Directing-Group-Assisted Non-Strained Ether C-O Bond Homolysis Mediated by Low-Valent Titanium.

Ether C-O bonds are typical constituents of organic molecules that are seldom regarded as reactive functional groups except when highly strained. With the assistance of appropriate directing groups, low-valent titanium was found to homolytically cleave non-strained C-O bonds. In particular, a newly designed catechol monoether directing group rendered a route toward the activation of non-benzylic C(sp3)-O bonds. This method has been applied to conventional radical addition reactions to alkenes.

Therapeutic targeting of mitochondrial ROS ameliorates murine model of volume overload cardiomyopathy.

Concomitant heart failure is associated with poor clinical outcome in dialysis patients. The arteriovenous shunt, created as vascular access for hemodialysis, increases ventricular volume-overload, predisposing patients to developing cardiac dysfunction. The integral function of mitochondrial respiration is critically important for the heart to cope with hemodynamic overload. The involvement, however, of mitochondrial activity or reactive oxygen species (ROS) in the pathogenesis of ventricular-overload-induced heart failure has not been fully elucidated. We herein report that disorganization of mitochondrial respiration increases mitochondrial ROS production in the volume-overloaded heart, leading to ventricular dysfunction. We adopted the murine arteriovenous fistula (AVF) model, which replicates the cardinal features of volume-overload-induced ventricular dysfunction. Enzymatic assays of cardiac mitochondria revealed that the activities of citrate synthase and NADH-quinone reductase (complex Ⅰ) were preserved in the AVF heart. In contrast, the activity of NADH oxidase supercomplex was significantly compromised, resulting in elevated ROS production. Importantly, the antioxidant N-acetylcysteine prevented the development of ventricular dilatation and cardiac dysfunction, suggesting a pathogenic role for ROS in dialysis-related cardiomyopathy. A cardioprotective effect was also observed in metformin-treated mice, illuminating its potential use in the management of heart failure complicating diabetic patients on dialysis.

Clinical Implications of Baroreflex Sensitivity in Type 2 Diabetes.

The evaluation of baroreflex sensitivity (BRS), which maintains systemic circulatory homeostasis, is an established tool to assess cardiovascular autonomic neuropathy in type 2 diabetes mellitus (T2DM). As BRS plays an important function in blood pressure regulation, reduced BRS leads to an increase in blood pressure variability, which further leads to reduced BRS. This sequence of events becomes a vicious cycle. The major risk factors for reduced BRS are T2DM and essential hypertension, but many other risk factors have been reported to influence BRS. In recent years, reports have indicated that glycemic variability (GV), such as short- and long-term GV that are considered important risk factors for macrovascular and microvascular complications, is involved in reductions in BRS independently of blood glucose levels. In this review, we discuss reduced BRS in T2DM, its features, and the potential for its reversal.

Seasonal Variations in the Achievement of Guideline Targets for HbA1c, Blood Pressure, and Cholesterol Among Patients With Type 2 Diabetes: A Nationwide Population-Based Study (ABC Study: JDDM49).

OBJECTIVE: Precise monthly achievement rates for reaching guideline targets for HbA1c, blood pressure (BP), and lipid levels remain unknown. We evaluated achievement rates on a monthly basis in persons with type 2 diabetes mellitus (T2DM) and explored related factors. RESEARCH DESIGN AND METHODS: This retrospective study initially analyzed data on 104,601 persons with T2DM throughout Japan. Patients whose HbA1c, BP, and LDL cholesterol were measured ≥12 times during a 24-month period were included. We evaluated monthly achievement rates. Achieved targets were defined as HbA1c <7%, BP <130/80 mmHg, and LDL cholesterol <100 mg/dL. Achievement of all targets was expressed as the "all ABC achievement." RESULTS: A total of 4,678 patients were analyzed. The achievement rates of all ABC, HbA1c, BP, and LDL cholesterol were lowest in winter, with those for systolic BP (SBP) being particularly low (all ABC, summer 15.6%, winter 9.6%; HbA1c, 53.1%, 48.9%; SBP, 56.6%, 40.9%; LDL cholesterol, 50.8%, 47.2%). In winter, age ≥65 years (odds ratio 0.47 [95% CI 0.34-0.63]) was independently related to decreased achievement rates for SBP, BMI ≥25 kg/m2 (BMI 25-30 kg/m2, 0.45 [0.29-0.70]; BMI ≥30 kg/m2, 0.35 [0.22-0.57]), and diabetes duration ≥10 years (0.53 [0.37-0.76]) were independently related to lower achievement rates for HbA1c. Insulin use and sulfonylurea use were independently associated with the decreased all ABC achievement rates in both summer and winter. CONCLUSIONS: The all ABC achievement rate for guideline targets changed on a monthly basis. Seasonal variations in the all ABC achievement rate should be considered when managing T2DM in ordinary clinical practices.

Possibility of a New Therapeutic Strategy for Left Ventricular Dysfunction in Type 2 Diabetes.

Type 2 diabetes mellitus (T2DM) substantially increases the risk of cardiovascular events, including heart failure (HF), due to complications such as hypertension, obesity and dyslipidemia based on metabolic syndrome, which plays the central pathological role in HF. A reason is that T2DM causes left ventricular (LV) diastolic dysfunction beginning in the early phase of the disease, which in turn increases the risk of development of HF independently of the control of blood glucose levels, blood pressure or the presence of coronary artery diseases. Intracellular metabolic disorders and increased oxidative stress due to hyperglycemia, increased insulin resistance and chronic inflammation are pathogenic mechanisms involved in the LV diastolic dysfunction caused by T2DM. These mechanisms lead to structural changes in the heart such as LV hypertrophy and interstitial fibrosis, resulting in HF. The prevalence of HF with preserved ejection fraction (HFpEF), the major pathology of LV diastolic dysfunction, has been increasing recently, and a high incidence of HFpEF in patients with T2DM was reported. An effective therapy has not been established for HFpEF because multiple comorbidities such as advanced age, hypertension, obesity, dyslipidemia, chronic kidney disease and atrial fibrillation as well as diabetes are involved in its pathology. In the present review, we review the involvement of associated conditions such as hypertension, obesity and advanced age from the aspect of the T2DM and LV diastolic dysfunction and discuss the possibility of the development of a new therapeutic strategy for LV diastolic dysfunction and HFpEF.

Type 2 Diabetes and Glycemic Variability: Various Parameters in Clinical Practice.

It has become possible to measure blood glucose levels continuously from 24 h to approximately 2 weeks due to the recent development of relevant devices such as continuous glucose monitoring and flash glucose monitoring systems. This has enabled not only medical professionals but also patients to monitor details of glycemic variability (GV) which was not possible in the past. Details of GV for both short and intermediate periods can now be obtained, and it is important in patient care to appropriately evaluate the data obtained. Types of GV in terms of time frame vary from short-term to long-term. Several studies reported that long-term GV was related to micro- and macro-angiopathies in patients with type 2 diabetes mellitus (T2DM). However, there are still unknown aspects regarding the relationships of various durations of GV with prognosis. Further clinical trials are required to examine the mechanism of GV and to evaluate whether GV can be a valuable therapeutic target in treatment of patients with T2DM.

Visit-to-visit HbA1c variability is inversely related to baroreflex sensitivity independently of HbA1c value in type 2 diabetes.

BACKGROUND: The relationship between long-term glycemic variability (GV) represented by visit-to-visit HbA1c variability and baroreflex sensitivity (BRS) in type 2 diabetes mellitus (T2DM) has not been clarified by previous literature. The present study is the first to examine the relationships between visit-to-visit HbA1c variability and BRS. METHODS: This retrospective study initially analyzed data on 94 patients with T2DM. Visit-to-visit HbA1c variability was evaluated using the intrapersonal coefficient of variation (CV), standard deviation (SD), and adjusted SD of 8 or more serial measurements of HbA1c during a 2-year period. The BRS was analyzed using the sequence method. Short-term GV was assessed by measuring the glucose CV during 24-h continuous glucose monitoring (CGM). The primary objective was to determine if there was a relationship between visit-to-visit HbA1c variability (HbA1c CV) and BRS. Secondary objectives were to examine the relationship between other variables and BRS and the respective and combined effects of long-term GV (HbA1c CV) and short-term GV (CGM CV) on BRS. RESULTS: A total of 57 patients (mean age 67.2 ± 7.7 years, mean HbA1c 7.3 ± 1.0%) who met this study's inclusion criteria were finally analyzed. In the univariate analysis, HbA1c CV (r = - 0.354, p = 0.007), HbA1c SD (r = - 0.384, p = 0.003), and adjusted HbA1c SD (r = - 0.391, p = 0.003) were significantly related to low levels of BRS. Multiple regression analysis showed that HbA1c CV, HbA1c SD, and adjusted HbA1c SD were inversely related to BRS. Furthermore, although the increase in either long-term GV (HbA1c CV) or short-term GV (CGM CV) as determined by 24-h CGM was inversely correlated with BRS, additional reductions in BRS were not shown in participants with both HbA1c CV and CGM CV values above the median. CONCLUSIONS: Visit-to-visit HbA1c variability was inversely related to BRS independently of the mean HbA1c in patients with T2DM. Therefore, visit-to-visit HbA1c variability might be a marker of reduced BRS in T2DM.

Effect of canagliflozin on left ventricular diastolic function in patients with type 2 diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) greatly increases the risks of cardiovascular disease and heart failure. In particular, left ventricular diastolic dysfunction that develops from the early stages of T2DM is an important factor in the onset and exacerbation of heart failure. The effect of sodium-glucose cotransporter 2 inhibitors on left ventricular diastolic function has not been elucidated. We have performed the first prospective study on the effects of canagliflozin on left ventricular diastolic function in T2DM. METHODS: This study was performed to evaluate the effects of additional treatment with canagliflozin for 3 months on left ventricular diastolic function in patients with T2DM. A total of 38 patients with T2DM were consecutively recruited for this study. Left ventricular diastolic function was assessed by echocardiography. The primary study outcome was a change in the septal E/e' as a parameter of left ventricular diastolic function. RESULTS: A total of 37 patients (25 males and 12 females) were included in the analysis. Mean age of participants was 64.2 ± 8.1 years (mean ± SD), mean duration of diabetes was 13.5 ± 8.1 years, and mean HbA1c was 7.9 ± 0.7%. Of the participants, 86.5% had hypertension, 100% had dyslipidemia, and 32.4% had cardiovascular disease. Canagliflozin significantly improved left ventricular diastolic function (septal E/e' ratio 13.7 ± 3.5-12.1 ± 2.8, p = 0.001). Furthermore, among the various parameters that changed through the administration of canagliflozin, only changes in hemoglobin significantly correlated with changes in the septal E/e' ratio (p = 0.002). In multiple regression analysis, changes in hemoglobin were also revealed to be an independent predictive factor for changes in the septal E/e' ratio. CONCLUSIONS: This study showed for the first time that canagliflozin could improve left ventricular diastolic function within 3 months in patients with T2DM. The benefit was especially apparent in patients with substantially improved hemoglobin values. Trial registration UMIN Clinical Trials Registry UMIN000028141.

Glycemic variability in continuous glucose monitoring is inversely associated with baroreflex sensitivity in type 2 diabetes: a preliminary report.

BACKGROUND: It is presently unclear whether glycemic variability (GV) is associated with baroreflex sensitivity (BRS), which is an early indicator of cardiovascular autonomic neuropathy. The present study is the first to examine the relationships between BRS and GV measured using continuous glucose monitoring (CGM). METHODS: This was a multicenter, prospective, open-label clinical trial. A total of 102 patients with type 2 diabetes were consecutively recruited for this study. GV was assessed by measuring the standard deviation (SD), glucose coefficient of variation (CV), and the mean amplitude of glycemic excursions (MAGE) during CGM. The BRS was analyzed from electrocardiogram and blood pressure recordings using the sequence method on the first day of hospitalization. RESULTS: A total of 94 patients (mean diabetes duration 9.7 ± 9.6 years, mean HbA1c 61.0 ± 16.8 mmol/mol [7.7 ± 1.5%]) were analyzed. In the univariate analysis, CGM-SD (r = - 0.375, p = 0.000), CGM-CV (r = - 0.386, p = 0.000), and MAGE (r = - 0.395, p = 0.000) were inversely related to BRS. In addition to GV, the level of BRS correlated with the coefficient of variation in the R-R intervals (CVR-R) (r = 0.520, p = 0.000), heart rate (HR) (r = - 0.310, p = 0.002), cardio-ankle vascular index (CAVI) (r = - 0.326, p = 0.001), age (r = - 0.519, p = 0.000), and estimated glomerular filtration rate (eGFR) (r = 0.276, p = 0.007). Multiple regression analysis showed that CGM-CV and MAGE were significantly related to a decrease in BRS. These findings remained after adjusting the BRS for age, sex, hypertension, dyslipidemia, HR, eGFR, CAVI, and CGM-mean glucose. Additionally, BRS was divided according to quartiles of the duration of diabetes (Q1-4). BRS decreased after a 2-year duration of diabetes independently of age and sex. CONCLUSIONS: GV was inversely related to BRS independently of blood glucose levels in type 2 diabetic patients. Measurement of BRS may have the potential to predict CV events in consideration of GV. Trial registration UMIN Clinical Trials Registry UMIN000025964, 28/02/2017.

Primary Aldosteronism With Type 2 Diabetes Mellitus Requires More Antihypertensive Drugs for Blood Pressure Control: A Retrospective Observational Study.

BACKGROUND: Diabetes mellitus (DM) and primary aldosteronism (PA) have been reported to induce drug-resistant hypertension and atherosclerosis. It is likely that blood pressure (BP) control becomes far more difficult in PA patients with DM. However, precise clinical characteristics of PA with type 2 DM especially in the aspect of BP control are not clear. METHODS: The study included 18 patients who were diagnosed as PA with DM and 52 PA patients without DM who matched age and sex and chosen as a control group. We have compared differences in BP control, use of antihypertensive agents and clinical characteristics between PA patients with and without DM. RESULTS: There was no difference with regard to the duration of hypertension and BP control between either group. Interestingly, the PA with DM group was found to require more antihypertensive agents than the PA without DM group (number of antihypertensive agents used, 2.0 ± 1.5 vs. 1.3 ± 1.1; P < 0.05, respectively). In the 28 patients who underwent measurement of central BP (CBP) values, plasma aldosterone concentration (PAC) was high in the PA with DM group. Furthermore, a positive correlation was shown between PAC and CBP (r = 0.58; P < 0.01); the higher the PAC, the higher the CBP of patient. CONCLUSIONS: These results might suggest that hypertension becomes more difficult to control in PA patients with DM in the future.

High Glucose Stimulates Mineralocorticoid Receptor Transcriptional Activity Through the Protein Kinase C ß Signaling.

Activation of mineralocorticoid receptor (MR) is shown in resistant hypertension including diabetes mellitus. Although protein kinase C (PKC) signaling is involved in the pathogenesis of diabetic complications, an association between PKC and MR is not known. Activation of PKCα and PKCß by TPA (12-O-Tetradecanoylphorbol 13-acetate) increased MR proteins and its transcriptional activities in HEK293-MR cells. In contrast, a high glucose condition resulted in PKCß but not PKCα activation, which is associated with elevation of MR protein levels and MR transcriptional activities. Reduction of endogenous PKCß by siRNA decreased those levels. Interestingly, high glucose did not affect MR mRNA levels, but rather decreased ubiquitination of MR proteins. In db/db mice kidneys, levels of phosphorylated PKCß2, MR and Sgk-1 proteins were elevated, and the administration of PKC inhibitor reversed these changes compared to db/+ mice. These data suggest that high glucose stimulates PKCß signaling, which leads to MR stabilization and its transcriptional activities.

Time-dependent effects of ipragliflozin on behaviour and energy homeostasis in normal and type 2 diabetic rats: continuous glucose telemetry analysis.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral antidiabetic drugs that promote urinary glucose excretion. Conversely, they cause behavioural changes, such as hyperphagia, that result in a positive energy balance. The relationship between energy homeostasis and SGLT2 inhibitors-induced behavioural changes remains unclear. Here we show that ipragliflozin, a SGLT2 inhibitor, time-dependently affects behaviour and enhances energy expenditure in normal and type 2 diabetic Goto-Kakizaki (GK) rats, using continuous glucose telemetry. Alongside increased urinary glucose excretion, ipragliflozin increased total food and water intakes in normal and GK rats. In normal rats, ipragliflozin treatment acutely disturbed the circadian rhythms of food and water intakes, activity, and body temperature. Subsequently, these rhythms gradually returned towards a normal state. However, activity and body temperature remained suppressed. In GK rats, ipragliflozin did not affect circadian rhythms. Blood glucose values assessed by glucose telemetry were significantly reduced in both ipragliflozin-treated groups. Despite these behavioural and glycaemic changes, ipragliflozin significantly increased oxygen consumption during dark and light periods in both groups. Ipragliflozin reduced body weight in normal rats only. Thus, ipragliflozin decreases blood glucose beyond compensatory hyperphagia in normal and GK rats, resulting in enhanced basal energy expenditure, despite acutely altering circadian rhythms in normoglycaemic individuals.

Association between day-by-day and ambulatory blood pressure variability in type 2 diabetes patients.

It remains unclear whether ambulatory blood pressure variability (BPV) contributes toward day-by-day BPV, despite the fact that not only day-by-day but also ambulatory BPV is reported to be a risk factor for type 2 diabetes patients. This study aimed to determine the association between day-by-day BPV and ambulatory BPV, which is especially distinguished between diurnal and nocturnal BPV, in type 2 diabetes patients. Day-by-day and ambulatory BPV were assessed in 30 type 2 diabetes patients (aged 54±15 years; 87% men; glycated hemoglobin: 9.1±1.9%) in inpatient settings. Day-by-day systolic BPV was correlated significantly with diurnal systolic BPV (r=0.426, P=0.019), but not nocturnal systolic BPV (r=0.175, P=0.354). Multiple regression analysis showed that diurnal systolic BPV and diurnal mean systolic blood pressure were associated independently with day-by-day systolic BPV. With respect to type 2 diabetes, these findings suggest that day-by-day BPV is reflected in diurnal BPV rather than nocturnal BPV.

The Durability of Basal Insulin Affects Day-to-Day Glycemic Variability Assessed by Continuous Glucose Monitoring in Type 2 Diabetes Patients: A Randomized Crossover Trial.

BACKGROUND: Not only within-day glycemic variability but also day-to-day glycemic variability is a risk factor for diabetic patients. However, the ways of controlling day-to-day glycemic variability are unclear. We hypothesized that the durability of basal insulin plays an important role in controlling day-to-day glycemic variability in type 2 diabetes patients, and we therefore aimed to evaluate whether glargine U300, which exhibits prolonged absorption compared with glargine U100 but the same composition as glargine U100, would lead to improved day-to-day glycemic variability. MATERIALS AND METHODS: This was a single-center, randomized, open-label, crossover study in type 2 diabetes patients using basal insulin therapy. After switching from 4 weeks of treatment with glargine U100 or U300, the patients performed continuous glucose monitoring (CGM) for 72 h in an environment with routine activities and mealtimes. The mean of daily difference (MODD) was assessed as day-to-day glycemic variability. RESULTS: We enrolled 22 patients, and 17 patients completed the study. The MODD assessed as day-to-day glycemic variability was significantly lower with glargine U300 than with glargine U100 (1.8 ± 0.6 mmol/L vs. 2.4 ± 0.9 mmol/L, P = 0.006). No significant difference was observed in short-term glycemic variability between the two glargine formulations as measured by the standard deviation, coefficient of variation, mean amplitude of glucose excursion. CONCLUSIONS: Compared with glargine U100 treatment, glargine U300 treatment improved the MODD as assessed by CGM in type 2 diabetes patients. These findings suggest that the durability of basal insulin may be associated with day-to-day glycemic variability in type 2 diabetes patients.

Effect of One-Week Salt Restriction on Blood Pressure Variability in Hypertensive Patients with Type 2 Diabetes.

BACKGROUND: Increased short-term blood pressure (BP) variability on 24-hour ambulatory BP monitoring (ABPM) is known to be a risk factor for cardiovascular events. However, very few studies have evaluated the effect of salt restriction on BP variability particularly in hypertensive patients with type 2 diabetes. This study aimed to investigate the effect of salt restriction on systolic BP (SBP) variability. METHODS AND RESULTS: 10 hypertensive patients with type 2 diabetes and not receiving antihypertensive agents were enrolled in the study. After admission, all patients received a salt-restricted diet and appropriate anti-diabetic treatments and were followed up for 7 consecutive days using ABPM. After the 7-day treatment, the median [interquartile range (IQR)] coefficient of variation (CV) for diurnal SBP variability changed from day 1 to day 7-13.0 [10.8 to 16.8] % to 13.3 [9.1 to 18.9] % (P = 0.959)--and the median [IQR] change between days 1 and 7 was -0.3 [-3.2 to 2.9] %. In addition, CV for BP variability and circadian rhythm of BP varied greatly on a day-by-day basis for 7 days, compared to mean BP values. Interestingly, increased SBP variability was associated with greater day-by-day changes in circadian rhythm of BP. CONCLUSIONS: Salt restriction during 7-day hospitalization led to a -0.3 [-3.2 to 2.9] (median [IQR]) % change from baseline in CV for diurnal SBP variability in 10 hypertensive patients with type 2 diabetes not receiving antihypertensive agents. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000016243.

Aldosterone-producing adrenocortical carcinoma with prominent hepatic metastasis diagnosed by liver biopsy: a case report.

BACKGROUND: Aldosterone-producing adrenocortical carcinoma is a rare malignancy, which is usually diagnosed by histopathological examination of the excised tumor. In inoperable cases, aldosterone-producing ACC diagnosed by immunohistochemical staining of the metastatic tumor for Cytochrome P450 (CYP) 11ß has not previously been reported and even in that case staining for adrenocortical-specific adrenal 4 binding protein/steroidogenic factor1 (Ad4BP/SF1) and steroidogenic enzymes has not been reported. CASE PRESENTATION: We report the case of a 67-year-old Japanese woman with aldosterone-producing adrenocortical carcinoma. Laboratory findings showed severe hypopotassemia. Endocrinological examination revealed an increased plasma aldosterone concentration and suppressed plasma renin activity. Plasma dehydroepiandrosterone sulfate (DHEA-S) was elevated. Diurnal variation in serum cortisol was lost and administration of 1 mg and 8 mg dexamethasone did not suppress serum cortisol levels. From the 24-h urine collection sample, urine aldosterone and urine cortisol levels were greatly increased. Therefore, autonomous excess production was observed for the three adrenal cortex hormones. Abdominal computed tomography and magnetic resonance imaging showed a right adrenal tumor and a huge liver tumor. Adrenocortical carcinoma with metastatic liver cancer was strongly suggested, however surgery could not be considered due to stage IV disease: the liver tumor was too large and cardiac ultrasonography indicated that her cardiac function was poor. Therefore, a liver biopsy was taken to properly determine the diagnosis. Immunohistochemical stains for Ad4BP/SF1 and steroidogenic enzymes were positive. Ad4BP/SF-1 was originally identified as a steroidogenic, tissue-specific transcription factor implicated in the expression of the steroidogenic CYP gene encoding cytochrome P450s. Hence we could diagnose the patient as having adrenocortical carcinoma with metastatic liver cancer. CONCLUSION: This rare case had severe hypopotassemia accompanied with not only increased cortisol and DHEA-S but also aldosterone. We reached the diagnosis of adrenocortical carcinoma with metastatic liver cancer based on positive immunohistochemical staining of Ad4BP/SF1 in the liver biopsy specimen. We have reported the first case of aldosterone-producing adrenocortical carcinoma diagnosed solely by immunohistochemical staining for adrenocortical-specific Ad4BP/SF1 and steroidogenic enzymes in a metastatic liver tumor.

Diabetic Cardiovascular Disease Induced by Oxidative Stress.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes mellitus (DM). DM can lead to multiple cardiovascular complications, including coronary artery disease (CAD), cardiac hypertrophy, and heart failure (HF). HF represents one of the most common causes of death in patients with DM and results from DM-induced CAD and diabetic cardiomyopathy. Oxidative stress is closely associated with the pathogenesis of DM and results from overproduction of reactive oxygen species (ROS). ROS overproduction is associated with hyperglycemia and metabolic disorders, such as impaired antioxidant function in conjunction with impaired antioxidant activity. Long-term exposure to oxidative stress in DM induces chronic inflammation and fibrosis in a range of tissues, leading to formation and progression of disease states in these tissues. Indeed, markers for oxidative stress are overexpressed in patients with DM, suggesting that increased ROS may be primarily responsible for the development of diabetic complications. Therefore, an understanding of the pathophysiological mechanisms mediated by oxidative stress is crucial to the prevention and treatment of diabetes-induced CVD. The current review focuses on the relationship between diabetes-induced CVD and oxidative stress, while highlighting the latest insights into this relationship from findings on diabetic heart and vascular disease.

Nicotine regulates the expression of UDP-glucuronosyltransferase (UGT) in humanized UGT1 mouse brain.

UDP-glucuronosyltransferase (UGT) is a family of enzymes that catalyze the glucuronidation of various compounds, and thereby has an important role in metabolism and detoxification of a large number of xenobiotic and endogenous compounds. UGTs are present highly in the liver and small intestine, while several investigations on quantification of UGT mRNA reported that UGTs were also expressed in the brain. However, reported expression patterns of UGT isoforms in human brain were often incongruous with each other. In the present study, therefore, we investigated UGT mRNA expressions in brains of humanized UGT1 (hUGT1) mice. We found that among the human UGT1 members, UGT1A1, 1A3, and 1A6 were expressed in the brain. We further observed that nicotine (3 mg/kg) induced the expression of UGT1A3 mRNA in the brain, but not liver. While it was not statistically significant, the nicotine treatment resulted in an increase in the chenodeoxycholic acid glucuronide-formation activity in the brain microsomes. UGT1A3 is involved in metabolism of various antidepressants and non-steroidal antiinflammatory drugs, which exhibit their pharmacological effects in the brain. Therefore, nicotine-treated hUGT1 mice might be useful to investigate the role of brain UGT1A3 in the regulation of local levels of these drugs and their response.

Underlying mechanism of drug-drug interaction between pioglitazone and gemfibrozil: Gemfibrozil acyl-glucuronide is a mechanism-based inhibitor of CYP2C8.

While co-administered gemfibrozil can increase the area under the concentration/time curve (AUC) of pioglitazone more than 3-fold, the underlying mechanism of the drug-drug interaction between gemfibrozil and pioglitazone has not been fully understood. In the present study, gemfibrozil preincubation time-dependently inhibited the metabolism of pioglitazone in the cytochrome P450 (CYP)- and UDP-glucuronosyltransferase (UGT)-activated human liver microsomes. We estimated the kinact and K'app values, which are the maximum inactivation rate constant and the apparent dissociation constant, of gemfibrozil to be 0.071 min(-1) and 57.3 µM, respectively. In this study, the kobs, in vivo value was defined as a parameter that indicates the potency of the mechanism-based inhibitory effect at the blood drug concentration in vivo. The kobs, in vivo values of potent mechanism-based inhibitors, clarithromycin and erythromycin, were estimated to be 0.0096 min(-1) and 0.0051 min(-1), respectively. The kobs, in vivo value of gemfibrozil was 0.0060 min(-1), which was comparable to those of clarithromycin and erythromycin, suggesting that gemfibrozil could be a mechanism-based inhibitor as potent as clarithromycin and erythromycin in vivo.

Expression of UDP-Glucuronosyltransferase 1 (UGT1) and Glucuronidation Activity toward Endogenous Substances in Humanized UGT1 Mouse Brain.

Although UDP-glucuronosyltransferases (UGTs) are important phase II drug-metabolizing enzymes, they are also involved in the metabolism of endogenous compounds. Certain substrates of UGTs, such as serotonin and estradiol, play important roles in the brain. However, the expression of UGTs in the human brain has not been fully clarified. Recently, humanized UGT1 mice (hUGT1 mice) in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus have been developed. In the present study, the expression pattern of UGT1As in brains from humans and hUGT1 mice was examined. We found that UGT1A1, 1A3, 1A6, and 1A10 were expressed in human brains. The expression pattern of UGT1As in hUGT1 mouse brains was similar to that in human brains. In addition, we examined the expression of UGT1A1 and 1A6 in the cerebellum, olfactory bulbs, midbrain, hippocampus, and cerebral cortex of hUGT1 mice. UGT1A1 in all brain regions and UGT1A6 in the cerebellum and cerebral cortex of 6-month-old hUGT1 mice were expressed at a significantly higher rate than those of 2-week-old hUGT1 mice. A difference in expression levels between brain regions was also observed. Brain microsomes exhibited glucuronidation activities toward estradiol and serotonin, with mean values of 0.13 and 5.17 pmol/min/mg, respectively. In conclusion, UGT1A1 and UGT1A6 might play an important role in function regulation of endogenous compounds in a region- and age-dependent manner. Humanized UGT1 mice might be useful to study the importance of brain UGTs in vivo.