Fluorine-19 magnetic resonance imaging probe for the detection of tau pathology in female rTg4510 mice.

Aggregation of tau into neurofibrillary tangles (NFTs) is characteristic of tauopathies, including Alzheimer's disease. Recent advances in tau imaging have attracted much attention because of its potential contributions to early diagnosis and monitoring of disease progress. Fluorine-19 magnetic resonance imaging (19 F-MRI) may be extremely useful for tau imaging once a high-quality probe has been formulated. In this investigation, a novel fluorine-19-labeling compound has been developed as a probe for tau imaging using 19 F-MRI. This compound is a buta-1,3-diene derivative with a polyethylene glycol side chain bearing a CF3 group and is known as Shiga-X35. Female rTg4510 mice (a mouse model of tauopathy) and wild-type mice were intravenously injected with Shiga-X35, and magnetic resonance imaging of each mouse's head was conducted in a 7.0-T horizontal-bore magnetic resonance scanner. The 19 F-MRI in rTg4510 mice showed an intense signal in the forebrain region. Analysis of the signal intensity in the forebrain region revealed a significant accumulation of fluorine-19 magnetic resonance signal in the rTg4510 mice compared with the wild-type mice. Histological analysis showed fluorescent signals of Shiga-X35 binding to the NFTs in the brain sections of rTg4510 mice. Data collected as part of this investigation indicate that 19 F-MRI using Shiga-X35 could be a promising tool to evaluate tau pathology in the brain.

Short duration of diabetes and disuse of sulfonylurea have any association with insulin cessation of the patients with type 2 diabetes in a clinical setting in Japan (JDDM 30).

Insulin therapy is often required to achieve good glycemic control for the patients with type 2 diabetes mellitus (T2DM), while protraction of glycemic control without insulin therapy may be preferable for patients. To determine the characteristics of and therapeutic regimen in outpatients with T2DM who were able to stop insulin therapy with satisfactory glycemic control in a real clinical practice setting in Japan by a case-control study. The present study was performed on 928 patients with T2DM who started insulin therapy in 2007. Data regarding age, sex, body mass index, duration of diabetes, HbA1c, postprandial plasma glucose, plasma fasting C-peptide immunoreactivity and treatment modality were compared between patients who were able to stop insulin therapy and those who continued with insulin. Of the 928 patients, 37 had stopped insulin therapy within 1 year. In the patients who stopped insulin therapy, the duration of diabetes was significantly shorter and the daily insulin dosage at initiation and the prevalence of sulfonylurea pretreatment significantly lower compared with patients who continued on insulin. In conclusion, almost 4% of T2DM patients were able to stop insulin therapy with satisfactory glycemic control in a real clinical practice setting in Japan. Shorter duration of diabetes and disuse of sulfonylureas prior to insulin may associate with stopping insulin therapy as a near-normoglycemic remission in outpatients with T2DM in Japan.

Differences in Dental Care Referral for Diabetic Patients Between General Practitioners and Diabetes Specialists in Japan, Analyzed from NSAID-Study 3.

INTRODUCTION: Periodontal disease is a common inflammation worldwide and is not only the foremost cause of tooth loss but also a cause of deterioration of glycemic control in patients with diabetes mellitus. In addition, effective glycemic management improves the control of periodontitis infection. The aim of this study was to clarify whether awareness of the need to refer their patients with diabetes to dentists differs between general practitioners and diabetes specialists. This was achieved by secondary analysis of data from the 2018 Nationwide Survey on Actual Intervention for Type 2 Diabetes Mellitus (T2DM) by Japanese Practitioners (NSAID Study). METHODS: Data from 380 general practitioners and 79 diabetes specialists who participated in the NSAID study and responded to the question of whether they referred T2DM patients to the dentist were analyzed in this study. RESULTS: The proportion of general practitioners who referred T2DM patients to dentists was significantly lower than that of diabetes specialists (35.4% vs. 64.1%, respectively). CONCLUSION: This result suggests that the general practitioners who participated in this study were less cognizant of oral hygiene in patients with diabetes than those who specialized in diabetes. It is also necessary to increase the opportunities for education of physicians who provide diabetic care to promote appropriate dental referrals.

Periodontal disease is a common inflammation worldwide and not only causes tooth loss but also the deterioration of glycemic control in patients with diabetes. In addition, effective glycemic management improves the control of periodontitis infection. Physicians who care for diabetes patients need to be aware of the increased risk and need for improved oral hygiene and to refer their patients to dentists. This study aims to clarify whether awareness of the need to refer their patients with diabetes to dentists differs between general practitioners and diabetes specialists. Responses from 380 general practitioners and 79 diabetes specialists are analyzed in this study. The proportion of general practitioners who refer type 2 diabetes patients to dentists is shown to be significantly lower than that of diabetes specialists. It is necessary to increase the opportunities for education of physicians who provide diabetic care to promote appropriate dental referrals.

Keto form of curcumin derivatives strongly binds to Aß oligomers but not fibrils.

The accumulation of ß-amyloid (Aß) aggregates in the brain occurs early in the progression of Alzheimer's disease (AD), and non-fibrillar soluble Aß oligomers are particularly neurotoxic. During binding to Aß fibrils, curcumin, which can exist in an equilibrium state between its keto and enol tautomers, exists predominantly in the enol form, and binding activity of the keto form to Aß fibrils is much weaker. Here we described the strong binding activity the keto form of curcumin derivative Shiga-Y51 shows for Aß oligomers and its scant affinity for Aß fibrils. Furthermore, with imaging mass spectrometry we revealed the blood-brain barrier permeability of Shiga-Y51 and its accumulation in the cerebral cortex and the hippocampus, where Aß oligomers were mainly localized, in a mouse model of AD. The keto form of curcumin derivatives like Shiga-Y51 could be promising seed compounds to develop imaging probes and therapeutic agents targeting Aß oligomers in the brain.

Trifluoromethoxy-benzylated ligands improve amyloid detection in the brain using (19)F magnetic resonance imaging.

The chemical properties of probes that improve amyloid detection by non-invasive (19)F magnetic resonance imaging (MRI) are of interest. We synthesized benzoxazole compounds with trifluoromethoxy groups, and found that these compounds displayed sharp (19)F nuclear magnetic resonance (NMR) signals in an assay buffer. However, the intensities of the (19)F NMR signals were dramatically reduced in mouse brain lysates. Our results indicate that the inhibitory effect of brain tissue on the (19)F NMR signals from these probes can be attributed to the hydrophobicity of the tissue. These results highlight the importance of using hydrophilic (19)F-MRI agents to avoid the inhibitory effects of brain tissues on (19)F NMR signals.

Effect of canagliflozin on the overall clinical state including insulin resistance in Japanese patients with type 2 diabetes mellitus.

AIMS: Information on the clinical efficacy of SGLT2 inhibitors in the Japanese population is limited. The aim of this single-arm, single-center, open-label study was to confirm the body weight- and fat mass-lowering effects of canagliflozin (CANA) and the accompanying improvement in insulin resistance in Japanese patients with Type 2 diabetes mellitus (T2DM). METHODS: Thirty-eight patients were enrolled and administered 100 mg CANA once daily for 24 weeks. Blood and anthropometric parameters were examined before and after treatment. In a subset of patients, insulin sensitivity was assessed based on the glucose infusion rate (GIR) during a hyperinsulinemic euglycemic clamp test. RESULTS: CANA treatment significantly decreased hemoglobin A1c, fasting plasma glucose, and plasma liver enzyme levels, and increased plasma adiponectin levels. In addition, a significant reduction in body weight, visceral and subcutaneous fat area, fat and lean mass, and liver steatosis was also observed. The change in plasma adiponectin levels significantly correlated with the changes in both body fat mass and visceral fat area. GIR increased from 3.25 ±â€¯1.53 to 4.11 ±â€¯1.30 mg/kg/min (P < 0.05). CONCLUSIONS: CANA improved insulin resistance and decreased visceral fat mass in Japanese patients with T2DM.

Association between body mass index and core components of metabolic syndrome in 1486 patients with type 1 diabetes mellitus in Japan (JDDM 13).

There is no recent study on the prevalence of overweight and obesity in patients with type 1 diabetes mellitus (T1DM) in Japan. Being overweight has a significant effect on the metabolic condition and glycemic control of such patients. In the present cross-sectional study, we investigated the effects of body mass index (BMI) on lipid profile, blood pressure, and glycemic control in patients with T1DM. In total, 1486 patients with T1DM (including 401 patients with early onset T1DM who were <20 years of age at diagnosis) were included. Patients were divided into four groups according to their BMI, and glycosylated hemoglobin (HbA1c), daily insulin dose per kg body weight, lipid profile, and blood pressure were compared between groups. We found that 15.7% of all patients were overweight (BMI >or= 25.0 kg/m(2)) and 2.0% were obese (BMI >or= 30.0 kg/m(2)), compared with 17.5% and 2.0%, respectively, in the early onset T1DM subgroup. Significant changes in lipid profiles and blood pressure were found with increasing BMI in both the entire population and the early onset T1DM subgroup. In the entire study population HbA1c and the body weight-adjusted daily insulin dose were significantly higher in patients with a BMI >or= 23 kg/m(2) compared with those with a BMI<23 kg/m(2); however, this was not the case in the early onset T1DM subgroup. This difference may be due to the relatively small number of patients in that subgroup. In conclusion, the prevalence of overweight and obesity in patients with T1DM was less than that in the normal Japanese population. For patients with T1DM, being overweight was associated with higher blood pressure and dyslipidemia. Furthermore, we cannot exclude an association between being overweight and the need for higher daily doses of insulin.

Comparison of the pharmacokinetic and pharmacodynamic profiles of biphasic insulin aspart 50 and 30 in patients with type 2 diabetes mellitus: a single-center, randomized, double-blind, two-period, crossover trial in Japan.

BACKGROUND: To overcome the complicated mixing procedures required in the use of insulin formulations, premixed formulations consisting of rapid-acting and intermediate-type insulin in various mixing proportions have been developed. Biphasic insulin aspart 50 (BIAsp50) and 30 (BlAsp30) are 2 premixed formulations containing the active ingredient insulin aspart (IAsp) and consisting of a rapid-acting component soluble IAsp) and intermediate-acting component (protamine-crystallized protracted IAsp) in ratios of 50/50 and 30/70, respectively. These formulations are provided with the expectation that BIAsp30 and BIAsp50 will be beneficial for patients needing to improve their postprandial blood glucose control without changing their dietary habits and lifestyles. BIAsp30 has been widely used in medical practice, whereas BIAsp50 is being investigated in clinical trials. OBJECTIVE: The aim of this study was to compare the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of BIAsp50 (test) and BIAsp30 (reference) after single-dose SC injection in patients with type 2 diabetes mellitus. METHODS: This single-center, randomized, doubleblind, 2-period, crossover trial was conducted at the H.E.C. Science Clinic, Yokohama, Japan. Male and female patients aged > or = 20 years with a > or = 1 year history of type 2 diabetes were eligible. Patients were randomly assigned to 1 of 2 treatment sequences: group A received BIAsp30 in period 1 and BIAsp50 in period 2; group B received BIAsp50 in period 1 and BIAsp30 in period 2. All treatments were administered as an SC injection of a single dose (0.3 U/kg). The study periods were separated by a washout period of 4 to 21 days. For PK analysis of IAsp (maximum serum IAsp concentration [C(max,IAsp); primary end point], AUC of serum IAsp 0 to 120, 240, and 480 minutes after administration [AUC(0-120 min,IAspl), AUC(0-240 min,IAsp), and AUC(0-480 min,IAsp5) respectively], and time to (Cmax,IAsp) [T(max,IAsp)] ), blood samples were drawn immediately before (baseline) and at prespecified time points over 480 minutes after administration. The PD profiles of BIAsp50 and BIAsp30 were also examined by comparing the time course of the glucose infusion rate (GIR) using the euglycemic clamp technique. The PD end points were AUC of GIR 0 to 120 minutes after administration (AUC(0-120 min,GIR)), maximum GIR (GIR(max)), and time to GIRmax (T(max,GIR)). Tolerability was assessed using physical examination, including vital sign measurement, electrocardiography, body weight, adverse events (AEs), and clinical laboratory analysis (hematology and serum biochemistry). RESULTS: Six men and 4 women were enrolled in the study (mean age, 62.4 years; mean body weight, 58.3 kg; mean body mass index, 22.22 kg/m(2); mean duration of diabetes, 9.53 years; and mean glycosylated hemoglobin concentration, 6.07%). Mean(Cmax,IAsp) with BIAsp50 was 63% higher than that for BIAsp30 (P < 0.002). The BIAsp50/BIAsp30 ratio with AUC(0-120 min,IAsp) was 1.68 (95% CI, 1.31-2.14). The BIAsp50/BIAsp30 ratiofor AUC(0-120 min,GIR) was 1.31 (95% CI, 1.02-1.68). A total of 9 AEs were reported in 5 patients, but none of the AEs were considered related to the study drug. CONCLUSION: In this small PK/PD study in adults with type 2 diabetes in Japan, mean C(max,IAsp) was significantly higher with BIAsp50 than with BIAsp30, and AUC(0-120 min,IAsp) and AUC(0-120 min,GIR) were higher with BIAsp50 than with BIAsp30.

Insulin degludec/insulin aspart versus biphasic insulin aspart 30 twice daily in insulin-experienced Japanese subjects with uncontrolled type 2 diabetes: Subgroup analysis of a Pan-Asian, treat-to-target Phase 3 Trial.

BACKGROUND: The present study was a subgroup analysis of a Pan-Asian Phase 3 open-label randomized treat-to-target trial evaluating insulin degludec/insulin aspart (IDegAsp) and biphasic insulin aspart 30 (BIAsp 30) in Japanese subjects with type 2 diabetes inadequately controlled on insulin. METHODS: Eligible subjects (n = 178) were randomized (2: 1) to twice-daily (b.i.d.) IDegAsp or BIAsp 30 with or without metformin for 26 weeks, titrated to a blood glucose target of between 3.9 and <5.0 mmol/L. Changes in HbA1c , the proportion of responders reaching the HbA1c target, and changes in fasting plasma glucose, nine-point self-monitored plasma glucose profiles, and body weight were assessed. RESULTS: At 26 weeks, the decrease in HbA1c was similar in both groups. Fasting plasma glucose was lower with IDegAsp than BIAsp 30 (estimated treatment difference -1.50 mmol/L; 95 % confidence interval [CI] -1.98, -1.01). Overall confirmed hypoglycemia rates were similar; the nocturnal confirmed hypoglycemia rate was lower with IDegAsp than BIAsp 30 (estimated rate ratio 0.44; 95 % CI 0.20, 0.99). No severe hypoglycemic episodes were reported. CONCLUSIONS: The results indicate that IDegAsp b.i.d. improves glycemic control and, compared with BIAsp 30, lowers the rate of nocturnal confirmed hypoglycemia.

Current status of achieving blood pressure target and its clinical correlates in Japanese type 2 diabetes.

AIMS/INTRODUCTION: To investigate the current status of achieved blood pressure levels in association with the number of antihypertensive drug classes as of 2013, and to explore the clinical correlates with achievement of target blood pressure in a large-scale cohort of Japanese subjects with type 2 diabetes. MATERIALS AND METHODS: A nationwide survey was conducted including 12,811 subjects with type 2 diabetes. Subjects were divided by achieved blood pressure, <130/80 or 140/90 mmHg, and the number of drug classes taken. RESULTS: The percentages achieving a blood pressure of <130/80 or 140/90 mmHg were 52.0% and 86.1%, respectively. The prevalence of hypertension, if defined as ≥130/80 mmHg or treated, became 67.9%. Among subjects taking antihypertensive drugs, a blood pressure of <130/80 or <140/90 mmHg was 46.7% and 83.2%, respectively. The percentages of <130/80 mmHg were 55.9% without drugs, 47.1% on 1, 42.5% on 2, 47.2% on 3, and 56.8% on ≥4 drugs, respectively. The most prescribed drugs were renin-angiotensin system inhibitors, followed by calcium channel blockers, diuretics, and ß-blockers. The multiple logistic regression analysis indicated that a blood pressure <130/80 mmHg was associated with lower values in age, body mass index, albuminuria, and glomerular filtration rate, higher proportions on targets for HbA1C and lipids, and less retinopathy. CONCLUSIONS: In type 2 diabetes, hypertension is common and only 52% achieved <130/80 mmHg, indicating a difficulty in blood pressure lowering. This was correlated with difficulties in glycemic and lipid management, obesity, and vascular complications, implying these clustering to be a serious problem. This article is protected by copyright. All rights reserved.

MR tracking of transplanted glial cells using poly-L-lysine-CF3.

Magnetic resonance (MR) imaging using super-paramagnetic iron oxides (SPIOs) is a powerful tool to monitor transplanted cells in living animals. Since, however, SPIOs are negative contrast agents, positive agents have been explored. In this study, we examined the feasibility of FITC-labeled poly-L-lysine-CF3 (PLK-CF3) using glial cells. FITC-labeled PLK-CF3 was easily internalized by neuroblastoma cells and glia as adding it into culture medium. No toxicity was seen at the concentration of less than 80 microg/ml. MR images positively detected labeled cells transplanted in the brain of living mouse. The results indicate that FITC-labeled PLK-CF3 is a useful positive contrast agent for MR tracking.

Actual usage and clinical effectiveness of insulin preparations in patients with Type 1 diabetes mellitus in Japan: CoDiC-based analysis of clinical data obtained at multiple institutions (JDDM 3).

To clarify the actual usage of insulin preparations and their effectiveness on glycaemic control in patients with Type 1 diabetes mellitus in Japan, we analyzed clinical data collected via CoDiC, an electronic system for diabetes data collection and management, at 28 institutes. Of 18,470 diabetic patients registered with CoDiC in June, 2003, 12,279 patients were being treated with insulin preparations and/or oral hypoglycemic agents, with 861 of these patients having Type 1 diabetes mellitus and 11,418 patients having Type 2 diabetes. Three analytical surveys were carried out with the Type 1 diabetes patients. Study I: Cross-sectional survey on the treatment in 2002. Six hundred and thirteen patients received intensive conventional insulin treatment (ICT). The number of patients receiving rapid-acting insulin analogue (RA) was greater than that of patients receiving regular insulin (R). Serum CPR was lower in the patients with ICT than in the patients with conventional insulin treatment (CT). Study II: Survey on the changes in the actual usage and clinical effectiveness of insulin preparations, based on the data input in 2001 and 2002. The number of patients with ICT using RA insulin markedly increased. Study III: Analysis of the participants' clinical course over the 18-month period of the study from the time of first consultation. The dose of insulin increased during the term. The average HbA1c level fell drastically and reached to 7.5% over the first 9 months of the study and then remained between a range of 7.5% and 8% for the rest of the study period. In conclusion, ICT is actively performed and the RA insulin analogues are widely used in Type 1 diabetic patients in Japan. Basal-bolus therapy should be used to treat Type 1 diabetic patients with postprandial serum CPR of less than 0.5 ng/ml. It is difficult to obtain the ideal glycaemic control in Type 1 diabetic patients with the currently available insulin preparations.

The status of diabetes control and antidiabetic drug therapy in Japan--a cross-sectional survey of 17,000 patients with diabetes mellitus (JDDM 1).

The number of diabetic patients has been increasing in Japan and consequently diabetic complications are the most important target to be prevented through improving glycemic control. In order to describe the glycemic control status and treatment of diabetic patients by specialists in Japan over three years, from 2000 to 2002, we examined HbA1c, other laboratory data and the modality of drug therapy in the study population, 8170 in 2000, 11,831 in 2001, and 16,934 in 2002. Patients were registered at clinics and hospitals that were members of the Japan Diabetes Clinical Data Management Study Group (JDDM). HbA1c levels, other laboratory data, and details of drug therapy were collected and analyzed using SPSS and MS Access. The mean HbA1c levels were essentially unchanged during the study periods, ranging from 7.9% to 7.8%, and from 7.1% to 7.0%, in type 1 and type 2 diabetic patients, respectively. In type 2 diabetes, the frequency of oral hypoglycemic agents (OHA) use increased from 44.9% to 51.4%, while the use of diet-only therapy decreased from 29.9% to 25.4% over the study period. Although the systolic blood pressure was slightly above target, the mean blood pressure and the mean lipid profile were mostly within the treatment goals set by the Japan Diabetes Society. This first report from a large scale study of the daily management of diabetes in Japan revealed that the average HbA1c level was superior to most of the results reported from other countries. Nonetheless, 66% of the patients still had HbA1c levels and half of the patients had other laboratory parameters including blood pressure and lipid profile that were greater than those recommended by the Japan Diabetes Society. The nature of diabetes drug therapy in Japan has gradually changed as new drugs have appeared in the market.

Pharmacokinetic and pharmacodynamic properties of insulin degludec in Japanese patients with type 1 diabetes mellitus reflect similarities with Caucasian patients.

INTRODUCTION: The present study aimed to evaluate the pharmacokinetic and pharmacodynamic properties of insulin degludec (IDeg) in Japanese patients with type 1 diabetes. MATERIALS AND METHODS: This was a randomized, single-center, double-blind, two-period, crossover, multiple-dose trial. Patients were randomized into two treatment sequences, and received IDeg or insulin detemir for 6 days and a washout period (7-21 days) before switching treatment. Blood samples for pharmacokinetic measurements were obtained before each dose and up to 120 h after the last dose of each treatment period. Pharmacodynamic measurements were obtained using a 26-h euglycemic clamp procedure after the last dose of each treatment period. RESULTS: A total of 22 patients were randomized (14 men, 8 women; mean glycosylated hemoglobin at baseline of 7.5% [based on Japanese Diabetes Society value]). At steady state, total glucose-lowering effect (area under the glucose infusion rate [GIR] curve during one dosing interval [τ, 0-24 h] at steady state [AUCGIR ,τ, SS]) was 1,446 mg/kg and total exposure (geometric mean) of IDeg (AUCID eg,τ, SS) was 81,270 pmol h/L. Both the glucose-lowering effect and the exposure of IDeg were evenly distributed over the dosing interval, with AUC for the first 12-h intervals being approximately 50% of the total (geometric mean; AUCGIR ,0-12h, SS/AUCGIR ,τ, SS = 48%; AUCID eg,0-12h, SS/AUCID eg,τ, SS = 53%). CONCLUSIONS: IDeg has a flat, consistent and ultra-long glucose-lowering effect that is evenly distributed across a 24-h interval and an ultra-long duration of action in Japanese patients with type 1 diabetes. These data support once-daily dosing of IDeg in all patients. Overall, the pharmacodynamic and pharmacokinetic end-points and safety observations are consistent with those previously reported in Caucasian patients.

Amyloid imaging using fluorine-19 magnetic resonance imaging ((19)F-MRI).

The formation of senile plaques followed by the deposition of amyloid-ß is the earliest pathological change in Alzheimer's disease. Thus, the detection of senile plaques remains the most important early diagnostic indicator of Alzheimer's disease. Amyloid imaging is a noninvasive technique for visualizing senile plaques in the brains of Alzheimer's patients using positron emission tomography (PET) or magnetic resonance imaging (MRI). Because fluorine-19 ((19)F) displays an intense nuclear magnetic resonance signal and is almost non-existent in the body, targets are detected with a higher signal-to-noise ratio using appropriate fluorinated contrast agents. The recent introduction of high-field MRI allows us to detect amyloid depositions in the brain of living mouse using (19)F-MRI. So far, at least three probes have been reported to detect amyloid deposition in the brain of transgenic mouse models of Alzheimer's disease; (E,E)-1-fluoro-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (FSB), 1,7-bis(4'-hydroxy-3'-trifluoromethoxyphenyl)-4-methoxycarbonylethyl-1,6-heptadiene3,5-dione (FMeC1, Shiga-Y5) and 6-(3',6',9',15',18',21'-heptaoxa-23',23',23'-trifluorotricosanyloxy)-2-(4'-dimethylaminostyryl)benzoxazole (XP7, Shiga-X22). This review presents the recent advances in amyloid imaging using (19)F-MRI, including our own studies.

Relationship between the efficacy of oral antidiabetic drugs and clinical features in type 2 diabetic patients (JDDM38).

AIMS/INTRODUCTION: We carried out an observational cohort study to examine the relationship between the efficacy of oral antidiabetic drugs and clinical features in type 2 diabetics. MATERIALS AND METHODS: We analyzed the CoDiC(®) database of the Japan Diabetes Data Management Study Group across 67 institutions in Japan. In a total of 3,698 drug-naïve patients who were initiated with metformin, dipeptidyl peptidase-4 inhibitor (DPP-4i) or sulfonylurea (SU) from 2007 to 2012, we evaluated body mass index (BMI) and hemoglobin A1c (HbA1c). The patients were stratified according to their clinical features, and matched using a propensity score to adjust for baseline factors. RESULTS: HbA1c was reduced with all drugs, with the largest effect elicited by DPP-4i and the smallest by SU (P = 0.00). HbA1c increased with SU after 6 months in the patients stratified by an age-of-onset of <50 years (P = 0.00). BMI increased with SU in the patients stratified by a BMI of <25 (P = 0.00), and decreased with metformin in the patients with a BMI >25 (P = 0.00). The reduction in HbA1c was larger in patients with HbA1c of ≥8%, compared with that in patients with HbA1c of <8% (P = 0.00). HbA1c during the study period was higher in patients who were added to or swapped with other drug(s), than in patients continued on the original drug (P = 0.00). CONCLUSIONS: The effect on bodyweight and glycemic control differed among metformin, DPP-4i and SU, and the difference was associated with clinical features.

Novel curcumin derivatives as potent inhibitors of amyloid ß aggregation.

Modulation of abnormal amyloid ß (Aß) aggregation is considered to be a potential therapeutic target for Alzheimer's disease (AD). Recent in vitro and in vivo experiments suggest that inhibition of Aß aggregation by curcumin would exert favorable effects for preventing or treating AD. We have previously synthesized a series of novel curcumin derivatives. In this study, we investigated the effects of our curcumin derivatives on Aß aggregation and the cell toxicities of Aß aggregates. According to sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) profiles, 14 of 41 compounds showed a significant increase in the densities of the bands of Aß (1-42) by incubation during the aggregation process relative to those of Aß (1-42) prepared in the presence of the vehicle control. Of the 14 compounds, four compounds additionally reduced cell toxicity of the Aß aggregates by incubation during the aggregation process. A significant positive correlation was observed between the cell viability and densities of the bands at ranges of 15-20, 20-37, 37-75, and 75-200 kDa in SDS-PAGE. On the basis of these results, we propose four curcumin derivatives with potential for preventing AD. These curcumin derivatives exhibited high inhibitory effects on Aß aggregation and induced the formation of lower molecular size Aß species that have weaker cell toxicity. These compounds may exert therapeutic effects on AD in future in vivo studies.

Curcumin derivative with the substitution at C-4 position, but not curcumin, is effective against amyloid pathology in APP/PS1 mice.

Recent evidence supports the amyloid cascade hypothesis that a pathological change of amyloid ß (Aß) in the brain is an initiating event in Alzheimer's disease (AD). Accordingly, modulating the abnormal Aß aggregation is considered a potential therapeutic target in AD. Curcumin, a low-molecular-weight polyphenol derived from the well-known curry spice turmeric, has shown favorable effects on preventing or treating AD pathology. The present study investigated the effects of curcumin and 2 novel curcumin derivatives, FMeC1 and FMeC2, on AD pathology in APPswe/PS1dE9 double transgenic mice. Mice fed a chow diet that contained FMeC1 for 6 months showed a reduction in insoluble Aß deposits and glial cell activity together with reduced cognitive deficits, compared to animals receiving a control diet or with curcumin or FMeC2 in their diet. Both curcumin and FMeC1 modulated the formation of Aß aggregates; however, only FMeC1 significantly attenuated the cell toxicity of Aß. These results indicate that FMeC1 may have potential for preventing AD.

Insulin degludec/insulin aspart versus biphasic insulin aspart 30 in Asian patients with type 2 diabetes inadequately controlled on basal or pre-/self-mixed insulin: a 26-week, randomised, treat-to-target trial.

AIMS: Insulin degludec/insulin aspart (IDegAsp) is a soluble co-formulation of IDeg and IAsp. This pan-Asian, 26-week trial investigated efficacy and safety of IDegAsp vs biphasic insulin aspart 30 (BIAsp 30) in Asian adults with type 2 diabetes (T2DM), inadequately controlled on once- or twice-daily (BID) basal, premixed or self-mixed insulin. METHODS: Participants (mean age 59.8 years, HbA1c 8.4%, FPG 7.9 mmol/L, BMI 25.4 kg/m(2)) were randomised 2:1 to BID IDegAsp (n=282) or BIAsp 30 (n=142) and continued existing metformin treatment. Insulins were administered with breakfast and main evening meal, titrated to a pre-breakfast and pre-main evening meal self-measured plasma glucose target of 4-5 mmol/L. RESULTS: IDegAsp achieved the primary endpoint of non-inferiority to BIAsp 30 for mean change in HbA1c (estimated treatment difference [ETD] IDegAsp-BIAsp 30: 0.05% points [95% CI -0.10; 0.20]). IDegAsp was superior in lowering fasting plasma glucose (FPG) (ETD -1.06 mmol/L, 95% CI -1.43; -0.70, p<0.001), and resulted in a lower final mean daily insulin dose (0.79 U/kg vs 0.99 U/kg, estimated rate ratio [RR] 0.79, 95% CI 0.73; 0.85, p<0.0001). Rates of overall confirmed and severe hypoglycaemia were similar between treatments, while rate of nocturnal confirmed hypoglycaemia was numerically (p=ns) lower with IDegAsp. During the maintenance period there was a trend (p=ns) towards lower hypoglycaemia rates for IDegAsp. CONCLUSION: In Asian adults with T2DM, IDegAsp BID effectively improves long-term glycaemic control, and compared to BIAsp 30, provides superior reductions in FPG with a lower dose, and numerically less nocturnal hypoglycaemia.

High serum concentrations of soluble E-selectin correlate with obesity but not fat distribution in patients with type 2 diabetes mellitus.

Serum concentrations of soluble adhesion molecules, eg, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin are elevated in patients with type 2 diabetes. However, little is known about the role of obesity or abnormal fat distribution in inducing upregulation of adhesion molecules. To investigate this issue, soluble ICAM-1, VCAM-1, and E-selectin levels were evaluated in 40 obese and 30 nonobese patients with type 2 diabetes. Both groups were matched for age, sex, and glycosylated hemoglobin (HbA(1c)) levels. Computed tomography (CT) was used to measure the abdominal subcutaneous and visceral fat areas. Soluble ICAM-1 and VCAM-1 levels did not differ significantly between obese and nonobese patients. However, serum concentrations of soluble E-selectin were significantly higher in obese than in nonobese patients (90 +/- 7 v 56 +/- 4 ng/mL, P <.01). Soluble E-selectin levels significantly correlated with body mass index, subcutaneous fat area, and visceral fat area (Rho = 0.48, 0.37, and 0.30, respectively). Stepwise multiple regression analysis showed that body mass index (F = 16.7), but not subcutaneous and visceral fat areas (F = 0.29 and 0.01, respectively), significantly and independently correlated with soluble E-selectin levels. Our results suggest that obesity may induce endothelial activation or increased shedding of cell surface E-selectin that leads to subsequent increase in soluble E-selectin levels. The high serum concentrations of E-selectin closely correlated with increased total fat volume, but not with regional fat distribution.