Associations between urinary 6-sulfatoxymelatonin excretion and diabetic vascular complications or arteriosclerosis in patients with type 2 diabetes

Aims/IntroductionThere are limited reports on the association between melatonin levels and vascular complications in patients with type 2 diabetes. The aim of this study was to determine the association between urinary 6‐sulfatoxymelatonin, which is a urinary metabolite of melatonin, and diabetic vascular complications or arteriosclerosis in patients with type 2 diabetes.Materials and MethodsThis retrospective study included patients (167 patients with type 2 diabetes and 27 patients without diabetes adjusted for age and sex) admitted to the hospital who underwent measurement of urinary 6‐sulfatoxymelatonin. The urinary 6‐sulfatoxymelatonin/creatinine ratio (6‐SMT) was calculated.ResultsThe natural logarithmically scaled 6‐SMT level (Ln 6‐SMT) was significantly lower in type 2 diabetes patients (1.9 ± 1.1) compared with patients without diabetes (2.8 ± 1.0, P < 0.001). Multivariate linear regression analysis identified duration of diabetes, smoking status, urinary albumin‐to‐creatinine ratio, retinopathy and coronary heart disease as factors that could influence Ln 6‐SMT levels in type 2 diabetes patients (R ² = 0.232, P < 0.001). Ln 6‐SMT was associated with decreased odds of diabetic retinopathy, even after adjustment for various confounding factors (odds ratio 0.559, 95% confidence interval 0.369–0.846, P = 0.006). Similarly, Ln 6‐SMT was associated with decreased odds of coronary heart disease (odds ratio 0.442, P = 0.030).ConclusionsOur results showed the presence of low levels of Ln 6‐SMT in type 2 diabetes patients relative to patients without diabetes. Furthermore, Ln 6‐SMT is an independent risk factor of diabetic retinopathy and coronary heart diseases. These findings suggest that 6‐SMT could be a useful biomarker for the prediction of micro‐ and macrovasculopathies in patients with type 2 diabetes.     

Blood pressure after treatment with sodium–glucose cotransporter 2 inhibitors influences renal composite outcome: Analysis using propensity score-matched models

Aims/IntroductionSodium–glucose cotransporter 2 inhibitors (SGLT2i) improve renal outcome in patients with type 2 diabetes mellitus, but the mechanism is not fully understood. The aim of this retrospective study was to assess the association of achieved blood pressure with renal outcomes in Japanese type 2 diabetes mellitus patients with chronic kidney disease.Materials and MethodsWe assessed 624 Japanese type 2 diabetes mellitus patients with chronic kidney disease taking SGLT2i for >1 year. The patients were classified as those with post‐treatment mean arterial pressure (MAP) of ≥92 mmHg (n = 344) and those with MAP of <92 mmHg (n = 280) for propensity score matching (1:1 nearest neighbor match with 0.04 of caliper value and no replacement). The end‐point was a composite of progression of albuminuria or a decrease in the estimated glomerular filtration rate by ≥15% per year.ResultsBy propensity score matching, a matched cohort model was constructed, including 201 patients in each group. The incidence of renal composite outcome was significantly lower among patients with MAP of <92 mmHg than among patients with MAP of ≥92 mmHg (n = 11 [6%] vs n = 26 [13%], respectively, P = 0.001). The change in estimated glomerular filtration rate was similar in the two groups; however, the change in the albumin‐to‐creatinine ratio was significantly larger in patients with MAP of <92 mmHg.ConclusionsIn Japanese type 2 diabetes mellitus patients with chronic kidney disease, blood pressure after SGLT2i administration influences the renal composite outcome. Blood pressure management is important, even during treatment with SGLT2i.     

Trends in the effects of pre-transplant diabetes on mortality and cardiovascular events after kidney transplantation

Aims/IntroductionIt is not clear whether survival in kidney transplant recipients with pre‐transplant diabetes has improved over the past decades. We compared the rates of mortality and major adverse cardiovascular events (MACE) after renal transplantation in patients with and without pre‐transplant diabetes. Furthermore, we investigated whether transplant era and recipient age affected the association between diabetes status and adverse events.Materials and MethodsThis retrospective cohort study included 691 patients who underwent renal transplantation between 1994 and 2016 at a single tertiary center. We compared the incidences of post‐transplant mortality and four‐point MACE in patients with and without pre‐transplant diabetes using Kaplan–Meier analysis and the Cox proportional hazard model, and assessed the interactions between diabetes status and transplant era and recipient age.ResultsOf 691 kidney recipients, 143 (20.7%) had pre‐transplant diabetes. The mean follow‐up duration was 94.5 months. Kaplan–Meier analysis showed that patients with pre‐transplant diabetes had higher incidences of post‐transplant mortality and four‐point MACE compared with those without pre‐transplant diabetes (log–rank test, P < 0.001 for both). After adjusting for potential confounding factors, pre‐transplant diabetes was associated with an increased risk of post‐transplant mortality and four‐point MACE (hazard ratio 1.90, 95% confidence interval 1.05–3.44, P = 0.034; and hazard ratio 1.75; 95% confidence interval 1.02–3.00, P = 0.043, respectively). The associations between pre‐transplant diabetes status and all‐cause mortality and four‐point MACE were not affected by transplant era or recipient age.ConclusionsPre‐transplant diabetes remains a significant risk factor for mortality and four‐point MACE in kidney transplant recipients.     

Serum vaspin levels are positively associated with diabetic retinopathy in patients with type 2 diabetes mellitus

Aims/IntroductionVaspin is linked to obesity and its metabolic abnormalities. However, the role of vaspin serum levels in diabetic retinopathy (DR) is unknown. In the present study, we investigated the association between serum levels of vaspin and both DR and vision‐threatening DR.Materials and MethodsThis was a cross‐sectional single‐center observational study from December 2018 to September 2019. We evaluated circulating serum levels of vaspin in 372 participants with type 2 diabetes. DR was screened through detailed ocular examination. DR patients were also divided two groups: vision‐threatening DR and non‐vision‐threatening DR. The relationship between vaspin and DR was investigated by univariate and multivariate logistic regression analyses, and the results are shown as odds ratios with 95% confidence intervals.ResultsThe vaspin serum levels of 372 patients were obtained, with a median value of 1.50 ng/mL (interquartile range 0.94–2.18 ng/mL). The median age of those patients was 53 years (interquartile range 44–62 years), and 44.4% were women. Patients with DR and VDTR had significantly increased vaspin serum levels (P < 0.001 andP < 0.001). A multivariable regression model found that patients with high levels of vaspin were approximately 1.85‐fold (odds ratio for per unit increase 1.85, 95% confidence interval 1.43–2.55; P < 0.001) more likely to experience DR, and 3.76‐fold (odds ratio for per unit increase 3.76, 95% confidence interval 2.05–6.55; P < 0.001) more likely to experience VTDR. The predictive value of vaspin was stronger in women than in men.ConclusionHigher vaspin serum levels were associated with an increased risk of DR and VDTR in patients with type 2 diabetes, which showed that vaspin is an important indicator factor for DR.     

Irisin plays an important role in the outcomes of newly diagnosed prediabetes in adults in Guiyang,China

Aims/IntroductionTo explore the potential role of irisin in the outcomes of newly diagnosed prediabetes.Materials and MethodsData were obtained from the Guiyang subcenter of the Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal (REACTION) study. A total of 2,530 participants had newly diagnosed prediabetes at baseline and completed follow up. The nested 1:1 case–control study included 161 participants who developed diabetes mellitus at follow up, and 161 age‐ and sex‐matched controls. The follow‐up study included 86 matched case–control pairs. Fasting serum irisin levels were measured using enzyme‐linked immunosorbent assay.ResultsBaseline serum irisin levels were higher in the cases than in the controls (P = 0.002); high baseline serum irisin levels were an independent risk factor for the development of diabetes (odds ratio 1.235, 95% confidence interval 1.025–1.488). After adjustment for age, sex, body mass index, glycated hemoglobin (HbA1c), smoking, exercise, and family history of diabetes, subjects in the highest quartile of irisin levels had a higher risk of diabetes than those in the lowest quartile (odds ratio 3.065, 95% confidence interval 1.511–6.218). The extent of decrease in irisin levels during follow‐up was greater in the cases than in the controls (P < 0.001). Baseline serum irisin levels were positively correlated with the extent of decrease in irisin during follow‐up (r = 0.773, P < 0.001). After adjustment for confounding factors, subjects with a decrease of irisin above the median had much higher risk for diabetes (odds ratio 5.077, 95% confidence interval 2.112–12.206).ConclusionsIrisin might play an important role in the outcomes of newly diagnosed prediabetes in adults in Guiyang, and can predict the risk for developing diabetes in these individuals.     

High urinary glucose is associated with improved renal prognosis in patients with diabetes mellitus

Aims/IntroductionThe relationship between renal function and urinary glucose is poorly understood in diabetes patients who are not using sodium–glucose cotransporter 2 inhibitors. This study aimed to investigate the association of urinary glucose excretion with renal function prognosis in such patients.Materials and MethodsThis retrospective cohort study included 1,172 patients with type 1 or 2 diabetes mellitus. Patients were recruited and data were collected between 1 January 2007 and 31 December 2011; follow‐up data were collected until 30 June 2015. The primary outcome was set as a 30% decline in estimated glomerular filtration rate relative to baseline. The relationship between this outcome and urinary glucose was investigated using Cox proportional hazards model. For analysis, patients were categorized into two groups: urinary glucose <5 g/day or ≥5 g/day. Interaction terms were analyzed.ResultsMultivariate analysis showed that the prognosis of renal function was significantly better in patients with high urinary glucose (≥5 g/day; adjusted hazard ratio 0.58, 95% confidence interval 0.35–0.96; P = 0.034). Significant interactions were observed between high urinary glucose and male sex (hazard ratio 0.33, 95% confidence interval 0.14–0.74; P = 0.007), and between high urinary glucose and longer duration of diabetes (≥10 years; hazard ratio 0.25, 95% confidence interval 0.11–0.58; P = 0.001).ConclusionsThe present study suggests that high urinary glucose is associated with prognosis in diabetes patients not taking sodium–glucose cotransporter 2 inhibitors. Measurement of 24‐h urinary glucose excretion might have clinical utility for predicting renal prognosis.     

Persons with type 2 diabetes and high insulin persistence were associated with a lower risk of mortality: A nationwide retrospective cohort study

Aims/IntroductionStudies assessing the long‐term outcomes of insulin persistence are scant. We compared the risk of all‐cause mortality among patients with different degrees of insulin persistence.Materials and MethodsIn total, 293,210 patients with type 2 diabetes mellitus undergoing insulin therapy were enrolled during 2002–2014. Insulin persistence was defined as continual insulin treatment without a 90‐day gap of discontinuation in the 2‐year observation period. Mortality rates were compared between 111,220 patients with ≥90% insulin persistence and 111,220 matched patients with <90% insulin persistence during the observational period.ResultsDuring the mean 5.37‐year follow‐up period, the mortality rates were 58.26 and 73.21 per 1,000 person‐years for patients with ≥90% and <90% of insulin persistence. The adjusted hazard ratio for mortality was 0.80 (95% confidence interval 0.79–0.81, P < 0.001). Patients with high insulin persistence had significantly lower risks than did those with low insulin persistence of death due to hypertension, diabetes, cardiovascular disease, liver disease, kidney disease, respiratory disease, sepsis and cancer.ConclusionsThis study showed that patients with ≥90% insulin persistence were associated with lower risks of all‐cause mortality than did patients with <90% insulin persistence.     

The PKM2 activator TEPP-46 suppresses kidney fibrosis via inhibition of the EMT program and aberrant glycolysis associated with suppression of HIF-1α accumulation

Aims/IntroductionTubulointerstitial fibrosis is a hallmark of diabetic nephropathy and is associated with an epithelial‐to‐mesenchymal transition (EMT) program and aberrant glycolysis. Dimeric pyruvate kinase (PK) M2 (PKM2) acts as a key protein kinase in aberrant glycolysis by promoting the accumulation of hypoxia‐inducible factor (HIF)‐1α, while tetrameric PKM2 functions as a pyruvate kinase in oxidative phosphorylation. The aim of the research is to study the effect of PKM2 tetramer activation on preventing kidney fibrosis via suppression of aberrant glycolysis and the EMT program.Materials and methods In vivo: Streptozotocin (STZ) was utilized to induce diabetes in 8‐week‐old CD‐1 mice; 4 weeks after diabetes induction, proteinuria‐induced kidney fibrosis was developed by intraperitoneal injection of bovine serum albumin (BSA: 0.3 g/30 g BW) for 14 days; The PKM2 activator TEPP‐46 was also administered orally simultaneously. In vitro: HK2 cells were co‐treated with high‐glucose media or/and TGF‐β1 and TEPP46 for 48 h, cellular protein was extracted for evaluation.ResultsDiabetic mice developed kidney fibrosis associated with aberrant glycolysis and EMT; BSA injection accelerated kidney fibrosis in both the control and diabetic mice; TEPP‐46 rescued the kidney fibrosis. In HK2 cells, TEPP‐46 suppressed the EMT program induced by TGF‐β1 and/or high‐glucose incubation. TEPP‐46‐induced PKM2 tetramer formation and PK activity resulted in suppression of HIF‐1α and lactate accumulation. Specific siRNA‐mediated knockdown of HIF‐1α expression diminished high glucose‐induced mesenchymal protein levels.ConclusionPKM2 activation could restore the tubular phenotype via suppression of the EMT program and aberrant glycolysis, providing an alternative target to mitigate fibrosis in diabetic kidneys.     

Anthropometry did not approach adequate predictive accuracies for detecting elevated fasting plasma glucose or hemoglobin A1c levels among Chinese children aged 7–9 years

Aims/IntroductionElevated concentrations of fasting plasma glucose (FPG) or hemoglobin A1c (HbA1c) are well‐established independent risk factors for progression to diabetes, cardiovascular comorbidities and mortality. Most previous studies on the relationships of anthropometric measures with hyperglycemia were carried out among adults and adolescents, but few data are available for the performance predication of the predictors for diagnosing elevated FPG or HbA1c among young children.Materials and MethodsInvolving 5,556 students of aged 7–9 years, a school‐based cross‐sectional survey was carried out between March and June 2019 in Shenzhen, China. Receiver operating characteristic curve analysis was utilized.ResultsThe median was 4.6 (interquartile range [IQR] 4.3–4.8) mmol/L for FPG and 5.3% (IQR 5.1–5.5%) for HbA1c levels for all participants. For detecting elevated FPG, weight (0.651, IQR 0.583–0.719) and waist circumference (0.650, IQR 0.584–0.717) showed the highest area under the curve and 95% confidence interval, followed by body mass index and the z‐score of body mass index (both 0.635, IQR 0.567–0.703); other anthropometric measures showed poorer diagnostic efficiencies or no ability. For detecting elevated HbA1c, lower efficiencies for the Conicity Index (0.651, IQR 0.583–0.719), waist‐to‐height ratio, waist‐to‐hip ratio and waist‐to‐chest ratio were shown. The correlations of FPG and HbA1c levels with anthropometric indices were weak (Spearman’s r ≤ 0.179).ConclusionsNone of the evaluated anthropometric indicators approached an adequate predictive accuracy for the detection of elevated FPG or HbA1c levels in Shenzhen children aged 7–9 years. The current study did not recommend anthropometry screening for prediabetes in young children.     

Fractional excretion of tumor necrosis factor receptor 1 and 2 in patients with type 2 diabetes and normal renal function

Aims/IntroductionIncreased concentrations of serum tumor necrosis factor (TNF) receptors (TNFRs; TNFR1 and TNFR2) are positively associated with the urinary albumin‐to‐creatinine ratio (ACR), and negatively associated with the estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes. However, the mechanism underlying this increase and the relationship between TNFRs in serum, and urine and kidney measures (ACR and eGFR) are unclear.Materials and MethodsThis was a cross‐sectional study that included 499 patients with type 2 diabetes and eGFR ≥60 mL/min/1.73 m². The concentrations of TNFRs in serum and urine, and their respective fractional excretion, were measured.ResultsSerum and urinary TNFR levels were positively associated with the ACR, and negatively associated with the eGFR. The fractional excretion of TNFRs did not differ between patients with an eGFR ≥90 and those with an eGFR 60–89 mL/min/1.73 m², and also did not correlate with eGFR. After adjustment for relevant covariates, the serum TNFRs were associated with a lower eGFR (60–89 mL/min/1.73 m²) and an increased ACR (≥30 mg/gCr), but urinary TNFRs were associated with an increased ACR (≥30 mg/gCr) alone, in the multivariate logistic model.ConclusionsThe pattern of fractional excretion TNFRs showed that an increase in serum TNFRs might result from their increased systemic production, including in the kidney, rather than being a simple reflection of GFR decline. Kidney measures appear to be strongly associated with serum TNFRs rather than urinary TNFRs in patients with type 2 diabetes and normal renal function.     

Sodium–glucose cotransporter 2 inhibitors reduce day-to-day glucose variability in patients with type 1 diabetes

Aims/IntroductionSodium–glucose cotransporter 2 inhibitors (SGLT2i) are used worldwide because of their multiple benefits for patients with type 2 diabetes. The purpose of this study was to determine the efficacy and safety of SGLT2i in patients with type 1 diabetes.Materials and MethodsPatients with type 1 diabetes who had been treated with SGLT2i for >12 weeks were included in this retrospective observation study. We recorded the changes in body mass, insulin dose, blood and urine test data, and adverse events. The changes in day‐to‐day glucose variability, as the primary end‐point, was evaluated using the interquartile range (P25/P75) of the ambulatory glucose data obtained using continuous glucose monitoring.ResultsA total of 51 patients (37 women; mean age 52.7 years) were included. Glycated hemoglobin and body mass significantly decreased by 0.4% and 1.6 kg, respectively. The total required insulin dose decreased by 9.4% (42.7 ± 26.6–38.7 ± 24.3 units/day). Continuous glucose monitoring data were obtained from 30 patients. P25/P75 decreased by 17.6 ± 20.7% during SGLT2i treatment (P < 0.001). The percentage of time per day within the target glucose range of 70–180 mg/dL significantly increased (from 42.2 to 55.5%, P < 0.001), without an increase in the percentage of time spent in the hypoglycemic range (<70 mg/dL). Urinary ketone bodies were detected in four patients (7.8%), but none developed ketoacidosis.ConclusionsSGLT2i improved day‐to‐day glucose variability and time in the target glucose range, without increasing frequency of hypoglycemia, in patients with type 1 diabetes, and reduced glycated hemoglobin, body mass and the required insulin dose.     

Association of crossing capillaries in the finger nailfold with diabetic retinopathy in type 2 diabetes mellitus

Aims/IntroductionCrossing capillaries in the finger nailfold might potentially be a novel diabetic retinopathy (DR) biomarker that could be assessed non‐invasively in the clinical setting. However, the association between crossing capillaries and DR is controversial. This study aimed to investigate the association between the percentage of crossing capillaries in the finger nailfold and DR in patients with type 2 diabetes mellitus.Materials and MethodsThis cross‐sectional study enrolled 108 type 2 diabetes mellitus patients (aged 40–75 years) who visited the outpatient diabetic clinic at Osaka University Hospital, Osaka, Japan, between May and October 2019. Capillary morphology was assessed using nailfold capillaroscopy based on the simple capillaroscopic definitions of the European League Against Rheumatism Study Group. Details of DR and other laboratory data were obtained from medical records. The association between the tertile of the percentage of the crossing capillary and DR was analyzed using multivariable logistic regression.ResultsAfter adjusting for age, sex, diabetes duration, glycated hemoglobin, systolic blood pressure, body mass index, and use of renin–angiotensin system inhibitor and antihyperlipidemic medication, the percentage of crossing capillaries was significantly associated with DR (multivariable‐adjusted odds ratios for increasing tertiles of the percentage of crossing capillary: 1 [reference], 2.05 [95% confidence interval 0.53–7.94], and 4.33 [95% confidence interval 1.16–16.21]; P‐trend = 0.028).ConclusionsA higher percentage of crossing capillaries in the nailfold was associated with a higher risk of DR, independent of traditional risk and inhibiting factors, in patients with type 2 diabetes mellitus.     

Comparison of spironolactone and trichlormethiazide as add‐on therapy to renin–angiotensin blockade for reduction of albuminuria in diabetic patients

To compare the efficacy of spironolactone and trichlormethiazide, as add‐on therapy to renin–angiotensin system (RAS) blockade, for reduction of albuminuria in diabetic patients with chronic kidney disease (CKD), we conducted this randomized, open‐labeled, parallel‐group, active‐controlled, per‐protocol‐design study. Type 2 diabetic patients receiving an angiotensin‐converting enzyme inhibitor or angiotensin II receptor blocker, with persistent albuminuria (≥100 mg/g creatinine) were randomly assigned to either spironolactone (25 mg/day) or trichlormethiazide (2 mg/day). The primary outcome was the change in albuminuria at 24 weeks of treatment. In patients who completed 24 weeks of treatment with spironolactone (n = 18) and trichlormethiazide (n = 15), albuminuria decreased significantly by −57.6 ± 21.3% (SD) (P < 0.001) and −48.4 ± 27.1% (P < 0.001), respectively. There was no significant difference in the change in albuminuria between groups (P = 0.270). This pilot study suggests add‐on therapy with spironolactone or trichlormethiazide to RAS blockade may be comparably beneficial to reducing albuminuria in type 2 diabetic patients. This trial was registered with UMIN‐CTR (no. UMIN000008914).     

Prediabetes and long-term outcomes in patients with three-vessel coronary artery disease: A large single-center cohort study

Aims/IntroductionWhether detection of prediabetes by routinely testing hemoglobin A_1c and fasting plasma glucose in three‐vessel disease patients could identify individuals at high risk of future cardiovascular disease events remains unclear. This study evaluated the relationship between different glycemic status and clinical outcomes in this specific population.Materials and MethodsThis study included 8,891 Chinese patients with three‐vessel disease. Patients were categorized according to their glycemic status (normoglycemia [NG], n = 3,195; prediabetes, n = 1,978; diabetes mellitus, n = 3,718).ResultsThe median follow‐up time was 7.5 years, during which 1,354 deaths and 2,340 major adverse cardiac and cerebrovascular events occurred. Compared with the NG group, patients in the prediabetes and diabetes mellitus groups had more comorbidities. After adjusting for confounders, the diabetes mellitus group had a higher risk of all‐cause death (hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.20–1.53; P < 0.001), cardiac death (HR 1.35, 95% CI 1.14–1.61; P = 0.001) and major adverse cardiac and cerebrovascular events (HR 1.22, 95% CI 1.11–1.34; P < 0.001) compared with the NG group, whereas the prediabetes and NG groups had no significant difference. The diabetes mellitus group also had a higher risk of stroke compared with the NG group (HR 1.22, 95% CI 1.02–1.46; P = 0.031).ConclusionsIn the context of three‐vessel disease, prediabetes patients have comparable long‐term outcomes in terms of major adverse cardiac and cerebrovascular events, cardiac death and all‐cause death to those with NG. Routine screening of glycemic metabolism based on hemoglobin A_1c and fasting plasma glucose might be valuable to identify individuals with diabetes mellitus who are at high risk of future cardiovascular disease events and individuals with prediabetes who are at high risk of progressing to diabetes mellitus.     

Point-of-care nerve conduction device predicts the severity of diabetic polyneuropathy: A quantitative,but easy-to-use,prediction model

Aims/IntroductionA gold standard in the diagnosis of diabetic polyneuropathy (DPN) is a nerve conduction study. However, as a nerve conduction study requires expensive equipment and well‐trained technicians, it is largely avoided when diagnosing DPN in clinical settings. Here, we validated a novel diagnostic method for DPN using a point‐of‐care nerve conduction device as an alternative way of diagnosis using a standard electromyography system.Materials and MethodsWe used a multiple regression analysis to examine associations of nerve conduction parameters obtained from the device, DPNCheck™, with the severity of DPN categorized by the Baba classification among 375 participants with type 2 diabetes. A nerve conduction study using a conventional electromyography system was implemented to differentiate the severity in the Baba classification. The diagnostic properties of the device were evaluated using a receiver operating characteristic curve.ResultsA multiple regression model to predict the severity of DPN was generated using sural nerve conduction data obtained from the device as follows: the severity of DPN = 2.046 + 0.509 × ln(age [years]) − 0.033 × (nerve conduction velocity [m/s]) − 0.622 × ln(amplitude of sensory nerve action potential [µV]), r = 0.649. Using a cut‐off value of 1.3065 in the model, moderate‐to‐severe DPN was effectively diagnosed (area under the receiver operating characteristic curve 0.871, sensitivity 70.1%, specificity 87.7%, positive predictive value 83.0%, negative predictive value 77.3%, positive likelihood ratio 5.67, negative likelihood ratio 0.34).ConclusionsNerve conduction parameters in the sural nerve acquired by the handheld device successfully predict the severity of DPN.     

Effect of the FreeStyle Libre™ flash glucose monitoring system on glycemic control in individuals with type 2 diabetes treated with basal–bolus insulin therapy: An open label,prospective, multicenter trial in Japan

Aims/IntroductionWe investigated the effect of FreeStyle Libre^TM on glycemic control in Japanese type 2 diabetes patients treated with basal–bolus insulin therapy.Materials and MethodsThis prospective, 90‐day single‐arm study enrolled 94 adults with type 2 diabetes treated with insulin. A 14‐day masked baseline phase was followed by an 11‐week treatment phase during which participants used the device to monitor glucose levels. The primary end‐point was time spent in hypoglycemia (<70 mg/dL) for baseline versus study end (days 76–90). Secondary end‐points included other measures of glycemic control, along with patient satisfaction using the Japanese Diabetes Treatment and Satisfaction Questionnaire.ResultsTime spent in hypoglycemia was low at baseline (0.51 ± 0.93 h/day) and did not significantly decrease at study end (0.47 ± 0.63 h/day, P = 0.6354). Time in range, time in hyperglycemia and estimated A1c all improved versus baseline (by +1.7 ± 3.0 h/day, −1.6 ± .4 h/day and −0.4 ± 0.8%, respectively, P < 0.0001 in each). Finger stick tests fell from 2.9 ± 1.3 to 1.9 ± 1.4/day, and mean scanning frequency during the intervention phase was 11.3/day. The mean treatment satisfaction score increased by 11.8 ± 5.3 (P < 0.0001). Two severe hypoglycemia‐related adverse events were reported; one of which was possibly related to the device. Three participants reported mild device‐related skin trauma, site discomfort or subcutaneous bleeding.ConclusionsUse of FreeStyle Libre by Japanese type 2 patients diabetes treated with basal–bolus insulin therapy showed a low baseline of hypoglycemia, and enabled improved glycemic control and treatment satisfaction.     

Dietary fiber intake and risk of type 2 diabetes in a general Japanese population: The Hisayama Study

Aims/IntroductionThe investigation of the influence of dietary fiber intake on the incidence of type 2 diabetes in a general Japanese population.Materials and MethodsA total of 1,892 individuals aged 40–79 years without diabetes at baseline were prospectively followed up for 14 years. The glucose tolerance status of participants was defined by a 75‐g oral glucose tolerance test with the 1998 World Health Organization criteria. Dietary fiber intake was estimated by a semiquantitative food frequency questionnaire and divided to quintile levels separately by sex. A Cox proportional hazards model was applied for computing the hazard ratios and their 95% confidence intervals for the incidence of diabetes.ResultsDuring the follow‐up period, 280 participants had developed diabetes. The age‐adjusted cumulative diabetes incidence decreased significantly with higher total dietary fiber intake (P‐for trend = 0.01). Participants in the highest quintile of total dietary fiber intake had a 0.53‐fold (95% confidence interval 0.31–0.90) lower risk of developing diabetes than those in the lowest quintile after for the adjustment with potential confounding factors. Total dietary fiber intake showed a moderate positive correlation to the intake of soybean and soybean products, green vegetables, and other vegetables. Similar associations with diabetes and food sources were observed for both of the soluble and insoluble dietary fiber intake.ConclusionsThe present study showed that higher dietary fiber intake was associated with a lower risk of type 2 diabetes in a general Japanese population. The intake of high dietary fiber foods might be useful for diabetes prevention.     

Impact of daily glucose fluctuations on cardiovascular outcomes after percutaneous coronary intervention for patients with stable coronary artery disease undergoing lipid-lowering therapy

Aims/IntroductionGlucose fluctuation (GF) is a residual risk factor for coronary artery disease (CAD). We investigated whether GF influenced clinical outcomes and progression of coronary stenosis in stable CAD patients.Materials and MethodsIn this prospective study, 101 consecutive lipid‐controlled stable CAD patients underwent percutaneous coronary intervention were enrolled, and GF was expressed as the mean amplitude of glycemic excursion (MAGE) obtained by continuous glucose monitoring before the procedure was evaluated. At 9 months after enrollment, culprit and non‐culprit (mild‐to‐moderate stenosis without ischemia) lesions were serially assessed by angiography. Cardiovascular events (CVE) consisting of cardiovascular death, non‐fatal myocardial infarction or ischemia‐driven revascularization during 2‐year follow up, rapid progression in non‐culprit lesions (defined as ≥10% luminal narrowing progression in lesions with stenosis ≥50%, ≥30% luminal narrowing progression in non‐culprit lesions with stenosis <50% or normal segment, or progression to total occlusion) were evaluated.ResultsCVE occurred in 25 patients, and MAGE was significantly higher in the CVE group (76.1 ± 24.8 mg/dL vs 59.3 ± 23.7 mg/dL; P = 0.003). Multivariate analysis showed that MAGE was an independent predictor of CVE (odds ratio 1.027, 95% confidence interval 1.008–1.047; P = 0.005). The optimal MAGE value to predict CVE was 70.7 mg/dL (area under the curve 0.687, 95% confidence interval 0.572–0.802; P = 0.005). Furthermore, MAGE was independently associated with rapid progression, and with the luminal narrowing progression in all non‐culprit lesions (r = 0.400, P < 0.05).ConclusionsDaily GF might influence future CVE in lipid‐controlled stable CAD patients.     

Serum arylhydrocarbon receptor transactivating activity is elevated in type 2 diabetic patients with diabetic nephropathy

Aims/Introduction

Evidence is emerging that exposure to persistent organic pollutants (POPs) is a risk factor for obesity‐related diseases and for diabetes mellitus (DM). We found that POPs could be measured by a cell‐based arylhydrocarbon receptor (AhR)‐dependent reporter assay. We tested if serum AhR transactivating (AHRT) activities are a risk factor for diabetic nephropathy in people with type 2 diabetes.

Materials and Methods

We enrolled diabetic patients with normoalbuminuria (n = 36), microalbuminuria (n = 29), macroalbuminuria (n = 8) and end‐stage renal disease (n = 31). Sera were tested for their AHRT activities, which were standardized by an AhR ligand, 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) and expressed as TCDD equivalents (TCDDeq pmol/L).

Results

Mean serum AHRT activities were higher in patients with microalbuminuria (40.1 ± 7.1 pmol/L), macroalbuminuria (37.4 ± 5.5 pmol/L) and end‐stage renal disease (59.1 ± 20.0 pmol/L) than in subjects with normoalbuminuria (12.7 ± 5.4 pmol/L; P < 0.05 for all comparisons). Serum AhR ligands showed a correlation with estimated glomerular filtration rate (eGFR; r = −0.663, P < 0.001), serum creatinine level (r = 0.635, P < 0.001), systolic blood pressure (r = 0.223, P = 0.026), glycated hemoglobim (r = 0.339, P < 0.001) and diabetic duration (r = 0.394, P < 0.001). In a multiple regression analysis, diabetic nephropathy was found to be an independent risk factor for higher AHRT activity after controlling for the confounding factors.

Conclusions

The present findings suggest serum AHRT activity, thus serum AhR ligands, is a risk factor for diabetic nephropathy. Further studies are required to clarify if an accumulation of POPs in the body is causally related to diabetic nephropathy.     

Predicting QT interval prolongation in patients diagnosed with the 2019 novel coronavirus infection

Introduction2019 novel coronavirus (COVID‐19) patients frequently develop QT interval prolongation that predisposes them to Torsades de Pointes and sudden cardiac death. Continuous cardiac monitoring has been recommended for any COVID‐19 patient with a Tisdale Score of seven or more. This recommendation, however, has not been validated.MethodsWe included 178 COVID‐19 patients admitted to a non‐intensive care unit setting of a tertiary academic medical center. A receiver operating characteristics curve was plotted to determine the accuracy of the Tisdale Score to predict QT interval prolongation. Multivariable analysis was performed to identify additional predictors.ResultsThe area under the curve of the Tisdale Score was 0.60 (CI 95%, 0.46–0.75). Using the cutoff of seven to stratify COVID‐19, patients had a sensitivity of 85.7% and a specificity of 7.6%. Risk factors independently associated with QT interval prolongation included a history of end‐stage renal disease (ESRD) (OR, 6.42; CI 95%, 1.28–32.13), QTc ≥450 ms on admission (OR, 5.90; CI 95%, 1.62–21.50), and serum potassium ≤3.5 mmol/L during hospitalization (OR, 4.97; CI 95%, 1.51–16.36).ConclusionThe Tisdale Score is not a useful tool to stratify hospitalized non‐critical COVID‐19 patients based on their risks of developing QT interval prolongation. Clinicians should initiate continuous cardiac monitoring for patients who present with a history of ESRD, QTc ≥450 ms on admission or serum potassium ≤3.5 mmol/L.