Sphingosine kinase 1-interacting protein is a dual regulator of insulin and incretin secretion.

Our previous study demonstrated that sphingosine kinase 1-interacting protein (SKIP, or Sphkap) is expressed in pancreatic ß-cells, and depletion of SKIP enhances glucose-stimulated insulin secretion. We find here that SKIP is also expressed in intestinal K- and L-cells and that secretion of gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) as well as insulin are significantly increased, and blood glucose levels are decreased in SKIP-deficient (SKIP-/-) mice compared with those in wild-type mice. Plasma triglyceride (Tg), LDL cholesterol, and mRNA levels of proinflammatory cytokines in adipose tissues, livers, and intestines were found to be significantly decreased in SKIP-/- mice. The phenotypic characteristics of SKIP-/- mice, including adiposity and attenuation of basal inflammation, were abolished by genetic depletion of GIP. The improvement of glucose tolerance and lipid profiles in SKIP-/- mice were cancelled by GLP-1 receptor antagonist exendin-(9-39) treatment. In summary, depletion of SKIP ameliorates glucose tolerance by enhancing secretion of insulin and incretins, improves lipid metabolism, and reduces basal inflammation levels. Thus, inhibition of SKIP action may emerge as a new option for treatment of type 2 diabetes mellitus with metabolic dysfunction.-Liu, Y., Harashima, S., Wang, Y., Suzuki, K., Tokumoto, S., Usui, R., Tatsuoka, H., Tanaka, D., Yabe, D., Harada, N., Hayashi, Y., Inagaki, N. Sphingosine kinase 1-interacting protein is a dual regulator of insulin and incretin secretion.

Nutrition-related factors associated with waiting list mortality in patients with interstitial lung disease: A retrospective cohort study.

Japanese patients with interstitial lung disease (ILD) sometimes die waiting for lung transplantation (LTx) because it takes about 2 years to receive it in Japan. We evaluated nutrition-related factors associated with waiting list mortality. Seventy-six ILD patients were hospitalized in Kyoto University Hospital at registration for LTx from 2013 to 2015. Among them, 40 patients were included and analyzed. Patient background was as follows: female, 30%; age, 50.3 ± 6.9 years; body mass index, 21.1 ± 4.0 kg/m2 ; 6-minute walk distance (6MWD), 356 ± 172 m; serum albumin, 3.8 ± 0.4 g/dL; serum transthyretin (TTR), 25.3 ± 7.5 mg/dL; and C-reactive protein, 0.5 ± 0.5 mg/dL. Median observational period was 497 (range 97-1015) days, and median survival time was 550 (95% CI 414-686) days. Survival rate was 47.5%, and mortality rate was 38.7/100 person-years. Cox analyses showed that TTR (HR 0.791, 95% CI 0.633-0.988) and 6MWD (HR 0.795, 95% CI 0.674-0.938) were independently correlated with mortality and were influenced by body fat mass and leg skeletal muscle mass, respectively. It is suggested that nutritional markers and exercise capacity are important prognostic markers in waitlisted patients, but further study is needed to determine whether nutritional intervention or exercise can change outcomes.

Efficacy and safety of canagliflozin as add-on therapy to a glucagon-like peptide-1 receptor agonist in Japanese patients with type 2 diabetes mellitus: A 52-week, open-label, phase IV study.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are antihyperglycaemic agents with weight-lowering effects. The efficacy and safety of the SGLT2 inhibitor canagliflozin as add-on therapy in Japanese patients with type 2 diabetes mellitus (T2DM) and inadequate glycaemic control with a GLP-1RA (≥12 weeks) were evaluated in this phase IV study. Patients received canagliflozin 100 mg once daily for 52 weeks. Efficacy endpoints included change in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight, systolic blood pressure (SBP) and HDL cholesterol from baseline to week 52. Safety endpoints included adverse events (AEs), hypoglycaemia and laboratory tests. Of the 71 patients treated with canagliflozin, 63 completed the study. At 52 weeks, HbA1c was significantly reduced from baseline (-0.70%; paired t test, P < .001). Significant changes were also observed in FPG (-34.7 mg/dL), body weight (-4.46%), SBP (-7.90 mm Hg), and HDL cholesterol (7.60%; all P < .001). The incidence of AEs, adverse drug reactions and hypoglycaemia was 71.8%, 32.4% and 9.9%, respectively. All hypoglycaemic events were mild. These findings suggest that the long-term combination of canagliflozin with a GLP-1RA is effective and well tolerated in Japanese patients with T2DM.

Long-term efficacy and safety of canagliflozin in combination with insulin in Japanese patients with type 2 diabetes mellitus.

AIM: The aim of this study was to assess the long-term efficacy and safety of canagliflozin as add-on therapy in Japanese patients with type 2 diabetes mellitus who had inadequate glycaemic control with insulin. MATERIALS AND METHODS: The study comprised a 16-week, double-blind period in which patients were randomized to either placebo (P; N = 70) or canagliflozin (100 mg, CAN; N = 76), followed by a 36-week open-label period in which all patients received canagliflozin. The efficacy endpoints included the change in HbA1c from baseline to end of treatment. The safety endpoints were adverse events, hypoglycaemic events, and laboratory test values. RESULTS: The changes from baseline (mean ± standard deviation, last observation carried forward) in the P/CAN and CAN/CAN groups, respectively, were -1.09% ± 0.85% and -0.88% ± 0.86% for HbA1c, -1.40% ± 2.54% and -2.14% ± 2.75% for body weight, and 7.84% ± 14.37% and 8.91% ± 10.80% for HOMA2-%B (all, P < .001). Adverse events occurred in 85.1% of the P/CAN group and 92.0% of the CAN/CAN group. Hypoglycaemic events occurred in 43.3% and 54.7%, respectively. All hypoglycaemic events were mild in severity and insulin dose reduction decreased the incidence rate of hypoglycaemic events. Post-hoc ordinal logistic modelling/logistic modelling showed that lower serum C-peptide at Week 0 was a risk factor for hypoglycaemia in both the P and CAN groups in the double-blind period as well as in the canagliflozin all-treatment period. CONCLUSIONS: This study demonstrates the long-term efficacy and safety of canagliflozin combined with insulin in Japanese patients.

Physical activity level significantly affects the survival of patients with end-stage lung disease on a waiting list for lung transplantation.

PURPOSE: Our objective was to investigate the factors predicting the survival of patients on the waiting list for lung transplantation (LT) during the waiting period, with a special emphasis on the physical activity level. METHODS: The study included 70 patients with end-stage pulmonary disease who were on the waiting list for LT at Kyoto University Hospital. We examined the association between the baseline characteristics, including the body mass index and body composition, serum albumin, serum C-reactive protein (CRP), steroid administration, physical activity level (calculated by the food frequency questionnaire) and survival during the waiting period using Kaplan-Meier curves and Cox proportional hazard regression models. RESULTS: A physical activity level of ≤1.2 was correlated with significantly decreased survival (1-year survival: 68 vs. 90.9%, p = 0.0089), with a hazard ratio (HR) of 2.24 (95% confidence interval (CI) 1.22-4.19, p = 0.0001). Hypo-albumin (HR 2.024, 95% CI 1.339-6.009, p = 0.004), a high level of CRP (HR 2.551, CI 1.229-4.892, p = 0.02), and the administration of steroids (HR 2.258, CI 1.907-5.032, p = 0.024) were also significant predictors of survival. CONCLUSIONS: Low levels of physical activity during the waiting period for LT led to decreased survival times among LT candidates.

Severe underweight decreases the survival rate in adult lung transplantation.

PURPOSE: The body mass index (BMI) before lung transplantation (LT) is a benchmark of the post-LT survival. The aim of the study is to determine the BMI inadequate for the post-LT survival. METHODS: We examined the survival after LT in patients grouped into the following BMI categories: <18.5 kg/m2 (underweight), 18.5-24.9 kg/m2 (normal weight), 25-29.9 kg/m2 (overweight), and ≥30.0 kg/m2 (obese) according to the World Health Organization (WHO) criteria. A more detailed categorization was made for further evaluation of the underweight group: mild (17.0 ≤ BMI < 18.5 kg/m2) and severely underweight (BMI <17.0 kg/m2). RESULTS: There was no statistically significant difference in the post-LT survival between underweight and normal-weight patients (5-year survival: 78.7 vs. 76.1%). Patients with BMI <17.0 kg/m2 had a worse prognosis than those with 17.0 ≤ BMI < 18.5 kg/m2 (5-year survival: 70.3 vs. 90.0%). CONCLUSIONS: Standard BMI categorization per the WHO criteria is inadequate for determining the post-LT survival, especially in underweight patients. For the nutritional evaluation of underweight pre-LT patients, BMI <17.0 kg/m2 should be used instead of BMI <18.5 kg/m2.

Efficacy and safety of canagliflozin in combination with insulin: a double-blind, randomized, placebo-controlled study in Japanese patients with type 2 diabetes mellitus.

BACKGROUND: Combination therapy with canagliflozin and insulin was investigated in a prescribed substudy of the canagliflozin Cardiovascular Assessment Study (CANVAS); however, it was not evaluated in Japanese patients with type 2 diabetes mellitus (T2DM). Since the usage profile of insulin therapy and pathologic features of Japanese patients differ from those of Caucasian patients, we determined the clinical benefit of such a combination therapy in Japanese patients. METHODS: Patients who had inadequate glycemic control despite insulin, diet and exercise therapies were randomized into placebo (n = 70) and canagliflozin 100 mg (n = 76) groups that were administered once daily in addition to their prior insulin therapy in this double-blind, placebo-controlled study. The primary endpoint was the change in glycated hemoglobin (HbA1c) levels from the baseline to week 16. RESULTS: There was a statistically significant decrease in HbA1c levels from the baseline in the canagliflozin group (-0.97 ± 0.08 %) compared with the placebo group (0.13 ± 0.08 %) at week 16 [last observation carried forward (LOCF)]. The decrease in HbA1c levels in the canagliflozin group was independent of the insulin regimen (premixed, long-acting and long-acting plus rapid- or short-acting). Compared with the placebo group, canagliflozin significantly decreased fasting plasma glucose levels (-34.1 ± 4.8 vs -1.4 ± 5.0 mg/dL) and body weights (-2.13 ± 0.25 vs 0.24 ± 0.26 %), and significantly increased HDL cholesterol (3.3 ± 1.0 vs -0.5 ± 1.0 mg/dL) and HOMA2- %B (10.15 ± 1.37 vs 0.88 ± 1.42 %). The overall incidence of adverse events was similar between the two groups. The incidence and incidence per subject-year exposure of hypoglycemia (hypoglycemic symptoms and/or decreased blood glucose) were slightly higher in the canagliflozin group (40.0 % and 7.97) than in the placebo group (29.6 % and 4.51). However, hypoglycemic events in both groups were mild in severity and dose-reduction of insulin by <10 % from the baseline following hypoglycemic events decreased the incidence per subject-year exposure in the canagliflozin group. The incidence of hypoglycemia between the groups did not differ according to the insulin regimen. CONCLUSION: Canagliflozin in combination with insulin was effective in improving glycemic control and reducing body weight and well tolerated by Japanese patients with T2DM. Trial Registration ClinicalTrials.gov identifier: NCT02220920.

DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells.

Metformin, one of the most commonly used drugs for patients with type 2 diabetes, recently has received much attention regarding its anti-cancer action. It is thought that the suppression of mTOR signaling is involved in metformin's anti-cancer action. Although liver cancer is one of the most responsive types of cancer for reduction of incidence by metformin, the molecular mechanism of the suppression of mTOR in liver remains unknown. In this study, we investigated the mechanism of the suppressing effect of metformin on mTOR signaling and cell proliferation using human liver cancer cells. Metformin suppressed phosphorylation of p70-S6 kinase, and ribosome protein S6, downstream targets of mTOR, and suppressed cell proliferation. We found that DEPTOR, an endogenous substrate of mTOR suppression, is involved in the suppressing effect of metformin on mTOR signaling and cell proliferation in human liver cancer cells. Metformin increases the protein levels of DEPTOR, intensifies binding to mTOR, and exerts a suppressing effect on mTOR signaling. This increasing effect of DEPTOR by metformin is regulated by the proteasome degradation system; the suppressing effect of metformin on mTOR signaling and cell proliferation is in a DEPTOR-dependent manner. Furthermore, metformin exerts a suppressing effect on proteasome activity, DEPTOR-related mTOR signaling, and cell proliferation in an AMPK-dependent manner. We conclude that DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in liver, and could be a novel target for anti-cancer therapy.

[DPP-4 inhibitor].

Now seven compounds of DPP-4 inhibitor are available in Japan. They can be used in any stage of type 2 diabetes if the insulin secretion capacity is retained; first-line choice to third-line choice or combination with insulin therapy. There is no apparent difference in effect of each DPP-4 inhibitor on glycemic control; HbA1c levels are decreased by 0.6- 1.0% by monotherapy. Generally the drug is more effective for improving glycemic control in Japanese population compared to that in Western population. In addition, basal insulin therapy could be switched to the combination therapy with DPP-4 inhibitor and sulfonyl- urea in Japanese type 2 diabetes in cases where insulin secretion capacity is sufficiently preserved. Here we summarize the effect of DPP-4 inhibitor on glycemic control and algorithm for DPP-4 inhibitor treatment.

Relationship Between Frailty and Diabetic Pharmacologic Therapy in Older Adults with Type 2 Diabetes: A Cross-Sectional Study.

BACKGROUND: Older adults with diabetes mellitus require drug treatment considering their frailty, cognitive function, and hypoglycemia. OBJECTIVE: We investigated the association between diabetic pharmacologic therapy and both diabetic complications and frailty across eight diabetes-specific outpatient clinics nationwide. METHODS: Participants (aged 60-80 years) who had type 2 diabetes and did not require nursing care were included in the study. Basic attributes, patient background, complications, hypoglycemic status, body weight, body composition, blood tests, grip strength, and Kihon Checklist (a frailty index) and self-care scores were obtained. Descriptive statistics, t-test, chi-square test, and regression analyses were employed for evaluation. RESULTS: Overall, 417 participants were included (224 men, 193 women, mean age 70.1 ± 5.4 years, diabetes duration 14.9 ± 10.9 years, body mass index 24.5 ± 3.8, glycated hemoglobin 7.22 ± 0.98%, proportion of individuals with frailty and prefrailty, 19.9% and 41.0%, respectively). All drugs were used more frequently in prefrailty conditions. Each diabetes medication was related to complications, body composition, and frailty, as follows: sulfonylurea (lower hypoglycemia); glinide (severe hypoglycemia, retinopathy, weaker grip strength, high Kihon Checklist score, decreased physical activities); alpha-glucosidase inhibitors (no association); biguanide (high body mass index, high body fat, stronger grip strength); thiazolidinedione (decreased instrumental activities of daily living); dipeptidyl-peptidase-4 inhibitors (no association); sodium-glucose cotransporter 2 inhibitors; retinopathy, high body mass index and Kihon Checklist score, and depressive mood); glucagon-like peptide-1 receptor agonists (high body mass index and body fat and poor nutritional status); and insulin preparations (hypoglycemia, retinopathy, neuropathy, nephropathy, cardiovascular diseases, weaker grip strength, and high Kihon Checklist score and physical inactivity). CONCLUSIONS: Some formulations, such as glinide, sodium-glucose cotransporter 2 inhibitors, and insulin, are associated with an increased frequency of frailty, warranting careful and individualized diabetes treatment.

Self-monitoring of blood glucose (SMBG) improves glycaemic control in oral hypoglycaemic agent (OHA)-treated type 2 diabetes (SMBG-OHA study).

BACKGROUND: We conducted a clinical research study to determine the effect of self-monitoring of blood glucose (SMBG) on glycaemic control and the value of a putatively less painful blood sampling technique on SMBG in oral hypoglycaemic agent-treated type 2 diabetes patients; SMBG has not been broadly applied in non-insulin-treated patients in Japan. METHODS: One hundred thirty-seven subjects were recruited for the 24-week, prospective, comparison study and randomized into three groups: 46, no SMBG group; 46, fingertip group; and 45, palm group. The primary endpoint was change in HbA(1c). The secondary endpoints were SMBG compliance, dropout rate, treatment changes, and patient's and physician's satisfaction. RESULTS: Six subjects in the fingertip group (13.2%) and one subject in the palm group (2.2%) were dropped because of pain. A(1C) level of all subjects at 24-week was decreased more in the fingertip (-0.23%) and palm (-0.16%) groups than that in the no SMBG group (+0.31%) (p < 0.05). SMBG compliance was higher in the fingertip group (2.17 times/day) than that in the palm group (1.65 times/day) (p < 0.05). A(1C) level of treatment-unchanged subjects was decreased more in the fingertip (-0.25%) and palm (-0.21%) groups than that in the no SMBG group (+0.30%) (p < 0.05). SMBG compliance was higher in the fingertip group (2.24 times/day) than that in the palm group (1.65 times/day) (p < 0.05). Patient's questionnaire showed that 84.1% of the fingertip group and 90.2% of the palm group were satisfied with SMBG. Physician's satisfaction was higher in the palm group (94.0%) than that in the fingertip group (80.0%) (p < 0.05). CONCLUSION: SMBG is beneficial for glycaemic control, and palm blood sampling is a useful procedure for oral hypoglycaemic agent-treated type 2 diabetes.

Purkinje cell protein 4 positively regulates neurite outgrowth and neurotransmitter release.

Purkinje cell protein 4 (PCP4), also called brain-specific polypeptide 19 (PEP19), is a neurospecific, small calmodulin-binding protein that binds both calcium-free and calcium-binding calmodulin to regulate the calmodulin-mediated signal. The expression level of this molecule is decreased in the brain in Alzheimer's disease, Huntington's disease, and alcoholism. However, little is known of the function of PCP4 regarding neuronal or neuroendocrine cell differentiation and neurotransmitter release. To address this, we established a PCP4 tetracycline-inducible rat chromaffin cell line, PC12. When PCP4 expression was induced with doxcycline, neurite outgrowth was significantly advanced in the presence of nerve growth factor (NGF) and dibutyryl cAMP, which was inhibited by W-7, a calmodulin inhibitor, and PD98059, an ERK inhibitor. In addition, size of the cell body also was increased by treatment with NGF in the PCP4-induced PC12 cells. Constitutive and potassium-evoked release of acetylcholine and dopamine was increased and apoptosis induced by hydrogen peroxide (H(2)O(2)) was inhibited in PCP4-induced PC12 cells. On the other hand, knockdown of PCP4 by siRNA transfection decreased neurite outgrowth and dopamine release and increased H(2)O(2)-induced apoptosis in PC12 cells. These results indicate that PCP4 promotes neuroendocrine cell differentiation and neurotransmitter release by activating calmodulin function.

Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents.

Transmembrane TNF-alpha, a precursor of the soluble form of TNF-alpha, is expressed on activated macrophages and lymphocytes as well as other cell types. After processing by TNF-alpha-converting enzyme (TACE), the soluble form of TNF-alpha is cleaved from transmembrane TNF-alpha and mediates its biological activities through binding to Types 1 and 2 TNF receptors (TNF-R1 and -R2) of remote tissues. Accumulating evidence suggests that not only soluble TNF-alpha, but also transmembrane TNF-alpha is involved in the inflammatory response. Transmembrane TNF-alpha acts as a bipolar molecule that transmits signals both as a ligand and as a receptor in a cell-to-cell contact fashion. Transmembrane TNF-alpha on TNF-alpha-producing cells binds to TNF-R1 and -R2, and transmits signals to the target cells as a ligand, whereas transmembrane TNF-alpha also acts as a receptor that transmits outside-to-inside (reverse) signals back to the cells after binding to its native receptors. Anti-TNF agents infliximab, adalimumab and etanercept bind to and neutralize soluble TNF-alpha, but exert different effects on transmembrane TNF-alpha-expressing cells (TNF-alpha-producing cells). In the clinical settings, these three anti-TNF agents are equally effective for RA, but etanercept is not effective for granulomatous diseases. Moreover, infliximab induces granulomatous infections more frequently than etanercept. Considering the important role of transmembrane TNF-alpha in granulomatous inflammation, reviewing the biology of transmembrane TNF-alpha and its interaction with anti-TNF agents will contribute to understanding the bases of differential clinical efficacy of these promising treatment modalities.

Overeating Risk in Overweight Young Women Is Divided into Two Types According to Appetite and Eating Behavior.

Background: The problem of obesity in young women leads to future chronic diseases, effects on reproductive health, and next-generation obesity. Thus, it is necessary to provide effective support for these women's behavioral change. The purpose of this study was to evaluate dietary-related indicators to clarify the appetite and eating behavior problems among young women. Methods: Healthy women 18-39 years of age were enrolled. Interoceptive awareness (IA) was quantified using a heartbeat perception task score. Eating behavior was examined in three ways: Three-Factor Eating Questionnaire (TFEQ), visual analog scales of subjective appetite sensations, and a food consumption test. Results: In all, 15 participants who were overweight and 50 with normal weight were analyzed. The overweight women were clustered into two groups according to the heartbeat perception task score: a low-score group (women with overweight who have low IA [OW-LOW]) and high-score group (women with overweight who have high IA [OW-HIGH]). The OW-LOW group had significantly smaller intermeal changes in hunger score compared with women with normal weight. The disinhibition score on the TFEQ for the OW-HIGH group was significantly higher than the normal-weight women, and the prospective consumption score in the fasting condition was significantly higher in women with normal weight and a high heartbeat perception task score. Conclusions: Overweight young women were characterized into two groups with different appetite and eating behavior, which is connected to the risk of overeating. An appetite characteristic is associated with a high risk of obesity among the normal-weight population. Individualized interventions tailored to the IA levels may help in improving and preventing obesity.

Impact of diabetes mellitus on postoperative outcomes in individuals with non-small-cell lung cancer: A retrospective cohort study.

OBJECTIVES: Studies showing that individuals with non-small cell lung cancer (NSCLC) and diabetes mellitus (DM) have reported poor outcomes after pulmonary resection with varying results. Therefore, we investigated the clinical impact of preoperative DM on postoperative morbidity and survival in individuals with resectable NSCLC. PATIENTS AND METHODS: Data of individuals who underwent pulmonary resection for NSCLC from 2000 to 2015 were extracted from the database of Kyoto University Hospital. The primary endpoint was the incidence of postoperative complications, and secondary endpoints were postoperative length of hospital stay and overall survival. The survival rate was analyzed using the Kaplan-Meier method. RESULTS: A total of 2,219 patients were eligible for the study. The median age of participants was 67 years. Among them, 39.5% were women, and 259 (11.7%) presented with DM. The effect of DM on the incidence of postoperative complications and postoperative length of hospital stay was not significant. Although the 5-year survival rates were similar in both patients with and without DM (80.2% versus 79.4%; p = 0.158), those with DM who had a hemoglobin A1c level ≥ 8.0% had the worst survival. CONCLUSIONS: In individuals with resectable NSCLC, preoperative DM does not influence the acute phase postoperative recovery. However, poorly controlled preoperative DM could lead to low postoperative survival rates.

Sex-related differences in frailty factors in older persons with type 2 diabetes: a cross-sectional study.

BACKGROUND: This cross-sectional study aimed to describe sex-related differences in diabetes-specific factors underlying the development of frailty in older persons with type 2 diabetes. METHODS: Older persons aged 60-80 years were sequentially enrolled. Frailty and sarcopenia were evaluated using the validated Kihon checklist (KCL) and Asian Working Group for Sarcopenia algorithm, respectively. Physical function and characteristics were measured by trained nurses independently. RESULTS: This study included 213 participants. The mean age, body mass index (BMI), and glycated hemoglobin (HbA1c) level were 70.4 years, 24.3 kg/m2, and 7.4%, respectively. Prevalence of frailty was higher in women. Social and cognitive functions were lower in the prefrailty stage, while physical function was lower in the frailty stage, although there was no decrease in skeletal muscle mass. After adjustment for age, the KCL score was significantly associated with peripheral neuropathy, diet score, and coronary artery disease (CAD); frailty, with CAD and inoccupation; prefrailty, with diet score; and sarcopenia, with living alone in men. Meanwhile, the KCL score was significantly associated with living alone and skeletal muscle percentage; prefrailty, with peripheral neuropathy; and sarcopenia, with diabetes duration, LDL-cholesterol level, diet score, and irregular lifestyle in women. CONCLUSIONS: Sex differences in the risk factors of frailty should be considered when selecting preventive strategies for older persons with type 2 diabetes, early in the prefrailty stage. In particular, it is important to evaluate social participation and diet therapy in men and skeletal muscle mass and psychosocial function in women.

Canagliflozin for the treatment of type 2 diabetes: a comparison between Japanese and non-Japanese patients.

INTRODUCTION: Canagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, improves various cardiometabolic parameters. Although canagliflozin was originally discovered in Japan, no comprehensive summary of its effects in Japanese patients has been reported. As differences exist in the pathologic features of diabetes between Japanese and non-Japanese populations, it is important to consolidate Japanese data for canagliflozin. Areas covered: The authors summarize Japanese clinical trial and post-marketing surveillance data for canagliflozin, and make comparisons with non-Japanese data. They also consider the therapeutic potential of canagliflozin in Japanese patients by presenting results from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. Expert opinion: In Japanese patients, canagliflozin 100 mg, administered as monotherapy or combination therapy, improved blood glucose, body weight, and blood pressure, and was well tolerated; the efficacy and safety profiles were comparable to previous clinical studies in other countries. In the CANVAS Program, canagliflozin reduced major cardiovascular events, and although Japan was not included in this program, canagliflozin may have cardiovascular benefits in Japanese patients, in whom control of multiple risk factors is important for preventing diabetic complications. Patients with high cardiovascular risk often have multiple comorbidities, so it is important to consider the risk-benefit balance of using SGLT2 inhibitors in individual patients.

Long-Term Effect of the Color Record Method in Self-Monitoring of Blood Glucose on Metabolic Parameters in Type 2 Diabetes: A 2-Year Follow-up of the Color IMPACT Study.

INTRODUCTION: This article evaluates the potential long-term effect of two different color indication methods for self-monitoring of blood glucose (SMBG), the color record (CR) and color display (CD), on metabolic parameters in insulin-treated type 2 diabetes in a post-intervention period. METHODS: 101 participants with type 2 diabetes who completed the Color IMPACT study were enrolled in a 2-year comparison follow-up study. Participants continued SMBG with their usual diabetes care. The study outcomes were differences in change in HbA1c levels, blood pressure (BP), body weight and lipid profiles between the CR and non-CR arms and the CD and non-CD arms during a 1- and 2-year period of the study. RESULTS: 98 participants were analyzed. Reductions in HbA1c levels, systolic BP and low-density lipoprotein cholesterol levels were maintained in the CR arm by - 0.40% (95% CI: - 0.73 to - 0.06, p = 0.020), -1 3.2 mmHg (95% CI: - 24.1 to - 2.3, p = 0.019), - 11.4 mg/dl (95% CI: - 18.1 to - 4.6, p = 0.001), respectively, in a 1-year period. However, HbA1c and BP returned to the baseline levels during an additional 1-year period. In contrast, there were no significant changes in outcome in the CD arm during the study period. CONCLUSION: Intervention promoting self-action such as the color record method in SMBG sustains a beneficial effect on metabolic parameters after the intervention. This long-term effect is helpful for people with type 2 diabetes to manage their diabetes ABCs (HbA1c, BP, cholesterol) and to prevent diabetic complications. TRIAL REGISTRATION: UMIN clinical trials registry identifier, UMIN000006865.

Bullous pemphigoid associated with dipeptidyl peptidase-4 inhibitors: A report of five cases.

Bullous pemphigoid (BP) is an autoimmune blistering skin disorder. Recently, BP induced by dipeptidyl peptidase-4 (DPP-4) inhibitors has been a concern. Although DPP-4 inhibitors are commonly used in the Asian population because of their safety and efficacy, BP associated with DPP-4 inhibitors is sometimes seen in clinical settings. Here, we report five Japanese cases of BP associated with the agents. In the present cases, BP occurred in older adults using four different DPP-4 inhibitors, which showed various clinical manifestations in terms of latency period for BP, sex, glycemic control and diabetes duration. Withdrawal of DPP-4 inhibitors was effective in improving BP, and achieved remission even in cases requiring oral steroid administration and intravenous immunoglobulin therapy. Clinicians should note the importance of early diagnosis of this clinical condition and initiate prompt withdrawal of DPP-4 inhibitors.