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Aims/Introduction We aimed to study the relationships among the copper (Cu)/zinc (Zn) ratio, inflammatory biomarkers, and the prevalence of diabetic kidney disease (DKD) in patients with type 2 diabetes. Materials and Methods A cross‐sectional study was performed on 651 patients with type 2 diabetes. DKD was defined as a urinary albumin‐to‐creatinine ratio of ≥30 mg/g creatinine and/or an estimated glomerular filtration rate using cystatin C of

Aims/Introduction There is little evidence on the role of postprandial glycemia in the incidence of diabetic retinopathy (DR) in a real‐world setting. We aimed to assess the effect of postprandial hyperglycemia at clinic visits on the incidence of DR in patients with type 2 diabetes, and whether its effect differs depending on glycated hemoglobin (HbA1c) values and age. Materials and Methods Intrapersonal mean blood glucose levels at 1–2 h post‐breakfast (1–2h‐PBBG), post‐lunch (1–2 h‐PLBG) and both (1–2h‐PBLBG) during 2 years from the first visit were used as baseline data. This retrospective cohort study enrolled 487, 323 and 406 patients who had 1–2h‐PBLBG, 1–2h‐PBBG and 1–2h‐PLBG measurements, respectively. These three groups were followed from 1999 up through 2017. Results DR occurred in 145, 92 and 126 patients in the 1–2h‐PBLBG, 1–2h‐PBBG and 1–2h‐PLBG groups, respectively. Multivariate Cox regression analysis showed that the mean 1–2h‐PBLBG, 1–2h‐PBBG and 1–2h‐PLBG levels were significant predictors of DR, independent of mean HbA1c. In patients with mean HbA1c, The present study shows that postprandial hyperglycemia at clinic visits is associated with the incidence of diabetic retinopathy, independent of glycated hemoglobin levels, in a real‐world setting in patients with type 2 diabetes. The effect of postprandial hyperglycemia on retinopathy is obvious in patients with well‐controlled glycated hemoglobin levels and in patients aged

We sought to estimate the exact causes of death, mortality rate and life expectancy of diabetes patients by analyzing death records in a diabetes specialist clinic in Japan. Of the 6,140 participants included in our analysis, the average age was 58.1 years and 77% were men. A total of 261 deaths were recorded during the total follow‐up period of 24,079 total person‐years. The leading causes of death were cancer, heart diseases and cerebrovascular diseases. Using a life table prepared from the mortality rates estimated with the exponential distribution model, a life expectancy at 40 years was 39.2 years (95% confidence interval 37.9–40.2 years) for men and 43.6 years (95% confidence interval 41.8–45.3 years) for women. Although the present results must be interpreted with caution, compared with populations with diabetes surveyed during similar periods by the Japan Diabetes Society, our diabetes patients had similar ranking of the causes of death., Among 6,140 patients in a diabetes specialist clinic in Japan, the leading causes of death were cancer, heart diseases and cerebrovascular diseases. A life expectancy at 40 years was 39.2 (95% confidence interval 37.9–40.2) in men and 43.6 (95% confidence interval 41.8–45.3) in women. Although our results must be interpreted with caution, because a healthy survivor bias might exist, compared with populations with diabetes surveyed during similar periods by the Japan Diabetes Society, our diabetes patients had similar ranking of the causes of death.

A retrospective case–controlled analysis was performed to identify drug candidates in the current use that may prevent colorectal cancer, outside of aspirin. A total of 37,510 patients aged ≥20 years were assessed to identify subjects who had been diagnosed with colorectal cancer by colonoscopy without a previous diagnosis of colorectal cancer, inflammatory bowel disease (IBD), or gastrointestinal symptoms; 1,560 patients were identified who were diagnosed with colorectal cancer by colonoscopy. The patients with colorectal cancer were matched with 1,560 age, gender, family history of colorectal cancer and comorbidity-matched control patients who were not diagnosed with colorectal cancer at colonoscopy. The medication histories were compared between the two groups. Next, candidate drugs that were more frequently used by the control patients were selected and their effects on human colorectal cancer cell lines in vitro and an inflammation-induced mouse model of colorectal cancer were tested. Putative colorectal cancer preventative agents were identified, including aspirin, vitamin D, vitamin B, vitamin C, vitamin E, xanthine oxidase inhibitor, alpha-blockers, angiotensin receptor blocker, nateglinide, probiotics, thienopyridine, folic acid, nitrovasodilators, bisphosphonates, calcium channel blockers, steroids, and statins (P < 0.05). Alpha-blockers and xanthine oxidase inhibitors were selected for further study because these agents have not been analyzed previously as factors that may affect colorectal cancer outcomes. In vitro doxazosin (alpha-blocker), but not febuxostat (xanthine oxidase inhibitor), suppressed the proliferation of human colorectal cancer cells. Doxazosin also decreased tumorigenesis in an AOM/DSS mouse colorectal cancer model. Alpha-blockers may prevent colorectal cancer.

Aims/Introduction Hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes mellitus fluctuate throughout the year. However, there are few studies that have evaluated the therapeutic effect of hypoglycemic agents while considering such fluctuations. In a multicenter study (Januvia Multicenter Prospective Trial in Type 2 Diabetes Study), pretreatment patients with type 2 diabetes mellitus were divided into seven groups and given sitagliptin for 1 year. The aim of the present study was to evaluate the differences in the therapeutic effect, and the efficacy of sitagliptin in patients with type 2 diabetes mellitus based on the month the administration of the drug began as a subanalysis of the Januvia Multicenter Prospective Trial in Type 2 Diabetes Study. Materials and Methods Patients with type 2 diabetes mellitus were divided into four groups according to the month of initiation of sitagliptin. Changes in HbA1c in each group were compared at 3 and 12 months after administration of sitagliptin. As a negative correlation has been reported between baseline HbA1c and the degree of change after administration of sitagliptin, an analysis using the residual error from the approximate line was carried out. Results In the analysis of the degree of change in HbA1c, patients in the group in which administration of sitagliptin was started between August and October had the lowest degree of improvement at 3 months after starting sitagliptin. However, there was no significant intergroup difference in improvement at 12 months after the start of sitagliptin. The same result was also obtained in residual analysis. Conclusions The present study suggested that the season of administration of sitagliptin influenced the subsequent hypoglycemic effect even after analysis excluding the influence of HbA1c value at the start of treatment. This study provides possibility, showing that seasonal fluctuations have an effect on the efficacy of antidiabetic drugs.

Objective To analyze the changes in the pharmacotherapy and glycemic control trends in elderly patients with type 2 diabetes mellitus (T2DM) in Japan. Methods We extracted the data of 7,590 patients (5,396 men and 2,194 women; median year of birth: 1945) with T2DM registered in the National Center Diabetes Database for the years 2005 to 2013, and conducted age-stratified (

Glial fibrillary acidic protein (GFAP) is expressed in peri-islet Schwann cells, as well as in glia cells, and has been reported to be an autoantigen candidate for type 1 diabetes mellitus (T1DM). We confirmed that the production of the autoantibodies GFAP and glutamic acid decarboxylase 65 (GAD65) was increased and inversely correlated with the concentration of secreted C peptide in female nonobese diabetic mice (T1DM model). Importantly, the development of T1DM in female nonobese diabetic mice at 30 wk of age was predicted by the positive GFAP autoantibody titer at 17 wk. The production of GFAP and GAD65 autoantibodies was also increased in KK-Ay mice [type 2 diabetes mellitus (T2DM) model]. In patients with diabetes mellitus, GFAP autoantibody levels were increased in patients with either T1DM or T2DM, and were significantly associated with GAD65 autoantibodies but not zinc transporter 8 autoantibodies. Furthermore, we identified a B-cell epitope of GFAP corresponding to the GFAP autoantibody in both mice and patients with diabetes. Thus, these results indicate that autoantibodies against GFAP could serve as a predictive marker for the development of overt autoimmune diabetes.-Pang, Z., Kushiyama, A., Sun, J., Kikuchi, T., Yamazaki, H., Iwamoto, Y., Koriyama, H., Yoshida, S., Shimamura, M., Higuchi, M., Kawano, T., Takami, Y., Rakugi, H., Morishita, R., Nakagumi, H. Glial fibrillary acidic protein (GFAP) is a novel biomarker for the prediction of autoimmune diabetes.

We explored whether visit-to-visit variability in both glycated hemoglobin (HbA1c) and systolic blood pressure (SBP) simultaneously predicted the development of microalbuminuria and retinopathy, and whether the predictive ability of these measurements changed according to mean HbA1c and SBP levels in people with type 2 diabetes.A retrospective observational cohort study was conducted on 243 type 2 diabetes patients with normoalbuminuria and 486 without retinopathy at the first visit and within 1year thereafter. The two cohorts were followed up from 1995 until 2012. Multivariate and stratified analyses were performed using Cox proportional hazard models.Microalbuminuria developed in 84 patients and retinopathy in 108. Hazard ratios (HRs) for the development of microalbuminuria associated with the coefficient of variation (CV) and variation independent of mean (VIM) of both HbA1c and SBP significantly increased. In participants with a mean SBP130mmHg, the HRs for the development of retinopathy associated with CV and VIM of HbA1c were abruptly elevated and significant compared with those with a mean SBP ≥130mmHg.Visit-to-visit variability in both HbA1c and SBP simultaneously predict the development of microalbuminuria. HbA1c variability may predict the development of retinopathy when the mean SBP is normal (130mmHg).

In 169 Japanese patients with type 2 diabetes mellitus with blood glucose levels that were inadequately controlled with diet and exercise therapy alone, or with diet and exercise therapy plus a sulfonylurea (SU) drug, we evaluated the safety and efficacy of global standard dose metformin given up to a maximum daily dose of 2250 mg for 54 weeks. The changes in HbA1c from baseline to the final evaluation visit were -1.32 ± 0.76% for metformin monotherapy and -1.29 ± 0.81% for metformin plus SU, both significantly lower than baseline. The incidences of adverse events and adverse drug reactions were 91.1% (154/169 patients) and 67.5% (114/169 patients), respectively. The most common adverse events were gastrointestinal symptoms, and most of the gastrointestinal symptoms were considered by investigators to be related to metformin treatment. An increased blood lactic acid level was observed in three subjects (1.8%); however, no clinical symptoms were reported, and there was no increase in mean lactic acid concentration throughout the evaluation period. Symptoms of hypoglycemia were reported in 16 patients, all receiving metformin plus SU, but none received metformin monotherapy. There was a decrease in mean body weight. Global standard dose metformin may be useful for maintaining good blood glucose control over the long term in the treatment of type 2 diabetes mellitus in Japanese patients.

Aims/Introduction We evaluated the impact of postprandial hyperglycemia at clinic visits on the incidence of cardiovascular diseases (CVD) and all-cause mortality independently of mean glycosylated hemoglobin in type 2 diabetes patients in a real-world setting. Materials and Methods The present retrospective observational cohort study included 646 type 2 diabetes patients. All of the participants had their initial consultations at the Institute for Diabetes Care and Research, Asahi Life Foundation affiliated Marunouchi Hospital, Tokyo, Japan, during the period from 1995 to 1996, visited the clinic ≥4 times, had their 2-h post-breakfast blood glucose (2h-PBBG) levels measured and were followed up for ≥1 year. The 646 patients were followed up for survival. Of the 646 patients, 618 had no history of CVD at the first visit and had measured 2h-PBBG until the first CVD onset or censorings. These two cohorts were followed up through June 2012, and subsequently questionnaires were mailed. Multivariate Cox proportional hazard models were used to evaluate the risk of CVD incidence and death. Results CVD occurred in 78 patients, and 56 patients died. The median follow-up periods of the CVD cohort and the mortality cohort were 15.6 and 15.9 years, respectively. The mean 2h-PBBG is a significant predictor of the CVD incidence and all-cause mortality after adjusting for the mean glycosylated hemoglobin, the number of 2h-PBBG measurements, age, sex and classical risk factors. Conclusions Postprandial hyperglycemia represented by the mean level of 2h-PBBG at clinic visits is associated with CVD incidence and all-cause mortality independently of the mean glycosylated hemoglobin level in type 2 diabetes patients. Prospective interventional trials are warranted to confirm the present findings.

[This corrects the article DOI: 10.1007/s13340-017-0330-2.].

Aims/Introduction Insulin degludec/insulin aspart (IDegAsp) is a soluble combination of insulin degludec (70%) and insulin aspart (30%). The present exploratory trial investigated the safety of switching unit-to-unit from twice-daily basal or pre-mix insulin to twice-daily IDegAsp in Japanese patients with type 2 diabetes. Materials and Methods In this 6-week, open-label, parallel-group, controlled trial, 66 participants were randomized (1:1) to receive either IDegAsp or biphasic insulin aspart 30 (BIAsp 30) twice daily at the same total daily dose as pre-trial insulin. During the trial, insulin doses were adjusted according to a pre-specified algorithm to achieve pre-breakfast and pre-dinner plasma glucose of 4.4–7.2 mmol/L. Results No severe hypoglycemic episodes occurred. There were no statistically significant differences in rates of confirmed hypoglycemia (rate ratio IDegAsp/BIAsp 30: 0.63, 95% confidence interval: 0.31–1.30) and confirmed nocturnal hypoglycemia (rate ratio: 0.49, 95% confidence interval: 0.10–2.38) for IDegAsp vs BIAsp 30. The hypoglycemia rate for IDegAsp was constant over the 6 weeks of treatment. IDegAsp and BIAsp 30 were both safe and well tolerated. Reduction in fasting plasma glucose was statistically significantly greater for IDegAsp than for BIAsp 30 (estimated treatment difference, IDegAsp-BIAsp 30: −1.6 mmol/L, 95% confidence interval: −2.4 to −0.8). The apparent decrease in mean postprandial plasma glucose increment (IDegAsp: 4.2–3.8 mmol/L; BIAsp 30: 4.5–2.8 mmol/L) was not statistically significantly different between treatments (estimated treatment difference: 1.0 mmol/L, 95% confidence interval: −0.1 to 2.2). Conclusions Switching unit-to-unit from basal or pre-mix insulin to IDegAsp seems not to be associated with any concerns related to hypoglycemia or general safety in Japanese patients with type 2 diabetes.

A retrospective case-controlled analysis was performed to identify drug candidates in the current use that may prevent colorectal cancer, outside of aspirin. A total of 37,510 patients aged ≥20 years were assessed to identify subjects who had been diagnosed with colorectal cancer by colonoscopy without a previous diagnosis of colorectal cancer, inflammatory bowel disease (IBD), or gastrointestinal symptoms; 1,560 patients were identified who were diagnosed with colorectal cancer by colonoscopy. The patients with colorectal cancer were matched with 1,560 age, gender, family history of colorectal cancer and comorbidity-matched control patients who were not diagnosed with colorectal cancer at colonoscopy. The medication histories were compared between the two groups. Next, candidate drugs that were more frequently used by the control patients were selected and their effects on human colorectal cancer cell lines

Glycemic control is important for diabetic retinopathy (DR), but not sufficient for the inhibition after proliferative DR (PDR). Uric acid in the vitreous is reportedly increased in patients with DR, especially in the PDR. Here, the involvement of xanthine oxidoreductase (XO), responsible for uric acid production, in worsening DR was examined in both mouse model and co-cultured angiogenesis model. First, retinal pericytes were abolished by anti-PDGFRβ antibody injection to C57/Bl6 neonatal mouse at P1. Pericyte dropout from endothelial cells is reportedly early histological change in DR, and induces bleeding, abnormal angiogenesis, inflammation, and retinal detachment with rapid progression at P9-11. The expression of XO level in retina was increasing after pericyte breakdown, and was proportional to VEGF, and preceding the increase of TNFalpha. When 3.6mg/kg Febuxostat (Fbx), an XO inhibitor was injected at P7, widespread edema and retinal detachment/funnel-like deformation were dramatically improved by Fbx treatment at P11. ICAM-1+ cells surrounding edema and CD11b+ cells were reduced. Next, we performed a 3D culture sprouting assay using HUVEC spheroids in collagen gel co-cultured with human lung fibroblast (hLF) in fibrin gel. By Fbx treatment within the physiological concentration, the branch sprouting, cellular migration to the distal side and mitosis in branch stems were inhibited. ICAM-1 increase in HUVEC was observed with hLF co-culture but was suppressed by Fbx treatment. Finally, these effects of Fbx were not shown on HUVEC in planar culture. On the other hand, dissolution of fibrin by hLF was delayed directly due to Fbx. VEGF and PAI-1 expression from hLF and MMP-9 activity in medium were decreased by Fbx treatment. In summary, XO inhibition improved retinal inflammation and injury after pericyte loss. These results suggest the role of humoral inflammatory factors from mesenchymal cells surrounding retinal vessels in the hyperpermeable state such as DR. Disclosure A. Kushiyama: Research Support; Self; Teijin Pharma Limited, Sanwa Kagaku Kenkyusho Co., Ltd., Kowa Pharmaceutical Co., Ltd, StaGen. Consultant; Self; RIZAP. T. Kikuchi: None. H. Yamazaki: None. T. Yamamotoya: None. H. Sakoda: None. M. Fujishiro: Research Support; Self; Johnson & Johnson Services, Inc.. Y. Nakatsu: None. A. Uemura: Research Support; Self; Daiichi Sankyo Company, Limited, Boehringer Ingelheim GmbH, KAN Research Institute, Inc. T. Shirakura: Employee; Self; Teijin Pharma Limited. T. Asano: Research Support; Self; Teijin Pharma Limited, Sanwa Kagaku Kenkyusho Co., Ltd., Sanofi K.K. Y. Iwamoto: Board Member; Self; Japan Diabetes Foundation.

Aims To determine the cutoff values of fasting plasma glucose (FPG) variability for detecting retinopathy and examine the threshold of FPG levels for predicting retinopathy incidence in type 2 diabetes. Methods Subjects comprised 170 patients with type 2 diabetes who had no retinopathy at their first visit, and continuously visited thereafter for 27 years. Retinopathy was evaluated by ophthalmologists at least annually. Results 114 patients developed retinopathy. 46 of them had advanced retinopathy. The optimal cutoff values of intrapersonal mean and standard deviation (SD) of FPG over 27 years and intrapersonal mean HbA1c from the initial measurement to the last visit for detecting retinopathy were 7.4 mmol/L, 1.4 mmol/L, and 7.2% (56 mmol/mol), respectively. Similarly, for advanced retinopathy, 7.7 mmol/L, 1.9 mmol/L, and 7.5% (59 mmol/mol), respectively. Hazard ratios of deciles of intrapersonal mean FPG (mmol/L) during the initial 2 years for retinopathy incidence significantly increased from eighth-decile (6.9–7.4), and were sharply elevated from ninth-decile (7.4–8.7). Conclusions Our study provides new cutoff values for FPG variability. Cutoff values of FPG and HbA1c were slightly higher than recommended targets of the current guideline. The threshold of FPG levels (6.9 mmol/L) is proposed to predict retinopathy incidence during the subsequent 25 years.

Objectives To determine if a discrepancy exists between subjective symptoms and the grade of endoscopic gastroesophageal reflux disease (GERD) in diabetes mellitus (DM) patients. Methods All 2,884 patients who underwent esophagogastroduodenoscopy completed the modified Gastrointestinal Symptom Rating Scale (GSRS), an interview-based rating scale consisting of 16 items including a question on acid regurgitation. Patients were divided into DM and non-DM groups (1,135 and 1,749 patients, respectively). GERD was diagnosed endoscopically and graded according to the Los Angeles classification. Grade B or more severe GERD was defined as severe endoscopic GERD. The intergroup GSRS score was compared statistically. Results In severe endoscopic GERD patients, the prevalence of patients with a positive GSRS score in the acid regurgitation question was statistically lower in DM patients than non-DM patients. Of the 60 non-DM patients with severe endoscopic GERD, 40 patients (67%) had a positive GSRS score for acid regurgitation; however, of the 51 DM patients with severe endoscopic GERD, 23 patients (45%) had a positive GSRS score. Multivariate analysis showed that severe endoscopic GERD (OR: 2.01; 95% CI: 1.21–3.33; p = 0.0066), non-DM (OR: 0.74; 95% CI: 0.54–0.94; p = 0.0157), younger age (OR: 0.98; 95% CI: 0.97–0.99; p = 0.0125), and hiatal hernia (OR: 1.46; 95% CI: 1.12–1.90; p = 0.0042) were associated with acid regurgitation symptoms. Conclusions There is a discrepancy between subjective symptoms and endoscopic GERD grade in DM patients. The ability of DM patients to feel acid regurgitation may be decreased.

As a subanalysis of the Januvia Multicenter Prospective Trial in Type 2 Diabetes (JAMP study), we examined factors that decreased blood glucose control effect of sitagliptin after 3 months and patients requiring an addition or increase of diabetes treatment. We selected patients in whom glycated hemoglobin (HbA1c) levels decreased by month 3 after initiation of sitagliptin treatment and conducted two analyses: (1) in patients who did not change drugs until month 12, we compared changes in HbA1c levels between concomitant drugs and examined factors that decreased blood glucose control effect of sitagliptin; (2) compared changes in HbA1c levels and backgrounds between patients who did and did not require an addition to or increased dose of the antidiabetic agent. Four hundred and ninety-eight patients were chosen. In 369 patients without drug change until month 12, changes in HbA1c levels during months 3–12 were not significantly different among concomitant drugs; factors causing rebound HbA1c were smoking and weight gain. Patient characteristics were compared between those who did and did not require an additional drug or a dose increase (n = 114) (n = 384). Drug changes were associated with longer disease duration, younger age, higher rate of smoking, and higher degree of insulin resistance but not with concomitantly administered drugs. Smoking and weight gain were factors that decreased the effect of sitagliptin on reducing blood glucose levels. Differences in concomitant drugs did not affect sitagliptin’s effects on glycemic control. A dose increase or the addition of the antidiabetic drug was not associated with concomitant drugs.

Background: The aim of the study was to determine the effects of sitagliptin on renal function in a diabetic population including patients with normal renal function. Methods: We analyzed the association between 12-month, 50 mg/day sitagliptin and renal function in outpatients with type 2 diabetes mellitus and poor blood glucose control in a subset of patients in the larger Januvia Multicenter Prospective Trial in Type 2 Diabetes observational study. Stratified analyses of changes in estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) were performed. Factors associated with changes in eGFR at 3 months were examined by multivariate regression analysis. Results: Of the 779 patients enrolled, 585 were followed up for 12 months. eGFR decreased significantly from baseline at 3 and 12 months in patients with a baseline eGFR of ≥ 90 mL/min/1.73 m 2 and in those with a baseline eGFR of ≥ 60 to < 90 mL/min/1.73 m 2 . Conversely, eGFR tended to increase at 3 and 12 months in patients with a baseline eGFR of ≥ 45 to < 60 mL/min/1.73 m 2 and in those with a baseline eGFR of ≥ 30 to < 45 mL/min/1.73 m 2 . UACR decreased significantly (-21.6 (-46.8, 7.8)) at 3 months in patients with a baseline UACR of ≥ 30 mg/g Cre. Multivariate regression analysis of factors associated with changes in eGFR at 3 months revealed that higher baseline eGFR and greater decline in UACR were associated with more conspicuous decreases in eGFR. Conclusions: In this group of diabetic patients receiving sitagliptin, eGFR declined in patients with high baseline eGFR, but not in those with a low baseline eGFR. J Clin Med Res. 2018;10(1):32-40 doi: https://doi.org/10.14740/jocmr3225w

To determine the efficacy and safety of sitagliptin when used with some therapeutic drugs to treat elderly patients. Sitagliptin (50 mg/day) was added to the pre-existing therapy for type 2 diabetes. Changes in the glycated hemoglobin (HbA1c) level after 3 months of treatment were compared with the baseline, and exploratory analysis was performed. These analyses were conducted as subanalyses of the JAMP study, which was an open-label observational study. For patients who were ≥65 years of age, the change in HbA1c level from baseline ranged from −0.50 to −0.87% at 3 months after starting treatment. There was no significant difference in the change in HbA1c level between the patients treated with different concomitant drugs. No significant difference in HbA1c variations at 3 and 12 months from baseline was noted among the three age groups (≥75, 65–74, and

To effectively prevent the worsening of hyperglycemia in type 2 diabetes mellitus, it is of interest to see the clinical efficacy of early introduction of pharmacotherapy in addition to lifestyle intervention which is not always easy to continue throughout life. This is a randomized unblinded comparative clinical study on suppressive effects of lifestyle intervention alone and additional monotherapies for mild hyperglycemia at an early stage of treatment-naive type 2 diabetic patients, whose fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) are less than 140 mg/dl and 7.4%, respectively. The control group (group N = arm N) received conventional lifestyle intervention assisted by routine facilities, while the pharmacological intervention group (group D composed of 4 arms) was additionally treated by monotherapy with one of four kinds of oral antihyperglycemic agents i.e., sulfonylurea (SU), α-glucosidase inhibitor, biguanide and dipeptidyl peptidase-4 inhibitor. The participants were scheduled to follow up for 3 years to maintain glycemic control below primary endpoint which was defined as the first occurrence of FPG ≥140 mg/dl and HbA1c ≥7.4% simultaneously even by increasing doses of oral drug in group D, if necessary. The outcomes of occurrences of primary endpoint were not different between group N and group D composed of 4 arms during 3 years by Kaplan-Meyer plots (p = 0.405). On the other hand, ΔFPG (Δ: incremental change from baseline) and ΔHbA1c in group D significantly decreased when compared to those of group N during 3 years (p

To better understand patient resistance to initiation of insulin therapy, this study examined the perception gap concerning initiation of insulin therapy between individuals with type 2 diabetes and their physicians by using data from the DAWN Japan study.The DAWN Japan study is a multi-center, questionnaire-based survey, conducted between 2004-2005. Patients recommended to start insulin therapy (n = 148) answered a questionnaire by rating degree of agreement with 16 statements concerning insulin therapy on a 5-point scale (1: strongly disagree to 5: strongly agree). Ratings of 1 and 2 were categorized as 'disagree' with a statement, and 3, 4, and 5 as 'agree'. Their attending physicians (n = 68) selected statements which could be associated with patient's concerns about insulin therapy.Nearly all the patients agreed with the statements 'I don't want to inject myself for the rest of my life' (95%), and 'I don't want to be bothered with doing injections' (90%); fewer than half agreed with 'My friendships may suffer' (46%), and 'I don't understand why insulin is necessary for me' (45%). Estimation by the physicians and the actual perceptions patients reported differed significantly for 13 statements. Physicians seemed to particularly under-estimate the impact associated with social aspects of insulin use (e.g., 'I don't want to be different from others', 55% patients vs 7% physicians). On the contrary, the statement 'Injections are painful' was the only concern over-estimated by the physicians.It was demonstrated that differences in perceptions regarding insulin therapy exist between physicians and patients, particularly in terms of social impacts. The data, obtained in 2004, may not precisely reflect the present situation, but still represents a barrier to insulin therapy widely held by patients and physicians. These results suggest that appropriate understanding of patients' concerns about insulin therapy is important to encourage timely insulin initiation.

A 29-year-old woman with diabetes mellitus was admitted to our hospital for severe congestive heart failure. She was suspected of having Prader–Willi syndrome (PWS) or Angelman syndrome. On admission, a chest X-ray showed pneumonia and cardiomegaly with massive pleural and pericardial effusion. Obstructive and central sleep apnea syndrome was suggested, because of severe obesity and episodes of apnea without breathing and movement of the rib cage. The causes of central sleep apnea syndrome include pneumonia, hypoxia, and high metabolic production of an anticonvulsant drug because of epileptic seizure, and she had an abnormal electroencephalogram. She went on to mechanical ventilation (for example BiPAP, CPAP, and SIMV) and treatment with antibiotics. She continued to receive pressure support ventilation and antiepileptic drug treatment, and her systemic condition improved markedly after transfer to another hospital. She was finally diagnosed as PWS by genetic testing. Unfortunately, she died suddenly after choking on a sputum clog 5 months after discharge from the hospital.

Introduction Insulin degludec (IDeg) is an ultra-long-acting basal insulin with a consistent action profile of >42 h. This trial compared the efficacy and safety of IDeg with insulin glargine (IGlar) in insulin-naive Asian patients with type 2 diabetes. Materials and Methods In this multinational, 26-week, open-label, treat-to-target trial, 435 participants (202 females, 233 males; mean age 58.6 years; mean body mass index 25 kg/m2; mean glycated hemoglobin [HbA1c] 8.5%) were randomized (2:1) to IDeg or IGlar, each administered once daily with ≥1 oral antidiabetic drug(s) (OAD). Results After 26 weeks, HbA1c had decreased by 1.24 and 1.35% in the IDeg and IGlar groups, respectively (treatment difference [IDeg – IGlar] 0.11%, 95% confidence interval [CI] −0.03 to 0.24), confirming non-inferiority. Rates of overall confirmed hypoglycemia were similar for IDeg and IGlar during the full trial period (3.0 vs 3.7 episodes/patient-year of exposure [PYE]; rate ratio [RR] 0.82, 95% CI 0.60 to 1.11, P = 0.20), but significantly lower (by 37%) for IDeg during the maintenance period (from week 16 onward; RR 0.63, 95% CI 0.42 to 0.94, P = 0.02). No significant difference in the rate of nocturnal confirmed hypoglycemia was found between IDeg and IGlar in the full trial period (0.8 vs 1.2 episodes/PYE; RR 0.62, 95% CI 0.38 to 1.04, P = 0.07) or maintenance period (RR 0.52, 95% CI 0.27 to 1.00, P = 0.05). Adverse event rates were similar between treatments. Conclusions Initiating insulin therapy with IDeg in Asian patients with type 2 diabetes, inadequately controlled with OADs, provides similar improvements in long-term glycemic control to IGlar, but at a significantly lower rate of overall confirmed hypoglycemia once stable glycemic control and insulin dosing are achieved. This trial was registered with www.clinicaltrials.gov (no. NCT01059799).

Purpose To assess whether stepwise insulin treatment in addition to current oral antidiabetic drug (OAD) therapy is useful for achieving the Japan Diabetes Society glycemic target (HbA1c

The Japan Diabetes Society (JDS) revised diagnostic criteria of diabetes mellitus in 2010 [1]. The major revision was that HbA1c became the first line, that a diagnosis of diabetes was enabled using HbA1c and the plasma glucose level at one time. Early diagnosis and treatment of diabetes are expected by this revision. Prior to it, the American Diabetes Association (ADA) proposed a revision of the diagnostic criteria for diabetes [2]. They also adopted HbA1c in diagnostic criteria to reflect chronic hyperglycemic states better. Revision of the diagnosis is the difficult problem because it is not the simple thing to replace it by something else. It needs the continuity with the previous diagnostic criteria, the scientific validity based on evidence, the consistency with overseas diagnostic criteria, and the clinical feasibility. In this paper, we will define problems of HbA1c and the international challenge in the future, referring to the history of the diagnosis of diabetes.

Objective As a part of the Diabetes Attitudes, Wishes and Needs (DAWN) Japan study, a multi-center, questionnaire-based survey conducted between 2004 and 2005, this analysis aimed to (1) explore patients' attitudes and beliefs contributing to their decision to start insulin therapy, and (2) assess the changes in their attitudes and beliefs after actual initiation. Methods Insulin-naive patients with type 2 diabetes who were recommended to start insulin therapy (n = 149) were invited to answer a 21-item questionnaire consisting of five clusters assessing their attitudes and beliefs toward insulin therapy. The questionnaire was administered twice: first upon insulin recommendation, and then 1 month after insulin initiation for those who started and 4 months after for those who did not. Results Of 130 patients included in the analysis, 74 patients (56.9%) started insulin therapy. 'Negative image of injections' and 'Positive image toward insulin therapy' were significantly associated with patient decision to start insulin therapy (odds ratios [95% CI]: 0.49 [0.32-0.76] and 2.58 [1.51-4.42], respectively). After insulin initiation, 'Negative image of injections', 'Positive image toward insulin therapy', 'Feelings of guilt regarding diabetes self-management', and 'Negative image toward insulin therapy' decreased significantly (P

Recent reports indicate that genomic rearrangements are novel causative mutations for maturity onset diabetes of the young (MODY). The aim of this study was to investigate genomic rearrangements in Japanese patients with MODY. Subjects diagnosed with diabetes before the age of 30 years and clinically suspected of having MODY but without identified causative mutations were included in the study (n = 223). Multiplex ligation-dependent probe amplification (MLPA) assays were performed to detect genomic rearrangements in HNF4A, GCK, HNF1A, and HNF1B. Array comparative genomic hybridization (aCGH) was performed to confirm the presence and extent of complete gene deletion or duplications. To examine variation in exon copy number, a custom MODY-CGH microarray using the web-based Agilent eArray database was performed. Four subjects with a hemizygous deletion mutation at 17q12, including HNF1B and spanning 1.4 Mb, were identified. The clinical features of these patients corresponded to those of MODY5 patients. In addition, one case each with an exon copy number variation of GCK7 and HNF1B3 were identified by MLPA and confirmed by array CGH. We identified four Japanese MODY cases with a genomic rearrangement in MODY5. Our data indicate that when diagnosing MODY5, the typical phenotype is more important than the family history because the cases detected occurred de novo. Moreover, we report the first Japanese cases with exonic copy number variation of the genes for MODY2 and 5.

In a phase III study, voglibose was shown to reduce the risk of development of type 2 diabetes mellitus (T2DM) by 40.5 % in Japanese individuals with impaired glucose tolerance (IGT), and appeared to promote reversion of IGT to normal glucose tolerance (NGT). In a retrospective, post hoc analysis, data from this study, plus follow-up findings from subjects who achieved NGT during the study and who were off-treatment, were analyzed to investigate serum insulin kinetic parameters which might be predictors of IGT reversion to NGT, and maintenance of NGT once achieved. The effects of voglibose on serum insulin kinetics in individuals with IGT were also assessed. Subjects with IGT (n = 1778) were randomized to receive voglibose (0.6 mg/day) or placebo for a mean of 48.1 weeks. During treatment, 1053 subjects achieved NGT, 569 continued to have IGT, and 156 developed T2DM. Analysis of baseline characteristics in each outcome group showed that subjects with higher 30-min serum immunoreactive insulin (IRI) levels in a 75 g oral glucose tolerance test (OGTT) or higher insulinogenic indexes at baseline were more likely to achieve NGT, whether they received voglibose or placebo. Among subjects who achieved NGT, the mean increase in OGTT 30-min IRI level from baseline to endpoint was significantly greater after treatment with voglibose than with placebo. Individuals who had higher OGTT 30-min IRI levels when achieving NGT seemed more likely to sustain this state. Thus, insulin secretion kinetics appeared to predict reversion of IGT to NGT and maintenance of NGT once achieved.

The aim of this study was to identify clinical factors that were associated with insulin sensitivity and secretion by multiple linear regression analysis in Japanese subjects with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT). A total of 2,983 subjects were classified into two groups, NGT and IGT, according to the oral glucose tolerance test criteria. To assess insulin sensitivity, homeostasis model assessment (HOMA)-S and the Matsuda index were used. To determine insulin secretion, HOMA-β, the insulinogenic index (IGI), basal disposition index (DI), and early phase DI were calculated. Stepwise multiple regression analyses were performed to examine the relationships between these indices and certain clinical factors, such as body mass index (BMI), HbA1c, age, sex, and family history. BMI was the only significant factor associated with HOMA-S. For the Matsuda index, the most important factor was BMI, followed by age and sex. BMI, HbA1c, age, sex, and family history were significantly associated with HOMA-β, IGI, basal DI, and early phase DI. The standardized partial regression coefficients of HOMA-β and IGI were highest for BMI. For basal DI and early phase DI, the highest standardized partial regression coefficient was found to be HbA1c, followed by age and BMI. Basal DI and early phase DI were more useful than HOMA-β and IGI to assess insulin secretion. The most important factors associated with insulin sensitivity and secretion are BMI and HbA1c, respectively. Age is more associated with insulin secretion than with insulin sensitivity.

Diabetic patients undergoing hemodialysis may have difficulty in self-injecting insulin due to physical impairment or other disabilities. We hypothesized that postdialysis administration of insulin glargine by medical staff would improve diabetes care in this high-risk patient group. In this report, we describe six hemodialysis patients with type 2 diabetes and inadequate glycemic control who were admitted to our hospital. All patients had an inability to self-inject insulin due to visual impairment and/or stroke symptoms. Therefore, they had been unable to receive insulin treatment at the outpatient dialysis clinics within the last few months. After admission, the patients were administered insulin glargine after each hemodialysis session, thrice-weekly. Regarding glycemic control, blood glucose profiles including the circadian variation of 13-point blood glucose values for 48 h, hemoglobin A1C (HbA1C), and glycated albumin (GA) were evaluated before and after insulin treatment. Post-dialysis administration of insulin glargine significantly reduced blood glucose levels, particularly during the first 24 h after injection. HbA1C and GA levels were significantly decreased after 6 months, with no increase in the incidence of severe hypoglycemic episodes. Although further large controlled studies are needed, post-dialysis administration of insulin glargine by medical staff may improve glycemic control in physically impaired diabetic patients undergoing hemodialysis at outpatient clinics.

We report the case of a female patient with type 1 diabetes mellitus who developed diabetes at 1 year and 7 months and is now over 60 years old (duration of type 1 diabetes, 59 years) and has experienced only mild diabetic complications. The patient developed diabetic coma in May 1952, at 1 year and 7 months. In April 1994, at 43 years old, she achieved favorable glycemic control after being switched to intensive insulin therapy. Mean HbA1c level over the past 14 years was 6.4% (JDS). Retinopathy was noted in 1968, at 18 years old. From 1973 to 1985, at 23–35 years old, she underwent a total of six photocoagulation procedures. Her retinopathy is currently stable. Urine albumin level was 5.6 mg/g Cr, indicating no nephropathy. In January 2007, at 56 years old, the right and left ankle brachial indices were 0.95 and 0.86, respectively. Magnetic resonance angiography of the lower extremities revealed vascular insufficiency in both lower legs, but examination of the intima-media complex thickness, head computed tomography, and nuclear cardiology revealed no abnormalities. Treatment with eicosapentaenoic acid and regular ambulation improved vascular insufficiency in both lower legs.

The Japan Prevention Trial of Diabetes by Pitavastatin in Patients with Impaired Glucose Tolerance (J-PREDICT study) is an open-label randomized controlled study in a population with impaired glucose tolerance (IGT) to evaluate the effect of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) pitavastatin on new onset of diabetes. Patients with IGT by World Health Organization (WHO) criteria [2-h plasma glucose ≥140 and

Aims/Introduction: To reveal whether visit-to-visit variability in HbA1c is associated with higher risk of cardiovascular disease (CVD) in patients with type 2 diabetes. Materials and Methods: The study was conducted on 689 Japanese patients with type 2 diabetes [295 women, 394 men; mean (±standard deviations (SD)) age 65 ± 11 years]. Variability in HbA1c was evaluated as the intrapersonal SD of serial measurements of HbA1c during the follow-up period for at least 12 months. Patients were divided into quartiles according to the SD of HbA1c, and the primary endpoint was defined as incident CVD. Cox’s proportional hazards model was used to calculate hazard ratios (HR) and 95% confidence intervals (CI). Results: During a median follow-up period of 3.3 years (range 1.0–6.3 years), 26 ± 14 measurements of HbA1c were obtained per patient and 61 episodes of incident CVD were recorded. The 5-year cumulative incidence of CVD in patients across the first, second, third, and fourth quartiles of SD in HbA1c was 4.9, 8.7, 17.1, and 26.2%, respectively (P

Background The impact of serum lipid abnormalities on the progression of diabetic kidney disease (DKD) remains conflicting. Furthermore, gender differences in the association between dyslipidaemia and outcome of DKD are largely unknown. We therefore conducted this single-centre observational cohort study to clarify gender differences in the association between serum lipid profiles and the progression of DKD. Methods Seven hundred and twenty-three Japanese type 2 diabetes mellitus (T2DM) patients with normoalbuminuria or microalbuminuria, 280 women and 443 men, with a mean (± SD) age of 63 ± 11 years were studied. The endpoint was the progression to a more advanced stage of albuminuria. For statistical analyses, Cox proportional hazard model analyses were conducted. Results During the mean follow-up period of 4.3 years, 62 of 477 patients with normoalbuminuria and 69 of 246 patients with microalbuminuria reached the endpoint. A significant interaction between high-density lipoprotein (HDL) cholesterol and gender was detected (P(interaction) = 0.04); therefore, separate analyses were conducted for men and women. Overall, in men, the univariate Cox proportional hazard model revealed that higher triglycerides and lower HDL cholesterol levels were significantly associated with higher risk of reaching the endpoint. In the multivariate Cox proportional hazard model, only HDL cholesterol levels remained as an independent predictor of the endpoint (hazard ratio 0.391, P = 0.01). In women, no serum lipid parameters were associated with the endpoint. Conclusions Lower HDL cholesterol levels seem to be associated with the progression of DKD in men but not in women.

Background Sirtuin is a member of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, and has been reported to play a pivotal role in energy expenditure, mitochondrial function and pathogenesis of metabolic diseases, including aging kidneys. In this study, we focused on the genes encoding sirtuin families, and examined the association between single nucleotide polymorphisms (SNPs) within genes encoding sirtuin families and diabetic nephropathy. Methods We examined 52 SNPs within the SIRT genes (11 in SIRT1, 7 in SIRT2, 14 in SIRT3, 7 in SIRT4, 9 in SIRT5, and 4 in SIRT6) in 3 independent Japanese populations with type 2 diabetes (study 1: 747 cases (overt proteinuria), 557 controls; study 2: 455 cases (overt proteinuria) and 965 controls; study 3: 300 cases (end-stage renal disease) and 218 controls). The associations between these SNPs were analyzed by the Cochran–Armitage trend test, and results of the 3 studies were combined with a meta-analysis. We further examined an independent cohort (195 proteinuria cases and 264 controls) for validation of the original association. Results We identified 4 SNPs in SIRT1 that were nominally associated with diabetic nephropathy (P

A 78-year-old diabetic woman experienced multiple sites of gangrene not only in fingers that were directly bitten by a dog but also in fingers and toes that had not beenbitten. Her glycemic control was fair and microvascular complications were mild. There were no clinical findings related to angitis, collagenosis or severe infection. The fingers and toes with gangrene were amputated. The pathological diagnosis was diabetic gangrene. This report presents a case of multiple sites of gangrene of the fingers and toes after a dog bite in an elderly patient with type 2 diabetes.

Hypertensive patients with diabetes have been reported to be considered at higher risk for the onset of cardiovascular diseases. Adiponectin, an anti-atherogenic adipocytokine, has been reported to improve insulin resistance. The aim of this study was to comparatively evaluate the effects of the angiotensin II receptor blockers, valsartan and telmisartan, on insulin resistance and adiponectin release in hypertensive patients with type 2 diabetes. Fifty-eight patients were randomly assigned to receive valsartan (n = 29) or telmisartan (n = 29). There was no difference in patient background in either group. Both agents reduced blood pressure to a similar degree, and homeostasis model assessment (HOMA-R) as a marker of insulin resistance was decreased in the valsartan group (3.78 ± 1.69 → 2.98 ± 1.50, p = 0.009) as well as in the telmisartan group (3.91 ± 1.65 → 3.39 ± 1.58, p = 0.046). However, adiponectin levels were significantly increased in the valsartan group (5.49 ± 2.12 → 5.81 ± 2.14 μg/ml, p = 0.028), but not in the telmisartan group (5.92 ± 2.19 → 5.87 ± 1.84 μg/ml, p = 0.781). These results suggest that both valsartan and telmisartan are appropriate anti-hypertensive agents providing improvement of insulin resistance; however, valsartan is the more beneficial agent due to the increase in adiponectin levels compared to telmisartan.

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.

Abdominal obesity has been implicated in the pathogenesis of microalbuminuria in patients with diabetes; however, the underlying mechanisms remain unclear. Increased leptin secretion by adipocytes may be one of the factors responsible for the relationship between abdominal obesity and microalbuminuria, because increased leptin secretion has been demonstrated to contribute to renal impairment. We therefore conducted a cross-sectional study to clarify the relationship between increased serum leptin levels associated with abdominal obesity and albuminuria in patients with type 2 diabetes mellitus (T2DM). We studied a total of 502 adult patients with T2DM, 220 women and 282 men, with a mean (±SD) age of 60 ± 13 years. Patients with macroalbuminuria and those with an estimated glomerular filtration rate of

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.

As populations with a higher prevalence of HLADRB1*0406 have been found to have a higher risk of developing insulin autoimmune syndrome (IAS), we report here the clinical features of Asian and Japanese IAS. There was female dominance in the 20- to 49-year-old age group at the onset of IAS development. Forty-two percent of Japanese IAS patients had received drugs or α-lipoic acid containing the sulfhydryl group, while 81% of Asian IAS patients outside Japan had received methimazole or carbimazole before the development of IAS.

Takii M, Uchigata Y, Kishimoto J, Morita C, Hata T, Nozaki T, Kawai K, Iwamoto Y, Sudo N, Kubo C. The relationship between the age of onset of type 1 diabetes and the subsequent development of a severe eating disorder by female patients. Objectives: To determine the age of onset of type 1 diabetes that is most closely related to the subsequent development of a severe eating disorder such as anorexia nervosa (AN) or bulimia nervosa (BN). Methods: Participants were 53 female type 1 diabetes patients with AN or BN referred to our outpatient clinic from the Diabetes Center of Tokyo Women's Medical University. Forty-nine female type 1 diabetes patients who regularly visited the Diabetes Center and had no eating disorder-related problems constituted the ‘direct control’ group, whereas 941 female patients who for the first time visited the Diabetes Center constituted the ‘historical control’ group. The kernel function method was used to generate a density estimation of the onset age of each group and the chi-square test was used to compare the distribution. Results: The control groups had similar density shapes for the onset age of type 1 diabetes, but both differed from the ‘eating disorder’ group. For onset age 7–18 yr, the density of the ‘eating disorder’ group was higher than those of the control groups, but for the younger and older onset ages the densities were lower. The ‘eating disorder’ group developed type 1 diabetes significantly more frequently than the ‘historical control’ group between 7 and 18 yr of age (χ2 = 9.066, p < 0.011). Conclusion: The development of type 1 diabetes in preadolescence or adolescence seems to place girls at risk for the subsequent development of AN or BN. Careful attention should be paid to these high-risk patients.