Kazuma Takahashi

Diagnostic criteria for acute-onset type 1 diabetes mellitus (2012): Report of the Committee of Japan Diabetes Society on the Research of Fulminant and Acute-onset Type 1 Diabetes Mellitus.

Type 1 diabetes is a disease characterized by destruction of pancreatic β‐cells, which leads to absolute deficiency of insulin secretion. Depending on the manner of onset and progression, it is classified as fulminant, acute‐onset or slowly progressive type 1 diabetes. Here, we propose the diagnostic criteria for acute‐onset type 1 diabetes mellitus. Among the patients who develop ketosis or diabetic ketoacidosis within 3 months after the onset of hyperglycemic symptoms and require insulin treatment continuously after the diagnosis of diabetes, those with anti‐islet autoantibodies are diagnosed with ‘acute‐onset type 1 diabetes mellitus (autoimmune)’. In contrast, those whose endogenous insulin secretion is exhausted (fasting serum C‐peptide immunoreactivity <0.6 ng/mL) without verifiable anti‐islet autoantibodies are diagnosed simply with ‘acute‐onset type 1 diabetes mellitus’. Patients should be reevaluated after certain periods in case their statuses of anti‐islet autoantibodies and/or endogenous insulin secretory capacity are unknown.

Association of Advanced Glycation End Products with coronary Artery Calcification in Japanese Subjects with Type 2 Diabetes as Assessed by Skin Autofluorescence

Aim: Advanced glycation end products (AGE) are considered to be among the critical pathogenic factors involved in the progression of diabetic complications. Skin autofluorescence (AF), a noninvasive measurement of AGE accumulation, has been recognized as a useful and convenient marker for diabetic vascular diseases in Caucasians. This study aimed to evaluate the association of tissue AGE, assessed using skin AF, with coronary artery calcification in Japanese subjects with type 2 diabetes. Methods: In total, 122 Japanese subjects with type 2 diabetes enrolled in this cross-sectional study underwent multi-slice computed tomography for total coronary artery calcium scores (CACS) estimation and examination with a skin AF reader. Results: Skin AF positively correlated with age, sex, diabetes duration, pulse wave velocity, systolic blood pressure, serum creatinine, and CACS. In addition, skin AF results negatively correlated with BMI, eGFR, and serum C-peptide concentration. According to multivariate analysis, age and systolic blood pressure showed strong positive correlation and eGFR showed negative correlation with skin AF values. Multiple linear regression analyses revealed a significant positive correlation between skin AF values and logCACS, independent of age, sex, diabetes duration, HbA1c, BMI, IMT, and blood pressure. However, skin AF showed no association with serum levels of AGE, such as Nε-(carboxymethyl) lysine and 3-deoxyglucosone. Conclusion: Skin AF results positively correlated with CACS in Japanese subjects with type 2 diabetes. This result indicates that AGE plays a role in the pathogenesis of diabetic macrovascular disease. Measurement of skin AF values may be useful for assessing the severity of diabetic complications in Japanese subjects.

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

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.

Positive association of free triiodothyronine with pancreatic β-cell function in people with prediabetes

To analyse the effects of thyroid hormones on β‐cell function and glucose metabolism in people with prediabetes who are euthyroid.

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 (Haldanes 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.

Association of the TNF-α-C-857T Polymorphism With Resistance to the Cholesterol-Lowering Effect of HMG-CoA Reductase Inhibitors in Type 2 Diabetic Subjects

OBJECTIVE An association of the C-857T polymorphism of the tumor necrosis factor-α (TNF-α) gene promoter region with LDL cholesterol levels has been reported. This study was designed to evaluate the relationship between the TNF-α-C-857T polymorphism and LDL cholesterol levels according to statin treatment in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS DNA was obtained from 322 Japanese subjects (160 male and 162 female) with type 2 diabetes, and TNF-α-C-857T polymorphisms were determined by direct sequencing. Serum LDL cholesterol was measured by a direct method. RESULTS Although serum LDL cholesterol levels were significantly higher in the T carriers (C/T + T/T) than in the non–T carriers (C/C) (3.14 ± 0.86 vs. 2.89 ± 0.75 mmol/l, P < 0.05), there was no difference in LDL cholesterol levels between the non–T carriers and the T carriers in statin-untreated subjects (2.87 ± 0.73 vs. 2.89 ± 0.76 mmol/l, NS), whereas in statin-treated subjects, LDL cholesterol levels were significantly higher in the T carriers than in the non–T carriers (3.43 ± 0.89 vs. 2.90 ± 0.78 mmol/l, P = 0.0007). There were no differences in HDL cholesterol and triglyceride levels between the non–T carriers and the T carriers in both statin-treated and -untreated subjects. The percent decrease in LDL cholesterol levels after administration of statins was significantly smaller in the T carriers compared with the non–T carriers (27.6 vs. 36.4%, P = 0.031). CONCLUSIONS The mutant allele of the C-857T promoter polymorphism of the TNF-α gene may predispose to resistance to the LDL cholesterol–lowering effect of statins and could be one of the markers used to predict the efficacy of statins.

Erratum to: Diagnostic criteria for slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) (2012): report by the Committee on Slowly Progressive Insulin-Dependent (Type 1) Diabetes Mellitus of the Japan Diabetes Society

Diagnostic criteria for slowly progressive insulin-dependent (Type 1) diabetes mellitus (SPIDDM) have been proposed by the Committee on Slowly Progressive Insulin-dependent (type 1) Diabetes Mellitus of the Japan Diabetes Society. Two criteria must be met for definitive diagnosis: the presence of glutamic acid decarboxylase antibodies (GADAb) and/or islet cell antibodies (ICA) at some time during the clinical course of the diabetes, and the absence of ketosis or ketoacidosis at the onset (or diagnosis) of diabetes mellitus and no need for insulin treatment to correct hyperglycemia immediately after diagnosis. It is still unclear whether insulinoma-associated antigen-2 autoantibodies (IA-2Ab), insulin autoantibodies (IAA), or zinc transporter 8 autoantibodies (ZnT8Ab) are essential markers for diagnosis for SPIDDM. Hence, the presence of IA-2Ab, IAA, and ZnT8Ab were excluded from these diagnostic criteria for SPIDDM. Furthermore, ketosis or ketoacidosis can be observed in cases in which SPIDDM is complicated by soft-drink ketosis. Supplementary information for diagnosis include: most SPIDDM patients will need insulin treatment more than 3 months after onset (or diagnosis) of diabetes mellitus and frequently progress to an insulin-dependent state; sometimes, for clinical reasons, early insulin treatment is started when GADAb or ICA are positive both for child and adult-onset cases; GADAb and/or ICA often become negative during the course of the disease; and a small proportion of patients might maintain endogenous beta-cell function more than 10 years after the onset (or diagnosis) of diabetes mellitus, irrespective of the titer of GADAb and ICA.

Lowered Expressions of the NF‐κB Family Members in Dendritic Cells from NOD Mice are Associated with a Reduced Expression of GATA‐2

In type 1 diabetes, dendritic cells (DCs) display defective phenotype and function and possibly play crucial roles in the pathogenesis of this disease. In the present study, we compared transcription profiles of CD11c+ bone marrow (BM)‐derived DCs from NOD mice with those from NON mice, focusing on the NF‐κB/Rel family members and associated molecules. The BMDCs from NOD mice displayed reduced mRNA expressions of NF‐κB components, p65, p50, p52, and RelB, compared to NON mice: the proportions of each molecule relative to those of NON DCs were 53.9, 54.1, 54.0, and 37.0%, respectively, which were accompanied with lowered expressions of downstream immunomodulatory molecules, including IL‐6, CD80, CD86, 4‐1BB, and CD40. The reduction of NF‐κB components possibly underlies the defective phenotype and function of DCs from NOD mice, and could predispose to autoimmunity.

Clinical and Genetic Characteristics of Non-Insulin-Requiring Glutamic Acid Decarboxylase (GAD) Autoantibody-Positive Diabetes: A Nationwide Survey in Japan

Aims Glutamic acid decarboxylase autoantibodies (GADAb) differentiate slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) from phenotypic type 2 diabetes, but many GADAb-positive patients with diabetes do not progress to insulin-requiring diabetes. To characterize GADAb-positive patients with adult-onset diabetes who do not require insulin therapy for >5 years (NIR-SPIDDM), we conducted a nationwide cross-sectional survey in Japan. Methods We collected 82 GADAb-positive patients who did not require insulin therapy for >5 years (NIR-SPIDDM) and compared them with 63 patients with insulin-requiring SPIDDM (IR-SPIDDM). Clinical and biochemical characteristics, HLA-DRB1-DQB1 haplotypes, and predictive markers for progression to insulin therapy were investigated. Results Compared with the IR-SPIDDM group, the NIR-SPIDDM patients showed later diabetes onset, higher body mass index, longer duration before diagnosis, and less frequent hyperglycemic symptoms at onset. In addition, C-peptide, LDL-cholesterol, and TG were significantly higher in the NIR-SPIDDM compared to IR-SPIDDM patients. The NIR-SPIDDM group had lower frequency of susceptible HLA-DRB1*04:05-DQB1*04:01 and a higher frequency of resistant HLA-DRB1*15:01-DQB1*06:02 haplotype compared to IR-SPIDDM. A multivariable analysis showed that age at diabetes onset (OR = 0.82), duration before diagnosis of GADAb-positive diabetes (OR = 0.82), higher GADAb level (≥10.0 U/ml) (OR = 20.41), and fasting C-peptide at diagnosis (OR = 0.07) were independent predictive markers for progression to insulin-requiring diabetes. An ROC curve analysis showed that the optimal cut-off points for discriminating two groups was the GADAb level of 13.6 U/ml, age of diabetes onset of 47 years, duration before diagnosis of 5 years, and fasting C-peptide of 0.65 ng/ml. Conclusions Clinical, biochemical and genetic characteristics of patients with NIR-SPIDDM are different from those of IR-SPIDDM patients. Age of diabetes onset, duration before GADAb-positivity, GADAb level, and fasting C-peptide at diagnosis must be carefully considered in planning prevention trials for SPIDDM.

Response to the dipeptidyl peptidase‐4 inhibitors in Japanese patients with type 2 diabetes might be associated with a diplotype of two single nucleotide polymorphisms on the interleukin‐6 promoter region under a certain level of physical activity

Muscle‐derived interleukin‐6 (IL‐6) has been reported to promote glucagon‐like peptide‐1 (GLP‐1) secretion, and we explored the association of single nucleotide polymorphisms (SNPs) in the human IL‐6 promoter region with the responsiveness to dipeptidyl peptidase‐4 inhibitors (DPP‐4Is), drugs that increase circulating GLP‐1.