Dynamic nuclear polarization magnetic resonance imaging and the oxygen-sensitive paramagnetic agent OX63 provide a noninvasive quantitative evaluation of kidney hypoxia in diabetic mice.

Renal hypoxia may play an important role in the progression of diabetic nephropathy. However, tools that noninvasively and quantitatively measure oxygen tension in the kidney are lacking. Here, we evaluated the feasibility of a noninvasive and quantitative imaging technique using dynamic nuclear polarization magnetic resonance imaging (DNP-MRI) in combination with the oxygen-sensitive paramagnetic agent OX63 for measuring oxygen tension in the kidney. Our results demonstrate that the DNP-MRI technique can yield quantitative maps of oxygen tension in the mouse renal cortex. Using this procedure, we also showed that oxygen tension was less elevated in the renal cortex of both streptozotocin-induced type 1 diabetic mice and db/db mice, a model of type 2 diabetes, than in the renal cortex of age-matched control mice of each respective model. Oxygen tension in streptozotocin-exposed mice was significantly improved by insulin treatment. Thus, the noninvasive and quantitative DNP-MRI technique appears to be useful for studying the pathophysiological role of hypoxia.

Efficacy and safety of pemafibrate in people with type 2 diabetes and elevated triglyceride levels: 52-week data from the PROVIDE study.

The aim of this study was to evaluate the efficacy and safety of pemafibrate in people with type 2 diabetes and hypertriglyceridaemia over a 52-week period. Participants were randomly assigned to receive treatment with placebo or pemafibrate at a dose of 0.2 or 0.4 mg/d for 24 weeks (treatment period 1). The main results from treatment period 1 have been reported previously. The assigned treatment was continued up to week 52, except that the placebo was changed to pemafibrate 0.2 mg/d after week 24 (treatment period 2). The percentage changes in fasting serum triglyceride (TG) levels at week 52 (last observation carried forward) were -48.2%, -42.3%, and -46.4% in the placebo/pemafibrate 0.2 mg/d (n = 57), pemafibrate 0.2 mg/d (n = 54), and pemafibrate 0.4 mg/d (n = 55) groups, respectively. Levels of TG, non-HDL cholesterol and total cholesterol stably decreased, whereas levels of HDL cholesterol increased with pemafibrate treatments over 52 weeks. Pemafibrate was well tolerated throughout the study period. The present study is the first to show that pemafibrate treatment substantially ameliorated lipid abnormalities and was well tolerated for 52 weeks in people with type 2 diabetes and hypertriglyceridaemia.

DNA methylation of the Klf14 gene region in whole blood cells provides prediction for the chronic inflammation in the adipose tissue.

Krüppel-Like Factor 14 (KLF14) gene, which appears to be a master regulator of gene expression in the adipose tissue and have previously been associated with BMI and Type 2 diabetes (T2D) by large genome-wide association studies. In order to find predictive biomarkers for the development of T2D, it is necessary to take epigenomic changes affected by environmental factors into account. This study focuses on ageing and obesity, which are T2D risk factors, and examines epigenetic changes and inflammatory changes. We investigated DNA methylation changes in the Klf14 promoter region in different organs of mice for comparing aging and weight. We found that methylation levels of these sites were increased with aging and weight in the spleen, the adipose tissue, the kidney, the lung, the colon and the whole blood cells. In addition, in the spleen, the adipose tissue and the whole blood, these epigenetic changes were also significantly associated with inflammatory levels. Moreover, not only Klf14, but also expression levels of some downstream genes were decreased with methylation in the spleen, the adipose tissue and the whole blood cells. Taken together, our results suggest that methylation changes of Klf14 in those tissues may be associated with changes in gene expression and inflammation on the adipose tissue of obesity and T2D. In addition, the methylation changes in the whole blood cells may serve as a predictive epigenetic biomarker for the development of T2D.

Proposed Cutoff Value of Brachial-Ankle Pulse Wave Velocity for the Management of Hypertension.

BACKGROUND: The optimal cutoff values of the brachial-ankle pulse wave velocity (baPWV) for predicting cardiovascular disease (CVD) were examined in patients with hypertension.Methods and Results:A total of 7,656 participants were followed prospectively. The hazard ratio for the development of CVD increased significantly as the baPWV increased, independent of conventional risk factors. The receiver-operating characteristic curve analysis showed that the optimal cutoff values for predicting CVD was 18.3 m/s. This cutoff value significantly predicted THE incidence of CVD. CONCLUSIONS: The present analysis suggests that the optimal cutoff value for CVD in patients with hypertension is 18.3 m/s.

Long-term outcomes after total pancreatectomy: special reference to survivors' living conditions and quality of life.

BACKGROUND: Although recent studies have confirmed the safety of total pancreatectomy (TP), appropriate selection of patients for TP has not been well documented. Because patients require lifelong medical treatment and self-management of pancreatic insufficiency after TP, indications for TP should be determined carefully according not only to disease factors but also to the social background of patients. We aimed to clarify long-term outcomes after TP, including the living conditions and quality of life (QoL), of surviving patients. METHODS: Medical records of 44 consecutive patients who underwent TP between 1990 and 2013 were reviewed retrospectively; 25 survivors completed cross-sectional clinical surveys and responded to a questionnaire about QoL using Short Form 36v2. RESULTS: Prevalence of morbidity and mortality after TP was 32 and 5 %, respectively. Postoperative complications occurred more frequently in elderly patients than in young patients (48 vs. 14 %; P = 0.02); however, there was no significant difference in mortality, postoperative hospital stay, or survival. Twenty-four of 25 survivors (96 %) could manage pancreatogenic diabetes by themselves, and the median level of glycosylated hemoglobin was 7.4 %. Although one-third of patients after TP complained of diarrhea and the QoL scores of patients with diarrhea were lower than those of patients without diarrhea, QoL scores after TP were virtually comparable with those of the national population, even in elderly patients. CONCLUSIONS: TP can be performed safely, even in elderly patients. QoL after TP seems to be acceptable if patients are capable of self-management.

Maternal high-fat diet induces insulin resistance and deterioration of pancreatic ß-cell function in adult offspring with sex differences in mice.

Intrauterine environment may influence the health of postnatal offspring. There have been many studies on the effects of maternal high-fat diet (HFD) on diabetes and glucose metabolism in offspring. Here, we investigated the effects in male and female offspring. C57/BL6J mice were bred and fed either control diet (CD) or HFD from conception to weaning, and offspring were fed CD or HFD from 6 to 20 wk. At 20 wk, maternal HFD induced glucose intolerance and insulin resistance in offspring. Additionally, liver triacylglycerol content, adipose tissue mass, and inflammation increased in maternal HFD. In contrast, extending previous observations, insulin secretion at glucose tolerance test, islet area, insulin content, and PDX-1 mRNA levels in isolated islets were lower in maternal HFD in males, whereas they were higher in females. Oxidative stress in islets increased in maternal HFD in males, whereas there were no differences in females. Plasma estradiol levels were lower in males than in females and decreased in offspring fed HFD and also decreased by maternal HFD, suggesting that females may be protected from insulin deficiency by inhibiting oxidative stress. In conclusion, maternal HFD induced insulin resistance and deterioration of pancreatic ß-cell function, with marked sex differences in adult offspring accompanied by adipose tissue inflammation and liver steatosis. Additionally, our results demonstrate that potential mechanisms underlying sex differences in pancreatic ß-cell function may be related partially to increases in oxidative stress in male islets and decreased plasma estradiol levels in males.

The Early Pathogenesis of Diabetic Retinopathy and Its Attenuation by Sodium-Glucose Transporter 2 Inhibitors.

The early pathogenetic mechanism of diabetic retinopathy (DR) and its treatment remain unclear. Therefore, we used streptozotocin-induced diabetic mice to investigate the early pathogenic alterations in DR and the protective effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors against these alterations. Retinal vascular leakage was assessed by dextran fluorescence angiography. Retinal thickness and vascular leakage were increased 2 and 4 weeks after onset of diabetes, respectively. Immunostaining showed that morphological change of microglia (amoeboid form) was observed at 2 weeks. Subsequently, increased angiopoietin-2 expression, simultaneous loss of pericytes and endothelial cells, decreased vessel density, retinal hypoxia, and increased vascular endothelial growth factor (VEGF)-A/VEGF receptor system occurred at 4 weeks. SGLT2 inhibitors (luseogliflozin and ipragliflozin) had a significant protective effect on retinal vascular leakage and retinal thickness at a low dose that did not show glucose-lowering effects. Furthermore, both inhibitors at this dose attenuated microglia morphological changes and these early pathogenic alterations in DR. In vitro study showed both inhibitors attenuated the lipopolysaccharide-induced activation of primary microglia, along with morphological changes toward an inactive form, suggesting the direct inhibitory effect of SGLT2 inhibitors on microglia. In summary, SGLT2 inhibitors may directly prevent early pathogenic mechanisms, thereby potentially playing a role in preventing DR.

A Novel Kidney Failure Prediction Model in Individuals with CKD: Impact of Serum Bilirubin Levels.

CONTEXT: Predicting the progression of chronic kidney disease (CKD) to end-stage kidney disease (ESKD) is crucial for improving patient outcomes. OBJECTIVE: To reveal the highly predictive activity of serum bilirubin levels for the progression of CKD to ESKD, and to develop and validate a novel ESKD prediction model incorporating serum bilirubin levels. METHODS: We assessed the relative importance of 20 candidate predictors for ESKD, including serum bilirubin levels, in a CKD cohort (15< eGFR <60 mL/min/1.73 m2), and subsequently developed a prediction model using the selected variables. The development cohort comprised 4,103 individuals with CKD who underwent follow-up at Kyushu University Hospital, Japan, from 2008 to 2018. The primary outcome was incident ESKD, defined as an eGFR <15 mL/min/1.73 m2, chronic dialysis, or renal transplantation. RESULTS: The mean follow-up time was 7.0 ± 4.2 years, during which 489 individuals (11.9%) progressed to ESKD. The Cox proportional hazard model selected eGFR, serum bilirubin, proteinuria, age, diabetes, gender, hypertension, serum albumin, and hemoglobin in order of their importance. The predictive performance of the model was optimized by incorporating these 9 variables in discrimination evaluated by time-dependent area under the curve (AUC). This model also demonstrated excellent calibration. Additionally, this model exhibited excellent predictive performance in both discrimination (2-year AUC: 0.943, 5-year AUC: 0.935) and calibration in a validation cohort (n=2,799). CONCLUSION: Serum bilirubin levels were strong predictors for the progression of CKD to ESKD. Our novel model that incorporates serum bilirubin levels could accurately predict ESKD in individuals with CKD.

CTLA-4Ig immunotherapy of obesity-induced insulin resistance by manipulation of macrophage polarization in adipose tissues.

It has been established that obesity alters the metabolic and endocrine function of adipose tissue and, together with accumulation of adipose tissue macrophages, contributes to insulin resistance. Although numerous studies have reported that shifting the polarization of macrophages from M1 to M2 can alleviate adipose tissue inflammation, manipulation of macrophage polarization has not been considered as a specific therapy. Here, we determined whether cytotoxic T-lymphocyte-associated antigen-4IgG1 (CTLA-4Ig) can ameliorate insulin resistance by induction of macrophages from proinflammatory M1 to anti-inflammatory M2 polarization in the adipose tissues of high fat diet-induced insulin-resistant mice. CTLA4-Ig treatment prevented insulin resistance by changing gene expression to M2 polarization, which increased the levels of arginase 1. Furthermore, flow cytometric analysis confirmed the alteration of polarization from CD11c (M1)- to CD206 (M2)-positive cells. Concomitantly, CTLA-4Ig treatment resulted in weight reductions of epididymal and subcutaneous adipose tissues, which may be closely related to overexpression of apoptosis inhibitors in macrophages. Moreover, proinflammatory cytokine and chemokine levels decreased significantly. In contrast, CCAAT enhancer binding protein α, peroxisome proliferator-activated receptor γ, and adiponectin expression increased significantly in subcutaneous adipose tissue. This novel mechanism of CTLA-4lg immunotherapy may lead to an ideal anti-obesity/inflammation/insulin resistance agent.

Downregulation of adipose triglyceride lipase in the heart aggravates diabetic cardiomyopathy in db/db mice.

Adipose triglyceride lipase (ATGL) was recently identified as a rate-limiting triglyceride (TG) lipase and its activity is stimulated by comparative gene identification-58 (CGI-58). Mutations in the ATGL or CGI-58 genes are associated with neutral lipid storage diseases characterized by the accumulation of TG in multiple tissues. The cardiac phenotype, known as triglyceride deposit cardiomyovasculopathy, is characterized by TG accumulation in coronary atherosclerotic lesions and in the myocardium. Recent reports showed that myocardial TG accumulation is significantly higher in patients with diabetes and is associated with impaired left ventricular diastolic function. Therefore, we investigated the roles of ATGL and CGI-58 in the development of myocardial steatosis in the diabetic state. Histological examination with oil red O staining showed marked lipid deposition in the hearts of diabetic fatty db/db mice. Cardiac triglyceride and diglyceride contents were greater in db/db mice than in db/+ control mice. Next, we determined the expression of genes and proteins that affect lipid metabolism, and found that ATGL and CGI-58 expression levels were decreased in the hearts of db/db mice. We also found increased expression of genes regulating triglyceride synthesis (sterol regulatory element-binding protein 1c, monoacylglycerol acyltransferases, and diacylglycerol acyltransferases) in db/db mice. Regarding key modulators of apoptosis, PKC activity, and oxidative stress, we found that Bcl-2 levels were lower and that phosphorylated PKC and 8-hydroxy-2'-deoxyguanosine levels were higher in db/db hearts. These results suggest that reduced ATGL and CGI-58 expression and increased TG synthesis may exacerbate myocardial steatosis and oxidative stress, thereby promoting cardiac apoptosis in diabetic mice.

Phycocyanin and phycocyanobilin from Spirulina platensis protect against diabetic nephropathy by inhibiting oxidative stress.

We and other investigators have reported that bilirubin and its precursor biliverdin may have beneficial effects on diabetic vascular complications, including nephropathy, via its antioxidant effects. Here, we investigated whether phycocyanin derived from Spirulina platensis, a blue-green algae, and its chromophore phycocyanobilin, which has a chemical structure similar to that of biliverdin, protect against oxidative stress and renal dysfunction in db/db mice, a rodent model for Type 2 diabetes. Oral administration of phycocyanin (300 mg/kg) for 10 wk protected against albuminuria and renal mesangial expansion in db/db mice, and normalized tumor growth factor-ß and fibronectin expression. Phycocyanin also normalized urinary and renal oxidative stress markers and the expression of NAD(P)H oxidase components. Similar antioxidant effects were observed following oral administration of phycocyanobilin (15 mg/kg) for 2 wk. Phycocyanobilin, bilirubin, and biliverdin also inhibited NADPH dependent superoxide production in cultured renal mesangial cells. In conclusion, oral administration of phycocyanin and phycocyanobilin may offer a novel and feasible therapeutic approach for preventing diabetic nephropathy.

Reduced expression of adipose triglyceride lipase enhances tumor necrosis factor alpha-induced intercellular adhesion molecule-1 expression in human aortic endothelial cells via protein kinase C-dependent activation of nuclear factor-kappaB.

We examined the effects of adipose triglyceride lipase (ATGL) on the initiation of atherosclerosis. ATGL was recently identified as a rate-limiting triglyceride (TG) lipase. Mutations in the human ATGL gene are associated with neutral lipid storage disease with myopathy, a rare genetic disease characterized by excessive accumulation of TG in multiple tissues. The cardiac phenotype, known as triglyceride deposit cardiomyovasculopathy, shows massive TG accumulation in both coronary atherosclerotic lesions and the myocardium. Recent reports show that myocardial triglyceride content is significantly higher in patients with prediabetes or diabetes and that ATGL expression is decreased in the obese insulin-resistant state. Therefore, we investigated the effect of decreased ATGL activity on the development of atherosclerosis using human aortic endothelial cells. We found that ATGL knockdown enhanced monocyte adhesion via increased expression of TNFα-induced intercellular adhesion molecule-1 (ICAM-1). Next, we determined the pathways (MAPK, PKC, or NFκB) involved in ICAM-1 up-regulation induced by ATGL knockdown. Both phosphorylation of PKC and degradation of IκBα were increased in ATGL knockdown human aortic endothelial cells. In addition, intracellular diacylglycerol levels and free fatty acid uptake via CD36 were significantly increased in these cells. Inhibition of the PKC pathway using calphostin C and GF109203X suppressed TNFα-induced ICAM-1 expression. In conclusion, we showed that ATGL knockdown increased monocyte adhesion to the endothelium through enhanced TNFα-induced ICAM-1 expression via activation of NFκB and PKC. These results suggest that reduced ATGL expression may influence the atherogenic process in neutral lipid storage diseases and in the insulin-resistant state.

[Disease management for diabetes mellitus to prevent the onset and progression of complications].

We developed a new critical pathway technique and an outbound-inbound call center system. The former is to support general physicians to care for outpatients with diabetes mellitus according to practice guidelines. We employed the "Overlay method" to develop personalized optimal critical pathways. Our overview critical pathways consist of basic sheets for regular examinations and optional sheets on which the kinds and frequencies of medical examinations are determined according to many parameters, such as methods of treatment, the severity of diabetic complications, and knowledge levels. The critical pathway is continually modified according to the change in the patient's condition. The latter is to maintain and enhance the treatment motivation of outpatients. Call center agents collect medical information, making outgoing calls using a questionnaire about the patient's health status and diabetic complications as well as receiving incoming calls. When patients do not visit on the appointment date, call center agents arrange the next consultation to prevent treatment dropout. These systems are now under evaluation in a clinical trial of outpatients with diabetes mellitus.

Relationship between serum indirect bilirubin levels and skeletal muscle mass in older male and female patients with type 2 diabetes.

OBJECTIVE: We previously showed that low serum bilirubin levels are associated with disability in quality of daily living in older patients with diabetes. However, the underlying mechanism is not fully understood. The aim of this study is to assess the relationship between serum bilirubin levels and skeletal muscle mass in older patients with type2 diabetes. METHODS: A total of 272 older patients with type2 diabetes (152 male and 120 female) aged 60 years and over were continuously recruited from April 2020 to July 2020. Body composition was evaluated by bioelectrical impedance analysis. The skeletal muscle mass index (SMI) was calculated as appendicular muscle mass divided by height squared (m2). RESULTS: The SMI was markedly lower in old-old patients (aged 75 years and over) than in young-old patients (aged 60-74 years) in both male and female (7.1 ± 0.8 kg/m2 vs 7.6 ± 0.9 kg/m2, P<0.001; 5.5 ± 0.9 kg/m2 vs 6.3 ± 0.8 kg/m2, P<0.001, respectively). Multivariate regression analysis showed that the SMI was associated with body mass index (BMI) (p<0.001) and age (p = 0.048) in male young-old patients, while it was associated with BMI (p<0.001), age (p = 0.008), and serum indirect bilirubin levels (p = 0.038) in male old-old patients. In female, the SMI was associated with BMI (p<0.001) and age (p = 0.042) in young-old patients and associated with BMI alone (p<0.001) in old-old patients. CONCLUSION: Serum indirect bilirubin levels may be associated with the decreased skeletal muscle mass in male older patients (aged 75 years and over) with type 2 diabetes.

Association of serum total bilirubin levels with progressive renal decline and end-stage kidney disease: 10-year observational cohort study in Japanese patients with diabetes.

OBJECTIVE: Previous reports have demonstrated the association of serum bilirubin levels with the progression of diabetic nephropathy. The objective of this study is to assess the association of basal bilirubin levels with progressive renal decline (PRD) and end-stage kidney disease (ESKD). METHODS: A total of 298 patients with diabetes who visited Kyushu University Hospital (Japan) were recruited and followed up for 10 years. PRD was defined as a negative change in estimated glomerular filtration ratio (eGFR) >3.7%/year, 2.5th percentile. Logistic regression analysis was performed to evaluate the association of total bilirubin levels with PRD and its cut-off point was determined by receiver operating characteristic (ROC) analysis. Kaplan-Meier method and Cox hazard regression analysis were used to evaluate the predictive ability of its cut-off point for ESKD. RESULTS: Logistic regression model showed that total bilirubin levels were significantly associated with PRD, and ROC analysis showed that its cut-off point was 0.5 mg/dL. Kaplan-Meier method showed that the percent of patients who reached two endpoints, composite endpoint (ESKD or doubling of creatinine level) or 30% eGFR decline, was significantly higher in the low bilirubin group than in the high bilirubin group (18.5% vs 11.0%, P = 0.045; 49.1% vs 42.1%, P = 0.045, respectively, log-rank test). Cox hazard regression models confirmed the independence of the predictive ability of its cut-off point. CONCLUSIONS: Serum total bilirubin levels were negatively associated with PRD in diabetic nephropathy and its cut-off point was 0.5 mg/dL. It may be clinically useful for identifying patients at high risk of ESKD.

A simplified prediction model for end-stage kidney disease in patients with diabetes.

This study aimed to develop a simplified model for predicting end-stage kidney disease (ESKD) in patients with diabetes. The cohort included 2549 individuals who were followed up at Kyushu University Hospital (Japan) between January 1, 2008 and December 31, 2018. The outcome was a composite of ESKD, defined as an eGFR < 15 mL min-1 [1.73 m]-2, dialysis, or renal transplantation. The mean follow-up was 5.6 [Formula: see text] 3.7 years, and ESKD occurred in 176 (6.2%) individuals. Both a machine learning random forest model and a Cox proportional hazard model selected eGFR, proteinuria, hemoglobin A1c, serum albumin levels, and serum bilirubin levels in a descending order as the most important predictors among 20 baseline variables. A model using eGFR, proteinuria and hemoglobin A1c showed a relatively good performance in discrimination (C-statistic: 0.842) and calibration (Nam and D'Agostino [Formula: see text]2 statistic: 22.4). Adding serum albumin and bilirubin levels to the model further improved it, and a model using 5 variables showed the best performance in the predictive ability (C-statistic: 0.895, [Formula: see text]2 statistic: 7.7). The accuracy of this model was validated in an external cohort (n = 5153). This novel simplified prediction model may be clinically useful for predicting ESKD in patients with diabetes.

Association of serum bilirubin levels with risk of cancer development and total death.

Serum levels of bilirubin, a strong antioxidant, may influence cancer risk. We aimed to assess the association between serum bilirubin levels and cancer risk. Data were retrieved from 10-year electronic medical records at Kyushu University Hospital (Japan) for patients aged 20 to 69 years old. The associations of baseline bilirubin levels with cancer risk (lung, colon, breast, prostate, and cervical) were evaluated using a gradient boosting decision tree (GBDT) model, a machine learning algorithm, and Cox proportional hazard regression model, adjusted for age, smoking, body mass index, and diabetes. The number of study subjects was 29,080. Median follow-up time was 4.7 years. GBDT models illustrated that baseline bilirubin levels were negatively and non-linearly associated with the risk of lung (men), colon, and cervical cancer. In contrast, a U-shaped association was observed for breast and prostate cancer. Cox hazard regression analyses confirmed that baseline bilirubin levels (< 1.2 mg/dL) were negatively associated with lung cancer risk in men (HR = 0.474, 95% CI 0.271-0.828, P = 0.009) and cervical cancer risk (HR = 0.365, 95% CI 0.136-0.977, P = 0.045). Additionally, low bilirubin levels (< 0.6 mg/dL) were associated with total death (HR = 1.744, 95% CI 1.369-2.222, P < 0.001). Serum bilirubin may have a beneficial effect on the risk of some types of cancers.

Relationship between serum bilirubin levels, urinary biopyrrin levels, and retinopathy in patients with diabetes.

OBJECTIVE: Previous reports have indicated that serum bilirubin levels may be associated with diabetic retinopathy. However, the detailed mechanism is not fully understood. In this study, we evaluated the relationship between the severity of diabetic retinopathy and various factors including bilirubin levels and factors influencing bilirubin metabolism. METHODS: The study participants consisted of 94 consecutive patients with diabetes mellitus admitted to Kyushu University Hospital from April 2011 to July 2012. The patients were classified into three groups: no retinopathy (NDR), simple retinopathy (SDR), and pre-proliferative or proliferative retinopathy (PDR). The relationship between the severity of retinopathy and various factors was evaluated using univariate and logistic regression analyses. In addition, multivariate regression analysis was performed to evaluate the significant determinants for bilirubin levels. RESULTS: In univariate analysis, a significant difference was found among NDR, SDR and PDR in bilirubin levels, duration of diabetes, systolic blood pressure, and macroalbuminuria. Logistic regression analysis showed that PDR was significantly associated with bilirubin levels, duration of diabetes, and systolic blood pressure (OR 0.737, 95% CI 0.570-0.952, P = 0.012; OR 1.085, 95% CI 1.024-1.149, P = 0.006; OR 1.036, 95% CI 1.011-1.062, P = 0.005, respectively). In turn, multivariate regression analysis showed that bilirubin levels were negatively associated with high-sensitivity C-reactive protein levels and PDR, but positively correlated with urinary biopyrrin levels, oxidized metabolites of bilirubin. CONCLUSION: PDR was negatively associated with bilirubin levels. This negative association may be due to a decreased production of bilirubin rather than its increased consumption considering the positive association between bilirubin and biopyrrin levels.

Bilirubin is inversely related to diabetic peripheral neuropathy assessed by sural nerve conduction study.

AIMS/INTRODUCTION: Diagnosis of diabetic peripheral neuropathy (DPN) depends on subjective findings, certain investigations for DPN risks have not been performed enough. Bilirubin protects against vascular complications by reducing oxidative stress in diabetes, but is not fully tested for DPN. This study aimed to evaluate sural nerve conduction impairments (SNCI) as an objective DPN marker and the contribution of bilirubin to SNCI. MATERIALS AND METHODS: Using DPN-Check® , SNCI was defined as a decline of amplitude potential or conduction velocity below the normal limit in 150 inpatients with diabetes. The correlations between SNCI and conventional DPN diagnosis criteria, the incidence of diabetic retinopathy/nephropathy, biomarkers for atherosclerosis, cardiac function by ultrasonic cardiogram, and bilirubin were statistically tested, followed by the comparison of logistic regression models for SNCI to find confounders with bilirubin. RESULTS: The incidence of SNCI was 72.0%. The sensitivity and specificity of SNCI for DPN prediagnosis by simplified criteria were 54.6 and 90.5%, respectively, and similarly corresponded with diabetic retinopathy and nephropathy (sensitivity 57.4 and 50.0%, respectively). SNCI significantly related to diabetes duration, declined estimated glomerular filtration rate, albuminuria and total bilirubin. SNCI incidence was attenuated in the higher bilirubin tertiles (89.8/65.3/54.8%, P < 0.001). Bilirubin was an independent inverse risk factor for SNCI, even after adjustment by known risk factors for DPN and markers for microvascular complications. CONCLUSIONS: SNCI is a comprehensive marker for diabetic complications. We first showed the independent inverse relationship between bilirubin and SNCI through the independent pathway with other complications, provably reducing oxidative stress, as previously reported.