Cerebral oxygenation changes in response to post-hemodialysis standing.

Few reports have examined the association between changes in cerebral oxygenation and clinical factors, including blood pressure (BP), upon standing after hemodialysis (HD). This study aimed to clarify the factors affecting the changes in cerebral regional oxygen saturation (rSO2) upon standing after HD and monitor the differences in cerebral rSO2 changes that occur upon standing after HD in patients with and without diabetes mellitus (DM). Changes in mean BP and cerebral rSO2 were tracked in 43 HD patients during 120 s of standing after HD using an INVOS 5100c oxygen saturation monitor. The post-HD cerebral rSO2 at rest was 55.8 ± 10.2%, while that at 120 s of standing decreased to 51.9 ± 9.6%; therefore, the percentage change in cerebral rSO2 at 120 s of standing was - 6.8 ± 6.4%, which was significantly lower than before HD (p < 0.001). This change was significantly correlated with the presence of DM, HD duration, mean BP at 120 s of standing, and percentage change in mean BP at 120 s of standing. A multivariable linear regression analysis showed that percentage change in cerebral rSO2 at 120 s of standing was independently associated with the percentage change in mean BP at 120 s of standing (standardized coefficient: 0.432; p = 0.004). Furthermore, there were significant decreases in percentage changes in cerebral rSO2 throughout the standing period in HD patients with versus without DM. Therefore, cerebral oxygenation deterioration upon standing after HD should receive attention, particularly in HD patients with DM.

Lack of Awareness of Own Hypercholesterolemia or Statin Medication among Adult Statin Users in the United States: Prevalence and Patient Characteristics in a Repeated Cross-Sectional Study.

Knowledge of a patient's medication is important in treating hyperlipidemia; however, little is known about this in practice. We carried out a repeated cross-sectional study to analyze a nationally representative sample of US adult statin users from the National Health and Nutrition Examination Survey, 1999−2018. We used medication bottle checks and self-reported survey data to estimate the percentage of individuals who are unaware of their hypercholesterolemia, type of medication, or how to take their medication. We used logistic regression to examine their characteristics. We included 8798 statin users; however, 17.6% were unaware of their hypercholesterolemia or statin use. Being older, male, non-Hispanic Black, taking a wider range of prescription medications, and previous diabetes or cardiovascular disease diagnosis were associated with lack of awareness. Serum low-density lipoprotein cholesterol level was lower among those lacking awareness (85.5 vs. 100.7 mg/dL; p < 0.001). Many of those unaware of drug type had been given little information about statins; 34.0% had no diagnosis of diabetes or cardiovascular disease, and of these, 27.1% were >75 years old. Roughly one in six lacked awareness, but no association was found with hypercholesterolemia control. Healthcare providers should ascertain a patient's understanding and consider the risks and benefits of statin medication.

A novel mechanism of imeglimin-mediated insulin secretion via the cADPR-TRP channel pathway.

AIMS/INTRODUCTION: Imeglimin is a novel oral hypoglycemic agent that improves blood glucose levels through multiple mechanisms of action including the enhancement of glucose-stimulated insulin secretion (GSIS), however, the details of this mechanism have not been clarified. In the process of GSIS, activation of the transient receptor potential melastatin 2 (TRPM2) channel, a type of non-selective cation channel (NSCCs) in ß-cells, promotes plasma membrane depolarization. The present study aimed to examine whether imeglimin potentiates GSIS via the TRPM2 channel in ß-cells. MATERIALS AND METHODS: Pancreatic islets were isolated by collagenase digestion from male wild-type and TRPM2-knockout (KO) mice. Insulin release and nicotinamide adenine dinucleotide (NAD+ ) production in islets were measured under static incubation. NSCC currents in mouse single ß-cells were measured by patch-clamp experiments. RESULTS: Batch-incubation studies showed that imeglimin enhanced GSIS at stimulatory 16.6 mM glucose, whereas it did not affect basal insulin levels at 2.8 mM glucose. Imeglimin increased the glucose-induced production of NAD+ , a precursor of cADPR, in islets and the insulinotropic effects of imeglimin were attenuated by a cADPR inhibitor 8-Br-cADPR. Furthermore, imeglimin increased NSCC current in ß-cells, and abolished this current in TRPM2-KO mice. Imeglimin did not potentiate GSIS in the TRPM2-KO islets, suggesting that imeglimin's increase of NSCC currents through the TRPM2 channel is causally implicated in its insulin releasing effects. CONCLUSIONS: Imeglimin may activate TRPM2 channels in ß-cells via the production of NAD+ /cADPR, leading to the potentiation of GSIS. Developing approaches to stimulate cADPR-TRPM2 signaling provides a potential therapeutic tool to treat type 2 diabetes.

Muscle mass evaluation using psoas muscle mass index by computed tomography imaging in hemodialysis patients.

BACKGROUND AND AIMS: The use of the psoas muscle mass index (PMI) using computed tomography (CT) has become a marker of interest to evaluate whole body muscle mass. However, in hemodialysis (HD) patients, reports about the clinical significance of psoas muscle evaluation are limited. We aimed to clarify the association between PMI and skeletal muscle mass index (SMI) using bioelectrical impedance analysis (BIA), and to investigate factors affecting PMI in HD patients. METHODS: In this prospective observational study, to evaluate muscle mass, SMI was measured using BIA after HD, and PMI was measured by the manual trace method on routinely available CT scans. PMI measurement was assessed twice by two physicians to compute intra-rater and inter-rater reliability. The correlations between PMI and the clinical factors were evaluated using Pearson's correlation coefficient and a linear regression analysis. Variables with a p-value < 0.05 in the simple linear regression analysis were included in the multivariable linear regression analysis to identify the factors that affected PMI of the HD patients. RESULTS: Fifty HD patients were recruited (31 males and 19 females; HD duration, 9.0 ± 8.8 years). The SMI was 6.10 ± 1.20 kg/m2, and the PMI was 4.79 ± 1.61 cm2/m2. Regarding the reliability of PMI measurements, intra-rater reliability [intra-class correlation (ICC) = 0.999] and inter-rater reliability (ICC = 0.998) were high in this study. The mean PMI of male patients was 5.40 ± 1.62 cm2/m2, while that of female patients was significantly lower (3.78 ± 0.98 cm2/m2; p < 0.001). The PMI was significantly and positively correlated with SMI (r = 0.630, p < 0.001), in addition to HD duration, body mass index (BMI), serum phosphate and serum creatinine (Cr). In the multivariate linear regression analysis by two models using SMI or BMI, they were respectively extracted as an independent factor associating with PMI, in addition to serum Cr and the difference of sex. CONCLUSIONS: PMI assessed with CT positively correlated with SMI measured using BIA. PMI might be one of the methods for evaluating the muscle mass in HD patients, when CT scans are taken as part of routine care.

Relationship between a Urine Protein-to-creatinine Ratio of 150 mg/gram Creatinine and Dipstick Grade in the Health Checkup: Substantial Number of False-negative Results for Chronic Kidney Disease.

OBJECTIVE: Proteinuria is a marker for cardiovascular diseases and all-cause mortality. In the Specific Health Checkups in Japan, when subjects show trace proteinuria (grade±) on dipstick assay, further examination is recommended to them. Although 150 mg/gCr is a threshold for diagnosing chronic kidney disease (CKD), little data on the relationship between dipstick grade± and the protein-creatinine ratio have been reported. METHODS: A cross-sectional study using urine specimens obtained in a single institute, JCHO Saitama Northern Medical Center, was performed from October 2014 to March 2016. The level of proteinuria was measured in fresh morning urine samples from 819 volunteer participants of the Specific Health Checkups by two methods: Eiken Uropaper III to detect and qualitatively grade proteinuria, and total protein concentration by the pyrogallol red method. RESULTS: Sensitivity, specificity, and the positive likelihood ratio to detect proteinuria of 30 mg/dL by 1+ were 90.3%, 97.8%, and 41.9, whereas 150 mg/gCr by ± were 45.3%, 81.4%, and 2.4, respectively. Therefore, screening for 150 mg/gCr by dipstick grade± had a false-negative rate of 54.7% and false-negative rate was significantly higher in women (8.0%) than in men (1.7%) (p < 0.0001). CONCLUSIONS: Although the dipstick assay is useful to detect clinically significant proteinuria, substantial numbers of false-negative results occur in checkups for identifying subjects with a risk of CKD.

ELKS/Voltage-Dependent Ca2+ Channel-ß Subunit Module Regulates Polarized Ca2+ Influx in Pancreatic ß Cells.

Pancreatic ß cells secrete insulin by Ca2+-triggered exocytosis. However, there is no apparent secretory site similar to the neuronal active zones, and the cellular and molecular localization mechanism underlying polarized exocytosis remains elusive. Here, we report that ELKS, a vertebrate active zone protein, is used in ß cells to regulate Ca2+ influx for insulin secretion. ß cell-specific ELKS-knockout (KO) mice showed impaired glucose-stimulated first-phase insulin secretion and reduced L-type voltage-dependent Ca2+ channel (VDCC) current density. In situ Ca2+ imaging of ß cells within islets expressing a membrane-bound G-CaMP8b Ca2+ sensor demonstrated initial local Ca2+ signals at the ELKS-localized vascular side of the ß cell plasma membrane, which were markedly decreased in ELKS-KO ß cells. Mechanistically, ELKS directly interacted with the VDCC-ß subunit via the GK domain. These findings suggest that ELKS and VDCCs form a potent insulin secretion complex at the vascular side of the ß cell plasma membrane for polarized Ca2+ influx and first-phase insulin secretion from pancreatic islets.

Effects of Repaglinide Versus Glimepiride on 1,5-Anhydroglucutol and Glycated Hemoglobin Levels in Japanese Patients With Type 2 Diabetes.

BACKGROUND: Postprandial hyperglycemia is a well-known risk factor for cardiovascular disease. We prospectively examined the effects of repaglinide on postprandial hyperglycemia in patients with type 2 diabetes. METHODS: During this 24-week, single-arm, prospective study, we enrolled 10 patients with type 2 diabetes who were previously being administered glimepiride (0.5 or 1 mg/day) and switched it with repaglinide (0.75 or 1.5 mg/day). Changes in their metabolic parameters were evaluated at the end of the study period. RESULTS: After replacing glimepiride with repaglinide, increases were observed in 1,5-anhydroglucitol levels (baseline, 5.46 ± 1.96 versus 24 weeks, 9.15 ± 4.48 µg/mL, P = 0.004) but not in glycated hemoglobin levels (baseline, 7.7 ± 0.5 versus 24 weeks, 7.4 ± 0.6%, P = 0.100). Body weight remained unchanged. CONCLUSION: Compared with glimepiride, repaglinide improved 1,5-anhydroglucitol levels but had no effect on glycated hemoglobin. This suggests that repaglinide is a useful option for treating postprandial hyperglycemia.

The Urinary Phosphate to Serum Fibroblast Growth Factor 23 Ratio, Deemed the Nephron Index, Is a Useful Clinical Index for Early Stage Chronic Kidney Disease in Patients with Type 2 Diabetes: An Observational Pilot Study.

Renal function decline is associated with progressive type 2 diabetes mellitus, which causes mineral and bone disorders. In the present study, we defined the ratio of urinary phosphate excretion (mg/day) to serum fibroblast growth factor 23 as the nephron index. We examined changes in the nephron index in type 2 diabetes patients with early stage chronic kidney disease (stages 1-3), enrolling 15 patients and retrospectively analysing the follow-up data. After follow-up at 5.4 years, we observed no significant changes in the estimated glomerular filtration rate; the nephron index, however, was significantly reduced between the baseline and the follow-up. We propose that the nephron index may be potentially useful as a biomarker for monitoring the decline of renal function in the early stages of diabetic chronic kidney disease patients.

Association between Urinary Calcium Excretion and Estimated Glomerular Filtration Rate Decline in Patients with Type 2 Diabetes Mellitus: A Retrospective Single-center Observational Study.

Urinary calcium excretion is not known to predict progression of renal dysfunction in patients with type 2 diabetes mellitus. This study aimed to investigate associations between urinary calcium excretion and progression of estimated glomerular filtration rate (eGFR) in type 2 diabetic patients. This study was a retrospective, single-center, observational cohort study. We enrolled a total of 89 patients with type 2 diabetes mellitus and the average follow-up period was 7.2 ± 1.0 years. We divided patients into two groups based on the median of annual decline in the slope of eGFR, then defined the over-median population as the progressed group and under-median population as the non-progressed group. Median of annual decline in the slope of eGFR was −1.1 mL/min/1.73 m²/year. Correlation coefficient analysis showed positive correlation of urinary calcium excretion with eGFR (r = 0.39, p < 0.001). Multivariate logistic analysis showed that baseline eGFR and urinary calcium excretion were independent variables for progression of eGFR decline. Urinary calcium excretion could be a useful metabolic parameter for predicting decline in slope of eGFR in patients with type 2 diabetes mellitus.

Relationship Between Angiopoietin-Like Protein 8 and Fasting Serum Triglyceride Level.

BACKGROUND: The aim of the study was to evaluate the correlation between angiopoietin-like protein 8 (ANGPTL8) and metabolic parameters in non-diabetic healthy humans. METHODS: We enrolled 30 healthy Japanese adults (25 men and five women). After 9 h of fasting, we collected blood samples and analyzed the ANGPTL8, lipoprotein lipase (LPL), plasma lipid and glucose metabolic parameters. In addition, we performed 75-g oral glucose tolerance test (OGTT) and measured adipokines (tumor necrosis factor-α, leptin and adiponectin). RESULTS: Median serum ANGPTL8 level was 224 (167 - 437) pg/mL, and serum ANGPTL8 level positively correlated with serum triglyceride level (r = 0.42, P = 0.021) and negatively correlated with LPL level (r = -0.44, P = 0.015). ANGPTL8 level showed no correlation with body mass index (BMI), waist-hip ratio, and homeostasis model assessment of insulin resistance (HOMA-IR) or with adipose tissue-derived adiponectin and leptin levels. Further, ANGPTL8 showed no association with glucose and insulin levels after 75-g OGTT. CONCLUSION: Serum ANGPTL8 level negatively correlated with LPL levels in healthy Japanese adults. Regulation of ANGPTL8 could be a promising therapeutic target for hypertriglyceridemia.

Daily variability in serum levels of calciprotein particles and their association with mineral metabolism parameters: A cross-sectional pilot study.

AIM: Calciprotein particles (CPPs), colloidal protein-mineral nanoparticles composed of solid-phase calcium phosphate and serum protein fetuin-A found in blood, are emerging as a novel component of chronic kidney disease-mineral and bone disorder (CKD-MBD). The relationship of CPPs with factors known to underlie the CKD-MBD pathophysiology is not well known.The aim of this study is to examine daily variations in CPPs as well as their association with mineral metabolism parameters in normal individuals and early-stage CKD patients. METHODS: Twenty subjects (10 healthy adults, 10 diabetic patients) were enrolled. Serum CPP Fetuin-A was measured and analyzed in relation to clinical parameters. RESULTS: Estimated glomerular filtration rates (eGFR) were 103 ± 11 and 75 ± 24 mL/min per 1.73 m2 in healthy adults and diabetic patients, respectively. Serum CPP Fetuin-A (g/L) were elevated at postprandial 2 h in diabetic patients. Furthermore, serum CPP Fetuin-A were inversely correlated with eGFR and serum 1,25-dihydroxyvitamin D3 and magnesium levels and were positively correlated with serum fibroblast growth factor-23. CONCLUSIONS: These findings indicated that serum CPP Fetuin-A were affected by food intake and may contribute to the pathophysiology of mineral metabolism in subjects with normal and moderately impaired renal function.

Diabetic ketoacidosis producing extreme hyperkalemia in a patient with type 1 diabetes on hemodialysis.

Diabetic ketoacidosis (DKA) is a critical complication of type 1 diabetes associated with water and electrolyte disorders. Here, we report a case of DKA with extreme hyperkalemia (9.0 mEq/L) in a patient with type 1 diabetes on hemodialysis. He had a left frontal cerebral infarction resulting in inability to manage his continuous subcutaneous insulin infusion pump. Electrocardiography showed typical changes of hyperkalemia, including absent P waves, prolonged QRS interval and tented T waves. There was no evidence of total body water deficit. After starting insulin and rapid hemodialysis, the serum potassium level was normalized. Although DKA may present with hypokalemia, rapid hemodialysis may be necessary to resolve severe hyperkalemia in a patient with renal failure. LEARNING POINTS: Patients with type 1 diabetes on hemodialysis may develop ketoacidosis because of discontinuation of insulin treatment.Patients on hemodialysis who develop ketoacidosis may have hyperkalemia because of anuria.Absolute insulin deficit alters potassium distribution between the intracellular and extracellular space, and anuria abolishes urinary excretion of potassium.Rapid hemodialysis along with intensive insulin therapy can improve hyperkalemia, while fluid infusions may worsen heart failure in patients with ketoacidosis who routinely require hemodialysis.

Anaphylactoid Purpura Associated with Streptococcal Cellulitis: A Case Report and Literature Review.

A 54-year-old Japanese man noticed painful swelling and redness of his left leg. He was admitted for treatment of cellulitis, which was accompanied with increased anti-streptolysin O and anti-streptokinase titers in his clinical course. After Piperacillin/Tazobactam administration, the skin lesion resolved. However, the patient then developed arthritis, palpable purpura, and intermittent abdominal pain, later found to be secondary to a severe duodenal ulcer. He was diagnosed with cellulitis-associated anaphylactoid purpura and was given prednisolone, which dramatically improved his symptoms. The anaphylactoid purpura was likely caused by Streptococcus-induced cellulitis, which was successfully treated with prednisolone. Association between these diseases is rare.

Effect of Liraglutide on Type B Insulin Resistance Syndrome and Insulin Allergy in Type 2 Diabetes: A Case Report.

INTRODUCTION: The appearance of anti-insulin antibodies or an allergy to insulin occasionally causes clinical problems with glycemic control in insulin users. METHODS: In the present report, we describe a therapeutic approach that was employed for a man with type 2 diabetes who had insulin allergy, anti-insulin antibodies, and anti-insulin receptor antibodies that developed during his insulin treatment. RESULTS: We started the patient on liraglutide, a glucagon-like peptide-1 receptor agonist, and attained glycemic control without incurring any side effects. Two years after liraglutide induction, his blood glucose was being maintained at a healthy level by liraglutide monotherapy. CONCLUSION: Liraglutide may be a therapeutic option for patients with insulin allergy, anti-insulin antibodies, and type B insulin resistance syndrome, as it represents an alternative strategy to insulin.

Eicosapentaenoic acid shows anti-inflammatory effect via GPR120 in 3T3-L1 adipocytes and attenuates adipose tissue inflammation in diet-induced obese mice.

BACKGROUND: Saturated fatty acids have been shown to cause insulin resistance and low-grade chronic inflammation, whereas unsaturated fatty acids suppress inflammation via G-protein coupled receptor 120 (GPR120) in macrophages. However, the anti-inflammatory effects of unsaturated fatty acids in adipocytes have yet to be elucidated. Hence, the aims of the present study were to evaluate the anti-inflammatory effects of eicosapentaenoic acid (EPA) via GPR120 in adipocytes. METHODS: We used 250 µM palmitate as a representative saturated fatty acid. 3T3-L1 adipocytes were used for in vitro studies. We further evaluated the effect of EPA supplementation in a high-fat/high-sucrose (HFHS) diet-induced adipose tissue inflammatory mouse model. RESULTS: EPA attenuated palmitate-induced increases in inflammatory gene expression and NF-κB phosphorylation in 3T3-L1 adipocytes. Silencing of GPR120 abolished the anti-inflammatory effects of EPA. In GPR120 downstream signal analysis, EPA was found to decrease palmitate-induced increases in TAK1/TAB1 complex expression. EPA supplementation suppressed HFHS-induced crown-like structure formation in epididymal adipose tissue and altered macrophage phenotypes from M1 to M2 in the stromal vascular fraction. Moreover, the EPA-containing diet attenuated increases in adipose p-JNK and phospho-p65 NF-κB levels. CONCLUSIONS: In conclusion, the findings of the present study demonstrate that EPA suppresses palmitate-induced inflammation via GPR120 by inhibiting the TAK1/TAB1 interaction in adipocytes. EPA supplementation reduced HFHS diet-induced inflammatory changes in mouse adipose tissues. These results demonstrate adipose GPR120 as a potential therapeutic target for decreasing inflammation.

Cross-Over Study Comparing Postprandial Glycemic Increase After Addition of a Fixed-Dose Mitiglinide/Voglibose Combination or a Dipeptidyl Peptidase-4 Inhibitor to Basal Insulin Therapy in Patients with Type 2 Diabetes Mellitus.

BACKGROUND Although the efficacy of combination therapy consisting of basal insulin and oral hypoglycemic agents (OHAs) has been shown, which OHAs are the most efficient remains unclear. MATERIAL AND METHODS Five patients with type 2 diabetes were enrolled and treated with insulin degludec and metformin as a basal therapy. The patients were randomized in a cross-over fashion to receive a combination of mitiglinide (10 mg) and voglibose (0.2 mg) (M+V) 3 times daily or linagliptin (5 mg) (L) once daily for 8 weeks. After 8 weeks, 2 kinds of meal tolerance tests were performed as breakfast on 2 consecutive days. The first breakfast contained 460 kcal (carbohydrates, 49.1%; protein, 15.7%; fat, 35.2%), while the second contained 462 kcal (carbohydrates, 37.2%; protein, 19.6%; fat, 43.2%). Self-monitoring blood glucose levels were measured at 0, 30, 60, and 120 min after the meal tests, and the increase in the postprandial area under the curve (AUC)0-120 min was determined. The HbA1c, glycated albumin, and 1,5-anhydroglucitol (AG) levels were measured, and continuous glucose monitoring was performed. RESULTS The increase in the postprandial AUC0-120 min was significantly smaller in the M+V group than in the L group after both meals. The 24-h average, 24-h standard deviations, 24-h AUC, and mean amplitude of glycemic excursion (MAGE) were similar for both groups and after both meals. The change in 1,5-AG was higher in the M+V group than in the L group. CONCLUSIONS The combination of M+V with basal therapy improved postprandial glucose excursion more effectively than L in T2DM patients.

High-density lipoprotein and apolipoprotein A-I inhibit palmitate-induced translocation of toll-like receptor 4 into lipid rafts and inflammatory cytokines in 3T3-L1 adipocytes.

Saturated fatty acids (SFAs) activate toll-like receptor 4 (TLR4) signal transduction in macrophages and are involved in the chronic inflammation accompanying obesity. High-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) produce anti-inflammatory effects via reverse cholesterol transport. However, the underlying mechanisms by which HDL and apoA-I inhibit inflammatory responses in adipocytes remain to be determined. Here we examined whether palmitate increases the translocation of TLR4 into lipid rafts and whether HDL and apoA-I inhibit inflammation in adipocytes. Palmitate exposure (250 µM, 24 h) increased interleukin-6 and tumor necrosis factor-α gene expressions and translocation of TLR4 into lipid rafts in 3T3-L1 adipocytes. Pretreatment with HDL and apoA-I (50 µg/mL, 6 h) suppressed palmitate-induced inflammatory cytokine expression and TLR4 translocation into lipid rafts. Moreover, HDL and apoA-I inhibited palmitate-induced phosphorylation of nuclear factor-kappa B. HDL showed an anti-inflammatory effect via ATP-binding cassette transporter G1 and scavenger receptor class B, member 1, whereas apoA-I showed an effect via ATP-binding cassette transporter A1. These results demonstrated that HDL and apoA-I reduced palmitate-potentiated TLR4 trafficking into lipid rafts and its related inflammation in adipocytes via these specific transporters.

Erratum to: Decreased glucagon levels and decreased insulin secretion after sitagliptin versus mitiglinide administration with similar glycemic levels following an oral glucose load: a randomized crossover pharmaceutical mechanistic study.

[This corrects the article DOI: 10.1007/s13340-015-0207-1.].