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IntroductionSodium-glucose cotransporter-2 inhibitors (SGLT2is) are proven to ameliorate kidney and heart failure in patients with type 2 diabetes (T2D), in addition to improving glycemic controls. Canagliflozin is a SGLT2i and has proved beneficial for kidney and heart diseases in addition to decreasing the incidence of the composite outcomes of cardiovascular diseases and stroke.Areas coveredThis paper reviews the development of canagliflozin and its effects on renal dysfunction, heart failure, and vascular diseases.Expert opinionCanagliflozin contributes to the inhibition of renal function, decline progression and, therefore, is effective for T2D patients with chronic kidney dysfunction and albuminuria. The Canagliflozin Cardiovascular Assessment Study (CANVAS) revealed that patients showed increased incidence of amputation via unknown mechanisms, which has not been observed in other studies that used real-world data. Moreover, canagliflozin has been proven effective for anemia-associated outcomes of chronic kidney failure. Meta-analyses have revealed that canagliflozin contributed to lower diastolic blood pressure when compared with other SGLT2is. A subanalysis of CANVAS data proved that canagliflozin reduced the risk of hemorrhagic stroke. Canagliflozin should be used for T2D patients with chronic kidney failure and/or albuminuria and those with vascular diseases, with monitoring for ulcers and/or the pulse on the lower limb.

Multiple daily injections of insulin, referred to basal–bolus regimen, are generally essential in achieving glycemic control and preventing ketosis in insulin-dependent diabetes, such as type 1 diabetes (T1D). A 75-year-old man with T1D receiving basal–bolus insulin therapy exhibited symptoms of dementia after hospitalization due to pyelonephritis and failed to continue insulin self-injection. Given that his social and familial circumstances allowed insulin injection once a day during the morning, bolus insulin injections needed to be discontinued. Ketonuria was observed the day following discontinuation of bolus insulin. Although increasing the basal insulin dose (degludec) from 10 to 15 units improved ketonuria, his preprandial glucose levels increased to ≥ 500 mg/dL before lunch and ≥ 400 mg/dL before dinner. Hence, another bolus insulin injection was simultaneously added to the basal insulin dose before breakfast, which, subsequently, decreased his preprandial glucose levels to ≤ 220 mg/dL before lunch and ≤ 350 mg/dL before dinner. For half a year after discharge, ketonuria or hypoglycemia had not been detected. After 6 months, he was able to restart intensive insulin therapy with familial support. Hence, in cases where elderly patients with diabetes exhibit symptoms of dementia and can receive insulin injection once a day due to their social circumstances, short-term one basal plus one bolus insulin injections a day might be considered to prevent life-threatening diabetes complications among those who are insulin-dependent.

AIMS/INTRODUCTION The diabetes knowledge test (DKT) is unavailable in Japan. In this study, we developed and evaluated a Japanese version of the DKT (J-DKT) for in-patients with type 2 diabetes before and after receiving diabetes education. MATERIALS AND METHODS The J-DKT contains 12 questions (0-12 points) to assess knowledge regarding diabetes, its complications, and diabetic nutrition therapy. During the median 10 days of hospitalization, 107 patients with type 2 diabetes received diabetes education (20 min private lessons every day from physicians, two nutrition counselling programs from dietitians, and a 2 h group session conducted by physicians, dietitians, and nurses). The J-DKT was administered on admission and before discharge. To confirm the J-DKT's reliability, we assessed the internal consistency using Cronbach's α (≥0.70 was considered acceptable). To evaluate its validity, we investigated changes in the J-DKT total scores after the education programs and examined the differences in the scores among groups classified based on patient characteristics such as age, diabetes-related hospitalization history, and hospitalization duration. RESULTS The J-DKT total scores increased from 5 to 8 (P ˂ 0.01) after the education programs. The J-DKT before and after the program showed a Cronbach's α of 0.48 and 0.73, respectively. Except for age, baseline characteristics such as history and period of hospitalization for diabetes were not associated with the J-DKT scores after the education program. CONCLUSIONS The validity and reliability of the J-DKT after the diabetes education program were acceptable in this study.

BACKGROUND Diabetic kidney disease (DKD) is one of the main complications of type 2 diabetes mellitus (T2DM). DKD is a known risk factor for end-stage renal disease, cardiovascular disease, and all-cause death. Effective intervention for early-stage DKD is vital to slowing down the progression of kidney disease and improve prognoses. Mobile health (mHealth) is reportedly effective in supporting patients’ self-care and improving glycemic control, but the impact of mHealth on DKD has yet to be shown. OBJECTIVE The purpose of this study is to evaluate the efficacy of standard therapy with the addition of a self-management support system, DialBetesPlus, in patients with DKD and microalbuminuria. METHODS This study is a prospective, randomized, open-label, multicenter clinical trial. The target population consists of 160 patients diagnosed with T2DM accompanied by microalbuminuria. We randomly assigned the patients to 2 groups—the intervention group using DialBetesPlus in addition to conventional therapy and the control group using conventional therapy alone. DialBetesPlus is a smartphone application that supports patients’ self-management of T2DM. The study period was 12 months, with a follow-up survey at 18 months. The primary outcome was a change in albuminuria levels at 12 months. Secondary outcomes included changes in physical parameters, blood test results (glycemic control, renal function, and lipid metabolism), lifestyle habits, self-management scores, medication therapy, and quality of life. RESULTS The study was approved in April 2018. We began recruiting patients in July 2018 and completed recruiting in August 2019. The final 18-month follow-up was conducted in March 2021. We recruited 159 patients and randomly allocated 70 into the intervention group and 61 into the control group, with 28 exclusions due to withdrawal of consent, refusal to continue, or ineligibility. The first results are expected to be available in 2021. CONCLUSIONS This is the first randomized controlled trial assessing the efficacy of mHealth on early-stage DKD. We expect that albuminuria levels will decrease significantly in the intervention group due to improved glycemic control with ameliorated self-care behaviors. CLINICALTRIAL UMIN-CTR UMIN000033261; https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000037924 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/31061

Background: Eating abnormalities have been observed in some patients with T2D. It is also known that food preferences and habits are affected by many factors, such as childhood food education, insulin secretion (which suppresses appetite after eating meals), and appetite control by executive functions. Meanwhile, blood flow in the cerebral frontal lobe has been reported to be decreased in patients with severe hyperglycemia, which might result in impaired executive function. Objective: This cross-sectional study aimed to identify factors affecting eating behavior among inpatients with T2D. Methods: A total of 27 inpatients were requested to complete a self-administered questionnaire using a 5-point scale, consisting of the following 3 questions (Qs): (1) Do you want to eat the same thing over and over? (2) Do you feel that your appetite cannot be suppressed? (3) Do you eat meals hungrily? Further, we investigated correlations between these Qs and the following variables: body weight (BW), HbA1c levels, glucagon-stimulated changes in plasma C-peptide concentrations(ΔCPR), and baseline characteristics on admission. Results: The mean age was 68 years; mean BW on admission, 69.5 kg; mean BW at the age of 20 years, 63.4 kg; maximum BW, 79.8 kg; mean HbA1c level, 10.2%; and medianΔCPR, 1.26 ng/ml. Q1 and Q2 were positively associated with all the BWs assessed in this study (Spearman r ≧ 0.33 and 0.23, respectively), with the association between Q1 and BW being strongest at the age of 20 (r =0.463, p Conclusions: From the strong relationship between the used questionnaire and BW at the age of 20, eating behavior was concluded to be determined in childhood. Our study also demonstrated that insulin secretion might suppress appetite, and that poor glycemic control did not contribute to appetite suppression via executive functions. Disclosure M. Takahashi: None. T. Minami: None. A. Kameda: None. T. Yamada: None. H. Hiiragi: None. F. Yoshida: None. K. Okubo: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Novo Nordisk, Sanofi, Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Speaker’s Bureau; Self; Abbott, Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.

Introduction: Many cross-sectional studies have reported that higher diabetes knowledge test (DKT) scores were associated with better glycemic controls in outpatients with type 2 diabetes. We investigated whether inpatients with high DKT scores could achieve better glycemic control after discharge. Method: This multicenter longitudinal study included 37 inpatients with type 2 diabetes, who had poor glycemic control from October 2018 to November 2019 in Japan. The exclusion criteria were history of stroke, dementia, and psychiatric conditions. The baseline characteristics were HbA1c level, 10.5%±2.5%; median age, 70 y (58-76); median (first to third quartile); diabetes duration, 6 y (1-20); and fasting plasma C-peptide level, 1.4 ng/ml (0.9-2.0 ng/ml). The patients underwent the original DKT at discharge, consisting of 14 items (full score, 14 points). The Cronbach’s α was 0.71. The questions included Q6 “When is a good time to improve the postprandial blood glucose level if you exercise?”, Q11 “How many calories are in 100 g steamed white rice?”, and Q12 “Which beverage is inappropriate during hyperglycemia?” We investigated whether DKT score and baseline characteristics correlated with the HbA1c level at 48 weeks after discharge. Result: The HbA1c level at 48 weeks after discharge was 7.2% (6.3%-7.6%); ΔHbA1c, −2.6 (−4.6 to −1.2); and total DKT score, 10 (6-11). The total DKT score was negatively associated with the HbA1c level at 48 weeks after discharge (Spearman r: −0.26) and ΔHbA1c (r: −0.30). The subjects with shorter diabetes durations and higher ΔCPR showed improved HbA1c levels. The patients who correctly answered Q6, Q11, and Q12 dependently got better HbA1c levels at 48 weeks after discharge compared with those with incorrect answers(p Conclusion: The better total DKT score improved HbA1c levels in patients with type 2 diabetes at 48 weeks after discharge. Knowledge of calorie intake and best exercise timing may contribute to better glycemic control. Disclosure K. Okubo: None. T. Minami: None. A. Kameda: None. T. Yamada: None. H. Hiiragi: None. F. Yoshida: None. M. Takahashi: None. Y. Suzuki: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Novo Nordisk, Sanofi, Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Speaker’s Bureau; Self; Abbott, Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.

Background and Aim Changes in treatment protocols for patients with diabetes mellitus (DM) may influence the functions of the digestive tract. This study examined possible clinical factors associated with the symptoms of constipation in patients with DM. Methods This was a multicenter study. Participants were consecutive Japanese patients undergoing treatment for type 1 or type 2 DM. Constipation was evaluated using the gastrointestinal symptom rating scale. Diabetic neuropathy was evaluated by the presence or absence of peripheral neuropathy of the lower limbs. Results Of 419 participants, 258 were men and 161 women (ratio: 1.6:1), with a mean age of 63.6 ± 12.5 years. In multivariate analysis, symptoms of constipation were significantly associated with age (odds ratio (OR)=1.02, 95% confidence interval (CI): 1.01–1.04, P=0.032), lower mental component summary (OR=3.31, 95% CI: 1.69–6.48, P

Aims/Introduction To our knowledge, no studies have reported that cognitive tests can be used to evaluate whether or not patients can acquire the insulin self-injection technique. We investigated whether or not the number of animal names recalled in 1 min by elderly diabetic patients could be used as a predictor of the patients’ ability to acquire the insulin self-injection technique within 1 week. Materials and Methods We enrolled 57 inpatients with type 2 diabetes aged over 60 years who were starting insulin therapy. We performed the mini-mental state examination and verbal fluency tests, which included recalling animal names and common nouns starting with the letters “a”, “ka” and “shi” (Japanese letters). We used 12 checkpoints for insulin self-injection to judge the patients’ levels of acquisition of the technique. The most predictive cognitive test was determined by multivariate logistic regression analysis. Results In this study, multivariate logistic analysis revealed that the number of animal names recalled was the most reliable predictor of the ability to acquire the insulin self-injection technique within 1 week. A figure of 11 animal names predicted a successful acquisition, with a sensitivity of 73% and a specificity of 91% being observed (area under the curve 0.87, 95% CI 0.76–0.97, p < 0.01). Conclusions The number of animal names recalled in 1 min was the most useful indicator of the ability of elderly diabetic patients to learn to manage insulin self-injection therapy within 1 week. The cutoff value was 11 animal names. This article is protected by copyright. All rights reserved.

OBJECTIVE: Patients with type 2 diabetes mellitus (T2DM) show more executive dysfunction than nondiabetics. However, how long poor glycemic control affects executive function remains unclear. Thus, we aimed to investigate the relationships in a cross-sectional study. METHODS: We studied 118 T2DM outpatients (age, ≥ 60 years; excluding history of stroke, dementia and severe hypoglycemia). HbA1c values were recorded every ≤ 12 weeks for ≥ 5 years. All patients underwent verbal-fluency tests (reflecting executive function) and Mini-Mental State Examination (MMSE). The correlation between past glycemic control values and both cognitive tests scores was investigated. As markers of past glycemic control, we used average hemoglobin A1c (HbA1c) values and glycemic control variability [coefficient of variation (CV) of HbA1c values (HbA1c-CV)]. RESULTS: Verbal-fluency tests scores correlated with HbA1c-CV, but not with average HbA1c values, after adjusting for age, years of education and sex. Verbal-fluency tests scores correlated with HbA1c-CV for the past 5 years, best compared with HbA1c-CV for past

Patients with end stage renal disease frequently show indigestion symptoms as a result of uremia. However, the association between the indigestion symptoms and the earlier stage of diabetic nephropathy is unclear. Therefore we conducted a multicenter study using self-administered questionnaires: the Gastrointestinal Symptom Rating Scale (GSRS).Patients were type1 or type 2 DM between 20-85 years old treated in 2 hospitals and 3 clinics in Yokohama and Tokyo during June 2016 to January 2017. We excluded patients if they were either 1) pregnant or 2) suffering from malignant disease or digestive disease. We defined diabetic nephropathy as stage 3 or later and clinically significant indigestion symptoms (CSIS) as GSRS≧3. We analyzed the association between diabetic nephropathy and CSIS.In total of 722 patients, 430 (61%) were male and 36 (5%) were Type 1 DM. Mean age was 65 years old, mean BMI was 25.0, mean HbA1c was 7.5% and mean duration of DM was 155 months. As for diabetic microangiopathy, 177 (26%) had nephropathy, 186 (30%) had peripheral neuropathy, 180 (29%) had retinopathy. GLP-1 receptor agonists were used in 62 (8.8%) patients. In comparison between patients with and without CSIS, age, BMI, HbA1c were not different. Duration of DM was longer in CSIS (193 ± 19 vs. 153 ± 5 months, p=0.046). Presence of diabetic nephropathy was associated with CSIS (OR=2.08, 95% CI: 1.10-3.91), in contrast, that of neuropathy and retinopathy was not. In multivariate analysis adjusting age, BMI, HbA1c and use of GLP-1 receptor agonist, CSIS were significantly associated with longer duration of DM (β=0.003, SD=0.001, p=0.01), and diabetic nephropathy (OR=1.95, 95% CI:1.01-3.71). Neuropathy and retinopathy had no significant association with CSIS. Our results suggest that not only in the end stage renal disease, earlier stage of diabetic nephropathy with proteinuria might be the risk of indigestion symptoms in patients with diabetes mellitus. Disclosure Y. Namiki: None. E. Yamada: None. Y. Takano: None. H. Takamine: None. H. Sasaki: None. K. Inazumi: None. T. Minami: None. S. Ito: None. N. Mantani: None. T. Iwasaki: None. M. Yamada: None. A. Nakajima: None. Y. Terauchi: Research Support; Self; MSD K.K.. Speaker's Bureau; Self; MSD K.K.. Advisory Panel; Self; MSD K.K.. Research Support; Self; Ono Pharmaceutical Co., Ltd.. Speaker's Bureau; Self; Ono Pharmaceutical Co., Ltd.. Research Support; Self; Novartis Pharma K.K., Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Advisory Panel; Self; Mitsubishi Tanabe Pharma Corporation. Research Support; Self; Daiichi Sankyo Company, Limited. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited. Advisory Panel; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Speaker's Bureau; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Advisory Panel; Self; Sanofi. Research Support; Self; Sumitomo Dainippon Pharma Co., Ltd.. Speaker's Bureau; Self; Sumitomo Dainippon Pharma Co., Ltd.. Research Support; Self; Shionogi & Co., Ltd.. Speaker's Bureau; Self; Shionogi & Co., Ltd., Bayer Yakuhin, Ltd., Astellas Pharma US, Inc., AstraZeneca. Advisory Panel; Self; AstraZeneca, Teijin Pharma Limited. U.N. Osada: None.

Type 2 diabetes (T2D) is a risk factor for Alzheimer’s disease. Executive dysfunction occurs in otherwise cognitively normal patients with T2D. To assess executive function, we investigated the relationship between executive function and glycemic controls using verbal fluency (VF) tests. The present study enrolled 130 patients with T2D (age, ≥60; including 11 patients with dementia) and excluded stroke survivors. Their HbA1c levels were recorded every ≤12 weeks for >5 years. All patients underwent VF tests. We analyzed the correlation between VF z-scores (standardized total scores) and glycemic control values (time-weighted average and maximum HbA1c levels for the past 5 years), or disease durations. As controls, we also investigated the relationships between stages of diabetic retinopathy (NDR/NPDR/PD) and past glycemic controls. The mean patient age was 74.7 years, the mean HbA1c at the baseline was 7.5%, median duration of education was 12 years, and mean disease duration was 18.3 years. Significant correlates for VF z-scores were age, years of education, and dementia in addition to glycemic control values. VF z-scores tended to correlate with average HbA1c levels, and significantly correlated with maximum HbA1c levels, for the past 5 years. The relationships between VF z-scores and maximum HbA1c levels remained significant after adjusting for age, years of education, and dementia. Generally, VF z-scores were strongly associated with maximum HbA1c levels for longer observation periods, i.e., VF z-scores correlated with maximum HbA1c levels for the past 5 years, best compared with maximum HbA1c levels for the past 4 years. As controls, diabetic retinopathy stages were also associated with average and maximum HbA1c levels. The diabetes duration was associated with diabetic retinopathy stages strongly, but not with VF z-scores. These results suggest that executive dysfunction may be caused by metabolic mechanisms other than diabetic retinopathy. Disclosure T. Minami: None. M. Yamada: None. Y. Ito: None. R. Furuta: None. S. Katsuragawa: None. S. Terui: None. T. Akiyama: None. F. Minagawa: None. Y. Terauchi: Research Support; Self; MSD K.K.. Speaker's Bureau; Self; MSD K.K.. Advisory Panel; Self; MSD K.K.. Research Support; Self; Ono Pharmaceutical Co., Ltd.. Speaker's Bureau; Self; Ono Pharmaceutical Co., Ltd.. Research Support; Self; Novartis Pharma K.K., Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Advisory Panel; Self; Mitsubishi Tanabe Pharma Corporation. Research Support; Self; Daiichi Sankyo Company, Limited. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited. Advisory Panel; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Speaker's Bureau; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Advisory Panel; Self; Sanofi. Research Support; Self; Sumitomo Dainippon Pharma Co., Ltd.. Speaker's Bureau; Self; Sumitomo Dainippon Pharma Co., Ltd.. Research Support; Self; Shionogi & Co., Ltd.. Speaker's Bureau; Self; Shionogi & Co., Ltd., Bayer Yakuhin, Ltd., Astellas Pharma US, Inc., AstraZeneca. Advisory Panel; Self; AstraZeneca, Teijin Pharma Limited.

Background: Insomnia is associated with the onset and development of diabetes. Melatonin affects sleep quality and glucose metabolism in diabetic patients with insomnia. We administered ramelteon, an agonist of melatonin, to type 2 diabetic patients and investigated its effects on glucose metabolism and insomnia. Methods: This multicenter, prospective, randomized, and observational pilot study was performed between April 2014 and April 2015 at three institutes in Japan. Patients were prescribed ramelteon 8 mg/day for 3 months (first period). And patients were divided at random into the continuation group that continued taking ramelteon and the discontinuation group that discontinued taking ramelteon for 3 additional months (second period). The primary endpoint was change in glycated hemoglobin (HbA1c) level. Secondary endpoints were changes in global Pittsburgh sleep questionnaire index (PSQI) score and other glucose metabolism makers. Results: We enrolled 42 patients, and 32 patients completed the first period. Their mean HbA1c was 6.7%, and global PSQI score was 8.1 on average. HbA1c level did not change but global PSQI score improved from 8.1 to 7.2 by ramelteon (P = 0.030). Thirty-one patients completed the second period. HbA1c level did not change in the continuation group, but it increased from 6.7% to 6.9% (P = 0.003) in the discontinuation group. Global PSQI score did not change in each group. There was no rebound insomnia. Conclusion: Treatment with ramelteon did not change the HbA1c level but improved sleep quality in type 2 diabetic patients with insomnia. Discontinuation of ramelteon slightly increased the HbA1c level and did not worsen sleep quality. J Clin Med Res. 2016;8(12):878-887 doi: http://dx.doi.org/10.14740/jocmr2754w

Background: Selective estrogen receptor modulators (SERMs) decrease homocysteine and cross-linking of pentosidine and reduce low-density lipoprotein cholesterol (LDL-C), and they are expected to improve bone quality and atherosclerosis. Therefore, the potential effects of bazedoxifene on bone (bone resorption, bone formation, and bone quality), as well as on glucose and lipid metabolism markers, were examined in Japanese postmenopausal women with type 2 diabetes mellitus (T2DM). Methods: Eligible patients received 20 mg of bazedoxifene tablets once daily and were followed up for 12 weeks. Bone resorption markers including tartrate-resistant acid phosphatase 5b (TRACP-5b), bone formation markers and bone quality markers such as homocysteine and serum pentosidine, total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and HbA1c were all measured. Results: Twenty patients completed this study. All bone resorption markers decreased significantly 4 weeks after bazedoxifene treatment. In particular, TRACP-5b decreased significantly at 12 weeks (median percent change: -20.6%), and the minimum significant change (MSC) achievement rate of TRACP-5b was 65%. Bazedoxifene also decreased bone formation markers. However, bazedoxifene did not improve bone quality markers. LDL-C, HDL-C, and non-HDL-C were decreased, but TG was unchanged. Glucose metabolism was not changed after bazedoxifene treatment. In a subgroup analysis, the group of patients in whom the percent change in TRACP-5b exceeded the MSC had no change in pentosidine levels at 12 weeks. However, in the group of patients in whom the percent change in TRACP-5b did not exceed the MSC, pentosidine levels tended to increase. Conclusions: Bazedoxifene may improve bone resorption markers and LDL-C without affecting glucose metabolism in Japanese postmenopausal women with T2DM. J Clin Med Res. 2015;7(10):762-769 doi: http://dx.doi.org/10.14740/jocmr2278w

Changes in treatment protocols for patients with diabetes mellitus (DM) may influence the functions of the digestive tract. This study examined possible clinical factors associated with the symptoms of constipation in patients with DM.This was a multicenter study. Participants were consecutive Japanese patients undergoing treatment for type 1 or type 2 DM. Constipation was evaluated using the gastrointestinal symptom rating scale. Diabetic neuropathy was evaluated by the presence or absence of peripheral neuropathy of the lower limbs.Of 419 participants, 258 were men and 161 women (ratio: 1.6:1), with a mean age of 63.6 ± 12.5 years. In multivariate analysis, symptoms of constipation were significantly associated with age (odds ratio [OR] = 1.02, 95% confidence interval [CI]: 1.01-1.04, P = 0.032), lower mental component summary (OR = 3.31, 95% CI: 1.69-6.48, P 0.001), diabetic retinopathy (OR = 1.99, 95% CI: 1.14-3.45, P = 0.015), and diabetic neuropathy (OR = 1.86, 95% CI: 1.10-3.16, P = 0.021). In patients with peripheral neuropathy of the lower limbs, regardless of the presence of other complications (diabetic nephropathy and diabetic retinopathy), the prevalence of symptoms of constipation was twice that of patients without peripheral neuropathy (40.0-49.1% vs 22.0%). Diabetic drugs were not associated with symptoms of constipation.Diabetic neuropathy, defined as peripheral neuropathy of the lower limbs, was significantly associated with symptoms of constipation. Peripheral neuropathy of the lower limbs is not a direct risk factor for constipation but may be a useful criterion when assessing whether constipation is associated with DM.

Housaku Monogatari (HM) is a plant activator prepared from a yeast cell wall extract. We examined the efficacy of HM application and observed that HM treatment increased the resistance of Arabidopsis thaliana and Brassica rapa leaves to bacterial and fungal infections. HM reduced the severity of bacterial leaf spot and anthracnose on A. thaliana and Brassica crop leaves with protective effects. In addition, gene expression analysis of A. thaliana plants after treatment with HM indicated increased expression of several plant defense-related genes. HM treatment appears to induce early activation of jasmonate/ethylene and late activation of salicylic acid (SA) pathways. Analysis using signaling mutants revealed that HM required SA accumulation and SA signaling to facilitate resistance to the bacterial pathogen Pseudomonas syringae pv. maculicola and the fungal pathogen Colletotrichum higginsianum. In addition, HM-induced resistance conferred chitin-independent disease resistance to bacterial pathogens in A. thaliana. These results suggest that HM contains multiple microbe-associated molecular patterns that activate defense responses in plants. These findings suggest that the application of HM is a useful tool that may facilitate new disease control methods.

Background A novel ribosomal S6 kinase, termed p70 S6 kinase β (p70β), has a highly homologous amino acid sequence to that of p70/p85 S6 kinase (p70α). This includes the critical phosphorylation sites, Thr252, Ser394 and Thr412 in p70α1, which correspond to Thr241, Ser383 and Thr401 in p70β1, respectively. However, the regulatory mechanism for p70β remains to be elucidated. Results We report here the expression and the mechanism of in vivo regulation of p70β. Two isoforms, p70β1 and p70β2, were expressed in a variety of tissues at a different level. p70β1 was mainly targeted to the nucleus, whereas p70β2 dispersed throughout the cytoplasm including nucleoplasm. The kinase activity of p70β1 was less sensitive to the inhibition induced by rapamycin, wortmannin and amino acid withdrawal than that of p70α. The portion of p70β activity inhibited by rapamycin was rescued by the rapamycin-resistant mutant of the mammalian target of rapamycin (mTOR). Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70β1 was indispensable for the kinase activity. In contrast, a p70β1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70β1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities. Conclusion These results indicate that p70β is regulated by the mTOR- and PDK1-signalling pathways through a synergistic interaction between phosphorylated Thr241 and Thr401, while Ser383 plays minor role in their activation mechanism. Activated p70β may be less sensitive to dephosphorylation mediated by putative phosphatases activated by rapamycin, amino acid withdrawal, and probably wortmannin.

A novel ribosomal S6 kinase, termed p70 S6 kinase beta (p70beta), which has a highly conserved amino acid sequence compared with that of p70/p85 S6 kinase (p70alpha) within the catalytic, kinase extension, and autoinhibitory pseudosubstrate domains, was identified. However, the amino acid sequence of p70beta differs from that of p70alpha in the noncatalytic amino-terminal region and in the carboxyl-terminal tail, which contains a proline-rich region. The majority of the regulatory phosphorylation sites identified in p70alpha are conserved in p70beta. Two isoforms of p70beta, referred to as beta1 (495 amino acids) and beta2 (482 amino acids), could be expressed from the single gene either by alternative mRNA splicing or by the use of alternative start codons. Here we report the characterization of p70beta2. Similarly to p70alpha, the catalytic activity of p70beta toward ribosomal protein S6 could be rapidly activated by serum, insulin, and phorbol ester in transiently transfected cells. The p70beta kinase was found to be significantly less sensitive to wortmannin and rapamycin than p70alpha. These results indicate that p70beta has the potential to participate in the regulation of protein synthesis and the cell cycle.

Hypertension is the prime risk factor for stroke, and primary aldosteronism (PA) is the most common cause of secondary hypertension. The prevalence of PA in stroke patients has never been reported. The aim of this study was to elucidate the prevalence of PA. A total of 427 consecutive patients with acute stroke were prospectively enrolled for this study. The screening tests were performed at the initial visit and a week after admission by measuring plasma aldosterone concentration and plasma renin activity. The rapid adrenocorticotropic hormone (ACTH) test was performed as the confirmatory test when both screening tests were positive. The primary endpoint was a final diagnosis of PA. The sensitivity of the dual screening system for the diagnosis of PA was 88.2 %, and PA was finally diagnosed in 4.0 % of acute stroke patients and in 4.9 % of stroke patients with a history of hypertension. Patients with PA were less likely to be male and have diabetes, and they had higher blood pressure at the initial visit, lower potassium concentration, and more intracerebral hemorrhage. The rapid ACTH test was performed safely even in acute stroke patients. The prevalence of PA is not low among acute stroke patients. Efficient screening of PA should be performed particularly for patients with risk factors. UMIN-CTR; UMIN000011021 . Trial registration date: June 23, 2013 (retrospectively registered).