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Background: To compare the efficacy and safety of pemafibrate with those of fenofibrate in a real-world setting in patients with hypertriglyceridemia and type 2 diabetes (T2D). Methods: This study included 155 patients with hypertriglyceridemia (>175 mg/dL) and T2D. Adjusted least square mean changes in the serum levels of triglycerides (TG), transaminases, γ-glutamyl transpeptidase (γGTP), and estimated glomerular filtration rates (eGFRs) were compared before and after a 3-month therapy with pemafibrate (0.2 mg), fenofibrate (160 mg), or bezafibrate (400 mg). Multivariate logistic regression analyses were performed to examine the association between fibrates, achievement of target TG levels, and deterioration of liver and renal function. Results: Pemafibrate therapy greatly reduced TG levels, which was three times better than fenofibrate therapy in achieving the target range for TG levels. The administration of pemafibrate, not fenofibrate, was significantly associated with a lower risk of increasing γGTP levels. Similarly, a lower risk of eGFR reduction was observed in the pemafibrate group than in the fenofibrate group. Conclusions: Pemafibrate achieved a greater reduction in TG levels toward the desired target range than did fenofibrate. Moreover, pemafibrate was associated with a lower risk profile for elevated γGTP and reduced eGFR than fenofibrate.

Background: This study clarifies the effects of adding a glucagon-like peptide-1 receptor agonist (GLP-1RA) to sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy on glycated hemoglobin (HbA1c) and body weight in Japanese patients with type 2 diabetes (T2D). Methods: This historical cohort study, part of the Diabetes Study from the Center of Tokyo Women's Medical University, included 80 adults with T2D (registered April 2014-July 2020) prescribed SGLT2i for ≥3 months before adding GLP-1RA. HbA1c and weight changes to 12 months after GLP-1RA prescription were assessed, overall and in subgroups based on previous dipeptidyl peptidase-4 inhibitor use, body mass index (BMI), baseline HbA1c levels, and insulin use. Results: HbA1c was significantly reduced from baseline (mean ± SD: 8.9 ± 1.6%) at all times, including 6 months (primary endpoint: 8.2 ± 1.3%; change: −0.76%, P = 0.002). At 12 months, 21.4% of individuals achieved HbA1c levels

Background: The effect of parity on adverse pregnancy outcomes is well established in healthy pregnant women; however, the influence of parity on pregnancy outcomes in women with diabetes remains poorly understood. Therefore, we examined the association between parity and glycemic control, as well as pregnancy outcomes, in women with pregestational diabetes. Methods: A retrospective observational study was conducted on 59 women with diabetes, including 43 with type 1 diabetes and 16 with type 2 diabetes, who had a second pregnancy. Maternal clinical characteristics and pregnancy outcomes were compared between the first and second pregnancies. Results: The second pregnancy was characterized by higher pre-pregnancy body weight, increased insulin requirements, and poorer glycemic control during the third trimester. The first pregnancy was associated with a higher prevalence of diabetic retinopathy deterioration and hospitalization for glycemic control. No significant differences were observed in the perinatal or neonatal complications between the first and second pregnancies, except for hypertensive disorders of pregnancy, which were more common in the first pregnancy. Conclusions: Our findings emphasize the need for increased vigilance for maternal complications during the first pregnancy, weight control between pregnancies, and appropriate adjustment of insulin dosage during subsequent pregnancies in women with diabetes.

Background: Statins are effective in reducing cardiovascular events. However, statin-associated adverse muscle events, often associated with falls, remain a concern. We investigated the association between statin use and risk of falls in older individuals with diabetes. Methods: This cross-sectional study included 1,896 Japanese individuals with diabetes aged ≥65 years. The risk of falls was evaluated using a self-administered questionnaire. Multivariable logistic regression models were used to examine the association between statin use and fall risk. The subgroup analysis was limited to patients with a history of cerebral infarction or ischemic heart disease. Results: The percentage of individuals with type 2 diabetes, body mass index, and glycated hemoglobin A1c was higher, whereas the percentage of men and mean low-density lipoprotein cholesterol levels was lower in statin users (n = 953) than that in non-users (n = 943). The percentages of individuals at high risk of falls were higher in statin users than those in non-users (p < 0.001). Multivariable analysis showed no associations between statin and risk of falls in overall (odds ratio [OR] 1.17, 95% confidence interval [CI] 0.95-1.44) or subgroup (OR 1.22, 95% CI 0.72-2.06). Conclusions: This study did not provide evidence of an increased risk of falls in statin-using older individuals with diabetes.

Background: Aortic valve calcification (AVC) has a strong association with cardiovascular outcomes in patients with type 2 diabetics (T2D). The objective of this study was to determine the prevalence and risk factors for AVC in Japanese T2D. Methods: We conducted a cross-sectional study of 193 consecutive T2D with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 and without overt heart disease (110 men, mean age 61 years). AVC was determined as bright echoes > 1 mm on at least one cusp of the aortic valve by echocardiography. Results: Eighty-two (42%) diabetic patients had AVC, 9 patients had aortic valve stenosis, and 25 had regurgitation. Patients with AVC were older (67 vs. 55 years), with longer diabetic duration (15 vs. 11 years), lower HbA1c (9.1 vs. 10.0%), higher presence of diabetic retinopathy (66 vs. 47%), lower BMI (24 vs. 26 kg/m2), and lower eGFR (82.1 vs. 90.4 mL/min/1.73 m2) (p < 0.01) than patients without AVC. By logistic regression analysis, older age (p < 0.001) and presence of diabetic retinopathy (p < 0.05) were independent risk factors for AVC in T2D. Conclusions: The prevalence of AVC was 42% in Japanese T2D. Diabetic retinopathy associates with presence of AVC.

Abstract Background This study investigated the sex differences in the risk of end‐stage kidney disease (ESKD) and mortality, as well as the effect modification of sex on associated factors in patients with type 2 diabetes. Methods This multicenter observational cohort study included 4328 patients with type 2 diabetes. Hazard ratios (HRs) with 95% confidence intervals (CIs) of sex for ESKD and death were estimated using Cox proportional regression with adjustment for baseline covariates. For assessing risk modification, HRs and incidence rates for ESKD and death were compared between sexes across patient characteristics using Cox proportional and Poisson regression models. Results During a median follow‐up of 7 years, 276 patients (70% men) developed ESKD, and 241 patients (68% men) died. Men had higher risks of ESKD (HR 1.34; 95% CI 1.02–1.75; p = .034) and death (HR 1.64; 95% CI 1.24–2.16; p = .001) versus women after adjusting for multiple covariates. Among patients with microalbuminuria, men had a substantially higher risk of ESKD versus women, compared to those with normo‐ and macroalbuminuria (p for interaction .04). Incidence rates were also increased in men versus women with albuminuria of around 300 mg/g. No differences were detected in the association of sex and death across baseline patient subgroups. Conclusions In type 2 diabetes, men had an increased risk of ESKD and death versus women. Moderately increased albuminuria was strongly associated with sex difference in developing ESKD.

Abstract Aims/Introduction The increase in the number of patients with type 2 diabetes mellitus is an important concern worldwide. The goal of this study was to investigate factors involved in the onset of type 2 diabetes mellitus, and sex differences in long‐term follow up of people with normal glucose tolerance. Materials and Methods Of 1,309 individuals who underwent screening at our facility in 2004, 748 individuals without diabetes were enrolled. Correlations of metabolic markers including serum adiponectin (APN) with onset of type 2 diabetes mellitus were examined over 15 years in these individuals. Results The Kaplan–Meier curve for onset of type 2 diabetes mellitus for 15 years in the decreased APN group was examined. Hazard ratios for the APN concentration for onset of diabetes were 1.78 (95% confidence interval [CI] 1.20–2.63, P = 0.004) in all participants, 1.48 (95% CI 0.96–2.29, P = 0.078) for men and 3.01 (95% CI 1.37–6.59, P = 0.006) for women. During the follow‐up period of 15 years, body mass index, estimated glomerular filtration rate, fatty liver, C‐reactive protein and alanine aminotransferase in men were significant in univariate analysis, but only estimated glomerular filtration rate and fatty liver were significantly related to onset of type 2 diabetes mellitus in multivariate analysis. In women, body mass index, systolic blood pressure, triglyceride, fatty liver and APN were significant in univariate analysis, and APN was the only significant risk factor in multivariate analysis (P

Abstract Aims/Introduction Several factors are associated with hypoglycemia unawareness and severe hypoglycemia, but few large studies have analyzed Japanese patients with type 1 diabetes. The aim of this study was to analyze the risk factors for hypoglycemia unawareness and severe hypoglycemia in Japanese type 1 diabetes patients. Materials and Methods A self‐administered questionnaire investigated events, complications and treatments associated with hypoglycemia in patients with type 1 diabetes. Multiple logistic regression analysis of factors associated with hypoglycemia unawareness and severe hypoglycemia requiring medical treatment was carried out. The coefficient of variation (CV) of blood glucose levels was determined using blood samples collected at six outpatient visits. Results Of the 1,619 participants, 44.2% and 10.4% experienced hypoglycemia unawareness and severe hypoglycemia, respectively. Mean HbA1c levels in patients with hypoglycemia unawareness were lower than those in patients without hypoglycemia unawareness. The type 1 diabetes subtype, glycated hemoglobin (HbA1c) level, CV of blood glucose levels and history of severe hypoglycemia requiring medical treatment were significant independent variables predicting the presence of hypoglycemia unawareness. The glucose CV and a history of hypoglycemia unawareness were significant independent variables predicting severe hypoglycemia requiring medical treatment. In stratified analyses of patients divided into four groups according to glucose CV and HbA1c levels, the high‐glucose‐CV/low‐HbA1c group had the highest odds ratios for hypoglycemia unawareness (2.60) and severe hypoglycemia requiring medical treatment (2.55). Conclusions The ambulant glucose CV correlated with both hypoglycemia unawareness and severe hypoglycemia. Patients with high glucose CV and low HbA1c are at high risk of such adverse events, and their treatment strategies should be reviewed.

Abstract Aims/Introduction We aimed to assess the association between bodyweight reduction and cardiovascular disease risk factors, and to identify the minimum bodyweight reduction associated with significant improvement in cardiovascular disease risk factors among obese Japanese patients with type 2 diabetes. Materials and Methods The cohort comprised 1,753 patients with type 2 diabetes and body mass index ≥25 kg/m2, who visited our clinic between 2013 and 2016. Multivariable linear regression analysis was carried out to assess the relationship between bodyweight changes and glycated hemoglobin A1c, serum lipids and blood pressure. Analyses of covariance were carried out to compare mean changes in cardiovascular disease risk factors across six groups of bodyweight change, 5% bodyweight reduction was associated with improved glycated hemoglobin A1c.

ABSTRACT Aims/Introduction To investigate the prevalence of depressive symptoms by the age of onset of type 1 diabetes, and its association with the condition of individuals with pediatric‐ and adolescent‐onset type 1 diabetes. Materials and Methods This single‐center cross‐sectional study enrolled Japanese participants with type 1 diabetes. All participants completed a questionnaire about their diabetes‐related condition and the Patient Health Questionnaire‐9, which was used to evaluate depression. Individuals with a Patient Health Questionnaire‐9 score of ≥10 points were defined as having moderate depressive symptoms. Results A total of 1,267 participants (mean age 40 years; mean duration of type 1 diabetes 21 years; 68% female; mean glycated hemoglobin 7.8%) were included and classified according to the age of onset of type 1 diabetes to identify the proportion of moderate depressive symptoms in each group: 21% (0–12 years), 18% (13–19 years) and 13% (20–40 years). The prevalence of moderate depressive symptoms was significantly higher among participants with pediatric‐onset type 1 diabetes (P

Background: The quantity and proliferative capacity of pancreatic β-cells have been shown to impact diabetes development, but their proliferative capacity and regulatory mechanism remain unclear. We examined the sequential changes in the proliferative ability of rat β-cells and the factors that contribute to these changes during the post-natal to young adult period. Methods: Pancreases of Sprague Dawley rats were collected at different times (1 day-8 weeks); pancreatic β-cell proliferation was analyzed using fluorescence immunostaining. Expression of cell cycle-related genes and proteins in pancreatic β-cells was examined using quantitative reverse transcription polymerase chain reaction (RT-PCR) and western blotting, respectively. Six-week-old rats were administered the p53 inhibitor pifithrin-α intraperitoneally for 2 weeks to clarify the relationship between the loss of β-cell proliferation and p53. Results: The percentages of Ki67- and phosphorylated histone H3 (PhH3) -positive cells in pancreatic and duodenal homeobox factor 1 (PDX1) positive β-cells were 8.5% and 1.9%, respectively, in 1-day-old rats (2% and 0.07% of cells were Ki67- and PhH3-positive at 8 weeks). p53 mRNA and protein expression levels increased significantly in the pancreas at 8 weeks. Treatment with the p53 inhibitor for 2 weeks remarkably attenuated the decrease in the percentage of PhH3-positive β-cells at 8 weeks. Conclusion: Rat β-cells lose their proliferative ability after birth through upregulation of p53.

A 57-year-old Japanese man with type 2 diabetes presented with bilateral pitting edema and pain of the hands and feet two months after being initiated on a dipeptidyl peptidase-4 (DPP-4) inhibitor, alogliptin. Laboratory tests showed elevated levels of C-reactive protein, matrix metalloproteinase-3 and vascular endothelial growth factor, and a negative rheumatoid factor. The computed tomography scan showed swelling in the dominant right wrist joint, and joint ultrasonography showed synovial swelling. He was diagnosed with remitting seronegative symmetrical synovitis and pitting edema (RS3PE) syndrome. Alogliptin was discontinued and prednisolone was initiated, thereafter, his symptoms quickly improved. As for his glycemic control, his hemoglobin A1c (HbA1c) went from an initial 9.1% to 8.3% once alogliptin was initiated. However, after being diagnosed with RS3PE syndrome, his treatment was changed from alogliptin to metformin, and his HbA1c remained between 6% and 7%. The diagnosis of RS3PE syndrome should be considered if pitting edema and arthralgia in the extremities are observed after initiating patients with type 2 diabetes on DPP-4 inhibitors.

Abstract Aims/Introduction This study aimed to determine the effect of depression on the progression to end‐stage renal disease (ESRD) and pre‐ESRD death in patients with advanced diabetic nephropathy. Materials and Methods This single‐center prospective cohort study enrolled Japanese patients with type 2 diabetes and advanced diabetic nephropathy. The total Patient Health Questionnaire‐9 score was used to evaluate depression at baseline and classified patients into: no, mild and severe depression groups. The outcomes were ESRD, defined as initiation of renal replacement therapy, and pre‐ESRD death. The relationship between the severity of depression and these outcomes was analyzed using a competing risks model, defining each outcome as the competing risk of the other outcome. Results Of the 486 patients with a mean estimated glomerular filtration rate of 37.1 ± 21.1 mL/min/1.73 m2, 345 were men. During the median follow up of 4.4 years, 164 patients progressed to ESRD and 50 died. The cumulative incidence function of ESRD was significantly higher in the severe depression group (Gray’s test, P = 0.003). The ESRD risk increased by 12.4% and 45.1% in patients with mild and severe depression, respectively, compared with those without depression, although these differences did not reach statistical significance in the multivariate subdistribution hazard model (P = 0.450 and 0.161, respectively). The cumulative incidence of death was similar for the study groups. Conclusion Depression potentially has a weak impact on progression to ESRD, however, the presence of comorbidities might have the possibility to reduce the effect of depression on the renal outcome in patients with advanced diabetic nephropathy.

Abstract Aims/Introduction To evaluate and compare the efficacy of insulin degludec (IDeg) and insulin glargine 300 U/mL (Gla300) 6 months after switching from other basal insulins by assessing the changes in glycated hemoglobin (HbA1c), body mass index (BMI), and insulin doses in patients with type 1 and type 2 diabetes in a real‐world clinical setting. Materials and Methods A total of 307 patients with type 1 diabetes and 294 patients with type 2 diabetes with HbA1c >7.0% were studied. Adjusted mean changes in HbA1c, BMI, and insulin doses were compared between IDeg (IDeg group) and Gla300 (Gla300 group) switchers. Multivariable logistic regression analyses were carried out to examine whether the IDeg or Gla300 group was associated with HbA1c or insulin dose reduction and BMI gain. Results HbA1c was significantly decreased in both the IDeg and Gla300 groups. Adjusted mean changes in HbA1c (approximately −0.3% and −0.5% in type 1 diabetes and type 2 diabetes patients, respectively) and BMI were similar between both groups. The mean change in insulin dose was slightly larger for dose reduction in the IDeg group than in the Gla300 group. Multivariable logistic regression models showed that the IDeg group was significantly associated with insulin dose reduction after adjusting for basal insulin type, insulin dose, and number of basal insulin injections at baseline and other confounding factors. Conclusions The current study suggested that IDeg and Gla300 have similar effects in reducing HbA1c and gaining BMI after switching from other basal insulins in Japanese patients with type 1 diabetes and type 2 diabetes. IDeg selection was associated with insulin dose reduction.

Gestational diabetes mellitus (GDM) is associated with an increased long-term risk of developing diabetes. We investigated the risk factors for early postpartum glucose intolerance in patients with GDM.A total of 148 patients with GDM were included in this study. Among them, 30 and 118 were diagnosed with GDM before (B20w group) and after (A20w group) 20 weeks of gestation, respectively. Oral glucose tolerance test (OGTT) was performed in all patients 58 days after delivery. In each group, the association between the postpartum OGTT results and the following parameters were analyzed: age, BMI, family history of diabetes, plasma glucose levels in diagnostic prenatal OGTT, number of abnormal OGTT values, glycated hemoglobin and glycated albumin (GA) levels at diagnosis of GDM, serum C-peptide levels, frequency of insulin therapy, and pregnancy outcomes.Postpartum OGTT revealed glucose intolerance in 9 and 35 patients in the B20w and A20w groups, respectively. In the B20w group, placental weight was an independent predictor for glucose intolerance. In the A20w group, GA level and family history were independent predictors for glucose intolerance.Elevated GA levels may be associated with a higher risk of postpartum glucose intolerance in patients with GDM diagnosed after 20 weeks of gestation.

Abstract Aims/Introduction For diabetes patients undergoing hemodialysis, vitreous hemorrhage seems to be a hemodialysis‐induced hemorrhagic complication because of the effect of systemic anticoagulation. However, it is unclear whether hemodialysis is associated with vitreous hemorrhage in diabetes patients. We therefore carried out this cohort study to clarify the relationship between hemodialysis and vitreous hemorrhage in diabetes patients with proliferative diabetic retinopathy. Materials and Methods This was a single‐center, retrospective, cohort study. We compared the incidence of vitreous hemorrhage in non‐vitrectomized proliferative diabetic retinopathy eyes between the hemodialysis group (145 eyes) and peritoneal dialysis group (36 eyes), which does not require the use of systemic anticoagulation (parallel‐group study), and in hemodialysis patients in the 12‐month period before and after the start of hemodialysis (before–after study). We also determined the risk factors for vitreous hemorrhage after the start of hemodialysis based on the patients’ systemic and ophthalmic characteristics. Results There was no significant difference in the first‐year incidence of vitreous hemorrhage between the hemodialysis (23.4%) and peritoneal dialysis groups (22.2%, P = 1.000). The incidence of vitreous hemorrhage in the dialysis period (23.4%) was significantly lower than that in the predialysis period (35.2%, P = 0.008). Only application of panretinal photocoagulation within the 6 months immediately before hemodialysis was significantly associated with the incidence of vitreous hemorrhage after the start of hemodialysis (P

Abstract Aims/Introduction Adipose‐derived mesenchymal stem cell (ASC) transplantation is a promising therapy for diabetic nephropathy (DN). However, intravascular administration of ASCs is associated with low engraftment in target organs. Therefore, we considered applying the cell sheet technology to ASCs. In this study, ASC sheets were directly transplanted into the kidneys of a DN rat model, and therapeutic consequences were analyzed. Materials and Methods Adipose‐derived mesenchymal stem cells were isolated from adipose tissues of 7‐week‐old enhanced green fluorescent protein rats, and ASC sheets were prepared using a temperature‐responsive culture dish. A DN rat model was established from 5‐week‐old Spontaneously Diabetic Torii fatty rats. Seven‐week‐old DN rats (n = 21) were assigned to one of the following groups: sham‐operated (n = 6); ASC suspension (6.0 × 106 cells/mL) administered intravenously (n = 7); six ASC sheets transplanted directly into the kidney (n = 8). The therapeutic effect of the cell sheets was determined based on urinary biomarker expression and histological analyses. Results The ASC sheets survived under the kidney capsule of the DN rat model for 14 days after transplantation. Furthermore, albuminuria and urinary tumor necrosis factor‐α levels were significantly lower in the ASC sheets transplanted directly into the kidney group than in the sham‐operated and ASC suspension administered intravenously groups (P

Abstract Background The association of glycated albumin (GA) with mortality is unclear in chronic hemodialysis patients with diabetes. We investigated the usefulness of GA by comparing it with hemoglobin A1c (HbA1c) in this patient population. Research design and methods This was a multi-center, prospective cohort study of 841 Japanese chronic hemodialysis patients with diabetes. There were 235 women and 606 men included, with a mean age of 64 years. The primary and secondary endpoints were the incidence of all-cause and cause-specific mortality, respectively. The hazard ratios of GA and HbA1c for the endpoints were estimated using the values at baseline and during the study period. Results During the mean follow-up period of 3.1 years, there were 184 deceased cases, in which 30 and 154 resulted from atherosclerotic cardiovascular disease (ASCVD) and non-ASCVD, respectively. The hazard ratio for a 1% increase in GA was 1.033 (95% confidence interval 1.006–1.060, p = 0.017) for all-cause mortality with a statistical significance when GA was treated as a time dependent variable, but not when the baseline levels or the mean levels during the follow-up period were used in the analysis (p = 0.815 and 0.517, respectively). GA was a significant predictor for ASCVD-related mortality in the above 3 models, but was not for non-ASCVD mortality. Higher levels of HbA1c were only associated with ASCVD-related mortality when HbA1c was treated as a time-dependent variable. Conclusions GA may be useful compared to HbA1c for predicting all-cause and ASCVD-related mortality in Japanese patients with diabetes undergoing chronic hemodialysis.

Abstract Aims/Introduction The aim of the present study was to compare the clinical and genetic characteristics between people with type 1 diabetes who were positive and negative for autoantibodies against glutamic acid decarboxylase (GADA) measured by enzyme‐linked immunosorbent assay (ELISA) with low‐titer GADA measured by radioimmunoassay. Materials and Methods Among Japanese people with type 1 diabetes in whom GADA were measured by both ELISA and radioimmunoassay, those who had low titers of GADA measured by radioimmunoassay (1.5–10 U/mL), regardless of positivity for GADA measured by ELISA, were studied. There were 65 participants with acute‐onset type 1 diabetes and 30 participants with slowly progressive insulin‐dependent diabetes mellitus. Clinical characteristics and human leukocyte antigen types were compared in ELISA‐positive (≥5 U/mL) and ELISA‐negative participants. Endogenous insulin secretion was evaluated by C‐peptide index. Results Among participants with slowly progressive insulin‐dependent diabetes mellitus, postprandial C‐peptide index was significantly higher in ELISA‐negative participants than in ELISA‐positive participants (r = 0.619, P = 0.002). Among 52 participants whose human leukocyte antigen typing was carried out, all of the participants with slowly progressive insulin‐dependent diabetes mellitus who had DRB1*09:01 were positive by GADA‐ELISA (P = 0.021). In acute‐onset type 1 diabetes participants, there were no significant differences for the C‐peptide index and human leukocyte antigen genotypes. Conclusions The difference in the positivity for GADA‐ELISA might reflect cytotoxicity toward pancreatic β‐cells and preservation of endogenous insulin secretion in people with slowly progressive insulin‐dependent diabetes mellitus. We also suggest that the difference in the GADA‐ELISA‐specific epitope depends on the human leukocyte antigen genotype.

Introduction Changes in albuminuria or estimated glomerular filtration rate (eGFR) can be used as a surrogate endpoint of end-stage kidney disease (ESKD) in people with type 2 diabetes. We investigated whether the combined changes in albuminuria and eGFR are more strongly associated with future risk of ESKD.Research design and methods Using data from a multicenter observational cohort study of people with type 2 diabetes, we evaluated the association of percentage change in urine albumin to creatinine ratio (UACR) and/or annual change in eGFR over 2 years with subsequent ESKD risk.Results Among 1417 patients with repeated albuminuria and eGFR over 2 years, 129 (9.1%) developed ESKD. Patients with >30% UACR decline had lower ESKD risk (HR 0.47; 95% CI 0.29 to 0.77), whereas those with >30% UACR increase had higher ESKD risk (HR 2.31; 95% CI 1.52 to 3.51), compared with those with minor UACR change. Patients with greater eGFR decline had an increased ESKD risk than those with minor eGFR change (a decline of 5 and 2.5–5 mL/min/1.73 m2/year, respectively. When the combined changes in UACR and eGFR were used, the highest ESKD risk (HR 5.60; 95% CI 2.08 to 15.09) was observed among patients with >30% UACR increase and an eGFR decline of >5 mL/min/1.73 m2/year compared with those with a minor change in UACR and eGFR.Conclusions Combined changes in albuminuria and eGFR over 2 years were strongly associated with future risk of kidney failure in patients with type 2 diabetes.

Background: Past clinical studies have shown the relationship between type 2 diabetes (T2D) and obstructive sleep apnoea (OSA), but little is known about type 1 diabetes (T1D). The purpose of this study is to examine clinical indicators associated with OSA in patients with different subtypes of diabetes.Methods: Self-administered questionnaires that asked if the patients had been diagnosed with OSA were distributed to patients with T1D and T2D. General and clinical information was confirmed with both questionnaires and medical records.Result: Among the 1,269 T1D patients and 5,838 T2D patients, 20 T1D patients and 421 T2D patients had received a diagnosis of OSA. OSA patients were more likely to be male, older, and to have a greater BMI and lower LDLC and HDLC. T1D patients with OSA were characterized by a significantly higher prevalence of severe hypoglycemia. On the other hand, T2D patients with OSA had high HbA1c, decreased renal function, high frequency of diabetic neuropathy, and correlated with macrovascular complications.Conclusion: The prevalence of OSA was significantly higher in T2D patients. It was suggested that OSA-related pathologies might differ between T1D and T2D patients.

Abstract Aim We aimed to determine the association between self‐efficacy of foot care behaviour and chronic complications in Japanese patients with diabetes. Methods We conducted a cross‐sectional study based on a questionnaire survey of 4571 patients with type 1 and type 2 diabetes who had (a) given consent to participate in the Diabetes Study from the Center of Tokyo Women's Medical University: DIACET 2017, and (b) completed all the questions of the Japanese Version of Foot Care Confidence Scale (J‐FCCS), consisting of 12 statements. Results A greater proportion of respondents answered that they were not confident in determining the condition of corns and/or calluses and the condition of toenails. The J‐FCCS total scores of the patients with retinopathy (p

To explore novel genetic loci for diabetic nephropathy, we performed genome-wide association studies (GWAS) for diabetic nephropathy in Japanese patients with type 2 diabetes. We analyzed the association of 5,768,242 single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes, 2,380 nephropathy cases and 5,234 controls. We further performed GWAS for diabetic nephropathy using independent Japanese patients with type 2 diabetes, 429 cases and 358 controls and the results of these two GWAS were combined with an inverse variance meta-analysis (stage-1), followed by a de novo genotyping for the candidate SNP loci (p < 1.0 × 10(-4)) in an independent case-control study (Stage-2; 1,213 cases and 1,298 controls). After integrating stage-1 and stage-2 data, we identified one SNP locus, significantly associated with diabetic nephropathy; rs56094641 in FTO, P = 7.74 × 10(-10). We further examined the association of rs56094641 with diabetic nephropathy in independent Japanese patients with type 2 diabetes (902 cases and 1,221 controls), and found that the association of this locus with diabetic nephropathy remained significant after integrating all association data (P = 7.62 × 10(-10)). We have identified FTO locus as a novel locus for conferring susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes.

BACKGROUND:According to studies by the National Kidney Foundation and Food and Drug Administration, 30% and 40% declines in estimated glomerular filtration rate (eGFR) could be used as surrogate endpoints of end-stage renal disease (ESRD). However, the benefits of using these endpoints in diabetic patients remain unclear. METHODS:This cohort study comprised Japanese patients with type 2 diabetes; those with repeated serum creatinine measurements during a baseline period of 2 years (n = 1868) or 3 years (n = 2001) were enrolled. Subsequent risks of ESRD following eGFR declines were assessed. RESULTS:In the 2-year baseline analysis, the cumulative prevalence of -20%, -30%, -40%, and -53% changes in eGFR were 23.9%, 11.1%, 6.8%, and 3.7%, respectively. There were 133 cases (7.1%) of subsequent ESRD during a median follow-up period of 6.5 years. In the 3-year baseline analysis, the corresponding proportions were 28.1%, 14.0%, 7.7%, and 3.9%, respectively, with 110 participants (5.5%) reaching ESRD during a median follow-up period of 5.5 years. The adjusted hazard ratios of subsequent ESRD following -53%, -40%, -30%, and -20% changes in eGFR during the 2-year baseline period were 22.9 (11.1-47.3), 12.8 (6.9-23.7), 8.2 (4.3-15.5), and 3.9 (2.2-7.0), respectively when compared with the no changes in eGFR. In the 3-year baseline analysis, the corresponding risks were 29.7 (10.8-81.9), 18.4 (7.6-44.7), 12.8 (5.2-32.2), and 5.4 (2.3-12.8), respectively. In the subgroup analysis, similar trends were observed in patients with macroalbuminuria at baseline. CONCLUSIONS:Declines in eGFR were strongly associated with subsequent risk of ESRD in Japanese type 2 diabetic patients. In addition to 30% and 40% declines, a 20% decline in eGFR over 2 years could be considered as a candidate surrogate endpoint of ESRD in diabetic kidney disease.

BACKGROUND: Several linkage analyses have mapped a susceptibility locus for diabetic nephropathy to chromosome 18q22-23, and polymorphisms within the carnosine dipeptidase 1 gene (CNDP1), located on 18q22.3, have been shown to be associated with diabetic nephropathy in European subjects with type 2 diabetes. However, the association of this locus with diabetic nephropathy has not been evaluated in the Japanese population. In this study, we examined the association of polymorphisms within the CNDP1/CNDP 2 locus with diabetic nephropathy in Japanese subjects with type 2 diabetes. METHODOLOGY/PRINCIPAL FINDINGS: We genotyped a leucine repeat polymorphism (D18S880) that is within CNDP1 along with 29 single nucleotide polymorphisms (SNPs) in the CNDP1/CNDP2 locus for 2,740 Japanese subjects with type 2 diabetes (1,205 nephropathy cases with overt nephropathy or with end-stage renal disease [ESRD], and 1,535 controls with normoalbuminuria). The association of each polymorphism with diabetic nephropathy was analysed by performing logistic regression analysis. We did not observe any association between D18S880 and diabetic nephropathy in Japanese subjects with type 2 diabetes. None of the 29 SNPs within the CNDP1/CNDP2 locus were associated with diabetic nephropathy, but a subsequent sex-stratified analysis revealed that 1 SNP in CNDP1 was nominally associated with diabetic nephropathy in women (rs12604675-A; p = 0.005, odds ratio [OR] = 1.76, 95% confidence interval [CI], 1.19-2.61). Rs12604675 was associated with overt proteinuria (p = 0.002, OR = 2.18, 95% CI, 1.32-3.60), but not with ESRD in Japanese women with type 2 diabetes. CONCLUSIONS/SIGNIFICANCE: Rs12604675-A in CNDP1 may confer susceptibility to overt proteinuria in Japanese women with type 2 diabetes.

Acetyl coenzyme A carboxylase B gene (ACACB) single nucleotide polymorphism (SNP) rs2268388 is reproducibly associated with type 2 diabetes (T2DM)-associated nephropathy (DN). ACACB knock-out mice are also protected from obesity. This study assessed relationships between rs2268388, body mass index (BMI) and gene expression in multiple populations, with and without T2DM. Among subjects without T2DM, rs2268388 DN risk allele (T) associated with higher BMI in Pima Indian children (n = 2021; p-additive = 0.029) and African Americans (AAs) (n = 177; p-additive = 0.05), with a trend in European Americans (EAs) (n = 512; p-additive = 0.09), but not Germans (n = 858; p-additive = 0.765). Association with BMI was seen in a meta-analysis including all non-T2DM subjects (n = 3568; p-additive = 0.02). Among subjects with T2DM, rs2268388 was not associated with BMI in Japanese (n = 2912) or EAs (n = 1149); however, the T allele associated with higher BMI in the subset with BMI≥30 kg/m(2) (n = 568 EAs; p-additive = 0.049, n = 196 Japanese; p-additive = 0.049). Association with BMI was strengthened in a T2DM meta-analysis that included an additional 756 AAs (p-additive = 0.080) and 48 Hong Kong Chinese (p-additive = 0.81) with BMI≥30 kg/m(2) (n = 1575; p-additive = 0.0033). The effect of rs2268388 on gene expression revealed that the T risk allele associated with higher ACACB messenger levels in adipose tissue (41 EAs and 20 AAs with BMI>30 kg/m(2); p-additive = 0.018) and ACACB protein levels in the liver tissue (mixed model p-additive = 0.03, in 25 EA bariatric surgery patients with BMI>30 kg/m(2) for 75 exams). The T allele also associated with higher hepatic triglyceride levels. These data support a role for ACACB in obesity and potential roles for altered lipid metabolism in susceptibility to DN.

It has been suggested that genetic susceptibility plays an important role in the pathogenesis of diabetic nephropathy. A large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes identified the gene encoding acetyl-coenzyme A carboxylase beta (ACACB) as a candidate for a susceptibility to diabetic nephropathy; the landmark SNP was found in the intron 18 of ACACB (rs2268388: intron 18 +4139 C > T, p = 1.4x10(-6), odds ratio = 1.61, 95% confidence interval [CI]: 1.33-1.96). The association of this SNP with diabetic nephropathy was examined in 9 independent studies (4 from Japan including the original study, one Singaporean, one Korean, and two European) with type 2 diabetes. One case-control study involving European patients with type 1 diabetes was included. The frequency of the T allele for SNP rs2268388 was consistently higher among patients with type 2 diabetes and proteinuria. A meta-analysis revealed that rs2268388 was significantly associated with proteinuria in Japanese patients with type 2 diabetes (p = 5.35 x 10(-8), odds ratio = 1.61, 95% Cl: 1.35-1.91). Rs2268388 was also associated with type 2 diabetes-associated end-stage renal disease (ESRD) in European Americans (p = 6 x 10(-4), odds ratio = 1.61, 95% Cl: 1.22-2.13). Significant association was not detected between this SNP and nephropathy in those with type 1 diabetes. A subsequent in vitro functional analysis revealed that a 29-bp DNA fragment, including rs2268388, had significant enhancer activity in cultured human renal proximal tubular epithelial cells. Fragments corresponding to the disease susceptibility allele (T) had higher enhancer activity than those of the major allele. These results suggest that ACACB is a strong candidate for conferring susceptibility for proteinuria in patients with type 2 diabetes.