[Show abstract][Hide abstract] ABSTRACT: Interferon regulatory factor (IRF)4 plays a critical role in lymphoid development and the regulation of immune responses. Genetic deletion of IRF4 has been shown to suppress autoimmune disease in several mouse models, but its role in autoimmune diabetes in NOD mice remains unknown.
To address the role of IRF4 in the pathogenesis of autoimmune diabetes in NOD mice, we generated IRF4-knockout NOD mice and investigated the impact of the genetic deletion of IRF4 on diabetes, insulitis and insulin autoantibody; the effector function of T cells in vivo and in vitro; and the proportion of dendritic cell subsets.
Heterozygous IRF4-deficient NOD mice maintained the number and phenotype of T cells at levels similar to NOD mice. However, diabetes and autoantibody production were completely suppressed in both heterozygous and homozygous IRF4-deficient NOD mice. The level of insulitis was strongly suppressed in both heterozygous and homozygous IRF4-deficient mice, with minimal insulitis observed in heterozygous mice. An adoptive transfer study revealed that IRF4 deficiency conferred disease resistance in a gene-dose-dependent manner in recipient NOD/severe combined immunodeficiency mice. Furthermore, the proportion of migratory dendritic cells in lymph nodes was reduced in heterozygous and homozygous IRF4-deficient NOD mice in an IRF4 dose-dependent manner. These results suggest that the levels of IRF4 in T cells and dendritic cells are important for the pathogenesis of diabetes in NOD mice.
Haploinsufficiency of IRF4 halted disease development in NOD mice. Our findings suggest that an IRF4-targeted strategy might be useful for modulating autoimmunity in type 1 diabetes.
[Show abstract][Hide abstract] ABSTRACT: Background
Recent studies have reported an association between both higher and lower levels of hemoglobin A1c (HbA1c) and higher mortality of diabetes patients. Like diabetes, carotid atherosclerosis is a well known lifestyle-related disease. However, no studies have yet reported an association between HbA1c levels and carotid atherosclerosis.
We conducted a cross-sectional study of 1,150 Japanese elderly men aged ≥60 years who were undergoing general health checkups. Carotid atherosclerosis was defined as a carotid intima-media thickness (CIMT) ≥1.1 mm. Since body mass index (BMI) is regarded as a cardiovascular risk factor that exerts a strong influence on both HbA1c levels and carotid atherosclerosis, we performed a stratified analysis of this risk based on BMI.
Using the intermediate HbA1c quintile as a reference group, the groups in the lowest HbA1c quintiles showed a significantly higher risk of carotid atherosclerosis in patients with low BMI (≤23 kg/m2) vs. no increased risk in those with high BMI (>23 kg/m2). The association of HbA1c with carotid atherosclerosis became slightly stronger when these analyses were limited to subjects who were not taking glucose-lowering medications or medications for hyperlipidemia and cardiovascular disease. After adjusting for classical cardiovascular risk factors, adjusted odds ratios (ORs) for carotid atherosclerosis were 1.36 (0.84 to 2.20) for total subjects, 2.29 (1.12 to 4.66) for low-BMI groups, and 0.68 (0.33 to 1.41) for high-BMI groups.
Lower HbA1c level is a significant risk factor for carotid atherosclerosis in rural community-dwelling elderly Japanese men with low, but not high BMI, particularly in those not taking glucose-lowering medication.
[Show abstract][Hide abstract] ABSTRACT: Aim:
Aim of the study was to retrospectively analyze the clinical parameters that contribute to the therapeutic outcome of GLP-1 analogues.
We enrolled 106 patients with type 2 diabetes mellitus (T2DM), treated with liraglutide (N.=69) or exenatide (N.=37) for longer than three months. The patients were divided into two groups: good responders and poor responders to GLP-1 analogues, based on pretreatment and post-treatment HbA1c levels. Good responders were those whose HbA1c level had decreased by 1% or more, or maintained at less than 7%. All other patients were categorized as poor responders. We used univariate and multivariate analyses to assess pretreatment parameters between the two groups.
Approximately 35% of the patients were poor responders. Our analysis of the pretreatment clinical parameters revealed that number of anti-diabetic agents and use of sulfonylurea were significantly associated with poor response to liraglutide (P=0.02 and P=0.03, respectively) in a multivariate analysis. We were not able to find any candidate related to clinical response to exenatide.
Our study showed that the therapeutic effects of GLP-1 analogues on T2DM patients were heterogeneous. T2DM patients who require multiple anti-diabetic agents, especially sulfonylurea, do not benefit from liraglutide treatment.
[Show abstract][Hide abstract] ABSTRACT: Objective
This study investigated the relationship between aortic 18F-fluoro-2-deoxy-D-glucose (18F-FDG) uptake and clinical and laboratory findings related to atherosclerosis in a general population.
18F-FDG uptake in the ascending aorta was measured on the positron emission tomography/computed tomography (PET/CT) scans of 211 Japanese adults. The maximum target-to-background ratio (TBR) was compared with clinical and laboratory atherosclerosis findings.
By multivariate regression analysis adjusted for age and sex, TBR-ascending aorta (TBR-A) was significantly correlated with various clinical and laboratory parameters, such as body mass index, log visceral fat area, low-density lipoprotein cholesterol (LDL-C), log fasting immunoreactive insulin, log homeostasis model assessment of insulin resistance, log total adiponectin and log-leptin, in all subjects. Furthermore, by multivariate linear regression analysis adjusted for confounding factors, TBR-A was significantly correlated with LDL-C (β = 0.001, p = 0.03) and log-leptin (β = 0.336, p<0.01) in all subjects.
TBR-A was significantly correlated with LDL-C and log-leptin independent from confounding factors. Our results suggest that aortic 18F-FDG uptake is a good marker of atherosclerosis, even in a general population.
PLoS ONE 11/2014; 9(11):e111990. DOI:10.1371/journal.pone.0111990 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypothalamic hyperphagia and obesity are characterized by a lack of satiety and an abnormally high appe-tite that is difficult to control. We herein report the cases of two patients with hypothalamic hyperphagia and obesity with MRI-detectable hypothalamic lesions. These patients suffered from diabetes mellitus associated with an abnormal eating behavior and weight gain. Liraglutide was successfully used to treat their diabetes mellitus and suppress their abnormal appetites. Glucagon-like peptide-1 analogues, including liraglutide, are promising treatment options in patients with hypothalamic hyperphagia and obesity, as these agents enhance the hypothalamic input of the satiety signal, which is lacking in such patients.
Internal Medicine 08/2014; 53(16):1791-1795. DOI:10.2169/internalmedicine.53.1646) · 0.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Several studies have reported that height is inversely associated with risk of cardiovascular disease but positively associated with cancer risk. On the other hand, evidence has been accumulating that anemia reflects poor health and increased vulnerability to poor outcomes in older persons. Moreover, alcohol consumption has also been reported to be associated with mortality. However, no studies have reported on a possible association between height and risk of anemia in relation to drinking status.
We conducted a cross-sectional study of 1287 men aged 40-89 years undergoing general health check-ups.
Independent from classic cardiovascular risk factors, we found a significant inverse association between height and anemia for non-drinkers and a J-shaped association for drinkers. The multivariable odds ratio (ORs) of an increment of 1 SD (standard deviation) in height (6.68 cm) for anemia for non-drinkers was 0.59 (0.45-0.77). For drinkers, with the second quartile of height (Q2) as the reference group, the multivariable OR of anemia was 2.68(0.90-7.96) (p = 0.075) for the lowest height quartile (Q1), 2.73(0.92-8.08) for the third quartile (Q3) and 4.82(1.65-14.10) for the highest quartile (Q4) (p = 0.004).
Height was found to be associated with anemia for rural Japanese men and drinking status is likely to affect those associations.
The Aging Male 07/2014; 18(2). DOI:10.3109/13685538.2014.942841 · 2.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent genome-wide association studies have identified Tribbles homolog 1 (TRIB1) as one of the candidate genes associated with lipid profiles. TRIB1 is known to interact with MAP kinases, thereby regulating their activities. The single nucleotide polymorphism rs2954029 of TRIB1 is located within an intron and is associated with lipid profiles. The aim of the present study is to investigate the TRIB1 rs2954029 (A>T polymorphism) with conventional predictors of coronary artery diseases such as carotid intima-media thickness (CIMT) and cardio-ankle vascular index (CAVI), and with lipid profiles in general population. This study enrolled 2,581 Japanese adults, 942 men and 1,639 women with a median age of 68 years (range 29 to 94 years), who participated in a screening program for the general population living in Goto City, Nagasaki Prefecture, Japan from 2008 to 2010. For the determination of TRIB1 rs2954029 genotypes, the polymerase chain reaction method was used. The differences in each parameter among the TRIB1 rs2954029 genotypes were evaluated using analysis of covariance. Genotype frequencies of TRIB1 rs2954029 in all participants were 25.5% for AA, 50.4% for AT, and 24.0% for TT. In women, the AA genotype showed significantly higher log triglyceride (TG) concentrations than the AT genotype (P = 0.004) and the AT + TT genotypes (P = 0.004). On the other hand, there were no associations with CIMT and CAVI among the TRIB1 rs2954029 genotypes. In conclusion, the TRIB1 rs2954029 is associated with serum TG concentrations in Japanese community-dwelling women.
The Tohoku Journal of Experimental Medicine 06/2014; 233(2):149-53. DOI:10.1620/tjem.233.149 · 1.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
Our previous study reported that categorizing diabetes patients according to the serum triglycerides-to-high-density lipoprotein cholesterol (TG-HDL) ratio is useful for estimating the risk of atherosclerosis, as a high TG-HDL ratio in patients with diabetes constitutes risk factors for atherosclerosis. Another study showed that a high hemoglobin level is associated with the risk of atherosclerosis. However, no previous studies have examined the association between the hemoglobin level and diabetes categorized by the TG-HDL ratio. In order to investigate these associations, we conducted a cross-sectional study of 3,733 (1,299 men and 2,434 women) Japanese participants 30-89 years of age undergoing a general health checkup.
We investigated the association between the hemoglobin levels and the incidence of diabetes in all subjects, who were divided into tertiles according to the TG-HDL ratio. Diabetes was defined as an HbA1c (NGSP) level of ≥ 6.5% and/or the initiation of glucose-lowering or insulin therapy.
Of the 265 diabetes patients identified in this study, 116 had a high TG-HDL ratio (high TG-HDL diabetes) and 71 had a low TG-HDL ratio (low TG-HDL diabetes). Independent from classical cardiovascular risk factors, the multivariate odds ratio of a 1 SD (standard deviation) increment in hemoglobin (1.30 g/dL for men, 1.16 g/dL for women) was 1.04 (95% confidence intervals (CI): 0.88-1.22) for all patients with diabetes, 1.44 (95%CI: 1.17-1.77) for the patients with high TG-HDL diabetes and 0.67 (95%CI: 0.54-0.83) for the patients with low TG-HDL diabetes.
The hemoglobin level is positively associated with high TG-HDL diabetes and inversely associated with low TG-HDL diabetes. These findings suggest that measuring the hemoglobin level is clinically relevant for estimating the risk of atherosclerosis in patients with diabetes categorized according to the TG-HDL ratio.
Internal Medicine 04/2014; 53(8):837-43. DOI:10.2169/internalmedicine.53.1423 · 0.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Renal impairment is known to be associated with atherosclerosis, which in turn is reported to be positively associated with hemoglobin levels. In addition, renal impairment is known to be associated with a form of anemia known as renal anemia.
To clarify the associations between renal impairment and anemia, we conducted a cross-sectional study of 1,105 60 to 89-year-old men, who were not taking medication for anemia and were undergoing general health check-ups.
Compared with non-chronic kidney disease, chronic kidney disease (CKD) with a glomerular filtration rate (GFR) <60 mL/min/1.73 m2 was found to constitute a significant risk of anemia. However, we noted that this risk was lower for mild renal impairment (60 mL/min/1.73 m2 <= GFR <90 mL/min/1.73 m2). Compared with the non-CKD reference group, the classical cardiovascular adjusted odds ratio (OR) for anemia was 1.81 (1.23 to 2.68) and compared with the normal renal function (GFR >=90 mL/min/1.73 m2) reference group, the ORs for mild renal impairment and CKD were 0.26 (0.15 to 0.47) and 0.60 (0.33 to 1.09).
Independent from classical cardiovascular risk factors, CKD, which was identified during general health check-ups, appeared to constitute a significant risk of anemia for older Japanese men. For mild renal impairment, however, this association was a reduced risk of anemia and thus possibly a higher risk of atherosclerosis.
[Show abstract][Hide abstract] ABSTRACT: Objective
The influence of hyperuricemia on atherosclerosis is controversial. Subclinical carotid atherosclerosis can be defined in two ways in terms of mean and maximum carotid intima-media thickness (CIMT): one with mean CIMT ≥ 1.1 mm and the other with maximum CIMT ≥ 1.1 mm. However, no studies have been reported of the association between hyperuricemia and subclinical carotid atherosclerosis while taking the two different ways of classification into account.
We conducted a cross-sectional study of 4133 subjects (1492 men and 2641 women) aged 30–89 years undergoing general health check-ups. For analysis of various associations, we calculated the multivariable odds ratios (ORs) for the two ways classifications of subclinical carotid atherosclerosis in relation to hyperuricemia.
Hyperuricemia-related renal impairment constitutes a significant marker for subclinical carotid atherosclerosis with mean CIMT ≥ 1.1 mm for both men and women, while hyperuricemia per se was found to be beneficially associated with risk of subclinical carotid atherosclerosis with maximum CIMT ≥ 1.1 mm for men. The classical cardiovascular risk factors without adjustment for glomerular filtration rate (GFR) of ORs for subclinical carotid atherosclerosis (mean CIMT ≥ 1.1 mm) and subclinical carotid atherosclerosis (maximum CIMT ≥ 1.1 mm) were 2.20(1.10–4.22) and 0.84(0.63–1.13) for men and 2.12(1.02–4.38) and 0.92(0.66–1.27) for women. After further adjustment for GFR, the corresponding values were 1.54(0.74–3.20) and 0.67(0.49–0.92) for men and 1.32(0.61–2.88) and 0.80(0.57–1.12) for women.
Hyperuricemia-related renal impairment is a significant marker for subclinical carotid atherosclerosis for both men and women, while hyperuricemia per se may be inversely associated with subclinical carotid atherosclerosis for men as seen in a rural community-dwelling Japanese population.
[Show abstract][Hide abstract] ABSTRACT: Objective:
The hemoglobin levels and blood pressure has been reported in a few studies, and a positive association between the hemoglobin levels and the body mass index (BMI) status has also been documented. A higher BMI may therefore affect the association between the hemoglobin levels and hypertension. However, no published studies have examined this association in relation to the BMI status. The primary purpose of this study was to assess the association between the hemoglobin levels and hypertension in relation to the BMI status.
A cross-sectional study of 3,203 non-anemic subjects (1,191 men and 2,012 women, 30-79 years old) who were undergoing general health checkups was conducted.
A positive association between the hemoglobin levels and hypertension was established for both men and women. For a one SD (standard deviation) increment in hemoglobin, the multivariable odds ratio (ORs) and 95% confidence interval (CIs) for hypertension were 1.21 (95%CI: 1.05-1.40) for men and 1.25 (95%CI: 1.13-1.39) for women. We also found that a significant association was confined to the participants with a BMI of <25 kg/m(2). Among the participants with a BMI of <25 kg/m(2), the multivariable ORs and 95% CIs for hypertension of a one SD increment in hemoglobin were 1.34 (95%CI: 1.12-1.60) for men and 1.31 (95%CI: 1.16-1.47) for women. Meanwhile, among those with a BMI of ≥25 kg/m(2), the corresponding values were 1.01 (95%CI: 0.79-1.30) and 1.09 (95%CI: 0.87-1.37).
An independent positive association between the hemoglobin levels and the risk of hypertension was observed for both non-anemic Japanese men and women, confined to participants with a BMI of <25 kg/m(2).
Internal Medicine 03/2014; 53(5):435-40. DOI:10.2169/internalmedicine.53.1353 · 0.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate associations between hemoglobin levels and arterial stiffness accounting for body mass index (BMI) in a large-scale cross-sectional study.
We investigated the association between hemoglobin levels and atherosclerosis evaluated by cardio-ankle vascular index (CAVI), which can assess arterial stiffness independently from blood pressure, while taking BMI status into account. Separate models were constructed for participants with or without anemia. In our main investigation for the association between hemoglobin levels and increased arterial stiffness, only participants without anemia (1064 men and 1886 women) were included to avoid the influence of chronic disease.
We found significantly positive associations between increased arterial stiffness and hemoglobin levels for both men and women, and that such associations were limited to subjects with BMI <25 kg/m(2) . The multivariable-adjusted odds ratios (OR) and 95% coincidence intervals (CI) of 1-standard deviation increments in hemoglobin levels for increased arterial stiffness were 1.17 (95% CI 1.00-1.38) for men and 1.17 (95% CI1.02-1.34) for women. For participants with BMI <25 kg/m(2) , the corresponding values were 1.40 (95% CI 1.14-1.73) and 1.19 (95% CI 1.02-1.40), and for those with BMI ≥25 kg/m(2) , they were 0.88 (95% CI 0.67-1.15) and 1.12 (95% CI 0.86-1.46).
Independent positive associations between hemoglobin levels and increased arterial stiffness were observed both for Japanese men and women, and those associations were limited to participants with BMI <25 kg/m(2) . Geriatr Gerontol Int 2013; ●●: ●●-●●.
[Show abstract][Hide abstract] ABSTRACT: Previous studies have reported an inverse association between height and risk of cardiovascular disease. However, evidence is limited for the association between risk of atherosclerosis and height. Further, although the association between atherosclerosis and body mass index (BMI) is reportedly positive, there have been no reports of studies on associations between height and atherosclerosis in relation to BMI.
We conducted a cross-sectional study of Japanese men aged 30 to 89 years undergoing general health check-ups.
Of the 1,337 men, 312 were diagnosed with carotid atherosclerosis (carotid intima-media thickness (CIMT) >= 1.1 mm), but no significant association was found between height and carotid atherosclerosis for the entire study group. Stratification by BMI status of those analytical findings disclosed a significant inverse association between height and carotid atherosclerosis among overweight (BMI >= 25 kg/m2) but not among non-overweight (BMI < 25 kg/m2) men. The classical cardiovascular risk factors-adjusted odds ratio (OR) and 95% confidence interval (CI) of carotid atherosclerosis for an increment of one SD (standard deviation) in height (6.70 cm) were 0.71 (0.54 to 0.94) for overweight (BMI >= 25 kg/m2) and 1.05 (0.87 to 1.27) for non-overweight (BMI < 25 kg/m2) men.
Independent from classical cardiovascular risk factors, height was found to be inversely associated with carotid atherosclerosis for overweight but not for non-overweight men.
[Show abstract][Hide abstract] ABSTRACT: We have previously reported the high levels of glutamic acid decarboxylase 65 autoantibodies (GAD65A) in patients with type 1 diabetes and autoimmune thyroid disease. Here we describe a 32-year-old Japanese female with a thirteen-year history of type 1 diabetes whose levels of GAD65A were elevated just after the emergence of anti-thyroid autoimmunity. At 19 years of age, she developed diabetic ketoacidosis and was diagnosed with type 1 diabetes. She had GAD65A, insulinoma-associated antigen-2 autoantibodies (IA-2A), and zinc transporter-8 autoantibodies (ZnT8A), but was negative for antibodies to thyroid peroxidase (TPOAb) and thyroglobulin (TGAb) at disease onset. ZnT8A and IA-2A turned negative 2-3 years after the onset, whereas GAD65A were persistently positive at lower level (approximately 40 U/mL). However, just after the emergence of TGAb at disease duration of 12.5 years, GAD65A levels were reelevated up to 5717 U/mL in the absence of ZnT8A and IA-2A. Her thyroid function was normal and TPOAb were consistently negative. She has a HLA-DRB1*03:01/*04:01-DQB1*02:01/*03:02 genotype. Persistent positivity for GAD65A might be associated with increased risk to develop anti-thyroid autoimmunity.
[Show abstract][Hide abstract] ABSTRACT: Background:
The glucokinase regulator gene (GCKR) rs780094 has been shown to be strongly associated with some metabolic traits and atherosclerotic parameters, while the association between GCKR rs780094 and carotid intima-media thickness (CIMT) has not been fully investigated in the general population. The associations between the GCKR rs780094 genotype and metabolic traits including CIMT were examined in a Japanese community-dwelling population.
A total of 2491 Japanese adults (907 men and 1584 women) who participated in a medical screening program for the general population from 29 to 94 years of age during 2008 to 2010 were enrolled. GCKR rs780094 was genotyped by the TaqMan polymerase chain reaction method, and associations with metabolic markers including CIMT were evaluated.
GCKR rs780094 AA genotype was significantly associated with higher TG (p<0.001 vs. GG), lower HDL-C (p=0.021 vs. GG), and lower HbA1c(p=0.023 vs. GG). The AA genotype showed significantly thinner CIMT (p=0.001 vs. GX). These associations were seen only in men.
GCKR rs780094 was associated with TG, HDL-C, and HbA1c levels, as well as with CIMT in Japanese community-dwelling men, but not women.
Clinical Chemistry and Laboratory Medicine 08/2013; 52(2):1-7. DOI:10.1515/cclm-2013-0092 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is well known that hypothyroidism is associated with anemia. It has also been reported that alcohol consumption may affect thyroid function. Furthermore, hemoglobin levels of drinkers are reportedly higher than those of non-drinkers. However, no published study has investigated the association between thyroid function evaluated with the free thyroxine (FT4) test and anemia while taking drinking status into account. We conducted a cross-sectional study of 843 men aged 30-89 years undergoing general health checks. While no significant associations were noted between FT4 and anemia for total subjects, when the analysis was limited to non-drinkers, a significant association was observed. After adjustment for classical cardiovascular risk factors and thyroid stimulating hormones (TSH), adjusted odds ratio (OR) and 95% confidence interval (CI) for an increment of 1SD (standard deviation) for FT4 (0.17 ng/dL) for anemia were 0.85 (0.67-1.09) for total subjects, 0.59 (0.41-0.85) for non-drinkers, and 1.23 (0.83-1.83) for drinkers. In conclusion, FT4 is inversely associated with anemia for non-drinking but not for drinking men. However, drinking may act as a confounding factor for this association.
[Show abstract][Hide abstract] ABSTRACT: Aims/hypothesis:
T helper type (Th) 17 cells have been shown to play important roles in mouse models of several autoimmune diseases that have been classified as Th1 diseases. In the NOD mouse, the relevance of Th1 and Th17 is controversial, because single-cytokine-deficient NOD mice develop diabetes similarly to wild-type NOD mice.
We studied the impact of IL-17/IFN-γ receptor double deficiency in NOD mice on the development of insulitis/diabetes compared with IL-17 single-deficient mice and wild-type mice by monitoring diabetes-related phenotypes. The lymphocyte phenotypes were determined by flow cytometric analysis.
IL-17 single-deficient NOD mice showed delayed onset of diabetes and reduced severity of insulitis, but the cumulative incidence of longstanding diabetes in the IL-17-deficient mice was similar to that in wild-type mice. The IL-17/IFN-γ receptor double-deficient NOD mice showed an apparent decline in longstanding diabetes onset, but not in insulitis compared with that in the IL-17 single-deficient mice. We also found that double-deficient NOD mice had a severe lymphopenic phenotype and preferential increase in regulatory T cells among CD4(+) T cells compared with the IL-17 single-deficient mice and wild-type NOD mice. An adoptive transfer study with CD4(+)CD25(-) T cells from young non-diabetic IL-17 single-deficient NOD mice, but not those from older mice, showed significantly delayed disease onset in immune-deficient hosts compared with the corresponding wild-type mice.
These results indicate that IL-17/Th17 participates in the development of insulitis and that both IL-17 and IFN-γ signalling may synergistically contribute to the development of diabetes in NOD mice.
[Show abstract][Hide abstract] ABSTRACT: Granzyme-B (GzmB) and perforin are proteins, secreted mainly by natural killer cells and cytotoxic T lymphocytes that are largely responsible for the induction of apoptosis in target cells. Since type 1 diabetes results from the selective destruction of beta cells and perforin deficiency effectively reduces diabetes in non-obese diabetic (NOD) mice, it can be deduced that beta-cell apoptosis involves the GzmB/perforin pathway. However, the relevance of GzmB remains totally unknown in NOD mice. We here focused on GzmB and examined the consequence of GzmB deficiency in NOD mice. We found that NOD.GzmB-/- mice spontaneously developed diabetes with kinetics similar to those of wild-type NOD (wt-NOD) mice. Adoptive transfer study with Treg-depleted SPCs into NOD-SCID mice or in vivo Treg-depletion by anti-CD25 antibody at 4 weeks of age comparably induced the rapid progression of diabetes in the NOD.GzmB-/- mice and wt-NOD mice. Expression of GzmA and Fas was enhanced in the islets from pre-diabetic NOD.GzmB-/- mice. In contrast to spontaneous diabetes, GzmB deficiency suppressed the development of cyclophosphamide-promoted diabetes in male NOD mice. Cyclophosphamide treatment led to a significantly lower percentage of apoptotic CD4+, CD8+ and CD4+CD25+ T cells in SPCs from NOD.GzmB-/- mice than those from wt-NOD mice. In conclusion, GzmB, in contrast to perforin, is not essentially involved in the effector mechanisms for beta-cell destruction in NOD mice.