loci contribute to T1D susceptibility across different ethnic groups. In addition, these loci may also be associated with the cooccurrence of thyroid autoimmunity in T1D.

Dopamine D1-like receptor antagonist, SCH23390, exhibits a preventive effect on diabetes mellitus that occurs naturally in NOD mice.

Dopamine receptors have five isoforms, termed D1-D5. The D1 and D5 receptors form the D1-like group that couples with the Galphas class of G proteins, while D2, D3 and D4 form the D2-like group that couples with the Galphai class of G proteins. In our previous studies, a D1-like-R antagonist, SCH23390, inhibited DC-mediated Th17 differentiation and exhibited preventive and therapeutic effects on experimental autoimmune encephalomyelitis (EAE) in mice. We herein demonstrate in the current study that in the pancreas obtained from NOD mice, islet infiltrates appear to be composed of mononuclear cells positive for IL-23R, one of the specific markers for Th17. Thereafter, NOD mice were orally administered SCH23390 from week 6 to week 26. At week 26, 67% and 25% of mice developed diabetes in the control and the SCH23390 groups, respectively (p<0.05). A histological examination of SCH23390-treated mice exhibited a typical normal islet structure with no signs of periductal and perivascular infiltrates, whereas the islets from vehicle controls showed insulitis. In week 26, spleen cells were re-stimulated with anti-CD3 and anti-CD28 antibodies in vitro and exhibited an augmentation of IFNgamma induction and the suppression of IL-17 induction in the SCH23390-treated mice. These findings indicate that antagonizing D1-like-R suppresses IL-17 expression, thereby leading to a decreased occurrence of NOD.