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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.

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.

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.

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.

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).

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

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.

Diabet. Med. 27, 1017–1023 (2010) Abstract Aims The relationship between type of diabetes and risk of chronic kidney disease has not been studied in detail. We conducted this study to determine the prevalence of chronic kidney disease in Japanese adults with diabetes, with a particular emphasis on the comparison of Type 1 and Type 2 diabetes. Methods We studied 3,575 Japanese patients with diabetes, 504 with Type 1 (mean ± SD age 38 ± 13 years; 350 women and 154 men) and 3071 with Type 2 diabetes (60 ± 13 years; 1187 women and 1884 men). Prevalence rates of albuminuria [urinary albumin/creatinine ratio (≥ 30 mg/g], decreased estimated glomerular filtration rate (eGFR

Diabet. Med. 27, 538–543 (2010) Abstract Aims Silent cerebral infarction (SCI) is an independent risk factor for future symptomatic stroke. Although the prevalence of SCI is closely related to kidney function in non-diabetic individuals, evidence is lacking whether albuminuria and/or reduced estimated glomerular filtration rate (eGFR) independently increase the risk of SCI in diabetic patients. We therefore examined the relationships between albuminuria, eGFR and SCI in patients with Type 2 diabetes mellitus (T2DM). Methods We studied 786 T2DM patients with an eGFR ≥ 15 ml/min 1.73/m2, including 337 women and 449 men [mean (± sd), age 65 ± 11 years]. All patients underwent cranial magnetic resonance imaging (MRI) to detect SCI. GFR was estimated using the modified three-variable equation for Japanese subjects. Albuminuria was defined as a first morning urinary albumin-to-creatinine ratio (ACR) ≥ 30 mg/g. Results SCI was detected in 415 (52.8%) of the subjects. The prevalence of SCI was significantly associated with both elevated ACR and decreased eGFR in univariate analysis. In multivariate logistic regression analysis, urinary ACR remained independently associated with SCI after adjusting for conventional cardiovascular risk factors [odds ratio (OR) of urinary ACR per logarithmical value: 1.89, 95% confidence interval (CI) = 1.41–2.51, P

We collated and analysed data from hospital records regarding the cause of death of 18,385 patients with diabetes who died in 282 medical institutions throughout Japan over the 10-year period between 1991 and 2000. Autopsy was carried out in 1750 cases. The most frequent cause of death in all 18,385 cases was malignant neoplasia, accounting for 34.1% of cases, followed by vascular diseases (including diabetic nephropathy, ischemic heart diseases and cerebrovascular diseases) in 26.8%, infections in 14.3%, and then diabetic coma in 1.2%. The most common malignancy was liver cancer, accounting for 8.6% of all the deaths. Of the deaths from vascular diseases, diabetic nephropathy was the cause of death in 6.8% of cases, and the frequency as cause of death for ischemic heart diseases and cerebrovascular diseases were similar at 10.2% and 9.8%, respectively. Myocardial infarction accounted for almost all the deaths from ischemic heart diseases, whereas deaths from cerebral infarction were 2.2-fold as common as those from cerebral hemorrhage. In the analyses of the relationship between age and causes of death in diabetic patients who underwent autopsy, the overall mortality rate as a result of vascular diseases increased with age, although the mortality rates from diabetic nephropathy and cerebrovascular diseases increased little from the fifth decade of life. The mortality rate from ischemic heart diseases increased with age, however, and was higher than the other forms of vascular diseases from the sixth decade of life, accounting for approximately 50% of vascular deaths in the eighth decade. Malignant neoplasia was the most frequent cause of death from the fifth decade of life, and was extremely common in the seventh decade, accounting for 46.3% of all the deaths. The mortality rate from infections varied little between age groups from the fifth decade of life. In the analyses of glycemic control and the age at the time of death, lifespans were 2.5 years shorter in males, and 1.6 years shorter in female diabetics with poor glycemic control than in those with good or fair glycemic control. This difference was greater for deaths as a result of infections and vascular diseases, particularly diabetic nephropathy, than for malignant neoplasia. Analysis of the relationship between glycemic control and the duration of diabetes and deaths as a result of vascular diseases showed no correlation between the level of glycemic control and death from diabetic nephropathy, ischemic heart diseases or cerebrovascular diseases. In diabetics with disease durations of less than 10 years, the mortality rate from macroangiopathy was higher than that as a result of diabetic nephropathy, a form of microangiopathy. Treatment for diabetes comprised of diet alone in 21.5%, oral hypoglycemic agents in 29.5%, and insulin with or without oral hypoglycemic agents in 44.2%, which was the most common. In particular, 683/1170 (58.4%) diabetics who died from diabetic nephropathy were on insulin therapy, a higher proportion than the 661/1687 (39.2%) who died from ischemic heart diseases, or the 659/1622 (40.6%) who died from cerebrovascular diseases. The average age at the time of death in the survey population was, 68 years for males and 71.6 years for females. These were 9.6 and 13 years, respectively, short of the average life expectancy for the Japanese general population. In comparison with the previous survey (1981–1990), the average age at the time of death had increased 1.5 years for males, and 3.2 years for females. The average life expectancy for the Japanese general population had also increased 1.7 and 2.7 years, respectively, over that period, showing that advances in the management and treatment of diabetes have not led to any improvement in patients’ life expectancies. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00019.x, 2010)

Aim: The rapid-acting insulin analogue insulin glulisine (glulisine) was compared with insulin lispro (lispro) for efficacy and safety in Japanese patients with type 1 diabetes mellitus (T1DM), using insulin glargine (glargine) as basal insulin. Methods: This was an open, randomized, parallel-group, comparative non-inferiority study. The primary efficacy measure was change in adjusted mean haemoglobin A1c (HbA1c) from baseline to endpoint. Safety and treatment satisfaction using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) were also assessed. Patients were treated for 28 weeks with either glulisine or lispro administered 0–15 min before a meal. Doses were titrated to obtain 2-h postprandial plasma glucose (2h-PPG) of 7.11–9.55 mmol/l (128–172 mg/dl). All patients were concomitantly treated with glargine at bedtime, titrated to obtain a fasting (prebreakfast) plasma glucose level of 5.27–7.11 mmol/l (95–128 mg/dl). Results: Baseline mean HbA1c values were similar for the glulisine (n = 132) and lispro (n = 135) groups (7.44 and 7.50% respectively). From baseline to endpoint, adjusted mean HbA1c increased by 0.10% in the glulisine group and by 0.04% in the lispro group. Non-inferiority of glulisine compared with lispro was shown. There were no significant differences between glulisine and lispro in adjusted mean 2h-PPG [glulisine, 9.06 mmol/l (163 mg/dl) vs. lispro, 8.13 mmol/l (146 mg/dl); p = 0.065] and change in adjusted mean daily rapid-acting insulin dose (glulisine, 0.26 U vs. lispro, 0.26 U; p = 0.994) at study endpoint. There was a significant difference for change in adjusted mean daily basal insulin dose from baseline to study endpoint (glulisine, –0.54 U vs. lispro, 0.26 U; p = 0.013). The most common serious adverse events were hypoglycaemia-related events (hypoglycaemia, hypoglycaemic seizure and hypoglycaemic coma) with no difference observed between the two groups [glulisine, 6.8% (9/132) vs. lispro, 4.4% (6/135); p = 0.437]. No noteworthy differences were observed for change in insulin antibodies from baseline to endpoint. Assessment of treatment satisfaction score and perceived frequency of hyperglycaemia and hypoglycaemia by DTSQ showed no changes from baseline in either group. Conclusions: Glulisine was as effective as lispro with respect to change in HbA1c and was well tolerated when used in combination with glargine in Japanese patients with T1DM.

We report a case of type 1 diabetes mellitus who was successfully treated with simultaneous pancreas and kidney (SPK) transplantation and both grafts survived for 16 yr. A 30-yr-old woman underwent SPK transplantation from a non-heart-beating donor in January 1992. She was treated with combined immunosuppressive therapy consisting of cyclosporine, azathioprine, methylprednisolone, and anti-lymphocyte globulin. Allograft kidney biopsy was performed 10 yr after transplantation to determine the cause of proteinuria, which revealed no recurrence of diabetic nephropathy, suggesting that long-term normalization of glycemic control achieved by successful pancreas transplantation can prevent recurrence of diabetic nephropathy in the kidney allograft.

Objective: To investigate which features of eating disorders are associated with retinopathy and nephropathy in Type 1 diabetic females with clinical eating disorders. Method: Participants were 109 Type 1 diabetic females with clinical eating disorders diagnosed by the structured clinical interview for DSM-IV (bulimia nervosa [n = 70], binge-eating disorder [n = 28], anorexia nervosa [n = 7], and eating disorder not otherwise specified [n = 4]). Retinopathy and nephropathy were screened and demographic, medical, and eating disorder related factors were investigated. To identify the factors associated with each complication, logistic regression analysis was done. Results: Duration of severe insulin omission and duration of Type 1 diabetes were significantly associated with retinopathy (odds ratios = 1.35 and 1.23, respectively) and nephropathy (odds ratio = 1.35 and 1.21, respectively) in multivariate regression analyses. Conclusion: Of the various problematic behavioral factors related to eating disorders, the duration of severe insulin omission was the factor most closely associated with the retinopathy and nephropathy of Type 1 diabetic females with clinical eating disorders by multivariate analysis. This finding may help patients who deliberately omit insulin become aware of medical risk of insulin omission. © 2007 by Wiley Periodicals, Inc. Int J Eat Disord, 2008

Aims To assess the prevalence of non-alcoholic fatty liver disease (NAFLD) and its association with impaired glucose metabolism in Japanese subjects. Methods One thousand, nine hundred and fifty subjects enrolled in a general health examination programme from September 2002 to February 2003 were recruited. NAFLD was diagnosed if a person showed ‘fatty liver’ on ultrasonography, and his/her alcohol consumption, estimated by questionnaire, was

Borjeson-Forssman-Lehmann (BFL) syndrome is an X-linked recessive disorder characterized by minor facial anomalies, obesity, epilepsy, and severe mental retardation. The phenotype of male patients is usually severe, whereas that of carriers is less severe, suggesting X-linked incompletely recessive inheritance. A recent linkage study mapped the BFL syndrome gene to Xq26-q27. The etiology of the condition in female patients with full manifestations is not known, although nonrandom X-chromosome inactivation has been considered. We recently developed an assay for X-inactivation studies based on the methylation-specific polymerase chain reaction (PCR) technique. Using the methylation-specific PCR assay, a woman with typical findings of this syndrome was shown to have an extremely skewed X-inactivation pattern. This finding suggests that the full manifestations of the BFL syndrome in carriers may be caused by skewed X inactivation with a high proportion of cells in which the X chromosome with a normal gene be inactivated, leaving the X chromosome with a mutant gene active.

The clinical efficacy of troglitazone, a new oral hypoglycaemic agent was investigated in Type 2 diabetes in combination with sulphonylureas. Two hundred and ninety-one patients with Type 2 diabetes (age 21-81 years) whose previous glycaemic control by sulphonylureas was judged stable but unsatisfactory (fasting plasma glucose (FPG) > 8.3 mmol I-1) were randomly allocated into the troglitazone treatment group (troglitazone group, n = 145) or the placebo treatment group (placebo group, n = 146). They were treated by test drugs for 12 weeks in combination with the same dose of sulphonylureas before the trial. One hundred and twenty-two patients who received troglitazone and 126 patients who received placebo were evaluated for efficacy. The baseline characteristics did not differ significantly between the two groups. In the troglitazone group, FPG and HbA(1c) decreased significantly after the treatment (before vs after, FPG: 10.8 +/- 2.0 mmol I(-1) vs 9.2 +/- 2.5 mmol I(-1), p< 0.001; HbA(1c): 9.2 +/- 1.4% vs 8.5 +/- 1.5%, p< 0.001). FPG and HbA(1c) did not change after the treatment in the placebo group (before vs after, FPG: 10.5 +/- 1.7 mmol I(-1) vs 10.7 +/- 2.2 mmol I(-1); HbA(1c): 9.0 +/- 1.5% vs 9.2 +/- 1.6 %). Serum total cholesterol and HDL-cholesterol did not change in either group, however, serum triglyceride significantly decreased in the troglitazone group. No serious adverse events occurred in either group. In conclusion, troglitazone 400 mg day(-1) had a significant hypoglycaemic effect in combination with sulphonylureas without any serious adverse events. Troglitazone, developed as an insulin action enhancer, can be a useful hypoglycaemic agent in the treatment of patients with Type 2 diabetes who are not well controlled by sulphonylureas alone.