COVID-19拡大のため本学では、4月の新入生健診と5月の定期健診を延期し、6月下旬に対象者と健診項目を限定し感染対策を施したうえで臨時の健診を実施した。対象者は医療系学部・研究科を主とする学生に限定し、健診項目は胸部X線撮影のみとした。期間は6月22日〜26日とし、健診会場は本学保健管理センター1階玄関広間および正面駐車場とした。受付は、全ての出入口扉を常時開放した1階玄関広間に3ヶ所設置した。撮影場所となる胸部X線撮影車は正面駐車場に連日3台設置した。各学生の健診日時は個々の学生自身によるWeb予約制とし、6月5日から予約を開始した。予約方法は、予約システム「スターリザーブ」を用いて、15分枠・男女別に受付けた。その結果、『3密』を回避した健診を実施することができ、健診後2週間が経過しても学生の新型コロナウイルス陽性者はいなかったことから、健診会場でのクラスター発生はないと考えられた。

© 2020 The Author(s). Background: Aciduria caused by urinary excretion of acidic metabolic wastes produced in daily life is known to be augmented in patients with chronic kidney disease (CKD). To evaluate the reno-protective effect of oral alkalizing agents for the improvement of metabolic acidosis and neutralization of intratubular pH in the patients with mild stages of CKD. Also, to identify reno-protective surrogate markers in the serum and urine that can closely associate the effect of urine alkalization. Methods: In this single-centered, open-labeled, randomized cohort study, patients with CKD stages G2, G3a and G3b, who visited and were treated at Tohoku University Hospital during the enrollment period were registered. We administered sodium bicarbonate or sodium-potassium citrate as the oral alkalinizing agents. A total of 150 patients with CKD will be randomly allocated into the following three groups: sodium bicarbonate, sodium-potassium citrate and standard therapy group without any alkalinizing agents. The data of performance status, venous blood test, spot urine test, venous blood-gas test, electrocardiogram, renal arterial ultrasonography and chest X-ray will be collected at 0, 6, 12 and 24 weeks (short-term study) from starting the interventions. These data will be also collected at 1 and 2 years (long-term study). The samples of plasma and serum and early-morning urine at every visit will be acquired for the analysis of renal function and surrogate uremic biomarkers. The recruitment for this cohort study terminated in March, 2018, and the follow-up period for all the enrolled subjects will be terminated in December, 2020. The primary endpoint will be the development of originally-defined significant renal dysfunction or the occurrence of any cerebrovascular disease in the short-term study. The secondary endpoint will be the same endpoints as in the long-term study, or the patients with significant changes in the suggested the surrogate biomarkers. Discussion: The findings of this study will address the importance of taking oral alkalizing agents in the patients with early stages of CKD, furthermore they could address any new surrogate biomarkers that can be useful from early stage CKD. Trial registration: Registered Report Identifier: UMIN000010059 and jRCT021180043. The trial registration number; 150. Date of registration; 2013/02/26.

Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease.

To ensure that experiences and lessons learned from the unprecedented 2011 Great East Japan Earthquake are used to improve future disaster planning, the Japan Diabetes Society (JDS) launched the "Research and Survey Committee for Establishing Disaster Diabetes Care Systems Based on Relevant Findings from the Great East Japan Earthquake" under the supervision of the Chairman of the JDS. The Committee conducted a questionnaire survey among patients with diabetes, physicians, disaster medical assistance teams (DMATs), nurses, pharmacists, and nutritionists in disaster areas about the events they saw happening, the situations they found difficult to handle, and the needs that they felt required to be met during the 2011 Great East Japan Earthquake. A total of 3,481 completed questionnaires were received. Based on these and other experiences and lessons reported following the 2011 Great East Japan Earthquake and the 2004 Niigata-Chuetsu Earthquakes, the current "Manual for Disaster Diabetes Care" has been developed by the members of the Committee and other invited authors from relevant specialties. To our knowledge, the current Manual is the world's first to focus on emergency diabetes care, with this digest English version translated from the Japanese original. It is sincerely hoped that patients with diabetes and healthcare providers around the world will find this manual helpful in promoting disaster preparedness and implementing disaster relief.

AIMS: To assess the benefits of intensive statin therapy on reducing cardiovascular (CV) events in patients with type 2 diabetes complicated with hyperlipidaemia and retinopathy in a primary prevention setting in Japan. In the intension-to-treat population, intensive therapy [targeting LDL cholesterol <1.81 mmol/L (<70 mg/dL)] was no more effective than standard therapy [LDL cholesterol ≥2.59 to <3.10 mmol/L (≥100 to <120 mg/dL)]; however, after 3 years, the intergroup difference in LDL cholesterol was only 0.72 mmol/L (27.7 mg/dL), and targeted levels were achieved in <50% of patients. We hypothesized that the intergroup difference in CV events would have been statistically significant if more patients had been successfully treated to target. MATERIALS AND METHODS: This exploratory post hoc analysis focused on intergroup data from patients who achieved their target LDL cholesterol levels. The primary endpoint was the composite incidence of CV events. A Cox proportional hazards model was used to estimate hazard ratios (HRs) for incidence of the primary endpoint in patients who achieved target LDL cholesterol levels in each group. RESULTS: Data were analysed from 1909 patients (intensive: 703; standard: 1206) who achieved target LDL cholesterol levels. LDL cholesterol at 36 months was 1.54 ± 0.30 mmol/L (59.7 ± 11.6 mg/dL) in the intensive group and 2.77 ± 0.46 mmol/L (107.1 ± 17.8 mg/dL) in the standard group (P < 0.05). After adjusting for baseline prognostic factors, the composite incidence of CV events or deaths associated with CV events was significantly lower in the intensive than the standard group (HR 0.48; 95% confidence interval 0.28-0.82; P = 0.007). CONCLUSIONS: This post hoc analysis suggests that achieving LDL cholesterol target levels <1.81 mmol/L may more effectively reduce CV events than achieving target levels ≥2.59 to <3.10 mmol/L in patients with hypercholesterolaemia and diabetic retinopathy.

OBJECTIVE: Diabetes is associated with high risk of cardiovascular (CV) events, particularly in patients with dyslipidemia and diabetic complications. We investigated the incidence of CV events with intensive or standard lipid-lowering therapy in patients with hypercholesterolemia, diabetic retinopathy, and no history of coronary artery disease (treat-to-target approach). RESEARCH DESIGN AND METHODS: In this multicenter, prospective, randomized, open-label, blinded end point study, eligible patients were randomly assigned (1:1) to intensive statin therapy targeting LDL cholesterol (LDL-C) <70 mg/dL (n = 2,518) or standard statin therapy targeting LDL-C 100-120 mg/dL (n = 2,524). RESULTS: Mean follow-up was 37 ± 13 months. LDL-C at 36 months was 76.5 ± 21.6 mg/dL in the intensive group and 104.1 ± 22.1 mg/dL in the standard group (P < 0.001). The primary end point events occurred in 129 intensive group patients and 153 standard group patients (hazard ratio [HR] 0.84 [95% CI 0.67-1.07]; P = 0.15). The relationship between the LDL-C difference in the two groups and the event reduction rate was consistent with primary prevention studies in patients with diabetes. Exploratory findings showed significantly fewer cerebral events in the intensive group (HR 0.52 [95% CI 0.31-0.88]; P = 0.01). Safety did not differ significantly between the two groups. CONCLUSIONS: We found no significant decrease in CV events or CV-associated deaths with intensive therapy, possibly because our between-group difference of LDL-C was lower than expected (27.7 mg/dL at 36 months of treatment). The potential benefit of achieving LDL-C <70 mg/dL in a treat-to-target strategy in high-risk patients deserves further investigation.

In diabetic patients, reduced urinary pH (UpH) is a predictive factor for cardiorenal-vascular disorders. Synthesis of glutathione, an anti-oxidative stress substance, is induced to counteract renal oxidative stress. UpH declines as glutamate is consumed, as does the synthesis of ammonia from glutamate. Glutathione is synthesized from glutamate and cysteine; however, in diabetes, the relationship between lowered UpH and the roles of renal amino acids is unknown. We, therefore, examined the relationship between amino-acid kinetics, UpH, and renal function. This cross-sectional study targeted 100 non-diabetic obese individuals (OG: obese group) and 100 diabetics (DG: diabetic group). We investigated their blood amino acids, urinary amino-acid excretion, the reabsorption rates of various amino acids, and their relationship with the UpH and estimated glomerular filtration rate (eGFR). The DG subjects showed higher blood cysteine concentration, urinary glutamate, and cysteine excretions than the OG subjects. Although the glutamate reabsorption rate declined in the DG subjects, that of cysteine increased due to the lowered eGFR. The DG subjects' urinary cysteine excretion correlated positively with UpH, making this urinary cysteine excretion the sole independent risk factor for lower UpH. In patients with diabetes, the reabsorbed amount of cysteine, not glutamate, regulates the amount of glutathione synthesis in the kidneys. The more an amount of cysteine reabsorption increases concurrently with a decline in eGFR, the more its urinary excretion decreases. Under these conditions, concurrently, the glutamate consumption then increases, resulting in decreased ammonia synthesis and UpH.

Intrarenal RAS has been suggested to be involved in the pathogenesis of hypertension. It was recently reported that urinary angiotensinogen excretion levels are associated with intrarenal RAS. However, few markers predicting intrarenal RAS have been investigated in obese young subjects. The present study evaluated the association between blood pressure and intrarenal RAS activity, inflammation and oxidative stress in obese young adults. Urinary angiotensinogen excretion and urinary monocyte chemotactic protein (MCP)-1, and urinary thiobarbituric acid reaction substance (TBARS) as markers of intrarenal RAS activity, inflammation, and oxidative stress, respectively, were determined from morning urine of 111 young male adults. Participants were divided into two groups based on the body mass index (BMI). Natural log-transformed urinary angiotensinogen excretion level was significantly associated with blood pressure, MCP-1 excretion, and TBARS excretion elevation in the obese group (BMI &gt;= 25 kg/m(2)). Multivariable analyses showed that every 1 standard deviation increase in natural-log transformed urinary angiotensinogen and MCP-1 excretion, but not TBARS excretion level was associated with elevated blood pressure in the obese group. These results indicate that urinary angiotensinogen and MCP-1 excretion were associated with blood pressure elevation in this population of obese young adults. It suggested that inappropriate RAS activity and inflammation precedes hypertension in obese young subjects and urinary angiotensinogen could be a screening maker for hypertension in young obese subjects.

Pink urine syndrome (PUS) is attributed to the precipitation of uric acid caused by low urinary pH (U-pH). However, the reasons for the lower U-pH are unclear. To investigate the occurrence of PUS and verified the cause of U-pH reduction. Participants comprised 4,940 students who had undergone a physical examination. Data on the presence [PUS (+)] or absence [PUS (-)] of PUS, as well as age, gender, body mass index (BMI), blood pressure (BP), heart rate (HR), and U-pH were collected. Of these participants, 300 randomly selected individuals were evaluated for their waist circumference, as well as their levels of urinary C-peptide, angiotensinogen, methylglyoxal, thiobarbituric acid-reactive substances (TBARS), and Na+ excretion. Independent risk factors of lower U-pH were decided by a multiple-regression analysis. PUS was observed in 216 students (4.4 %). A greater number of men comprised the PUS (+) group compared with the PUS (-) group, and subjects in this group had high BMI, BP, and HR values, as well as low U-pH. A logistic regression analysis revealed that the BMI and U-pH were independent risk factors for PUS (+). The decrease of U-pH was closely related to the progress of chronic kidney disease (CKD). BMI value was related to PUS (+) in the CKD (-) subjects. On the other hand, low U-pH was related to PUS (+) in the CKD (+) subjects. All factors other than HR showed a significant negative correlation with U-pH. However, multiple-regression analysis revealed that TBARS and angiotensinogen were independent risk factors. Obesity and lower U-pH were each independently related to PUS, whereas increased intrarenal oxidative stress and exacerbation of the renin-angiotensin system activation were associated with the lowering of U-pH. U-pH low value is related to potential CKD.

Aims/IntroductionThe nature of the action of concomitant liraglutide to stabilize postprandial blood glucose level (PBG) in patients on intensive insulin therapy with unstable PBG remains unclear. The aim was to identify the nature of liraglutide's actions to stabilize PBGs. Materials and MethodsThe study participants consisted of 20 diabetes patients showing unstable PBGs after dinner despite undergoing intensive insulin therapy. The dose of bolus insulin was reduced by three units for each meal, and 0.9mg/day of liraglutide was added and used in combination. We evaluated the participants' data after the first evaluation (immediately before using liraglutide in combination) and the second evaluation (16weeks after starting concomitant therapy). PBGs after dinner were measured every day for a period of 28days immediately before carrying out both evaluations. The mean value of the 28 sets of blood glucose data and their standard deviation (SD) values were established as PBGs after dinner, as well as the SD for each participant. The changes in the mean values of the 20 participants, as well as their SD between before and after concomitant therapy, were evaluated. ResultsThe mean value of PBGs (12.01.0 to 10.1 +/- 0.9mmol/L) and SD values (5.1 +/- 0.7-3.5 +/- 0.8) after dinner both declined. A multiple regression analysis showed that the combined use of liraglutide was a significant independent variable of the SD values of PBGs after dinner. ConclusionThe treatment of reducing the dose of insulin and using liraglutide in combination not only suppresses PBGs, but also stabilizes their blood glucose fluctuations.

Background and objectives: A lower urinary pH (UpH) is closely linked to diabetes. However, its relation to diabetic renovascular damage is unclear. This study aimed to identify the relationship between UpH and the exacerbation of diabetic renovascular disorders. Methods: This is a 10-year observational study targeting 400 outpatients with diabetes who registered in 2003. We investigated the relationship between UpH in 2003 and renovascular damage from 2003 to 2013. Results: A total of 350 participants were eligible for the analysis. During their 10-year outpatient treatment, a decrease was seen in glycated hemoglobin levels, blood pressure, and estimated glomerular filtration rates (eGFRs), and an increase was seen in their urinary albumin–creatinine ratios (ACRs), uric acid (UA) levels, and intima-media thickness (IMT). UpH negatively correlated with urinary 8-hydroxy-20- deoxyguanosine (8-OHdG), body mass index, UA, and ACR, and positively correlated with eGFR. The results of a multiple regression analysis showed that the independent risk factors for UpH were 8-OHdG, UA, eGFR, and ACR. UpH also negatively correlated with the percent change in IMT (%IMT), the percent change in pulse wave velocity (%PWV), and the change in log ACR (Δlog ACR), and positively correlated with the percent change in eGFR. A multiple regression analysis revealed that UpH was an independent risk factor for the %IMT, %PWV and Δlog ACR. Obese patients with low UpH values frequently suffered from sleep apnea syndrome. Conclusions: These results suggest that UpH is a useful marker for predicting the onset of renovascular disorder in patients with diabetes.

Hemodialysis is known to decrease blood glucose concentration (BGC), insulin, and methylglyoxal levels. However, the effects of decreases in these factors on the increase in post-hemodialysis BGC remain unknown. This study identifies the effects of hemodialysis-induced changes in concentrations of these elements on post-hemodialysis BGC. Study subjects included seventeen insulin-treated diabetes patients receiving hemodialysis. The fluctuations in BGC on hemodialysis-treatment days and non-hemodialysis-treatment days were evaluated using a continuous glucose monitoring system. BGC was evaluated before breakfast, before starting hemodialysis, at the end of hemodialysis, 1 h post-hemodialysis (lunch), and 6 h post-hemodialysis (dinner). BGC, insulin, and methylglyoxal levels were measured at the start and end of hemodialysis. This study also evaluated the changes in the concentrations of glucose and insulin in the arterial line and the venous line during hemodialysis. Hemodialysis decreases BGC, insulin, and methylglyoxal levels. Concentrations of glucose and insulin in the arterial line gradually decreased during dialysis, while concentrations in the venous line approached their original concentrations in the dialysis solution. BGC rose sharply after eating lunch 1 h post-hemodialysis. The blood glucose, insulin, and methylglyoxal concentrations at the end of hemodialysis were associated with the M values and the mean amplitude of glycemic excursion values between before lunch and dinner. In particular, methylglyoxal concentration at the end of hemodialysis was strongly related to the post-hemodialysis increase in BGC. Hemodialysis-induced decreases in methylglyoxal concentrations and methylglyoxal concentration at the end of hemodialysis influence post-hemodialysis fluctuations in BGC.

2012年度と2013年度の学生健診受診者4940名(男性3651名、女性1289名)を対象とし、混濁尿の頻度を調査するとともに、混濁尿を認めた者(以下;濁(+)群)の尿を遠心分離し、鏡検にて析出物質を特定した。また、濁(+)群と(-)群とで「性別」「年齢」「尿pH」「BMI」「収縮期血圧(SBP)」「拡張期血圧(DBP)」「心拍数(HR)」を比較検討した。調査の結果、混濁尿を認めたのは216名(4.4%)であった。検討の結果、濁(+)群は(-)群に比べて、男性の割合が高く、[尿pH]が有意に低値で、[BMI][SBP][DBP][HR]が有意に高値であった。濁(+)の独立危険因子を明らかにするためロジスティック回帰分析を行った結果、[BMI][尿pH][HR]が抽出された。

The Joint Committee on Diabetic Nephropathy has revised its Classification of Diabetic Nephropathy (Classification of Diabetic Nephropathy 2014) in line with the widespread use of key concepts, such as the estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD). In revising the Classification, the Committee carefully evaluated, as relevant to current revision, the report of a study conducted by the Research Group of Diabetic Nephropathy, Ministry of Health, Labor and Welfare of Japan. Major revisions to the Classification are summarized as follows: (i) eGFR is substituted for GFR in the Classification (ii) the subdivisions A and B in stage 3 (overt nephropathy) have been reintegrated (iii) stage 4 (kidney failure) has been redefined as a GFR &lt 30 mL/min/1.73 m2, regardless of the extent of albuminuria and (iv) stress has been placed on the differential diagnosis of diabetic nephropathy versus non-diabetic kidney disease as being crucial in all stages of diabetic nephropathy.

The Committee on Diabetic Nephropathy revised the classification of diabetic nephropathy in view of the current status of eGFR and CKD in Japan. To make revisions for the classification of diabetic nephropathy 2014, the Committee carefully evaluated the report of the Research Group on Diabetic Nephropathy, Ministry of Health, Labour, and Welfare of Japan. The major revisions made were as follows: 1. eGFR can be used for the evaluation of GFR; 2. In stage 3 (overt nephropathy), A and B were combined; 3. Stage 4 (renal failure) was defined as GFR less than 30 mL/min/1.73 m2, regardless of albuminuria; and 4. The importance of differential diagnosis was stressed in all stages.

The Joint Committee on Diabetic Nephropathy has revised its Classification of Diabetic Nephropathy (Classification of Diabetic Nephropathy 2014) in line with the widespread use of key concepts, such as the estimated glomerular filtration rate (eGFR) and chronic kidney disease. In revising the Classification, the Committee carefully evaluated, as relevant to current revision, the report of a study conducted by the Research Group of Diabetic Nephropathy, Ministry of Health, Labour and Welfare of Japan. Major revisions to the Classification are summarized as follows: (1) eGFR is substituted for GFR in the Classification (2) the subdivisions A and B in stage 3 (overt nephropathy) have been reintegrated (3) stage 4 (kidney failure) has been redefined as a GFR less than 30 mL/min/1.73 m2, regardless of the extent of albuminuria and (4) stress has been placed on the differential diagnosis of diabetic nephropathy versus non-diabetic kidney disease as being crucial in all stages of diabetic nephropathy.

Background: In diabetic patients with renal artery arteriosclerosis (RAAS), the factors associated with a greater risk for cardiovascular-renal events (CVREs) remain unclear: the decline in estimated glomerular filtration rate (eGFR) caused by RAAS or the advance of arteriosclerosis that causes RAAS. Hence, the features to determine which best predicts the onset of CVREs in such patients were compared. Methods and Results: The renal arteries of 162 type 2 diabetes patients were assessed by using magnetic resonance angiography (RAAS diagnosed as arteriosclerotic stenosis &gt;= 50%) and they were studied longitudinally over 7 years. The influence of the presence/absence of RAAS, a decline in eGFR, clinical factors, surrogate arteriosclerotic markers and ischemic markers on patient's CVREs were assessed. A Cox regression analysis showed the detection of RAAS to be an independent risk factor for CVREs (bilateral RAAS was an extremely strong risk factor for the development of CVREs within 1,000 days), as was the decline in eGFR in a logistic regression analysis; the latter being a more powerful risk factor for CVREs. A multiple regression analysis revealed angiopoietin-2, a marker of ischemia, to be a risk factor for the decline in eGFR. Conclusions: A decline in renal function but not the renal arterial stenotic lesion itself appears to be associated with an increased incidence of CVREs in type 2 diabetic patients with RAAS.

BACKGROUND It is unclear when angiotensin II receptor blockers (ARBs) produce their strongest antialbuminuric effect (AAE) in patients with diabetic nephropathy. ARBs produce stronger AAEs when urinary excretion of reactive oxygen species (ROS) and/or of angiotensinogen (AGT) is higher before treatment, although the relationship between ROS, AGT, and the urinary albumin-to-creatinine ratio (ACR) is unclear. We sought to define the relationship between ROS and ACR and establish the stage at which ARBs exert maximal AAEs. METHODS Urinary ROS and AGT and the ACR were measured in 277 hypertensive type 2 diabetic patients before ARB treatment, and changes in the ACR were analyzed oven l 6 weeks. RESULTS Urinary AGT and ROS showed similar changes as the disease progressed, and the increase in ACR often observed in patients with lower ROS and AGT reflects the mild AAE produced by ARBs. ROS and AGT levels and the AAE were all highest in albuminuric patients (ACR = 30-1,000 mg/g creatinine), whereas normoalbuminuric patients (ACR &lt; 30 mg/g creatinine) displayed variable ROS values and AAEs.Glycemic control exerted a stronger AAE than ARBs in normoalbuminuric patients, whereas it had a weak AAE in most nephrotic (ACR &gt;= 1,000 mg/g creatinine) patients, who had low basal ROS and AGT values. Lowering blood pressure was effective at all stages and appeared to promote an AAE, even in nephrotic patients. CONCLUSIONS ARBs produce a maximal AAE in albuminuric patients, and lowering blood pressure enhances the AAE in patients at all stages, including the nephrotic stage.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega 3-polyunsaturated fatty acids mainly contained in the blue-backed fish oil, and are effective in decreasing the lipids disorder and the cardiovascular incidence among diabetic patients. Moreover, it has been suggested that EPA and DHA may improve the insulin resistance and glucose metabolism. However, the clinical effects of EPA and DHA on glucose metabolism remain unclear. We aimed to clarify the effects of EPA/DHA treatment on glycemic control in type 2 diabetes mellitus. This study was a multicenter prospective randomized controlled trial involving 30 elderly type 2 diabetic patients on a liquid diet. Their exercises were almost zero and the content of their meals was strictly managed and understood well. Therefore, the difference by the individual's life was a minimum. The subjects were divided into two groups: those receiving EPA/DHA-rich liquid diet [EPA/DHA (+)] or liquid diet lacking EPA/DHA [EPA/DHA (-)]. Changes in factors related to glucose and lipid metabolism were assessed after the three-month study. Serum concentrations of EPA rose in EPA/DHA (+), although the levels of DHA and fasting C-peptide remained unchanged in EPA/DHA (+). In addition, there was a significant decline in the fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), fasting remnant-like particles and apolipoprotein (apo) B in EPA/DHA (+), compared with the values in EPA/DHA (-). EPA/DHA-rich diet might improve glucose metabolism in elderly type 2 diabetic patients on a liquid diet. This phenomenon may be due to the improved insulin resistance mediated by the rise in serum EPA concentrations.

One major precursor of carbonyl stress, methylglyoxal (MG), is elevated in the plasma of chronic kidney disease (CKD) patients, and this precursor contributes to the progression of vascular injury, hypertension and renal injury in diabetic nephropathy patients. This molecule induces salt-sensitive hypertension via a reactive oxygen species-mediated pathway. We examined the role of MG in the pathogenesis of hypertension and cardio-renal injury in Dahl salt-sensitive (Dahl S) rats, which is a rat model of CKD. Nine-week-old Dahl S rats were fed a 1% NaCl diet, and 1% MG was added to their drinking water for up to 12 weeks. Blood pressure and cardio-renal injuries were compared with rats treated with tap water alone. The angiotensin II receptor blocker (ARB), candesartan (10 mg kg -1 day -1), was administered to MG Dahl S rats to determine the impact of this drug on the pathogenesis of MG-induced CKD. A progressive increase in systolic blood pressure was observed (123±1-148±5 mm Hg) after 12 weeks of MG administration. MG administration significantly increased urinary albumin excretion, glomerular sclerosis, tubular injury, myocardial collagen content and cardiac perivascular fibrosis. MG also enhanced the renal expression of Nε-carboxyethyl-lysine (an advanced glycation end product), 8-hydroxydeoxyguanosine (a marker of oxidative stress), macrophage (ED-1) positive cells (a marker of inflammation) and nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase activity. Candesartan treatment for 4 weeks significantly reduced these parameters. These results suggest that MG-induced hypertension and cardio-renal injury and increased inflammation and carbonyl and oxidative stress, which were partially preventable by an ARB. © 2013 The Japanese Society of Hypertension All rights reserved.

Prader-Willi syndrome (PWS) is a genetic disease characterized by severe morbid obesity in association with hyperphagia and type 2 diabetes mellitus. Liraglutide is a glucagon-like peptide (GLP)-1 analog that controls appetite, decreases body weight and improves glycemic control. However, it is unclear if PWS patients with diabetes experience similar benefits of liraglutide therapy. In a 25 year-old female hyperglycemic PWS patient, liraglutide monotherapy improved her Hemoglobin A1 c remarkably (12.6% to 6.1%) while steadily decreasing her body mass index (BM 1: 39.1 kg/m(2) to 35.7 kg/m(2)). We offered this patient continued liraglutide therapy for one year to determine the effect on various metabolic parameters. Her hyperphagia was controlled so on after liraglutide treatment commenced and remained so throughout the treatment. The metabolic parameters changed as follows: visceral fat area fell from 150.1 to 113.2 (cm(2)); plasma insulin rose from 108.1 to 277.0 (pmol/L); plasma active GLP-1 dropped from 2.1 to 1.2 (fmol/L); plasma active ghrelin diminished from 137.0 to 27.7 (pmol/L). While plasma active ghrelin before treatment was abnormally high, even though her GLP-1 was normal, both decreased following liraglutide therapy. These results suggest that in addition to its insulinotropic effects, other potential mechanisms activated by liraglutide therapy may reduce the plasma ghrelin levels elevated in PWS, leading to an improvement in overeating, BM I and visceral fat, as well as glycemic control.

Objectives: Blockade of the T-type calcium channel (TCC), which is expressed in the renal efferent arterioles of the juxtamedullary nephron and vasa recta, has been shown to protect against renal injury. Studies were designed to determine the effects of a specific TCC blocker, R(-) efonidipine [R(-) EFO], on the regulation of renal circulation. Methods and results: Renal medullary blood flux (MBF) and cortical blood flux (CBF) were simultaneously monitored using laser-Doppler flowmetry in Sprague-Dawley rats. Responses were also determined in rats with angiotensin II (AngII) induced renal ischemia. Intravenous (i.v.) or renal interstitial (r.i.) infusion of R(-) EFO (0.25 mg/h, i.v. or r.i.) significantly increased MBF by 24.0 +/- 7.0 and 21.0 +/- 4.4%, respectively, but without changing CBF or mean arterial pressure. The nitric oxide (NO) synthase inhibitor NG-nitro-L-argininemethylester (L-NAME, 1 mu g/kg per min, i.v. or r.i.) significantly attenuated R(-) EFO-induced increase in MBF. R(-) EFO inhibited the AngII-mediated (50 ng/kg per min, i.v.) reduction of MBF (28.4 +/- 1.7%), which was associated with increased urinary NO2- + NO3- excretion and decreased urinary hydrogen peroxide (H2O2) excretion. Intracellular H2O2 fluorescence (real-time fluorescence imaging) in the epithelial cells of isolated medullary thick ascending limb (mTAL) significantly increased following AngII stimulation (1 mu mol/L, 235 +/- 52 units), which was significantly inhibited by pre and coincubation with R(-) EFO. R(-) EFO stimulation also increased the intracellular NO concentration in the epithelial cells of mTAL (220 +/- 62 units). Conclusion: These results suggest that TCC blockade with R(-) EFO selectively increases MBF, an effect that appears to be mediated by changes in renal NO and oxidative stress balance, which may protect against ischemic renal injury in the renal medullary region.

The renin-angiotensin system (RAS) is involved in the pathogenesis of insulin sensitivity (IS). The role of RAS in insulin resistance and muscular circulation has yet to be elucidated. Therefore, this study sought to determine the mechanisms of angiotensin II receptor blockers (ARBs) and/or diuretics on IS and capillary density (CD) in fructose-fed rats (FFRs). Sprague-Dawley rats were fed either normal chow (control group) or fructose-rich chow for 8 weeks. For the last 4 weeks, FFRs were allocated to four groups: an FFR group and groups treated with the thiazide diuretic hydrochlorothiazide (HCTZ), with the ARB losartan, or both. IS was evaluated by the euglycemic hyperinsulinemic glucose clamp technique at week 8. In addition, CD in the extensor digitorum longus muscle was evaluated. Blood pressure was significantly higher in the FFRs than in the controls. HCTZ, losartan and their combination significantly lowered blood pressure. IS was significantly lower in the FFR group than in the controls and was even lower in the HCTZ group. Losartan alone or combined with HCTZ significantly increased IS. In all cases, IS was associated with muscular CD, but not with plasma adiponectin or lipids. These results indicate that losartan reverses HCTZ-exacerbated insulin resistance, which can be mediated through the modulation of muscular circulation in rats with impaired glucose metabolism. © 2012 The Japanese Society of Hypertension All rights reserved.

1. Salt-sensitive hypertension is commonly associated with diabetes, obesity and chronic kidney disease. The present review focuses on renal mechanisms involved in the development of this type of hypertension. 2. The renal medullary circulation plays an important role in the development of salt-sensitive hypertension. In vivo animal studies have demonstrated that the balance between nitric oxide (NO) and reactive oxygen species (ROS) in the renal medulla is an important element of salt-sensitive hypertension. The medullary thick ascending limb (mTAL) in the outer medulla is an important source of NO and ROS production and we have explored the mechanisms that stimulate their production, as well as the effects of NO superoxide and hydrogen peroxide on mTAL tubular sodium reabsorption and the regulation of medullary blood flow. 3. Angiotensin II-stimulated NO produced in the mTAL is able to diffuse from the renal mTAL to the surrounding vasa recta capillaries, providing a mechanism by which to increase medullary blood flow and counteract the direct vasoconstrictor effects of angiotensin II. Enhanced oxidative stress attenuates NO diffusion in this region. 4. Carbonyl stress, like oxidative stress, can also play an important role in the pathogenesis of chronic kidney disease, such as insulin resistance, salt-sensitive hypertension and renal vascular complications. 5. Despite the large number of studies undertaken in this area, there is as yet no drug available that directly targets renal ROS. Oxidative and / or carbonyl stress may be the next target of drug discovery to protect against salt-sensitive hypertension and associated end-organ damage.

Objective: To examine the effects of a huge tsunami resulting from the Great East Japan Earthquake on blood pressure (BP) control and glycaemic control in diabetic patients. Design: A retrospective study. Setting: Tohoku University, Japan. Participants: 63 patients were visiting Rikuzentakata Hospital for diabetic treatment before the earthquake and returned to the clinic in July after the earthquake, and they were analysed in the present study. The subjects were divided into two groups: those who were hit by the tsunami, the Tsunami (+) group (n=28), and those who were not, the Tsunami (-) group (n=35), and the groups' parameters and their changes were compared. Primary outcome measure: Changes of HbA1c. Secondary outcome measures: Changes of BP, body mass index. Results: HbA1c and both BP increased, while the numbers of most drugs taken decreased in both groups. Parameter changes were significantly greater in the Tsunami (+) group. All medical data stored at the hospital was lost in the tsunami. The Tsunami (+) patients also had their own records of treatment washed away, so it was difficult to replicate their pre-earthquake drug prescriptions afterwards. In comparison, the Tsunami (-) patients kept their treatment information, making it possible to resume the treatment they had been receiving before the earthquake. The BP rose only slightly in men, whereas it rose sharply in women, even though they had not been directly affected by the tsunami. BP rose markedly in both genders affected by the tsunami. Conclusions: All medical information was lost in the tsunami, and glycaemic and BP controls of the tsunami-affected patients worsened more than those of patients who had been affected by the earthquake alone. Women may be more sensitive to changes in the living environment that result from a major earthquake than are men.

Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is a newly developed oral hypoglycemic agent. Sitagliptin increases the level of glucagon-like polypeptide (GLP)-1 that increases insulin secretion. In addition, GLP-1 decreases salt intake and increases urinary salt excretion. Therefore, the sitagliptin treatment might lower blood pressure in hypertensive patients with type 2 diabetes. It also remains to be examined whether the reduction in blood pressure with sitagliptin treatment is related to the blood glucose improvement and the body weight decrease. To identify beneficial effects of sitagliptin treatment, we administered sitagliptin (50 mg) on alternate days to seventeen type 2 diabetes outpatients with insufficient blood glucose control (8 males and 9 females; mean age of 67.1 years). The patients were also treated with oral hypoglycemic agents and antihypertensive drugs for six months before and during the sitagliptin administration. We measured the level of hemoglobin (Hb) A1c, systolic blood pressure (SBP), and body mass index (BMI) for up to six months thereafter. Their BMIs remained unchanged. The levels of HbA1c were dropped from 6.5 +/- 0.3% to 5.8 +/- 0.3%, while SBP was also dropped from 130.0 +/- 37.2 mmHg to 119.7 +/- 9.4 mmHg. However, the degree of the decrease in HbA1c levels was not significantly correlated with that of SBP (r = 0.24). In conclusion, the present findings suggest that sitagliptin lowers SBP without reducing BMI, independent of the blood glucose reduction. The hypotensive effect is apparent with the alternate-day regimen of sitagliptin at a lower dose compared to the everyday medication.

Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are one of the renin angio-tensin system (RAS) inhibitors widely used for the treatment of hypertension. Recently, Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) meta-analysis showed that ACEIs had the blood pressure independent beneficial effects on coronary heart events. In this review, we summarized our current knowledge about ACEIs especially imidapril and re-evaluated ACEIs among other RAS inhibitors (RASIs) because ACEIs have wide ranges of beneficial effects in addition to the ACE inhibition which other RASIs do not have such as the up-regulation of bradykinin level, substance P level, the inhibition of matrix metalloproteinase (MMP) activity and stabilization of coronary plaque. © the author(s), publisher and licensee Libertas Academica Ltd.

We test whether plasma level of methylglyoxal (MG) is an independent risk factor predicting the progression of diabetic macroangiopathy or microangiopathy in type 2 diabetic patients. We measured in 50 type 2 diabetic patients plasma levels of MG and 3-deoxyglucosone (DG) using an electrospray ionization-liquid chromatography-mass spectrometry. We assessed the correlations between baseline levels of MG or DG and the percentage changes after 5 years of clinical parameters linked to diabetic macroangiopathy or microangiopathy, that is, intima-media thickness (IMT), systolic blood pressure (SBP), the amount of urinary albumin excretion (ACR), pulse wave velocity (PWV), and estimated glomerular filtration rate (eGFR). Multiple regression analysis was performed using the percentage changes in IMT, SBP, ACR, PWV, and eGFR over the 5-year period as the independent or objective variables and the values of MG, DG, glycohemoglobin A1c, body mass index, triglyceride, and diabetic duration at the baseline as the dependent variables. The values of IMT, PWV, SBP, and ACR all increase, but eGFR reduces with time during the 5-year period. Baseline level of MG correlates significantly with the percentage changes of IMT, SBP, ACR, PWV, and eGFR, whereas that of DG does only with ACR. A multiple regression analysis reveals that MG is an independent risk factor for the percentage changes of IMT, PWV, and SBP but not for those of ACR and eGFR. DG is an independent risk factor for the percentage change of ACR. MG is a predictor in type 2 diabetic patients of intima-media thickening, of increase of PWV, and of elevation of SBP. (Hypertension. 2010;56:471-476.)

最近、糖尿病動物モデルにおいて高血糖が腎皮質内脂質を増加させることが報告された。また、抗アレルギー薬のtranilastがTGF-β依存性に糖尿病性腎障害を改善することが知られているが、その機序の詳細は不明である。そこで我々は、「糖尿病性腎障害においてインスリンは腎内脂質を減少させ、tranilastは血糖および腎内脂質非依存性に腎保護作用を示す」という仮説を立て、Dahl食塩感受性高血圧ラットに糖尿病を誘発したモデルを用いて検証を行った。その結果、仮説は立証され、インスリンによる腎内脂質減少の機序に酸化ストレスが関与している可能性が示唆された。

Objectives Methylglyoxal, a metabolite of the glycolysis pathway, may play an important role in the development of diabetes and hypertension, but the exact mechanism has not been fully elucidated. The present study was designed to investigate whether methylglyoxal could directly induce insulin resistance and salt sensitivity in Sprague-Dawley rats. Methods Rats were allocated to four groups: control (normal drinking water), 1% methylglyoxal in drinking water, 1% methylglyoxal plus N-acetyl cysteine (NAC) (800 mg/kg per day), a methylglyoxal scavenger, or TM2002 (100 mg/kg per day), an advanced glycation endproducts (AGEs) inhibitor. After 4-week treatment insulin resistance was evaluated by an euglycemic hyperinsulinemic glucose clamp technique. In another set of rats, either a high-salt diet (4%) alone, standard rat chow with 1% methylglyoxal in drinking water or high-salt diet plus methylglyoxal was given for 4 weeks. Immunohistochemistry was performed to measure nitrotyrosine and methylglyoxal-induced AGEs, N(epsilon)-carboxyethyl-lysine (CEL) in the kidney. Results Four-week treatment with NAC or TM2002 completely improved methylglyoxal-induced insulin resistance. Co-administration of methylglyoxal and high-salt diet significantly increased systolic blood pressure, urinary albumin excretion, urinary thiobarbituric acid-reactive substances excretion and the renal nitrotyrosine expression in the kidney (markers of oxidative stress)compared with methylglyoxal or high-salt diet alone. Renal CEL was significantly increased in methylglyoxal-treated rats compared with nonmethylglyoxal-treated rats. Conclusion These results indicate that methylglyoxal-induced insulin resistance and salt sensitivity at least in part by increasing oxidative stress and/or AGEs formation in Sprague-Dawley rats. The present study provides further evidence for methylglyoxal as one of the causative factors in the pathogenesis of insulin resistance and salt-sensitive hypertension. J Hypertens 27: 1664-1671 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

This study determined the role of angiotensin II type-1 (AT1) receptor in the salt sensitivity of blood pressure. The mean arterial blood pressure (MAP) of Sprague-Dawley rats was monitored by radio telemetry and, after baseline measurements, rats were treated either with (1) vehicle, (2) AT1 receptor blocker (ARB) olmesartan (OLM, 100 nmol kg(-1) h(-1), subcutaneously), (3) OLM with hydrochlorothiazide (HCTZ, 40 mg kg(-1) day(-1), orally), (4) angiotensin II (AngII, 100 ng kg(-1) min(-1), subcutaneously) or with (5) AngII with OLM. Rats were fed a 0.5% salt diet during the baseline and first 7 days of treatment period, and the diet was then switched to one containing 8% salt for another 7 days. Urinary samples were collected in a metabolic cage at the end of each period. MAP of the vehicle group did not change throughout the study. In AngII-infused rats, BP increased only when rats were fed an 8% salt diet. OLM and OLM with AngII significantly reduced MAP when rats were on a 0.5% salt diet, but not on an 8% salt diet, indicating an enhanced salt sensitivity by OLM. Co-treatment with HCTZ reduced the salt sensitivity of OLM. The urinary level of the oxidative stress marker was increased by an 8% salt diet and was not altered by either OLM alone or in combination with HCTZ. However, OLM attenuated the salt-induced renal NAD(P) H (nicotinamide adenine dinucleotide phosphate) oxidase activity. These results indicate that AT1 receptor blockade increases salt sensitivity, which is reversed by diuretics. We conclude that OLM and HCTZ could be a useful combination for reduction of blood pressure even under high salt intake without changes in urinary oxidative stress levels. Hypertension Research (2009) 32, 513-519; doi: 10.1038/hr.2009.40; published online 1 May 2009

We encountered two patients who developed daytime hyperglycemia and early morning hypoglycemia because of insulin antibody (IA) that the affinity was extremely lower and the capacity extremely higher than those of IA in the insulin autoimmune syndrome, after their insulin treatment were changed from human insulin to analog insulin. © 2009 Elsevier Ireland Ltd. All rights reserved.

糖尿病を伴ったDahl食塩感受性(DahlS)ラットの腎障害に対するインスリンの影響について検討した。実験1)DahlSラットにストレプトゾトシン(STZ)を腹腔内投与して糖尿病を誘発したSTZ群と溶解液腹腔内投与のコントロール群と比較した。その結果、尿中アルブミン排泄量および尿中H2O2排泄量はコントロール群に比しSTZ群で有意に増加し、クレアチニンクリアランス(Ccr)は両群間に有意差はみられなかった。実験2)DahlSラットにSTZを腹腔内投与し、8日後にインスリンを投与したSTZ+INS群と生理食塩水を投与したSTZ群と比較した。その結果、食事摂取量は経過中有意差はなかったが、体重はSTZ群に比しSTZ+INS群で有意に増加した。随時血糖は実験開始時に両群間に有意差はなかったものの、STZ+INS群ではINS投与後に一時低下し、7日以降有意に上昇した。尚、平均動脈圧日内変動ならびに尿中H2O2排泄量は両群間で有意差はなく、尿中アルブミン排泄量とCcrはSTZ群に比しSTZ+INS群で有意に増加していた。

慢性腎臓病(CKD)の進展に対するMethylglyoxal(MGO)の影響について検討した。方法は8週齢のDahl食塩感受性高血圧(DahlS)ラットに1%MGOを4〜12週間経口飲水投与したMGO単独投与群、MGO投与+カンデサルタン投与群、MGOを経口飲水投与したSprague Dawley(SD)ラット群、そしてコントロール群に分け、これらを比較した。その結果、1)MGO単独投与群ではコントロール群に比し血圧および尿中アルブミン排泄が有意に上昇し、糸球体硬化指数、オステオポンチンの発現領域、糸球体ED-1発現細胞数、更に腎組織中のNAD(P)H oxidase 活性、CEL、CML、8-OHdGが有意に増加していた。2)カンデサルタンはMGOによる血圧上昇と尿中アルブミン排泄を完全に抑制し、糸球体硬化指数、オステオポンチン発現領域、糸球体ED-1発現細胞数、また、腎組織中NAD(P)H oxidase 活性、CEL、CML、8-OHdGが有意に減少していた。3)MGOはDahlSラットの収縮期血圧を上昇させたが、SDラットでは血圧の上昇は認められなかった。

A calcium channel blocker (CCB), azelnidipine (AZ), is reported to inhibit oxidative stresses, particularly when administered under blockade of the renin-angiotensin system (RAS). The purpose of this study was to investigate whether AZ inhibits oxidative stresses more potently than other CCBs under blockade of RAS and exerts renoprotection in type 2 diabetic nephropathy. Subjects were hypertensive type 2 diabetics with nephropathy, taking RAS inhibitors. The patients were randomly assigned to two groups, an AZ group (n=21, 16 mg/d) and a nifedipine-CR (NF) group (n=17, 40 mg/d). The plasma levels of monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), high-sensitive C-reactive protein (hsCRP), adiponectin and tumor necrosis factor-alpha (TNF alpha), the urinary excretion of 8-epi-prostagiandin F-2 alpha (8-epi-PGF(2 alpha)) and 8-hydroxy-deoxyguanosine (8-OHdG), and the urinary albumin-to-creatinine ratios (ACR) were determined before and after 16-week treatment. Neither metabolic parameters nor blood pressure levels differed between the two groups not only at baseline but also after the treatment. However, significant decreases in MCPA, IL-6, hsCRP, TNF alpha, 8-epi-PGF(2 alpha), 8-OHdG and ACR levels, and a significant increase in the plasma adiponectin level were detected in the AZ group, but not in the NF group. The % change in the urinary oxidative stress markers correlated with that in ACR. Our results indicate that, in hypertensive patients with diabetic nephropathy, a combination therapy of RAS inhibitors and AZ is an effective therapeutic modality for decreasing not only blood pressure but also inflammations and oxidative stresses.

Background and objectives: Sarpogrelate has been shown to reduce albuminuria in diabetic nephropathy. For examination of whether this is based on the same mechanisms as angiotensin II receptor blockers or thiazolidinedione, effects of sarpogrelate on atherosclerotic inflammatory molecules and their relations to albuminuria in patients who had diabetes and had already been treated with angiotensin II receptor blockers and with or without thiazolidinedione were examined. Design, setting, participants, & measurements: Forty patients who had diabetes with nephropathy and arteriosclerosis obliterans and had already been treated with angiotensin H receptor blocker (n = 40) were randomly assigned to sarpogrelate (300 mg/d; n = 20) or aspirin group (100 mg/d; n = 20). Plasma monocyte chemoattractant protein-1 and urinary albumin-to-creatinine ratio and monocyte chemoattractant protein-1 were measured at baseline and 16 wk after administration. Results: Only the sarpogrelate group showed increases in plasma adiponectin and decreases in both plasma and urinary monocyte chemoattractant protein-1 and albumin-to-creatinine ratio levels. Moreover, percentage change of monocyte chemoattractant protein-1 level correlated positively to that of albumin-to-creatinine ratio. Even when the sarpogrelate group was further divided into two groups with (n = 9) or without thiazolidinedione (n = 11), changes in monocyte chemoattractant protein-1 or albumin-to-creatinine ratio did not differ. Conclusions: Sarpogrelate can reduce albuminuria and plasma and urinary monocyte chemoattractant protein-1 levels while increasing plasma adiponectin in diabetic nephropathy. These effects seem to be mediated via mechanisms that are different from those of angiotensin II receptor blocker or thiazolidinedione.

We examined the effects of increasing the recommended initial doses of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), or of switching to combination therapy with both drugs, on diabetic nephropathy. Hypertensive type 2 diabetic patients with urinary albumin excretion (ACR) between 100 and 300 mg/g creatinine (Cre) were assigned to the following five groups in which an antihypertensive drug was administered at a recommended initial dose for 48 weeks, and then either the dose was doubled or an additional drugs was added to regimen for the following 48 weeks: N, nifedipine-CR (N) 20 mg/day (initial dose) T, ACEI temocapril (T) 2 mg/day C, ARB candesartan (C) 4 mg/day T+C, T first and then addition of C C+T, C first and then addition of C. ACR decreased in the T (n=34), C (n=40), T+C (n=37) and C+T (n=35) groups, but not in the N group (n=18). However, the anti-proteinuric effect was less in the T than in the C, T+C or C+T groups, while no differences existed among the latter three. In each group, there were significant linear relationships between attained BP and ACR however, the regression lines were shifted toward lower ACR level in the renin-angiotensin system-inhibition groups compared with the N group. These results indicate that an ACEI and/or ARB is superior to a CCB in retarding diabetic nephropathy, while the combination of low doses of ACEI and ARB has effects similar to those of high-dose ARB. Even among patients treated with an ACEI and/or ARB, lowering BP is important.

1. Over the course of treatment with angiotensin-converting enzyme inhibitor (ACEI), plasma levels of aldosterone have been shown to increase and this increase would blunt the effectiveness of the ACEI (aldosterone escape phenomenon). 2. In the present study, we assessed a potential renal benefit of additional aldosterone blockade with spironolactone in hypertensive diabetic patients treated with ACEI showing the phase of aldosterone escape. 3. The present clinical study was a randomized prospective study to assess difference between the clinical effects of spironolactone and furosemide. Thirty hypertensive type II diabetics (DM2) with a urinary alubumin : creatinine ratio (ACR) above 30 mg/g creatinine (showing albuminuria) and plasma B-type natriuretic peptide (BNP) levels above 100 pg/mL (showing mild heart failure) were treated with an ACEI (imidapril 5 mg/day) for 1 year and then randomly divided into two groups, one group receiving additional spironolactone (25 mg/day) treatment and the other receiving furosemide (20 mg/day) treatment. Blood pressure, ACR and plasma BNP levels were monitored in both groups. 4. Treatment with the ACEI reduced ACR initially but, in 1 year, ACR tended to increase. Additional spironolactone treatment progressively reduced ACR, whereas furosemide treatment did not show any effect. Plasma BNP levels were reduced by ACEI and were further reduced by additional spironolactone treatment, but not furosemide treatment. Blood pressure levels in both groups were comparable. 5. In conclusion, additional therapy with spironolactone in ACEI treatment exerts a renoprotective, as well as cardioprotective, effect in hypertensive diabetes.

We tested the hypothesis that blockade of angiotensin II type 1 receptors reduces oxidative stress markers in parallel with urinary albumin and type IV collagen excretions. Sixty-six diabetic patients with nephropathy were randomly assigned to either the angiotensin II receptor blocker ( ARB; n = 33) or trichlormethiazide ( n = 33) group. The majority of patients had been treated with angiotensin-converting enzyme inhibitors or calcium channel blockers for &gt;= 1 year before the present study. Reduction of blood pressure was not different between the 2 groups, and HbA1c levels did not change over the study period ( 8 weeks). Treatment with ARB ( candesartan 8 mg/day, n = 11 or valsartan 80 mg/day, n = 22) for 8 weeks reduced the levels of plasma monocyte chemoattractant protein 1, interleukin 6, urinary 8-epi-prostaglandin F2 alpha, 8-hydroxydeoxyguanosine, albumin, and type IV collagen, whereas the levels of these markers were not altered with trichlormethiazide ( 2 mg/day). Significant correlation was observed between the reduction of the urinary 8-epi-prostaglandin F2 alpha and 8-hydroxydeoxyguanosine and those of the urinary albumin and type IV collagen. Subjects with large oxidative stress had large reduction rates because of ARB administration and showed large urinary albumin suppression. These results suggest that ARBs reduce oxidative stress and inflammation in diabetic patients independent of their effects on blood pressure. In addition, increases in oxidative stress caused by angiotensin II may play an important role in the progression of diabetic nephropathy. Our results may help to explain the clinical observation that ARB reduces urinary albumin excretion very efficiently in some patients but not in others.

Recent studies have shown the important role of proinflammatory cytokines and chemokines in the pathogenesis of atherosclerosis and diabetes mellitus (DM). Interferon-inducible protein of 10kD (IP-10/CXCL 10), a member of the C-X-C chemokine superfamily, is a potent chemoattractant for activated T lymphocytes and is reported to be involved in various disease states including atheroma plaque formation, inhibition of tumor angiogenesis and maintenance of podocyte function. However, the involvement of IP-10 in type 2 DM, especially in its vascular and renal complications, is largely unknown.<br>To elucidate the etiopathological role of IP-10 in type 2 DM, we measured the concentrations of IP-10 together with IFN-γ, TNF-α, IL-18, IL-6 and MCP-1 in plasma samples from 103 type 2 DM patients with various degrees of nephropathy.<br>A significant difference in the plasma level of IP-10 was observed between the patients and the control subjects (183.3±12.5pg/m<i>l</i> vs 65.6±9.3pg/m<i>l</i>, p<0.05). IP-10 correlated IL-18, IL-6, TNF-α and MCP-1. The IFN-γ level was below the detectable range. IP-10 levels became higher with the progression of nephropathy: IP-10 levels were 148.9±14.5, 174.2±17.2 and 231.9±31.3pg/m<i>l</i> in patients with an urinary albumin creatinine ratio of <30, 30 to 300 and >300μg/mg Cr, respectively. Similarly, IL-18, IL-6, MCP-1 and TNF-α levels in patients with overt albuminuria were significantly higher as compared with those without albuminuria (IL-18, 367.3±45.6 vs 203.5±17.6pg/m<i>l</i>; IL-6, 1.61±0.26 vs 0.87±0.13pg/ml; TNF-α, 1.83±0.48 vs 0.61±0.07pg/m<i>l</i>; p<0.05, respectively) in consistent with previous reports.<br>These results suggested that IP-10 may have an etiopathogenic role in type 2 DM and diabetic nephropathy as one of the downstream effectors of proinflammatory cytokines.

Aim: This study was designed to examine the therapeutic effect of acarbose on serum triglyceride (TG), free fatty acid (FFA), very low-density lipoprotein (VLDL) and chylomicron (CM) in the meal tolerance test (MTT) before and after acarbose treatment in type 2 diabetes mellitus (DM2). Methods: Effects of acarbose on postprandial lipid metabolism were examined in DM2 patients. The subjects with normotriglyceridaemia (TG less than or equal to 1.7 mmol/l, n = 60) were divided to three groups (A, B and Q, and DM2 patients with hypertriglyceridaemia (TG &gt; 1. 7 mmol/l, n = 20) were designated group D. Group A was a control, and group B was designed to examine the one-dose effect of acarbose (100 mg) on lipid levels in MTT using the balanced food of 400 kcal. In groups C and D, acarbose 300 mg/day was administered for 8 weeks, and MTT with the one-dose acarbose administration was performed. We determined the levels of fasting and postprandial levels of glucose, insulin, FFA and TG-rich lipoproteins such as CM and VLDL. Results: Acarbose treatment lowered plasma glucose levels and insulin secretion. In comparison among study groups A, B and C, acarbose significantly lowered serum TG levels in postprandial state. In group D, after the 8-week acarbose administration, fasting or postprandial FFA, TG and VLDL levels were also lowered. Interestingly, postprandial increase in CM was suppressed by acarbose administration in group B, C or D. Conclusions: Acarbose lowers postprandial TG and CM levels in DM2 with either normotriglyceridaemia or hypertriglyceridaemia. Improvement of insulin resistance with acarbose may also reduce fasting TG levels in DM2 with hypertriglyceridaemia. Acarbose is a beneficial therapeutic agent to reduce TG levels in DM2 patients, thereby leading to suppression of cardiovascular events.

The localization of cytochrome P-450 4A, peroxisome proliferator-activated receptor (PPAR) alpha, and PPARgamma proteins, and the inducibility of P-450 4A expression and activity by PPAR agonists were determined in the rat kidney. The expressions of these proteins in isolated nephron segments were evaluated by immunoblot analysis, and the production of 20-hydroxyeicosatetraenoic acid (20-HETE) was measured as P-450 4A activity. P-450 4A proteins were expressed predominantly in the proximal tubule (PT), with lower expression in the preglomerular arteriole (Art), glomerulus (Glm), and medullary thick ascending limb (mTAL), but their expression was not detected in the inner medullary collecting duct (IMCD). PPARalpha protein was expressed in the PT and mTAL, and PPARgamma protein was expressed in the IMCD and mTAL. Treatment with clofibrate, the PPARalpha agonist, increased P-450 4A protein levels and the production of 20-HETE in microsomes prepared from the renal cortex, whereas treatment with pioglitazone, the PPARgamma agonist, affected neither of them. These results indicate that PPARalpha and PPARgamma proteins are localized in different nephron segments and the inducibility of P-450 4A expression and activity by the PPAR agonists correlates with the nephron-specific localization of the respective PPAR isoforms.

We monitored the change in plasma ANP and BNP levels (as markers for left ventricular dysfunction (LVD)) in DM2 patients treated with pioglitazone (Pio) for 4 weeks. Thirty DM2 patients with no sign of heart failure were treated with Pio (15mg/day), and their plasma ANP (normal levels less than or equal to43 pg/ml) and BNP levels (normal levels less than or equal to 18.4 pg/ml) were examined. We also examined those levels in no drug-treatment group (n = 10) as well as buformine treatment group (n = 10). Among these groups, there were no significant differences in clinical profiles related to DM control. Pio treatment was terminated when BNP (above 100 pg/ml) and ANP levels (above 50 pg/ml) suggested the left ventricular dysfunction (LVD). The patients (n = 12) whose BNP levels reached to the LVD-positive levels showed the basal BNP levels above the normal upper limit (18 pg/ml), while the rest of subjects (n = 18) whose basal BNP levels within normal limits did not showed the LVD-positive levels in the Pio-treatment. On the other hand basal ANP levels did not predict the development to LVD. In conclusion, BNP levels are suggested to be a good marker of Pio-induced LVD, and the Pio treatment of DM2 patients with BNP levels above the normal limit should be carefully carried out by monitoring BNP levels.

Over a 4-yr period in the northeast region of Japan (Tohoku), 3643 patients for whom a renal biopsy was available were screened. In addition, 2370 biopsied patients for whom hepatitis C virus (HCV) serology was available were evaluated. The prevalence of HCV infection was investigated in the 2370 biopsied patients. The highest prevalence of HCV infection was found in type II diabetic-related glomerulosclerosis (II-DGS) (24 of 123 19.5%). At renal biopsy, clinical and laboratory findings and histologic parameters were comparable between the HCV-positive and -negative II-DGS groups. After renal biopsy, the decline of renal function reflected by the slope of reciprocal serum creatinine (1/S(Cr)) was significantly greater in the HCV- positive group than in the HCV-negative group (P = 0.001). The log-rank test performed on the renal survival curves showed a significant difference in the two groups (P = 0.019). According to a multiple linear regression analysis adjusted for the effect of age, gender, BP, HbA1c, urinary protein excretion, and histologic parameters as covariates, urinary protein excretion (P = 0.011), severe arteriolar hyalinosis (P = 0.006), and HCV infection (P &lt 0.001) were significantly associated with 1/S(Cr) slope. Finally, HCV infection was randomly examined in 545 outpatients and inpatients with type II diabetes mellitus who did not undergo renal biopsy. Of these, 56 patients were positive for HCV antibody (10.3%), and their proteinuria was heavier than in 489 HCV-negative patients (P = 0.001). This study reveals that HCV infection is present at a high rate in type II diabetic-related nephropathy and may have an adverse effect on the progression of the disease.

The clinical efficacy of bezafibrate was examined with special reference to glucose metabolism in patients with type 2 diabetes mellitus (DM2). In protocol 1, 342 patients with DM2 and hyperlipidemias were randomly divided into 2 groups, Is-week bezafibrate treatment (n = 174) and no bezafibrate treatment (n = 168). In protocol 2, 20 DM2 patients were randomly divided into 2 groups, 8-week bezafibrate treatment (n = 10) and no bezafibrate treatment (n = 10), and a meal tolerance test (MTT) was performed. In protocol 1, bezafibrate treatment significantly reduced the fasting levels of triglyceride (TG) by 50% +/- 1.6%, total cholesterol (TC) by 12% +/- 1.1%, plasma glucose (PG) from 151.3 +/- 3.5 to 128.6 +/- 3.4 mg/dL, and hemoglobin A(10) (HbA(1c)) from 7.2% +/- 0.1% to 6.9% +/- 0.1%, and significantly increased high-density lipoprotein cholesterol (HDL-C) by 20% +/- 0.8%. In protocol 2, fasting TG, PG, and insulin levels were significantly reduced by bezafibrate treatment. Moreover, in the MTT, postprandial increments of TG were significantly blunted after bezafibrate treatment, whereas postprandial PG and insulin levels were not significantly changed. Leptin levels were significantly decreased, while tumor necrosis factor alpha (TNF-alpha) levels were not changed. In conclusion, both hyperglycemia and hyperlipidemia can be im proved by bezafibrate treatment in DM2. Copyright (C) 2000 by W.B. Saunders Company.

1. Therapeutic effects of a 5-HT2 receptor antagonist sarpogrelate on microalbuminuria and thromboxane (TX)A(2) biosynthesis were examined in non-insulin-dependent diabetes mellitus (NIDDM) patients. 2, In protocol I, the ankle-brachial pressure index (API; an indicator of peripheral blood flow) and urinary albumin excretion (UalbV; an indicator of renal function) were determined in 42 NIDDM patients who had been treated with 300 mg/day sarpogrelate for 8 weeks, In an analysis of the results, the NIDDM patients were divided into four groups based on the severity of either vasculopathy or nephropathy as follows: group A, API &lt; 0.9, UalbV greater than or equal to 100 mg/day; group B, API &lt; 0.9, UalbV &lt; 100 mg/day; group C API greater than or equal to 0.9, UalbV greater than or equal to 100 mg/day; and group D, API greater than or equal to 0.9, UalbV &lt; 100 mg/day, 3, In protocol TT, 10 NIDDM patients with UalbV values &gt; 100 mg/day were divided into two groups to further confirm the effect of sarpogrelate on albuminuria: group E, the sarpogrelate treatment group (n = 5); and group F,the no treatment group (n = 5), 4, In protocol I, the incidence of a cold sensation in the lower extremities was reduced from 45.2 to 21.4% following sarpogrelate treatment. In patients with UalbV greater than or equal to 100 mg/day (groups A and C), UalbV was significantly decreased independent of API, while it did not change in patients with UalbV &lt; 100 mg/day (groups B and D), Plasma TXB2 levels were significantly decreased following sarpogrelate treatment, whereas plasma 6-keto-prostaglandin F-1 alpha levels were not. 5, In protocol II, in the sarpogrelate treatment group (group E), albuminuria was significantly improved and both plasma levels TXB2 and urinary TXB2 excretion H-ere significantly decreased, In contrast, in the untreated group (group E), neither plasma levels TXB2 nor urinary TXB2 excretion was changed. 6, In conclusion, microalbuminuria was improved by treatment with the 5-HT2 receptor antagonist sarpogrelate independent of latent vasculopathy, Blockade of 5-HT2 receptors is suggested to be beneficial for the treatment of nephropathy in NIDDM patients. It is possible that the inhibition of TXA(2) biosynthesis is involved in the therapeutic effect of 5-HT2 receptor antagonists.

Neuropeptide Y (NPY) is a potent vasoconstrictor peptide that is abundant in the brain and the peripheral sympathetic nervous system. In the present study we investigated possible changes in plasma immunoreactive (IR)-NPY concentrations and urinary IR-NPY excretion in patients with noninsulin dependentdiabetes mellitus (NIDDM) and the relationship to diabetic complications, such as nephropathy and neuropathy. IR-NPY in plasma and urine was measured by radioimmunoassay in 69 patients with NIDDM. Plasma IR-NPY concentrations in patients with advanced nephropathy (creatinine clearance &lt;30 ml/min) (100.5 +/- 10.3 pmol/l, n=9, mean +/- SEM) were higher than in the control subjects (55.0 +/- 6.8 pmol/l, n=15) (P&lt;0.02). Urinary excretion of IR-NPY and fractional excretion of NPY were also increased in the patients with advanced nephropathy. Sephadex G-50 column chromatography of the urine extracts obtained from healthy subjects, diabetic patients with renal failure and non-diabetic patients with renal failure showed an immunoreactive peak eluting in the NPY position. On the other hand, neither plasma nor urinary IR-NPY was high in patients with retinopathy, or in patients with peripheral neuropathy. The present study has, for the first time, shown high plasma IR-NPY concentrations and urinary IR-NPY excretion in NIDDM patients with advanced nephropathy.

Hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) is a common intermediate metabolite of cholesterol synthesis and ketone formation in the liver. In order to study the effect of HMG-CoA reductase inhibitor (pravastatin) on ketone formation, changes in the plasma levels of ketone bodies by treatment with pravastatin were studied in 18 non-insulin dependent diabetics with hypercholesterolemia. Body mass index, diabetic control, and plasma free fatty acid levels were not changed during the study, and the plasma levels of cholesterol decreased significantly from 250+/-25 to 211+/-34 mg/100 ml after 6 months of pravastatin treatment. The plasma levels of acetoacetic acid also significantly decreased from 37.7+/-22.6 to 28.4+/-13.4 mu mol/l, and those of 3-hydroxybutyric acid and total ketone bodies also tended to decrease after pravastatin treatment. These results suggest that pravastatin decreases ketone formation in hepatic mitochondria besides cholesterol synthesis in hepatic microsome.

当科外来通院患者で糖化ヘモグロビンA1c (HbA<SUB>1</SUB>c) が6.8%以上の121名 (男性62名, 女性59名, インスリン依存糖尿病4名, インスリン非依存糖尿病117名) にボグリボース0.6mg3×1を投与, その前後で空腹時血糖 (FPG), 体重, HbA<SUB>1</SUB>cを6カ月後まで毎月追跡した. FPGは投与後4カ月より下降, 投与前153から投与後128-38mg/dlとなった. 体重減少もみられたが (投与前58.1, 後56.3-57.5kg), HbA1cは変化しなかった. 治療法別でみてもその効果に差は認められなかった. また食事療法のボグリボースの効果に及ぼす影響について, 糖質の摂取状況により食事療法遵守群 (n=47) と非遵守群 (n=74) に分け, 検討した.遵守群におけるHbA<SUB>1</SUB>cは下降した (投与前7.2, 後6.5) が非遵守群では変化しなかった. 以上の変化は体重の変化とは相関しなかった.ボグリボースの効果発現には食事摂取量, 特に糖質摂取量の遵守が重要であると思われた.

Although angiotensin II type 2 (AT(2)) receptor has recently been cloned, its functional role is not well understood. We tested the hypothesis that selective activation of AT(2) receptor causes vasodilation in the preglomerular afferent arteriole (Af-Art), a vascular segment that accounts for most of the preglomerular resistance. We microperfused rabbit Af-Arts at 60 mmHg in vitro, and examined the effect of angiotensin II (Ang II; 10(-11)-10(-8) M) on the luminal diameter in the presence or absence of the Ang II type 1 receptor antagonist CV11974 (CV; 10(-8) M). Ang II was added to both the bath and lumen of preconstricted Af-Arts, Ang II further constricted Af-Arts without CV (by 74 +/- 7% over the preconstricted level at 10(-8) M; P &lt; 0.01, n = 7). In contrast, in the presence of CV, Ang II caused dose-dependent dilation; Ang II at 10(-8) M increased the diameter by 29 +/- 2% (n = 7, P &lt; 0.01). This dilation was completely abolished by pretreatment with an AT(2) receptor antagonist PD123319 (10(-7) M, n = 6), suggesting that activation of AT(2) receptor causes vasodilation in Af-Arts, The dilation was unaffected by inhibiting either nitric oxide synthase (n = 7) or cyclooxygenase (n = 7), however, it was abolished by either disrupting the endothelium (n = 10) or inhibiting the cytochrome P-450 pathway, particularly the synthesis of epoxyeicosatrienoic acids (EETs, n = 7), These results suggest that in the Af-Art activation of the AT(2) receptor may cause endothelium-dependent vasodilation via a cytochrome P-450 pathway, possibly by EETs.