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1.  Possible Contribution of Taurine to Distorted Glucagon Secretion in Intra-Islet Insulin Deficiency: A Metabolome Analysis Using a Novel α-Cell Model of Insulin-Deficient Diabetes 
PLoS ONE  2014;9(11):e113254.
Glycemic instability is a serious problem in patients with insulin-deficient diabetes, and it may be due in part to abnormal endogenous glucagon secretion. However, the intracellular metabolic mechanism(s) involved in the aberrant glucagon response under the condition of insulin deficiency has not yet been elucidated. To investigate the metabolic traits that underlie the distortion of glucagon secretion under insulin deficient conditions, we generated an αTC1-6 cell line with stable knockdown of the insulin receptor (IRKD), i.e., an in vitro α-cell model for insulin-deficient diabetes, which exhibits an abnormal glucagon response to glucose. A comprehensive metabolomic analysis of the IRKD αTC1-6 cells (IRKD cells) revealed some candidate metabolites whose levels differed markedly compared to those in control αTC1-6 cells, but also which could affect the glucagon release in IRKD cells. Of these candidates, taurine was remarkably increased in the IRKD cells and was identified as a stimulator of glucagon in αTC1-6 cells. Taurine also paradoxically exaggerated the glucagon secretion at a high glucose concentration in IRKD cells and islets with IRKD. These results indicate that the metabolic alterations induced by IRKD in α-cells, especially the increase of taurine, may lead to the distorted glucagon response in IRKD cells, suggesting the importance of taurine in the paradoxical glucagon response and the resultant glucose instability in insulin-deficient diabetes.
PMCID: PMC4231115  PMID: 25393115
2.  Dermatomyositis as a complication of interferon-α therapy: a case report and review of the literature 
Rheumatology International  2014;34(9):1319-1322.
Autoimmune disorder is one of the important side effects of interferon-α therapy. Some polymyositis cases as complication of interferon-α therapy were reported, but dermatomyositis were rarely. We report a case of dermatomyositis as a complication of interferon-α therapy for hepatitis C. A 52-year-old Japanese man was treated by combination therapy with pegylated interferon-α-2b and ribavirin for hepatitis C. Three months after the initiation of therapy, he showed erythema in the posterior cervical to dorsal and anterior cervical to thoracic regions, weight loss, general malaise, muscle pain, and severe increase in levels of muscle enzymes. We made a diagnosis of dermatomyositis according to these clinical features, proximal muscle-predominant myogenic change on electromyography, and infiltration of monocytes and CD4+-dominant lymphocytes on skin biopsy, although myositis-associated antibodies were absent. He was successfully treated with intravenous immunoglobulin and tacrolimus in addition to glucocorticoid. This is a very rare case of dermatomyositis associated with interferon-α therapy. We reviewed several similar published cases and the association of dermatomyositis and type I interferon.
PMCID: PMC4145214  PMID: 24638953
Dermatomyositis; Polymyositis; Interferon-α; Hepatitis C; Tacrolimus
3.  Pre-Treatment Ferritin Level and Alveolar-Arterial Oxygen Gradient Can Predict Mortality Rate Due to Acute/Subacute Interstitial Pneumonia in Dermatomyositis Treated by Cyclosporine A/Glucocorticosteroid Combination Therapy: A Case Control Study 
PLoS ONE  2014;9(2):e89610.
Acute/subacute interstitial pneumonia in dermatomyositis (DM-A/SIP) is a disease associated with a poor prognosis that resists treatment with glucocorticosteroids (GC) and progresses rapidly in a period of weeks to months to death. We retrospectively studied outcomes, prognostic factors, and their relations with survival rate in patients with DM-A/SIP treated with early cyclosporine A (CSA)/GC combination therapy and 2-hour postdose blood concentration monitoring.
This study comprised 32 DM-A/SIP patients who were simultaneously treated with CSA and prednisolone. Clinical and laboratory findings were compared between those who died due to DM-A/SIP and those surviving 24 weeks after beginning of therapy. Prognostic factors were extracted, and their relations with the survival rate were evaluated.
Of the 32 DM-A/SIP patients, 25 survived, 5 died of DM-A/SIP, and 2 died of infections. In those who died due to DM-A/SIP, ferritin level and the alveolar-arterial oxygen gradient were significantly increased compared with the survivors (P<0.001 and P = 0.002, respectively). Multivariate analyses showed that ferritin and alveolar-arterial oxygen gradient were independent prognostic factors of poor outcome. The survival rate 24 weeks after beginning of treatment was significantly lower in those with a ferritin level of ≥600 ng/ml and alveolar-arterial oxygen gradient of ≥45 Torr (P<0.001 and P<0.001, respectively). All patients with both prognostic factors died, and the outcome was significantly poorer in these patients than in those with one or neither of the prognostic factors (P<0.001).
We identified pre-treatment high serum ferritin level and high alveolar-arterial oxygen gradient as poor prognostic factors in DM-A/SIP patients undergoing early CSA/GC combination therapy and showed that the outcomes were poor in patients with both factors.
PMCID: PMC3931830  PMID: 24586910
4.  Effect of combination therapy with repaglinide and metformin hydrochloride on glycemic control in Japanese patients with type 2 diabetes mellitus 
We investigated the efficacy and safety of repaglinide as an add‐on therapy for Japanese patients with type 2 diabetes mellitus receiving metformin monotherapy (at a dose of 1,500 mg/day, mainly) in addition to diet and exercise.
Materials and methods
In the 16‐week multicenter, placebo‐controlled, randomized, double‐blind, parallel‐group trial (the phase III study), patients with type 2 diabetes mellitus with metformin monotherapy were randomly assigned to the repaglinide or placebo group. Thereafter, a 36‐week, multicenter, uncontrolled, dose‐titration method study was extended to a total duration of 52 weeks (the long‐term study). The primary end‐point of each study was a change in glycated hemoglobin (HbA1c) from baseline.
After 16 weeks, mean reductions in HbA1c were significantly greater for the repaglinide group than for the placebo group (–0.98 ± 0.72% vs 0.13 ± 0.63%, P < 0.001). In the long‐term study, the mean change in HbA1c was −0.76 ± 0.83%. The rate of adverse events was 60.6 and 50.0% in the repaglinide and placebo groups, respectively, in the phase III study, and 78.3% in the long‐term study. Hypoglycemia was reported in 11.7, 0 and 13.3% of patients in the repaglinide group, placebo group and long‐term study, respectively.
Combination therapy with repaglinide and metformin resulted in an approximately 1% reduction in HbA1c at week 16 and in a significant long‐term improvement in HbA1c at the end of the study. No safety problems were noted during the concomitant use of repaglinide and metformin. These studies were registered with JapicCTI (nos. JapicCTI‐101202 and JapicCTI‐101203).
PMCID: PMC4025226  PMID: 24843740
Combination therapy; Metformin; Repaglinide
5.  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.
PMCID: PMC4025242  PMID: 24843746
Criteria; Diagnosis; Type 1 diabetes
6.  Use of Color Doppler Ultrasonography to Measure Thyroid Blood Flow and Differentiate Graves' Disease from Painless Thyroiditis 
European Thyroid Journal  2013;2(2):120-126.
Color Doppler ultrasonography (CDU) has not yet been established as a method to investigate the pathogenesis of thyrotoxicosis.
Our first objective was to determine whether the measurement of peak systolic blood-flow velocity in the superior thyroid artery (STV) and thyroid tissue blood flow (TBF) using CDU could differentiate Graves' disease (GD) from painless thyroiditis (PT). The second objective was to examine the factors mediating increased blood flow to the thyroid gland in GD.
Recruited patients had untreated GD or PT and visited the Department of Internal Medicine (I), Osaka Medical College, between April 1, 2006 and May 31, 2010. Age, gender, blood pressure, pulse rate, thyroid-stimulating hormone, free thyroxine, tri-iodothyronine, TSH receptor antibody and thyroid volume were evaluated in patients. In addition, bilateral measurements of STV, TBF and peak systolic velocity in the common carotid artery (CCV) were also performed. TBF was quantified by calculating the ratio of blood-flow pixels to total pixels in the region of interest using sagittal section images of the thyroid gland. Receiver-operating characteristic curve analysis was performed to determine the ability of STV and TBF measurements to differentiate GD from PT.
For the average of STV measured on both sides, the area under the receiver-operating characteristic curve (AUC) was 0.956. For the average of TBF measured on both sides, the AUC was 0.920. At an average STV cut-off value of 43 cm/s, the sensitivity to discriminate GD from PT was 0.87 and the specificity was 1.00. At an average TBF cut-off value of 3.8%, the sensitivity was 0.71 and the specificity was 1.00. In the GD group, neither blood pressure nor pulse rate correlated with the average STV or TBF. Moreover, there was no correlation between STV and CCV or between TBF and CCV on either side. However, STV was correlated with TBF (right side: R = 0.47; left side: R = 0.52).
The results demonstrate that STV and TBF are useful for differentiating GD from PT. Furthermore, the increased STV and TBF found in GD are not related to hyperthyroidism-induced increases in systolic blood pressure, pulse rate or CCV.
PMCID: PMC3821509  PMID: 24783050
Color Doppler ultrasonography; Thyroid blood flow; Graves’ disease; Painless thyroiditis; Superior thyroid artery

7.  Baseline and 1-year interim follow-up assessment of Japanese patients initiating insulin therapy who were enrolled in the cardiovascular risk evaluation in people with type 2 diabetes on insulin therapy study: an international, multicenter, observational study 
The Cardiovascular Risk Evaluation in people with type 2 Diabetes on Insulin Therapy (CREDIT) study is an international, multicenter, observational study designed to assess metabolic parameters and cardiovascular risk of patients with type 2 diabetes mellitus (T2DM) on insulin therapy. The present report summarizes results at baseline and 1-year follow-up for the cohort of Japanese patients.
Male and female patients (n = 511), aged >40 years, with T2DM for >1 year, treated with insulin therapy for ≥1 month and <6 months were eligible for participation in the study. Glycemic and lipid parameters, duration of diabetes, diabetic complications, oral antidiabetic medications, and all hypoglycemic episodes were recorded. Effectiveness was assessed based on changes in clinical parameters and attainment of target HbA1c levels. Safety was evaluated based on episodes of hypoglycemia and weight gain.
At baseline, the mean ± SD duration of diabetes was 11.8 ± 8.8 years. Microvascular and macrovascular diabetic complications were present in 83.4% and 25.1% of patients, respectively. At the 1-year follow-up, significant improvements were observed in mean HbA1c (10.3 ± 2.0% vs. 7.5 ± 1.3%, P < .001), fasting plasma glucose (217.3 ± 80.8 mg/dL vs. 139.0 ± 48.7 mg/dL, P < .001), and postprandial plasma glucose levels (296.1 ± 96.0 mg/dL vs. 178.2 ± 68.6 mg/dL, P < .001) compared with baseline. Mean total cholesterol (P < .001), low-density lipoprotein cholesterol (P < .001), triglycerides (P < .01), and diastolic blood pressure (P < .01) also significantly decreased. Good glycemic control (HbA1c < 7.0%) was achieved in 40% of patients at the 1-year follow-up. Glycemic control tended to be better in patients with lower baseline HbA1c levels (P < .01). Patients with a shorter duration of diabetes were more likely to achieve glycemic control and discontinue insulin for diabetes control at the 1-year follow-up (P < .05 for trend). Symptomatic hypoglycemic episodes occurred in 21.8% of patients over 6 to 12 months.
Our results suggest that insulin treatment is an effective and safe therapeutic option in Japanese patients with T2DM, and earlier insulin initiation might be associated with better glycemic control.
PMCID: PMC3846906  PMID: 24011395
Type 2 diabetes mellitus; Insulin therapy; Real-life clinical data
8.  A Patient with Systemic Lupus Erythematosus Complicated by Neurological Symptoms of Toluene Poisoning 
Case Reports in Rheumatology  2013;2013:390960.
We report a patient with systemic lupus erythematosus complicated by toluene poisoning. She had erythema, alopecia, arthralgia, and various neurological symptoms. Laboratory findings showed leukocytopenia, low levels of complements, and anti-dsDNA antibody. However, normal interleukin-6 level and IgG index of cerebrospinal fluid and brain magnetic resonance imaging and single photon emission computed tomography findings suggested that her neurological symptoms were caused by metabolic disorder but not neuropsychiatric systemic lupus erythematosus. Erythema, alopecia, and arthralgia improved rapidly after administration of prednisolone and tacrolimus, whereas neurological symptoms improved only gradually. Because of a history of exposure to toluene, her neurological symptoms were considered to be due to toluene poisoning. The differentiation of toluene poisoning from neuropsychiatric systemic lupus erythematosus based on symptoms is difficult because both induce various neuropsychiatric disorders. Laboratory findings of cerebrospinal fluid, radiological findings, and medical interview were useful for differentiation of toluene poisoning from neuropsychiatric systemic lupus erythematosus.
PMCID: PMC3728548  PMID: 23956915
9.  Postural Abnormality as a Risk Marker for Leg Deep Venous Thrombosis in Parkinson’s Disease 
PLoS ONE  2013;8(7):e66984.
Pulmonary thromboembolism is a common cause of death in patients with autopsy-confirmed Parkinsonism. This study investigated the incidence of leg deep vein thrombosis in Parkinson’s disease and relationships between deep vein thrombosis and clinical/laboratory findings, including postural abnormalities as assessed by photographic measurements.
This cross-sectional study assessed the presence of deep vein thrombosis using bilateral leg Doppler ultrasonography in 114 asymptomatic outpatients with Parkinson’s disease.
Deep vein thrombosis was detected in 23 patients (20%) with Parkinson’s disease. Deep vein thrombosis was located in the distal portion in 18 patients and in the proximal portion in 5 patients. No significant differences in age, sex, body mass index, disease duration, Hoehn-Yahr stage, anti-Parkinson’s drugs, or daily levodopa-equivalent dose were seen between deep vein thrombosis-positive and -negative groups. Univariate analysis for developing deep vein thrombosis in patients with Parkinson’s disease identified the following markers: long-term wheelchair use, bent knee, bent spine, and D-dimer elevation. Bending angles were significantly greater in the deep vein thrombosis-positive group at the knee and spine than in the deep vein thrombosis-negative group. Half of Parkinson’s disease patients with camptocormia had deep vein thrombosis. Among diabetes mellitus cases, long-term wheelchair use, bent knee over 15°, camptocormia, D-dimer elevation, the more risk markers were associated with a higher incidence of DVT. The presence of risk markers contributed to the development of deep vein thrombosis. On multivariate logistic regression analysis, a bent knee posture was strongly associated with an increased risk of deep vein thrombosis.
Presence of leg deep vein thrombosis correlated with postural abnormalities in Parkinson’s disease. We recommend non-invasive ultrasonographic screening for leg deep vein thrombosis in these high-risk patients with Parkinson’s disease.
PMCID: PMC3699565  PMID: 23843975
10.  Report of the Committee of the Japan Diabetes Society on the Research of Fulminant and Acute‐onset Type 1 Diabetes Mellitus: New diagnostic criteria of fulminant type 1 diabetes mellitus (2012) 
We have revised a part of the diagnostic criteria for fulminant type 1 diabetes. The new criteria were set both to express the essence of this disease of rapid increase of patients' blood glucose and to be highly sensitive to reduce the misdiagnosis. After analyzing the data of 382 patients with newly‐diagnosed fulminant type 1 diabetes, we adopted the glycated hemoglobin (HbA1c) level of 8.7% (National Glycohemoglobin Standardization Program [NGSP] value). The new criterion indicates 100% of sensitivity and the best value by receiver operating characteristic curve analysis. In addition, we added a comment that ‘This value (HbA1c <8.7% in NGSP) is not applicable for patients with previously diagnosed glucose intolerance’ in the new criteria and also a comment that ‘Association with human leukocyte antigen DRB1*04:05‐DQB1*04:01 is reported’ as a related finding. We did not revise the screening criteria and the other part of the diagnostic criteria, because they are still reliable.
PMCID: PMC4015434  PMID: 24843620
Criteria; Diagnosis; Fulminant
11.  A rare case of primary clear cell sarcoma of the pubic bone resembling small round cell tumor: an unusual morphological variant 
BMC Cancer  2012;12:538.
Clear cell sarcoma (CCS) and malignant melanoma share overlapping immunohistochemistry with regard to the melanocytic markers HMB45, S100, and Melan-A. However, the translocation t(12; 22)(q13; q12) is specific to CCS. Therefore, although these neoplasms are closely related, they are now considered to be distinct entities. However, the translocation is apparently detectable only in 50%–70% of CCS cases. Therefore, the absence of a detectable EWS/AFT1 rearrangement may occasionally lead to erroneous exclusion of a translocation-negative CCS. Therefore, histological assessment is essential for the correct diagnosis of CCS. Primary CCS of the bone is exceedingly rare. Only a few cases of primary CCS arising in the ulna, metatarsals, ribs, radius, sacrum, and humerus have been reported, and primary CCS arising in the pubic bone has not been reported till date.
Case presentation
We present the case of an 81-year-old man with primary CCS of the pubic bone. Histological examination of the pubic bone revealed monomorphic small-sized cells arranged predominantly as a diffuse sheet with round, hyperchromatic nuclei and inconspicuous nucleoli. The cells had scant cytoplasm, and the biopsy findings indicated small round cell tumor (SRCT). Immunohistochemical staining revealed the tumor cells to be positive for HMB45, S100, and Melan-A but negative for cytokeratin (AE1/AE3) and epithelial membrane antigen. To the best of our knowledge, this is the first case report of primary CCS of the pubic bone resembling SRCT. This ambiguous appearance underscores the difficulties encountered during the histological diagnosis of this rare variant of CCS.
Awareness of primary CCS of the bone is clinically important for accurate diagnosis and management when the tumor is located in unusual locations such as the pubic bone and when the translocation t(12; 22)(q13; q12) is absent.
PMCID: PMC3517754  PMID: 23170958
Clear cell sarcoma; Small round cell tumor; Pubic bone; Immunohistochemistry
12.  Successful Treatment of Long-Term Severe Progressive Interstitial Pneumonia with Low-Dose Corticosteroid and Azathioprine in a Patient with Diffuse Systemic Sclerosis 
Case Reports in Rheumatology  2012;2012:143927.
For progressive interstitial pneumonia (progressive IP) that accompanies diffuse systemic sclerosis (diffuse SSc), no treatment guidelines have yet been established, and it is a complication with a poor prognosis. We herein report a case in which combination therapy of a low-dose corticosteroid and low-dose azathioprine was performed for progressive SSc-IP in a 64-year-old female whose respiratory function was severely damaged for a long period of time and for whom improvement was achieved. The beneficial effect has continued for 3 years with no side effects being observed during the course.
PMCID: PMC3469081  PMID: 23082272
13.  An approach for diagnosing plasma cell myeloma by three-color flow cytometry based on kappa/lambda ratios of CD38-gated CD138+ cells 
Diagnostic Pathology  2012;7:131.
World Health Organization (WHO) criteria are commonly used to diagnose plasma cell myeloma (PCM); however, these criteria are complex and require several laboratory parameters. For differentiating reactive plasmacytosis from clonal plasma cell (PC) neoplasms such as PCM, it is important to accurately determine the expression of cytoplasmic immunoglobulin light chains.
We retrospectively analyzed the records of 27 selected patients with PCM who underwent bone biopsies for confirmative diagnosis according to WHO criteria. Twenty-three controls were also investigated. In the present study, all the samples were analyzed using flow cytometry (FC) in the side scatter vs. CD38 histogram mode, and the CD38-gated PC population was identified. Bivariate histograms of CD138/kappa and CD138/lambda were assessed, and the ratios of dual-positive cells to the CD138+ PC population were calculated. The kappa/lambda ratio was defined as the ratio of CD138/kappa to CD138/lambda.
PCM cells were distinguished from normal PCs using cutoff levels between 0.76 and 1.5, at a sensitivity of 96.3% and specificity of 95.7%.
Three-color FC analysis is simple to perform and inexpensive, with clinically relevant data obtained soon after the completion of FC measurements. The detection of the cytoplasmic kappa/lambda ratio of CD38-gated CD138+ PCs may be a useful tool in the diagnosis of PCM. To the best of our knowledge, this report represents the first diagnostic assessment of the cytoplasmic kappa/lambda ratio in CD38-gated CD138+ PCs using FC analysis. This method may help in more simple, efficient, rapid, and accurate diagnosis of PCM.
Virtual slides
The virtual slide(s) for this article can be found here:
PMCID: PMC3523077  PMID: 23021410
Plasma cell myeloma; Diagnosis; kappa/lambda ratio; CD138; CD38
14.  Type 1 Diabetes and Interferon Therapy 
Diabetes Care  2011;34(9):2084-2089.
Interferon therapy can trigger induction of several autoimmune diseases, including type 1 diabetes. To assess the clinical, immunologic, and genetic characteristics of type 1 diabetes induced by interferon therapy, we conducted a nationwide cross-sectional survey.
Clinical characteristics, anti-islet autoantibodies, and HLA-DR typing were examined in 91 patients for whom type 1 diabetes developed during or shortly after interferon therapy.
Median age at the onset of type 1 diabetes was 56 (interquartile range 48–63) years and mean ± SD BMI was 20.8 ± 2.7 kg/m2. The time period from the initiation of interferon therapy to type 1 diabetes onset in patients receiving pegylated interferon and ribavirin was significantly shorter than that in patients with nonpegylated interferon single therapy (P < 0.05). Anti-islet autoantibodies were detected in 94.5% of patients at diabetes onset. Type 1 diabetes susceptibility HLA-DRs in the Japanese population, DR4 and DR9, were also associated with interferon treatment–related type 1 diabetes. Furthermore, the prevalence of HLA-DR13 was significantly higher in interferon treatment–related type 1 diabetes than in healthy control subjects (odds ratio 3.80 [95% CI 2.20–7.55]; P < 0.0001) and classical type 1 diabetes (2.15 [1.17–3.93]; P < 0.05).
Anti-islet autoantibodies should be investigated before and during interferon therapy to identify subjects at high risk of type 1 diabetes. Stronger antiviral treatment may induce earlier development of type 1 diabetes. Furthermore, patients who develop interferon-induced type 1 diabetes are genetically susceptible.
PMCID: PMC3161293  PMID: 21775762
15.  Pulmonary tumor thrombotic microangiopathy caused by gastric cancer 
Annals of Thoracic Medicine  2012;7(3):168-169.
Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal cancer-related pulmonary complication with rapidly progressing dyspnea, and occasionally induces sudden death. Here, we describe a postmortem-diagnosed PTTM case caused by gastric cancer, with the complaint of progressing dyspnea for 5 days.He did not have any abdominal symptoms or cancer history. PTTM should be considered in patients with rapidly worsening respiratory conditions, even if there is no cancer history.
PMCID: PMC3425052  PMID: 22924078
Dyspnea; gastric cancer; PTTM
16.  Efficacy and safety of repaglinide vs nateglinide for treatment of Japanese patients with type 2 diabetes mellitus 
Aims/Introduction:  Repaglinide is a short‐acting insulin secretagogue. We assessed the efficacy and safety of repaglinide in comparison with nateglinide in Japanese patients with type 2 diabetes previously treated with diet and exercise.
Materials and Methods:  In this 16‐week randomized, multicenter, double‐blind, parallel‐group, active‐controlled superiority trial, Japanese patients with type 2 diabetes and glycated hemoglobin (HbA1c) of ≥6.9 and ≤9.4% were enrolled. Patients were randomly assigned to receive 0.5 mg repaglinide (n = 64) or 90 mg nateglinide (n = 66) three times a day. The primary end‐point was changes in HbA1c from baseline to the end of treatment.
Results:  Mean reductions of HbA1c were significantly greater for the repaglinide group than the nateglinide group (−1.17 ± 0.62 vs −0.81 ± 0.39%, P < 0.001). The target HbA1c values of <6.9% were achieved by 75.0% of the repaglinide group vs 59.1% for nateglinide. Mean changes in fasting plasma glucose also showed significantly greater efficacy for repaglinide than nateglinide (−26.0 ± 20.9 vs −18.3 ± 17.8 mg/dL, P < 0.001). There were no differences in the adverse event rates between the repaglinide and the nateglinide group, by 57.8% (37/64) and 60.6% (40/66), respectively. Incidences of hypoglycemic symptoms were 17.2% (11/64, 28 events) in the repaglinide group and 6.1% (4/66, 20 events) in the nateglinide group, respectively.
Conclusions:  In type 2 diabetic patients treated with diet and exercise, repaglinide monotherapy gives greater glycemic improvement than nateglinide monotherapy in reducing HbA1c and fasting plasma glucose values after 16 weeks. This trial was registered with JapicCTI (no. JapicCTI‐080521). (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00188.x, 2011)
PMCID: PMC4014954  PMID: 24843581
Nateglinide; Repaglinide; Type 2 diabetes
18.  Class II HLA genotype in fulminant type 1 diabetes: A nationwide survey with reference to glutamic acid decarboxylase antibodies 
Aims/Introduction:  Fulminant type 1 diabetes is a subtype of type 1 diabetes characterized by a remarkably abrupt onset of insulin‐deficient hyperglycemia within a few days. The aim of the present study was to clarify characteristic class II HLA genotypes in a large number of patients with fulminant type 1 diabetes to date.
Materials and Methods:  We analyzed the HLA‐DRB1 and DQB1 genotypes, and their haplotypes in 207 patients with fulminant type 1 diabetes and 325 control subjects in the Japanese population.
Results:  The frequencies of the DRB1*04:05‐DQB1*04:01 and DRB1*09:01‐DQB1*03:03 haplotypes were significantly higher, and those of the DRB1*01:01‐DQB1*05:01, DRB1*15:02‐DQB1*06:01 and DRB1*08:03‐DQB1*06:01 haplotypes were significantly lower in patients with fulminant type 1 diabetes than in the control subjects. Combination analysis showed that the frequencies of homozygotes with DRB1*04:05‐DQB1*04:01 [odds ratio (OR) 7.0] and DRB1*09:01‐DQB1*03:03 (OR 9.5) were significantly higher in patients with fulminant type 1 diabetes. Within a limited portion of patients with fulminant type 1 diabetes with antibodies to glutamic acid decarboxylase (GADab; n = 25), the frequency of DRB1*09:01‐DQB1*03:03, but not DRB1*04:05‐DQB1*04:01, was significantly higher than in control subjects (44.0% vs 13.7%; Pc < 0.05, OR 5.0).
[Correction to last line of Results, added after online publication 29 July 2011: “OR 5.1” is changed to “OR 5.0”.]
Conclusions:  Our large‐scale study showed the characteristic class II HLA genotypes in fulminant type 1 diabetes, and implicated that genetic contribution to disease susceptibility is distinct between GADab‐positive and GADab‐negative fulminant type 1 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00139.x, 2012)
PMCID: PMC4014934  PMID: 24843547
Fulminant type 1 diabetes; HLA; Glutamic acid decarboxylase
19.  The Relation of Urinary 8-OHdG, A Marker of Oxidative Stress to DNA, and Clinical Outcomes for Ischemic Stroke 
Oxidative stress/free radical generation after ischemic stroke contributes to neuronal cell injury. We evaluated the utility of an oxidative stress marker, urinary 8-hydroxy-2-deoxyguanosine (8-OHdG), to demonstrate an association between the changes of 8-OHdG and outcomes after acute ischemic stroke.
We enrolled 44 patients (26 males and 18 females) who visited our hospital due to acute ischemic stroke. Urine was collected on admission and on Days 7, and 8-OHdG was measured by ELISA. The relationships between 8-OHdG levels, stroke subtypes, and clinical outcomes based on the NIHSS and modified Rankin Scale (mRS) upon discharge was evaluated.
In the overall cohort, the mean urinary level of 8-OHdG on Day 7 was increased than that on Day 0. The 8-OHdG levels on Day 0 were not different between patients with poor and good outcomes. However, an increasing rate from Day 0 to 7 (Δ 8-OHdG) in stroke patients with a poor outcome(mRS ≥3) was significantly higher than those with a good outcome (mRS ≤2) (2.54 vs 39.44, p = 0.004).
The biochemical changes related to 8-OHdG and oxidative stress may be considered a marker of ischemic brain injury and clinical outcome of ischemic stroke.
PMCID: PMC3386501  PMID: 22754596
Ischemic stroke; Oxidative stress; 8-OHdG; Clinical outcome; Radical scavenger; Edaravone.
20.  Interferon-β1b Increases Th2 Response in Neuromyelitis Optica 
A Japanese randomized controlled study showed that Interferon â (IFN-â1b) therapy is clinically effective in decreasing the frequency of attacks in multiple sclerosis (MS), even in optico-spinal MS (OSMS). However, recent studies have shown that IFN-â (IFN-â1a/IFN-â1b) treatment was not effective in neuromyelitis optica (NMO) patients and that the diminished benefit of IFN-â treatment in NMO may be due to different immune responses to IFN-â. We determined longitudinally the expression of CCR5, CXCR3 and CCR4 on CD4+ T and CD8+ T cells in the blood from patients with NMO and MS treated with IFN-â1b. During a 12-month period of IFN-â1b therapy, the annualized relapse rate decreased in MS patients but not in NMO patients. There was no significant difference in the expression of the chemokine receptors between NMO and MS at baseline. The percentages of CD4+CCR5+ and CD4+CXCR3+ T cells, representative of the Th1 response, were decreased in both NMO and MS after treatment. The percentage of CD4+CCR4+ T cells, representative of the Th2 response, was decreased in MS, but those for NMO was significantly increased compared with the pretreatment levels. Our results indicate that IFN-â1b-induced up-modulation of the Th2 response in NMO patients may be the source of differences in the therapeutic response to IFN-â1b therapy. In the present study, Th2 predominance is involved in the pathogenesis of NMO.
PMCID: PMC3497267  PMID: 23202893
neuromyelitis optica; multiple sclerosis; IFN-â1b; chemokine receptor; CCR5; CXCR3; CCR4; Th1; Th2
21.  The thyroid function of Graves' disease patients is aggravated by depressive personality during antithyroid drug treatment 
We previously reported that depressive personality (the scores of hypochondriasis, depression and psychasthenia determined by the Minnesota Multiphasic Personality Inventory (MMPI)) and daily hassles of Graves' disease (GD) patients treated long trem with antithyroid drug (ATD) were significantly higher in a relapsed group than in a remitted group, even in the euthyroid state. The present study aims to examine the relationship among depressive personality, emotional stresses, thyroid function and the prognosis of hyperthyroidism in newly diagnosed GD patients.
Sixty-four untreated GD patients responded to the MMPI for personality traits, the Natsume's Stress Inventory for major life events, and the Hayashi's Daily Life Stress Inventory for daily life stresses before and during ATD treatment.
In the untreated thyrotoxic state, depressive personality (T-scores of hypochondriasis, depression or psychasthenia greater than 60 points in MMPI) were found for 44 patients (69%). For 15 (23%) of these patients, the scores decreased to the normal range after treatment. However, depressive personality persisted after treatment in the remaining 29 patients (46%). Normal scores before treatment were found for 20 patients (31%), and the scores were persistently normal for 15 patients (23%). The remaining 5 patients (8%) had higher depressive personality after treatment. Such depressive personality was not associated with the severity of hyperthyroidism. Serum TSH receptor antibody activity at three years after treatment was significantly (p = 0.0351) greater in the depression group than in the non- depression group. The remission rate at four years after treatment was significantly (p = 0.0305) lower in the depression group than in the non- depression group (22% vs 52%).
The data indicate that in GD patients treated with ATD, depressive personality during treatment reflects the effect of emotional stress more than that of thyrotoxicosis and that it aggravates hyperthyroidism. Psychosomatic therapeutic approaches including antipsychiatric drugs and/or psychotherapy appears to be useful for improving the prognosis of hyperthyroidism.
PMCID: PMC3174109  PMID: 21827669
22.  Pathogenic Role of Macrophages in Intradermal Infection of Methicillin-Resistant Staphylococcus aureus in Thermally Injured Mice▿  
Infection and Immunity  2010;78(10):4311-4319.
Intradermal infection of methicillin-resistant Staphylococcus aureus (MRSA) in burned mice was pathogenically analyzed. An abscess was formed in normal mice intradermally infected with 108 CFU/mouse of MRSA, and all of these mice survived after the infection; however, abscess formation was not demonstrated to occur in burned mice similarly exposed to the pathogen, and all of these mice died within 5 days of infection. In burned mice, MRSA infected at the burn site intradermal tissues spread quickly throughout the whole body, while in normal mice, the pathogen remained localized at the infection site. Macrophages (Mφ) isolated from the infection site tissues of normal mice produced interleukin-12 (IL-12) but not IL-10 and were characterized as M1Mφ. These M1Mφ were not isolated from the infection site tissues of burned mice. When normal-mouse infection site tissue Mφ were adoptively transferred to burned mice at the MRSA infection site, an abscess formed, and the infection did not develop into sepsis. In contrast, an abscess did not form and sepsis developed in normal mice that were inoculated with burned-mouse infection site tissue Mφ. These Mφ produced IL-10 but not IL-12 and were characterized as M2Mφ. These results indicate that abscess formation is a major mechanism of host resistance against intradermal MRSA infection. M1Mφ in the tissues surrounding the infection site play a pivotal role in abscess formation; however, the abscess is not formed in burned mice where M2Mφ predominate. M2Mφ have been described as inhibitor cells for Mφ conversion from resident Mφ to M1Mφ.
PMCID: PMC2950336  PMID: 20679444
23.  Correlation of glycated albumin but not hemoglobin A1c with endogenous insulin secretion in fulminant type 1 diabetes mellitus 
Aims/Introduction:  Fulminant type 1 diabetes mellitus (FT1DM) develops as a result of very rapid and almost complete pancreatic β‐cell destruction. We hypothesized that in patients with FT1DM who have less endogenous insulin secretion, disease progression is more rapid, and thus glycated albumin (GA) levels are lower. This study was designed to prove this hypothesis.
Materials and Methods:  The present study included 42 patients with FT1DM (24 men, 18 women) in whom glycated hemoglobin (HbA1c), GA and daily urinary C‐peptide (CPR) were measured at the time of diagnosis. Patients with complications, such as liver disease, kidney disease, anemia, or who were pregnant were excluded.
Results:  Urinary CPR (log transformed) was not correlated with HbA1c (R = 0.168, P = 0.287), but was positively correlated with GA (R = 0.336, P = 0.030). It was weakly, but not significantly, correlated with GA/HbA1c ratio (R = 0.281, P = 0.072). In patients with GA < 24.0%, urinary CPR was significantly lower than in patients with GA ≥ 24.0%. In addition, in patients with GA/HbA1c ratio <3.8, urinary CPR was significantly lower than in patients with GA/HbA1c ratio ≥ 3.8.
Conclusions:  Our findings suggest that in patients with FT1DM, GA at the time of diagnosis was correlated with endogenous insulin secretion. GA < 24.0% at the time of diagnosis is predictive for less endogenous insulin secretion in patients with FT1DM. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00050.x, 2010)
PMCID: PMC4014892  PMID: 24843444
Glycated albumin; Fulminant type 1 diabetes mellitus; C‐peptide
24.  Endogenous insulin secretion even at a very low level contributes to the stability of blood glucose control in fulminant type 1 diabetes 
Fulminant type 1 diabetes is characterized by almost complete β‐cell destruction, resulting in scarce insulin secretion. In the present study, we aimed to clarify clinical features related to serum C‐peptide levels measured by a high sensitivity method, chemiluminescent enzyme immunoassay, in 12 patients with fulminant type 1 diabetes. Serum C‐peptide was detected (0.007–0.10 nmol/L) in four patients and was not detected in eight patients. A negative correlation was observed between serum C‐peptide levels and daily dosages of insulin (P < 0.01). The patients with detectable C‐peptide showed a significantly lower M‐value than those without (P = 0.01). In conclusion, our present results suggest that even very low levels of endogenous insulin secreting capacity can improve daily dosages of insulin and stabilize blood glucose levels. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.0059.x, 2010)
PMCID: PMC4014893  PMID: 24843445
Fulminant type 1 diabetes; Serum C‐peptide; M‐value
25.  Report of the Committee on the Classification and Diagnostic Criteria of Diabetes Mellitus 
Concept of Diabetes Mellitus:
Diabetes mellitus is a group of diseases associated with various metabolic disorders, the main feature of which is chronic hyperglycemia due to insufficient insulin action. Its pathogenesis involves both genetic and environmental factors. The long‐term persistence of metabolic disorders can cause susceptibility to specific complications and also foster arteriosclerosis. Diabetes mellitus is associated with a broad range of clinical presentations, from being asymptomatic to ketoacidosis or coma, depending on the degree of metabolic disorder.
Classification (Tables 1 and 2, and Figure 1):
 Etiological classification of diabetes mellitus and glucose metabolism disorders
Note: Those that cannot at present be classified as any of the above are called unclassifiable.
The occurrence of diabetes‐specific complications has not been confirmed in some of these conditions.
 Diabetes mellitus and glucose metabolism disorders due to other specific mechanisms and diseases
The occurrence of diabetes‐specific complications has not been confirmed in some of these conditions.
 A scheme of the relationship between etiology (mechanism) and patho‐physiological stages (states) of diabetes mellitus. Arrows pointing right represent worsening of glucose metabolism disorders (including onset of diabetes mellitus). Among the arrow lines, indicates the condition classified as ‘diabetes mellitus’. Arrows pointing left represent improvement in the glucose metabolism disorder. The broken lines indicate events of low frequency. For example, in type 2 diabetes mellitus, infection can lead to ketoacidosis and require temporary insulin treatment for survival. Also, once diabetes mellitus has developed, it is treated as diabetes mellitus regardless of improvement in glucose metabolism, therefore, the arrow lines pointing left are filled in black. In such cases, a broken line is used, because complete normalization of glucose metabolism is rare.
The classification of glucose metabolism disorders is principally derived from etiology, and includes staging of pathophysiology based on the degree of deficiency of insulin action. These disorders are classified into four groups: (i) type 1 diabetes mellitus; (ii) type 2 diabetes mellitus; (iii) diabetes mellitus due to other specific mechanisms or diseases; and (iv) gestational diabetes mellitus. Type 1 diabetes is characterized by destruction of pancreatic β‐cells. Type 2 diabetes is characterized by combinations of decreased insulin secretion and decreased insulin sensitivity (insulin resistance). Glucose metabolism disorders in category (iii) are divided into two subgroups; subgroup A is diabetes in which a genetic abnormality has been identified, and subgroup B is diabetes associated with other pathologic disorders or clinical conditions. The staging of glucose metabolism includes normal, borderline and diabetic stages depending on the degree of hyperglycemia occurring as a result of the lack of insulin action or clinical condition. The diabetic stage is then subdivided into three substages: non‐insulin‐ requiring, insulin‐requiring for glycemic control, and insulin‐dependent for survival. The two former conditions are called non‐insulin‐dependent diabetes and the latter is known as insulin‐dependent diabetes. In each individual, these stages may vary according to the deterioration or the improvement of the metabolic state, either spontaneously or by treatment.
Diagnosis (Tables 3–7 and Figure 2):
 Criteria of fasting plasma glucose levels and 75 g oral glucose tolerance test 2‐h value
*Casual plasma glucose ≥200 mg/dL (≥11.1 mmol/L) and HbA1c≥6.5% are also regarded as to indicate diabetic type.
Even for normal type, if 1‐h value is 180 mg/dL (10.0 mmol/L), the risk of progression to diabetes mellitus is greater than for <180 mg/dL (10.0 mmol/L) and should be treated as with borderline type (follow‐up observation, etc.). Fasting plasma glucose level of 100–109 mg/dL (5.5–6.0 mmol/L) is called ‘high‐normal’: within the range of normal fasting plasma glucose.
Plasma glucose level after glucose load in oral glucose tolerance test (OGTT) is not included in casual plasma glucose levels. The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%).
 Procedures for diagnosing diabetes mellitus
*The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%). **Hyperglycemia must be confirmed in a non‐stressful condition. OGTT, oral glucose tolerance test.
 Disorders and conditions associated with low HbA1c values
 Situations where a 75‐g oral glucose tolerance test is recommended
*The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%).
 Definition and diagnostic criteria of gestational diabetes mellitus
(IADPSG Consensus Panel, Reference 42, partly modified with permission of Diabetes Care).
 Flow chart outlining steps in the clinical diagnosis of diabetes mellitus. *The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%).
Categories of the State of Glycemia:  Confirmation of chronic hyperglycemia is essential for the diagnosis of diabetes mellitus. When plasma glucose levels are used to determine the categories of glycemia, patients are classified as having a diabetic type if they meet one of the following criteria: (i) fasting plasma glucose level of ≥126 mg/dL (≥7.0 mmol/L); (ii) 2‐h value of ≥200 mg/dL (≥11.1 mmol/L) in 75 g oral glucose tolerance test (OGTT); or (iii) casual plasma glucose level of ≥200 mg/dL (≥11.1 mmol/L). Normal type is defined as fasting plasma glucose level of <110 mg/dL (<6.1 mmol/L) and 2‐h value of <140 mg/dL (<7.8 mmol/L) in OGTT. Borderline type (neither diabetic nor normal type) is defined as falling between the diabetic and normal values. According to the current revision, in addition to the earlier listed plasma glucose values, hemoglobin A1c (HbA1c) has been given a more prominent position as one of the diagnostic criteria. That is, (iv) HbA1c≥6.5% is now also considered to indicate diabetic type. The value of HbA1c, which is equivalent to the internationally used HbA1c (%) (HbA1c [NGSP]) defined by the NGSP (National Glycohemoglobin Standardization Program), is expressed by adding 0.4% to the HbA1c (JDS) (%) defined by the Japan Diabetes Society (JDS).
Subjects with borderline type have a high rate of developing diabetes mellitus, and correspond to the combination of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) noted by the American Diabetes Association (ADA) and WHO. Although borderline cases show few of the specific complications of diabetes mellitus, the risk of arteriosclerosis is higher than those of normal type. When HbA1c is 6.0–6.4%, suspected diabetes mellitus cannot be excluded, and when HbA1c of 5.6–5.9% is included, it forms a group with a high risk for developing diabetes mellitus in the future, even if they do not have it currently.
Clinical Diagnosis:  1 If any of the criteria for diabetic type (i) through to (iv) is observed at the initial examination, the patient is judged to be ‘diabetic type’. Re‐examination is conducted on another day, and if ‘diabetic type’ is reconfirmed, diabetes mellitus is diagnosed. However, a diagnosis cannot be made only by the re‐examination of HbA1c alone. Moreover, if the plasma glucose values (any of criteria [i], [ii], or [iii]) and the HbA1c (criterion [iv]) in the same blood sample both indicate diabetic type, diabetes mellitus is diagnosed based on the initial examination alone. If HbA1c is used, it is essential that the plasma glucose level (criteria [i], [ii] or [iii]) also indicates diabetic type for a diagnosis of diabetes mellitus. When diabetes mellitus is suspected, HbA1c should be measured at the same time as examination for plasma glucose.2 If the plasma glucose level indicates diabetic type (any of [i], [ii], or [iii]) and either of the following conditions exists, diabetes mellitus can be diagnosed immediately at the initial examination.• The presence of typical symptoms of diabetes mellitus (thirst, polydipsia, polyuria, weight loss)• The presence of definite diabetic retinopathy3 If it can be confirmed that the above conditions 1 or 2 existed in the past, diabetes mellitus can be diagnosed or suspected regardless of the current test results.4 If the diagnosis of diabetes cannot be established by these procedures, the patient is followed up and re‐examined after an appropriate interval.5 The physician should assess not only the presence or absence of diabetes, but also its etiology and glycemic stage, and the presence and absence of diabetic complications or associated conditions.
Epidemiological Study:  For the purpose of estimating the frequency of diabetes mellitus, ‘diabetes mellitus’ can be substituted for the determination of ‘diabetic type’ from a single examination. In this case, HbA1c≥6.5% alone can be defined as ‘diabetes mellitus’.
Health Screening:  It is important not to misdiagnose diabetes mellitus, and thus clinical information such as family history and obesity should be referred to at the time of screening in addition to an index for plasma glucose level.
Gestational Diabetes Mellitus:  There are two hyperglycemic disorders in pregnancy: (i) gestational diabetes mellitus (GDM); and (ii) diabetes mellitus. GDM is diagnosed if one or more of the following criteria is met in a 75 g OGTT during pregnancy:
1 Fasting plasma glucose level of ≥92 mg/dL (5.1 mmol/L)2 1‐h value of ≥180 mg/dL (10.0 mmol/L)3 2‐h value of ≥153 mg/dL (8.5 mmol/L)
However, diabetes mellitus that is diagnosed by the clinical diagnosis of diabetes mellitus defined earlier is excluded from GDM. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00074.x, 2010)
PMCID: PMC4020724  PMID: 24843435
Diabetes mellitus; Clinical diagnosis; HbA1c

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