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Background: Although several studies have shown that SGLT2 inhibitors exert ameliorating effects on hepatic steatosis, the mechanism remains unknown. Therefore, we compare the glucose-lowering effects of the SGLT2 inhibitor, dapagliflozin on hepatic steatosis with those of insulin glargine. Methods: Six-week-old db/db mice were assigned to one of four groups: untreated (Placebo), treated with dapagliflozin (Dapa), treated with insulin glargine (Gla), and treated with both dapagliflozin and insulin glargine (Dapa+Gla). After 8 weeks of treatment, blood glucose levels, liver triglyceride (TG) content and liver gene expression profiles were examined. Results: Fed blood glucose levels were significantly lower in the three treatment groups compared with the Placebo group (Placebo 904.2 ± 35.6, Dapa 425.0 ± 26.7, Gla 406.1 ± 25.8, Dapa+Gla 347.3 ± 24.0 mg/dL). HE staining and oil red O staining of the liver revealed that there was high fat and lipid droplets accumulation in the Gla group compared with that in the other three groups. The liver TG content was significantly increased in the Gla group compared with the others (Placebo 24.1 ± 5.7, Dapa 30.6 ± 6.4, Gla 128 ± 25, and Dapa+Gla 54.4 ± 7.1 mg per gram liver). Microarray analysis revealed that Cidea, Cidec and Mogat1 were upregulated in the Gla group compared with the Placebo group. Real-time quantitative PCR revealed that expression levels associated in fatty acid synthesis, such as Fas, Elovl6, Scd1 and Mogat1 significantly upregulated in the Gla group compared with the Placebo group. As for the expression levels of genes related to fatty acid uptake and storage, Cidea and Cidec, elevated in the Gla group compared with the Placebo group. Pparg2, which is associated with Fas, Elovl6, Scd1, Mogat1 and Cidec significantly increased in the Gla group compared with the Placebo group. Conclusion: Hepatic steatosis was prevented in db/db mice, after 8 weeks of treatment with dapagliflozin and/or insulin glargine, but not with insulin glargine alone. Disclosure K. Omori: None. A. Nakamura: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Ono Pharmaceutical Co., Ltd. H. Miyoshi: Research Support; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kowa Pharmaceutical Europe Co. Ltd., Mitsubishi Tanabe Pharma Corporation, MSD, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceutical Europe Co. Ltd., Mitsubishi Tanabe Pharma Corporation, MSD, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. H. Nomoto: None. H. Kameda: None. K. Cho: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. T. Atsumi: Research Support; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Takeda Pharmaceutical Company Limited, UCB, Inc. Funding AstraZeneca

Studies on glucagon-like peptide 1 receptor agonists (GLP-1-RA) and dipeptidyl peptidase-4 inhibitors (DPP-4-I) have suggested positive effects on beta-cells. However, direct comparison between weekly GLP-1-RA: dulaglutide (Dula) and weekly DPP-4-I: trelagliptin (Trela) effects on beta-cell function is not known. Thus, we compared the effects of Dula and Trela on beta-cell function in patients with type 2 diabetes (T2D) in an open-label, parallel-group, randomized controlled 24-week trial, with an additional 28 weeks of extension follow-up. Beta-cell function and insulin resistance were assessed by HOMA2-%β and HOMA2-IR, respectively. Body composition was also assessed by the bioelectrical impedance method. Fifty metformin ± basal insulin-treated patients with type 2 diabetes (T2D) were randomized to Dula 0.75 mg/week or Trela 100 mg/week. Forty-eight patients entered the 28-weeks extension study and continued their allocated therapy. Forty-six completed (Dula: n = 23, Trela: n = 23) the 52-week exposure and were included in the analysis. HOMA2-%β was higher in the Dula group than in the Trela group throughout the 52 weeks (24 weeks: Dula: +50.6 ± 9.9% vs. Trela: +7.5 ± 9.5%, p = 0.003; 52 weeks: Dula: +54.5 ± 8.7% vs. Trela: +3.0 ± 8.7%, p In conclusion, Dula increased HOMA2-%β level more than Trela over the 52 weeks, without a significant change in HOMA2-IR level. Dula reduced body fat mass without skeletal muscle mass loss. Disclosure Y. Kondo: None. S. Satoh: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.

Diabetics often have vascular diseases and other comorbidities. Sleep apnea syndrome (SAS) is a disorder characterized by repeated episodes of apnea and hypopnea during nocturnal sleep. Risk factors for SAS include obesity, male gender, and advanced age. It was reported that type 2 diabetes patients (T2DM) without obesity often have SAS. Among the 1,367 ambulant T2DM who were being treated at our institution, 245 (165 men, 80 women) with a BMI Disclosure S. Kawasaki: None. H. Misawa: None. T. Kondo: None. Y. Kondo: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.

Some categories of drugs are known for causing hyperglycemia or diabetes such as steroids, antipsychotics, and immunosuppressant. However, there has been little evidence from studies about the proportion of each drug in the context of drug-induced diabetes. In this study, we used data from the Japanese Adverse Drug Event Report (JADER) database, a spontaneous reporting system database maintained at the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan, reported between April 2004 and June 2017. Among 459,250 reports of adverse drug reactions in JADER database, reported instances of the adverse event of hyperglycemia or diabetes were extracted. After the exclusion of anti-diabetes drugs, the drugs frequently implicated in the development of hyperglycemia or diabetes, including prednisolone, tacrolimus, everolimus, ribavirin, quetiapine, aripiprazole, interferon alfa-2b, risperidone, atorvastatin, dexamethasone, ciclosporin, nilotinib, methylprednisolone, or nivolumab, were identified. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, was manifested as the third most frequently associated drug with hyperglycemia or diabetes (340 cases), following prednisolone (694 cases) and tacrolimus (393 cases), and the reporting odds ratio (ROR 8.56, 95% CI 7.65-9.57) of this drug was higher than that of the two aforementioned drugs (ROR 3.96, 95% CI 3.66-4.28 and ROR 3.51, 95% CI 3.17-3.89). These results suggest that there is a potent association of evelolimus with hyperglycemia in clinical practice in Japan.

Diagnosing obstructive sleep apnea (OSA) usually involves high cost, patient inconvenience, and the need for examination at a specialized center. This study employed a portable, wearable, diagnostic device (WatchPAT) to investigate the prevalence of OSA in nonobese Japanese patients with type 2 diabetes.Patients with type 2 diabetes were tested for OSA over one night using the WatchPAT. Logistic regression analysis was used to estimate the odds ratios (ORs) of risk factors for OSA in nonobese subjects.A total of 200 eligible patients with type 2 diabetes were studied (64.5% men; aged 60.1 ± 13.6 years; body mass index [BMI], 26.3 ± 5.2 kg/mA high prevalence of OSA was observed in this nonobese population of Japanese patients with type 2 diabetes. The triglyceride level was associated with OSA among nonobese patients.AHI = apnea-hypopnea Index; BMI = body mass index; CI = confidence interval; ESS = Epworth Sleepiness Scale; HbA1c = glycated hemoglobin; OR = odds ratio; OSA = obstructive sleep apnea; PAT = peripheral arterial tone; T2D = type 2 diabetes; TG = triglyceride.

Stem cell therapy using islet-like insulin-producing cells derived from human pluripotent stem cells has the potential to allow patients with type 1 diabetes to withdraw from insulin therapy. However, several issues exist regarding the use of stem cell therapy to treat type 1 diabetes. In this review, we will focus on the following topics: (1) autoimmune responses during the autologous transplantation of stem cell-derived islet cells, (2) a comparison of stem cell therapy with insulin injection therapy, (3) the impact of the islet microenvironment on stem cell-derived islet cells, and (4) the cost-effectiveness of stem cell-derived islet cell transplantation. Based on these various viewpoints, we will discuss what is required to perform stem cell therapy for patients with type 1 diabetes.

Aims: This study investigated the hypoglycemia risk in people with type 2 diabetes (T2D) who initiated or switched to insulin glargine 300 U/mL (Gla-300) by stratifying them by age and renal function. Methods: We examined data from 4621 people with T2D (1227 insulin-naïve and 3394 insulin-experienced) of the X-STAR study, a prospective, observational, 12-month study conducted from December 2015 to August 2018 in Japan. Participants were stratified by age (

Aims To investigate changes in glucose tolerance, insulin secretion and insulin sensitivity in Japanese recipients before and 1 year after renal transplantation. Methods We conducted a study of Japanese recipients without diabetes who underwent renal transplantation at Hokkaido University Hospital. A 75-g oral glucose tolerance test was performed before and 1 year after renal transplantation in these recipients. Insulin sensitivity was estimated using the Matsuda index and homeostasis model assessment of insulin resistance (HOMA-IR). Insulin secretion was evaluated based on the insulin secretion sensitivity index-2 (ISSI-2). Results Of the 62 renal transplant recipients, 31 were diagnosed as having impaired glucose tolerance before transplantation. Among these 31 recipients, after 1 year, four had developed new-onset diabetes after transplantation, and nine had impaired glucose tolerance. Unexpectedly, 18 changed from impaired to normal glucose tolerance. When these recipients with impaired glucose tolerance were classified into a non-amelioration group and an amelioration group, the ISSI-2 was significantly reduced, with no significant changes in the Matsuda index or HOMA-IR, in the non-amelioration group 1 year after renal transplantation. By contrast, ISSI-2 and Matsuda index values were significantly increased, with no significant changes in HOMA-IR values in the amelioration group. Conclusions More than half of Japanese renal transplant recipients with impaired glucose tolerance had normal glucose tolerance 1 year after renal transplantation. These results suggest that an increase in insulin secretion and whole insulin sensitivity was associated with improvement in glucose tolerance in these recipients. This article is protected by copyright. All rights reserved.

Hepatic insulin signalling involves insulin receptor substrates (Irs) 1/2, and is normally associated with the inhibition of gluconeogenesis and activation of lipogenesis. In diabetes and obesity, insulin no longer suppresses hepatic gluconeogenesis, while continuing to activate lipogenesis, a state referred to as ‘selective insulin resistance'. Here, we show that ‘selective insulin resistance' is caused by the differential expression of Irs1 and Irs2 in different zones of the liver. We demonstrate that hepatic Irs2-knockout mice develop ‘selective insulin resistance', whereas mice lacking in Irs1, or both Irs1 and Irs2, develop ‘total insulin resistance'. In obese diabetic mice, Irs1/2-mediated insulin signalling is impaired in the periportal zone, which is the primary site of gluconeogenesis, but enhanced in the perivenous zone, which is the primary site of lipogenesis. While hyperinsulinaemia reduces Irs2 expression in both the periportal and perivenous zones, Irs1 expression, which is predominantly in the perivenous zone, remains mostly unaffected. These data suggest that ‘selective insulin resistance' is induced by the differential distribution, and alterations of hepatic Irs1 and Irs2 expression., Type 2 diabetes and obesity are associated with increased hepatic gluconeogenesis and lipogenesis, known as selective insulin resistance. Here Kubota et al. explain selective insulin resistance in the liver with the zonal distribution and selective insulin-mediated regulation of Irs1 and Irs2.

We compared the efficacy and safety of taking miglitol dissolved in water during a meal and taking a miglitol tablet just before a meal. Primary efficacy parameter is the area under the curve (AUC) for postprandial plasma glucose.Miglitol was administered according to three different intake schedules in each subject: intake schedule A, no miglitol; intake schedule B, administration of miglitol (50 mg) just before breakfast; intake schedule C, dissolving miglitol (50 mg) in water and taking it just before (1/3), during (1/3), and just after breakfast (1/3). Blood samples were collected at 0, 30, 60, 120, and 180 min after breakfast.The AUCs for plasma glucose, insulin, and total glucose-dependent insulinotropic polypeptide (GIP) were significantly lower for intake schedules B and C, compared with those for intake schedule A. The AUC for total glucagon like peptide-1(GLP-1) was higher for intake schedule C than for intake schedule A. The coefficient of variation (CV) of plasma glucose was significantly lower for intake schedule C than for intake schedules A and B.Taking miglitol dissolved in water was equivalent to taking a miglitol tablet. The CV of plasma glucose was significantly lower for the dissolved-dose regimen.

Diazoxide is a non-diuretic benzothiadiazine derivative, one of a group of substances introduced into clinical practice in the 1950s for the treatment of hypertension. Fajans reported the use of diazoxide for the treatment of insulinoma in 1979. Although patients with hyperinsulinemic hypoglycemia worldwide have been treated with diazoxide for more than 30 years, there are no recent reports about the adverse effects of this drug in Asian patients, including Japanese patients. Herein, we report the results of our retrospective clinical record review of 6 Japanese patients (3 females and 3 males, ranging in age from 58 to 91 years) with hyperinsulinemic hypoglycemia and inoperable insulinoma treated with diazoxide. Diazoxide improved control of hypoglycemic symptoms and maintained normoglycemia in 5 of the 6 patients, and was ineffective in one patient. Surprisingly, although all 6 patients received diazoxide according to the treatment strategy recommended in Western patients, 5 of the 6 patients developed edema and two developed congestive heart failure. Thus, when starting treatment with diazoxide in Japanese patients, the symptoms and signs of fluid retention should be evaluated carefully. Also, appropriate protocols for treatment with diazoxide should be evaluated by means of clinical trials in Japanese patients with hyperinsulinemic hypoglycemia.

Non-alcoholic fatty liver disease (NAFLD) is associated with various metabolic disorders, and the therapeutic strategies for treating NAFLD and non-alcoholic steatohepatitis (NASH) have not been fully established. In the present study, we examined whether lipid-lowering agents inhibited the progression of NAFLD and tumorigenesis in a non-alcoholic steatohepatitis-derived hepatocellular carcinoma model mouse (STAM mice) generated by streptozotocin injection and a high-fat diet. Seven-week-old STAM mice were divided into groups fed a high-fat diet (Ctl) or a high-fat diet supplemented with ezetimibe (Ez), fenofibrate (Ff), rosuvastatin (Rs), ezetimibe plus fenofibrate (EF), or ezetimibe plus rosuvastatin (ER) for 4 weeks. At the end of the experiments, an oral glucose tolerance test, an insulin tolerance test, biochemical analyses using serum and liver, and a histological analysis of liver were performed in 11-week-old STAM mice. The lipid-lowering agents did not affect the body weight or the casual blood glucose levels in any of the groups. The serum triglyceride level was significantly decreased by Ff, Rs, and EF. Glucose tolerance was improved by Ez and Ff, but none of these agents improved insulin sensitivity. A histochemical analysis revealed that the lipid-lowering agents, with the exception of Rs, significantly inhibited the progression of hepatic steatosis. Nonetheless, no significant changes in the incidence of hepatic tumors were observed in any of the groups. Lipid-lowering agents inhibited the progression of hepatic steatosis without suppressing tumorigenesis in STAM mice. Our data has implications for the mechanism underlying steatosis-independent hepatic tumorigenesis in mice.

We investigated the relationship between the results of the octreotide test and somatostatin receptor (SSTR) 2 expression in insulinoma patients, to evaluate the usefulness of this test for predicting SSTR2 expression in insulinomas in Japanese patients. Five females and one male were included in the study. All patients underwent the octreotide test before the surgery carried out to resect the tumor, and histopathological examination of the resected tumor was performed by a single experienced pathologist. SSTR2 expression was evaluated by the SSTR2 immunohistochemistry scoring system. Insulinoma was clinically diagnosed and surgically resected in all six patients. In the octreotide test, suppression of insulin secretion was sufficient after loading in patients 1-4 and 6. In patient 5, however, the suppression of insulin secretion was insufficient, which resulted in severe hypoglycemia with endogenous relative hyperinsulinemia after the octreotide loading. The histopathological findings revealed SSTR2 expression in the insulinomas of patients 1-4 and 6, but not in the insulinoma of patient 5. In conclusion, improvement of hyperinsulinemic hypoglycemia by octreotide in Japanese insulinoma patients was associated with SSTR2 expression in the tumor. Our results suggest that the octreotide test could be useful for predicting SSTR2 expression in the tumor.

Aims/Introduction ‘The Standard Diabetes Manual’ has been developed by clinical researchers from multiple major institutions in Japan, such as the National Center for Global Health and Medicine, as a comprehensive disease management program, including collaboration between primary care physicians (PCPs) and specialist services. The present study evaluated the efficacy of the manual as a quality improvement strategy in diabetes care by PCPs. Materials and Methods A total of 42 PCPs in eight domestic districts of the Japan Medical Association were allocated to either the intervention group or the control group in a cluster‐randomized design. The PCPs in both groups were provided with a copy of the Diabetes Treatment Guide published by the Japan Diabetes Society, and the PCPs in the intervention group additionally received a copy of the manual and a 30‐min relevant seminar at the inception of the intervention. The primary end‐point was the adherence to the following performances as quality indicators: evaluation of retinopathy, and urinary albumin excretion measurements and serum creatinine measurements, as recommended by the Japan Medical Association. Results A total of 416 patients were enrolled by 36 PCPs. During the 1‐year follow‐up period, the proportion of PCPs who adhered to recommendation‐concordant measurements of urinary albumin excretion was significantly higher in the intervention group than in the control group (adherence: 17.9% vs 5.3%, P = 0.016). The other parameters were not statistically different between the two groups. Conclusions Implementation of ‘The Standard Diabetes Manual’ potentially leads to an improved quality of diabetes management by PCPs.

This study assessed indicators of the need for insulin therapy and the effect of treatment on pregnancy outcomes in Japanese patients with gestational diabetes mellitus (GDM). All patients diagnosed with GDM were hospitalized for three days. Plasma glucose profiles in patients under strict dietary management and the characteristics of GDM patients with high daily glucose levels were investigated. Patients who failed to achieve glycemic targets were treated with insulin. Indicators of the need for insulin treatment were investigated. Pregnancy outcomes in patients prescribed dietary management and patients prescribed insulin treatment were compared. The study included 112 patients with GDM. GDM patients with high daily glucose levels in the hospital exhibited significantly higher 1-h and 2-h plasma glucose levels in oral glucose tolerance tests (OGTTs) at diagnosis. In our hospital, 102 GDM patients with singleton pregnancies were followed until delivery; 32 (31.3%) were treated with insulin. Univariate analysis identified significant associations of insulin requirement with family history of diabetes and with 1-h and 2-h OGTT values at diagnosis. Multivariate analysis showed that the 1-h OGTT plasma glucose level at diagnosis was an independent predictor of the need for insulin. In perinatal outcomes, insulin treatment was associated with low birth weight.

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: Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is an effective oral antidiabetic agent as both monotherapy and when combined with insulin. Data from three observational studies performed in patients with type 2 diabetes receiving sitagliptin therapy in the routine clinical setting were integrated to conduct factor analysis of the changes in hemoglobin A1c (HbA1c), body weight, and estimated glomerular filtration rate (eGFR) over 12 months. Methods: Among patients with type 2 diabetes attending medical institutions affiliated with Kanagawa Physicians Association, those using sitagliptin were followed for 1 year. In the ASSET-K and ASSIST-K studies, patients were managed by diabetologists, while they were managed by non-diabetologists in the ATTEST-K study. Patients were not administered insulin in ASSET-K, whereas insulin was administered in ASSIST-K. HbA1c (National Glycohemoglobin Standardization Program), blood glucose (fasting/postprandial), body weight, and renal function (serum creatinine and eGFR) were the efficacy endpoints. Factor analysis was performed by analysis of variance using the magnitude of the change in HbA1c, body weight, and eGFR after 12 months of sitagliptin therapy as response variables, and the study, sex, and age as explanatory variables. Results: Of 1,327 patients registered in ASSET-K (diabetologists/without insulin), 1,167 patients in ASSIST-K (diabetologists/with insulin), and 530 patients in ATTEST-K (non-diabetologists), statistical analysis was carried out on 1,074, 854, and 411 patients, respectively. There were significant inter-study differences in patient characteristics (complications, duration of diabetes, and baseline HbA1c), the sitagliptin dose, and the use of other antidiabetic agents. HbA1c decreased significantly in all three studies. According to factor analysis, the magnitude of the change in HbA1c over 12 months showed significant inter-study differences and was also significantly influenced by the age, duration of diabetes, and baseline HbA1c. Conclusions: Comparison of three observational studies identified differences in patient characteristics, treatment of diabetes (use/non-use of insulin), and the level of specialist care (diabetologist/non-diabetologist). Despite such differences, consistent reduction of HbA1c by sitagliptin was demonstrated in all three studies. The patients showing most improvement in HbA1c with sitagliptin therapy were older patients with a short duration of diabetes and high baseline HbA1c level. J Clin Med Res. 2016;8(6):461-471 doi: http://dx.doi.org/10.14740/jocmr2540w

We evaluated the influence of short-term treatment with exenatide twice daily or liraglutide once daily on daily blood glucose fluctuations in 40 patients with type 2 diabetes inadequately controlled by sulfonylureas. The patients in a multicenter, open-label trial were randomly assigned to receive add-on exenatide (10 μg/day, n = 21) or add-on liraglutide (0.3-0.9 mg/day, n = 19), and underwent 24-hour continuous subcutaneous glucose monitoring. There was no significant between-group difference in glucose fluctuations during the day, as assessed by calculating mean amplitude of glycemic excursion (MAGE) and standard deviation (SD). However, the mean blood glucose levels at 3 hours after breakfast and dinner were significantly lower in the exenatide group than the liraglutide group (breakfast: 127.3 ± 24.1 vs. 153.4 ± 28.7 mg/dL; p = 0.006, dinner: 108.7 ± 17.3 vs. 141.9 ± 24.2 mg/dL; p < 0.001). In contrast, mean blood glucose levels and their SD were significantly lower between 0000 h and 0600 h in the liraglutide group than the exenatide group (average glucose: 126.9 ± 27.1 vs. 107.1 ± 24.0 mg/dL; p = 0.029, SD: 15.2 ± 10.5 vs. 8.7 ± 3.8; p = 0.020). Both groups had similar glucose fluctuations despite differences in 24-hour blood glucose profiles. Therefore, each of these agents may have advantages or disadvantages and should be selected according to the blood glucose profile of the patient.

The brain and nervous system play an important role in pancreatic β-cell function. This study investigated the role of muscarinic agonists or acetylcholine, which is the major neurotransmitter in the vagal nerve, in regulating pancreatic β-cell mass and glucose homeostasis. Administration of the muscarinic agonist bethanechol increased insulin secretion and improved glucose tolerance in insulin-receptor substrate 2 (IRS2)-knockout (IRS-2−/−) mice and diet-induced obesity mice. Oral administration of bethanechol increased β-cell mass and proliferation in wild-type mice, but not IRS-2−/− mice. The muscarinic agonist also increased the incorporation of 5-bromo-2′-deoxyuridine (BrdU) into islets isolated from wild-type mice and pancreatic β-cell line MIN6. The phosphorylation of protein kinase B (Akt) induced by oral administration of bethanechol was observed in wild-type mice, but not IRS-2−/− mice. The secretion of glucagon-like peptide-1 (GLP-1) was also stimulated by bethanechol in wild-type mice, and a GLP-1 antagonist partially inhibited the bethanechol-induced increase in β-cell mass. These results suggest that the muscarinic agonist exerted direct and indirect effects on β-cell proliferation that were dependent on the IRS-2/Akt pathway. The bethanechol-stimulated release of GLP-1 may be indirectly associated with β-cell proliferation.

Type 2 diabetes is a metabolic disorder that is characterized by an impaired capacity to secrete insulin, insulin resistance, or both. Dehydroepiandrosterone (DHEA), a steroid hormone produced by the adrenal cortex, has been reported to have beneficial effects on diabetes mellitus and obesity in animal models. DHEA and DHEA-sulfate (DHEA-S) have been reported to increase not only insulin secretion of the pancreas but also insulin sensitivity of the liver, adipose tissue, and muscle. We investigated the effects of DHEA on glucose metabolism in animal models and reported decrease of liver gluconeogenesis. Recently, we reported the effect of DHEA on the liver and muscle by using insulin-stimulated insulin receptor substrate 1 and 2 (IRS1 and IRS2)-deficient mice. DHEA increased Akt phosphorylation in the liver of C57BL6 IRS1- and IRS2-deficient mice fed with a high-fat diet (HFD), which suggests that the increase in DHEA-induced Akt signaling is sufficient in the presence of IRS1 or IRS2. In addition, other studies have also reported the effect of DHEA on diabetes mellitus in the liver, muscle, adipose tissue, and pancreatic β-cell and its effect on obesity in animal models. A meta-analysis in elderly men and women has found that DHEA supplementation has no effects on blood glucose levels. However, DHEA supplementation to patients with type 2 diabetes has not been fully elucidated. Therefore, further studies are needed to provide greater insight into the effect of DHEA on diabetes and obesity in animal and human models.

Objective: In patients with diabetes, The use of GLP-1 receptor agonist expected to decreases the number of injections and improves blood glucose control. In this study, the effects were evaluated when changed from intensive insulin therapy to combination therapy of long-acting GLP-1 receptor agonist, duraglutide, and long-acting insulin. Methods: We examined patients with type 2 diabetes who were admitted to our department and started blood glucose management with intensive insulin therapy, followed by flash glucose monitoring (FGM); we then switched to dulaglutide + long-acting insulin therapy. We analyzed the blood glucose excursion on intensive insulin therapy, 5 and 12 days after dulaglutide + long-acting insulin combination therapy change. Furthermore, we evaluated HbA1c and GA after 1 month of the change. Result: We enrolled 20 patients with type 2 diabetes (age: 70.1 ± 11.1 years; history of diabetes: 20.8 ± 9.27 years). The blood glucose excursions during intensive insulin therapy and 5 and 12 days after dulaglutide + long-acting insulin combination therapy were 134.3 ± 43.1, 125.4 ± 28.2, and 110.1 ± 225.7 mg/dL, respectively. A significant decrease was observed in the blood glucose average on the day of intensive insulin therapy and 5 days after dulaglutide + long-acting insulin combination therapy. In addition, the blood glucose average was significantly decreased between days 5 and 12 after the dulaglutide + long-acting insulin combination therapy. Furthermore, the blood glucose standard deviation exhibited a declining trend after changing to dulaglutide + long-acting insulin combination therapy. After 1 month of the change, HbA1c and GA decreased significantly (−1.37% ± 1.87%, P = 0.007 and −7.01% ± 4.51%, P = 0.016, respectively). Conclusions: The transition from intensive insulin therapy to dulaglutide + long-acting insulin therapy demonstrated better blood glucose control with reduced blood glucose excursion and the number of self-injections. Disclosure K. Ito: None. Y. Kondo: None. S. Satoh: 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.

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.

Although sleep apnea syndrome reportedly increases nocturnal blood glucose (BG) variability, few studies have assessed the effect of the lowest oxygen saturation (SpO2) during sleep on short-term BG levels. Thus, this prospective study of BG fluctuations while sleeping was conducted on subjects fitted with a continuous glucose monitoring (CGM) device and a WatchPAT®, allowing simple evaluation of sleep-disordered breathing. Ninety-two patients with type 2 diabetes were fitted with the two devices overnight in the hospital when the glycemia was stable (∼7-10 days) in order to avoid the effects of hyperglycemia. The subjects were aged at least 18 years. Results: The subjects were categorized according to their lowest SpO2 by WatchPAT (SpO2 ≥90%, 85%≤ and Conclusions: Even without differences in nocturnal fluctuations of BG levels, because of treatment, hypoxemia during sleep causes short-term worsening of glycemia. Moreover, the greater the degree of hypoxemia, the earlier the worsening is likely. Disclosure M. Shinoda: None. T. Yamakawa: None. R. Sakamoto: None. J. Suzuki: None. K. Takahashi: 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.

Uncoupling protein 2 (UCP2) is a mitochondrial protein, which uncouples the oxidative phosphorylation. UCP2 protein level is reportedly upregulated in pancreatic islets of patients with type 2 diabetes; however, the functional role and mechanism of the upregulated UCP2 remain unclear. In this study, we undertook both in vitro regulation of gene expression and in vivo transgenic approaches to assess the significance of UCP2 in β cells. The expression of UCP2 was significantly upregulated by the stimulation with glucose, glucokinase activator, or insulin in mouse isolated islets (n=3-5, p Disclosure R. Inoue: None. J. Shirakawa: None. Y. Togashi: 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.

Introduction: Diabetes treatment has unique aspects that require behavior modification among patients in terms of food consumption, exercise and others. The emotional burden among patients that is caused by diabetes treatment and diabetes-related morbidity in itself often causes patients to have trouble carrying out daily activities and makes the maintenance of glycemic control difficult. The aim of this study was to investigate the association between glycemic control and the Problem Areas in Diabetes (PAID) scores which is an indicator of emotional burden among Japanese patients with type 2 diabetes mellitus (T2DM) on a large scale. Methods: Data from 3511 patients with T2DM were obtained from the Diabetes Registry in Kanagawa. We used PAID scores to evaluate diabetes-related emotional distress. For 3432 patients who answered completely, we assessed the association between PAID scores and HbA1c and other background factors, while adjusting for possible confounding factors. Results: The mean age, body mass index, disease duration and HbA1c level were 63.2 years, 25.3 kg/m2, 12.5 years, and 7.53%, respectively. The mean PAID score was 43.3 points. Five point five percent were severely burdened patients who scored more than 70 points. There was a significant correlation between PAID scores and HbA1c (ρ=0.025, p Conclusions: Treatment to maintain normal levels of HbA1c may prevent the onset of diabetic retinopathy; moreover, it will reduce the emotional burden among patients with diabetes. Disclosure K. Takahashi: None. M. Shinoda: None. R. Sakamoto: None. J. Suzuki: None. T. Yamakawa: 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: Although several studies have shown that SGLT2 inhibitors exert protective effects on pancreatic beta cells and hepatic steatosis, the mechanism remains unknown. Therefore, we compared the glucose-lowering effect of the SGLT2 inhibitor dapagliflozin (dapa) on pancreatic beta cell mass and hepatic steatosis with those of insulin glargine. Methods: Six-week-old db/db mice were assigned to one of four groups: untreated (Placebo), treated with dapa (Dapa), treated with insulin glargine (Gla), or treated with both dapa and insulin glargine (Dapa+Gla). After 8 weeks of treatment, we determined blood glucose levels, beta cell mass and liver triglyceride (TG) content. Results: Fed blood glucose levels were significantly lower in the treated groups compared with the Placebo group (Placebo 904.2 ± 35.6 mg/dL, Dapa 425.0 ± 26.7 mg/dL, Gla 406.1 ± 25.8 mg/dL, Dapa+Gla 347.3 ± 24.0 mg/dL). Immunohistochemical analysis revealed that pancreatic beta cell mass was significantly increased in the Dapa and Dapa+Gla groups, but not the Gla group, compared with the Placebo group (Placebo 2.25 ± 0.45 mg, Dapa 5.01 ± 0.52 mg, Gla 3.79 ± 0.32 mg, Dapa+Gla 5.19 ± 0.56 mg). Liver TG content was significantly increased in the Gla group compared with the others (Placebo 24.1 ± 5.7 mg, Dapa 30.6 ± 6.4 mg, Gla 128 ± 25 mg, and Dapa+Gla 54.4 ± 7.1 mg per gram liver). Microarray analysis revealed genes involved in hepatic steatosis such as Cidec and Pparg were significantly upregulated in the Gla group compared with the Placebo group. As for hepatic fatty acid composition, concentrations of C16:0 and C18:1n-9 were significantly increased in the Gla group compared with the Placebo group, while C18:0 was not significantly different between groups. There was no difference in safety including mortality. Conclusion: Beta cell mass was maintained, and hepatic steatosis was not induced, after 8 weeks of treatment with dapa, but with insulin glargine, in db/db mice. Disclosure K. Omori: None. A. Nakamura: Research Support; Self; Sanofi, Mitsubishi Tanabe Pharma Corporation, MSD K.K., Novo Nordisk Inc., Novartis Pharma K.K., AstraZeneca, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd. H. Miyoshi: Speaker's Bureau; Self; Astellas Pharma US, Inc., AstraZeneca, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Kissei Pharmaceutical Co., Ltd., Novo Nordisk A/S, Sanofi. Research Support; Self; Astellas Pharma US, Inc., AstraZeneca, Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; MSD K.K.. K. Takahashi: None. N. Kitao: 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. T. Atsumi: Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical Co., Ltd., Astellas Pharma US, Inc., Takeda Pharmaceuticals U.S.A., Inc., Pfizer Inc., AbbVie Inc.. Research Support; Self; Astellas Pharma US, Inc., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceuticals U.S.A., Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Otsuka Holdings Co., Ltd..

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.

Aims/Introduction: The short-term efficacy and safety of insulin degludec (IDeg) in patients with type 2 diabetes have not previously been reported. We evaluated target glycemic control and glucose variability in hospitalized patients with type 2 diabetes. Material and Methods: In an open-label, multicenter, randomized controlled trial, 74 patients were randomly assigned to an insulin glargine U100 (IGla) group (38 patients) or insulin degludec group (36 patients) and were administered Basal-bolus therapy during hospitalization. Continuous glucose monitoring was performed on Day 11 after the insulin treatment commenced, to verify that day’s glucose variability. Results: The proportion of patients achieving a fasting blood glucose level of 110 mg/dl and 2-hour postprandial blood glucose level of 180 mg/dl throughout at least a day during the observation period was 30.6% [95% confidence interval 18.2-45.5%, one-sided p-value = 0.057] (11/36) in the IGla group, and 31.3% [95% confidence interval 18.0-47.2%, one sided p-value = 0.056] (10/32) in the IDeg group. Although no significant difference was noted on the 6-point SMBG profiles in mean blood glucose levels between the groups, the IDeg group showed a significant improvement in the percentage change from baseline of mean blood glucose before lunch on Day 7 (p = 0.021) and after dinner on Day 12 (Day 7 before lunch: IGla group -29.5 ± 26.3%, IDeg group -44.5 ± 22.1%, p = 0.021; Day 12 after dinner: IGla group -34.2 ± 22.5%, IDeg group -51.1 ± 21.7%, p = 0.021). No significant differences were noted between the groups in the incidence of hypoglycemia or the glucose variability parameter data on continuous glucose monitoring. Conclusion: This study suggests that IDeg is comparable with IGla in short-term efficacy and safety for patients with type 2 diabetes in the initial phase of basal-bolus therapy. Disclosure J. Suzuki: None. T. Yamakawa: None. M. Shinoda: None. R. Sakamoto: None. K. Takahashi: 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.

Some studies of glucagon-like peptide 1 receptor agonists (GLP-1-RA) and dipeptidyl peptidase-4 inhibitors (DPP-4-I) have shown positive effects on beta-cells. A direct comparison between weekly GLP-1-RA: dulaglutide (Dula) and weekly DPP-4-I: trelagliptin (Trela) effects on beta-cell function has not yet been performed. We compared the effects of Dula and Trela on beta-cell function in type 2 diabetes (T2D) patients in an open-label, parallel-group, randomized controlled trial. Patients received Dula 0.75 mg/week or Trela 100 mg/week for 24 weeks. Beta-cell function was assessed using a glucagon stimulation test (GST)-based disposition index (DI = area under the curve of C-peptide during 6 min GST ÷ HOMA2-IR). The primary endpoint was the difference between the two groups in the change in DI over the 24-week treatment period. Body composition was assessed using the bioelectrical impedance method. Fifty metformin ± basal insulin-treated patients with T2D were randomized to Dula or Trela. Forty-eight patients completed 24 weeks of weekly administration of Dula (n = 23) or Trela (n = 25). The change in DI during 24 weeks was not different between the groups (Dula: +0.34 ± 0.49, Trela: +0.57 ± 0.47, p = 0.74). However, the change in HOMA2-%β was higher in the Dula group than in the Trela group (Dula: +50.6 ± 9.9% vs. Trela: +7.5 ± 9.5%, p = 0.003). HbA1c decreased to a greater extent in the Dula group (Dula: -0.77 ± 0.07%, Trela: -0.57 ± 0.07%, p = 0.04). Body weight reduced more in the Dula group than the Trela group (Dula: -1.4 ± 0.3 kg vs. Trela: -0.3 ± 0.3 kg, p = 0.02). Body fat mass reduced more in the Dula group than the Trela group (Dula: -1.2 ± 0.3 kg vs. Trela: -0.3 ± 0.2 kg, p = 0.02). Dula did not reduce skeletal muscle mass (-0.2 ± 0.1 kg, p = 0.31). In conclusion, the effects of Dula and Trela on beta-cell function were not different in GST-based DI. However, Dula increased the HOMA2-%β level more than Trela. Dula reduced body fat mass without causing skeletal muscle mass loss. Disclosure Y. Kondo: None. S. Satoh: 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.

Diabetic patients often have various diseases such as vascular diseases and other comorbidities. Sleep apnea syndrome (SAS) in such patients may lead to acute deterioration due to nocturnal hypoxia. Among the 1,367 ambulant patients with type 2 diabetes (T2DM) who were being treated at our institution, 483 (313 men and 170 women) who agreed to undergo a portable sleep polygraph test were evaluated to identify risk factors for SAS, with a focus on microangiopathy and stable comorbidities. The rates of intracranial lesions, respiratory diseases, cardiovascular diseases, cancer, thyroid diseases, and mental illness were 22%, 9.9%, 39.8%, 16.1%, 7.7%, and 5.8%, respectively. The rates of microangiopathy were as follows: retinopathy (30.6%) and nephropathy (48.5%). The patients had an apnea-hypopnea index (AHI) of 15.4±14.3 (mean±standard deviation) (16.8±14.5 in men and 12.9±13.8 in women). The prevalence of SAS (AHI≥15) was 40.6% (127/313) in men and 29.4% (50/170) in women. Intracranial lesions, cardiovascular diseases, and cancer were more common among patients with SAS than among those without SAS (AHI Disclosure S. Kawasaki: None. H. Misawa: None. R. Kaneda: None. T. Kondo: None. Y. Kondo: 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.

Oral semaglutide (sema), the first GLP-1 receptor agonist in a tablet formulation, is in late-stage development for the treatment of T2D. The effect and safety of oral sema (3, 7, or 14 mg once daily) was assessed in this randomized, double-blind, placebo-controlled phase 3a trial in drug-naïve patients with T2D uncontrolled on diet and exercise (n=703). Primary endpoint was change from baseline in HbA1c at week 26. The primary estimand (treatment policy) evaluated the effect regardless of trial product discontinuation or rescue medication use (effectiveness). A secondary estimand (hypothetical) evaluated the effect of trial product while on treatment without rescue medication (efficacy) using a mixed model for repeated measures (MMRM), and is the method used in many previous T2D studies. Oral sema resulted in clinically meaningful reductions in both HbA1c (all doses) and body weight (higher doses) at week 26 (Table). Adverse events (AEs) occurred in 58, 53 and 57% for 3, 7 and 14 mg oral sema, respectively, and 56% with placebo. The most common AE with oral sema was transient mild or moderate nausea. Nausea occurred in 5-16% of patients with oral sema vs. 6% with placebo. Oral sema demonstrated superiority vs. placebo in reducing HbA1c (all dose levels) and body weight (14 mg) and was well tolerated in T2D uncontrolled on diet and exercise (ClinicalTrials.gov NCT02906930). Disclosure V.R. Aroda: Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc., AstraZeneca, Calibra Medical, Eisai Inc., Sanofi. Consultant; Self; Sanofi. Research Support; Self; Theracos, Inc.. Employee; Spouse/Partner; Merck & Co., Inc.. Other Relationship; Self; American Diabetes Association. Consultant; Self; ADOCIA. J. Rosenstock: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Consultant; Self; Sanofi. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Merck & Co., Inc., Pfizer Inc., Sanofi, Novo Nordisk Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Intarcia Therapeutics, Inc., Genentech, Inc. 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. O. Jeppesen: Employee; Self; Novo Nordisk A/S. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. E. Christiansen: Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Self; Novo Nordisk A/S. C.L. Hertz: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. M. Haluzik: None.

Reportedly, patients with type 2 diabetes at a high risk for cardiovascular events receiving empagliflozin, compared with placebo, have a lower rate of the primary composite cardiovascular outcome and death from any cause. This study compares the effect of empagliflozin and glimepiride on the endothelial function in patients with type 2 diabetes by flow-mediated dilation (FMD). This prospective, randomized, parallel-group comparison study enrolled 31 patients who were continuously treated with metformin and glargine before bedtime for 12 weeks, followed by the random addition of 10-mg empagliflozin (empagliflozin group, n = 13) or 0.5-mg glimepiride (glimepiride group, n = 18) for 12 weeks. FMD was assessed before and after additional treatment. The primary outcome was a change in FMD (δFMD) with additional treatment before and after 12 weeks. The key secondary outcomes were changes in HbA1c, GA, FPG, body weight, LDL-C, and systolic and diastolic blood pressures. No significant difference existed in age, HbA1c, FMD, and doses of metformin and glargine, and δFMD had no significant difference (empagliflozin, −0.79% ± 1.35%; glimepiride, −0.62% ± 2.78%; P = 0.84). Although HbA1c of both groups improved significantly, the change was not statistically significant. The body weight increased only in the glimepiride group (baseline, 69.6 ± 14.5 kg; 12 weeks later, +1.17 ± 1.99 kg; P = 0.02), but the change was not statistically significant. Likewise, changes in GA, FPG, LDL-C, and systolic and diastolic blood pressures were not significant. In conclusion, empagliflozin besides metformin and glargine did not affect the endothelial function significantly compared with glimepiride in patients with type 2 diabetes. In empagliflozin group, body weight was not changed significantly for 12 weeks. Insulin usage may affect body weight, and that may affect these results. The effect of empagliflozin on endothelial function was not clear in this study. Disclosure H. Tamura: None. Y. Kondo: None. K. Ito: None. S. Satoh: 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.

Effectiveness of real time continuous glucose monitoring (RT-CGM) compared with intensive self-monitoring of blood glucose (SMBG) is not clear. To analyze the effectiveness of RT-CGM, retrospective CGM and, intensive SMBG in adults with type 2 diabetes, we conducted a randomized, open-labelled clinical trial. Patients were type 2 diabetes adults admitted to our hospital from August 2016 to August 2017. Patients of age over 85 years, pregnant, admission less than 1 week were excluded. Patients were randomized to SMBG with RT-CGM using the Medtronic MiniMed 620G, SMBG with retrospective CGM using Medtronic iPro2, or SMBG alone. Both CGMs were worn for 6 days. SMBG was done 6 times a day at every pre-meal and 2 hours post-meal. Primary outcome was the change in HbA1c from baseline to 12weeks. As the secondary outcomes, change in mean glucose level from the admission day to discharge day, and frequency of in-hospital hypoglycemia were evaluated. We also evaluated patients’ satisfaction to treatment using Diabetes Treatment Satisfaction Questionnaire (DTSQ). As the result, 111 patients were enrolled and 33 patients were allocated to RT-CGM group, 26 to retrospective CGM group, and 52 to SMBG group. Among these 111 patients, 63 (56.8%) were male, mean age was 65.1 years, diabetes duration was 8.3 years, BMI was 26.3 kg/m^2, and HbA1c was 9.1%. Overall, glycemic control was improved after treatment for both HbA1c and the mean glucose level; HbA1c from 9.1±1.7% to 6.8±1.0%, mean glucose level from 189±56mg/dl to 137±19mg/dl. However, the changes were not significantly different between the groups. As the safety profile, 34 hypoglycemia was seen during hospitalization with no difference in frequency between the groups (P=0.11). There were no differences in patients’ satisfaction to treatment assessed by DTSQ, either. In conclusion, among adults with type 2 diabetes, intensive SMBG may have the equivalent effect to RT-CGM and retrospective CGM. Disclosure Y. Takano: None. Y. Namiki: None. H. Hiiragi: None. T. Yamada: None. H. Sasaki: None. Y. Murohashi: None. H. Takamine: None. K. Inazumi: 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.

Several pharmacological treatment options are available for type 2 diabetes; however, many patients do not achieve optimum glycaemic control and therefore new therapies are necessary. We assessed the efficacy and safety of semaglutide, a glucagon-like peptide-1 (GLP-1) analogue in clinical development, compared with insulin glargine in patients with type 2 diabetes who were inadequately controlled with metformin (with or without sulfonylureas).We did a randomised, open-label, non-inferiority, parallel-group, multicentre, multinational, phase 3a trial (SUSTAIN 4) at 196 sites in 14 countries. Eligible participants were insulin-naive patients with type 2 diabetes, aged 18 years and older, who had insufficient glycaemic control with metformin either alone or in combination with a sulfonylurea. We randomly assigned participants (1:1:1) to either subcutaneous once-weekly 0·5 mg or 1·0 mg semaglutide (doses reached after following a fixed dose-escalation regimen) or once-daily insulin glargine (starting dose 10 IU per day, then titrated weekly to a pre-breakfast self-measured plasma glucose target of 4·0-5·5 mmol/L [72-99 mg/dL]) for 30 weeks. In all treatment groups, previous background metformin and sulfonylurea treatment was continued throughout the trial. We did the randomisation using an interactive voice or web response system. The primary endpoint was change in mean HbABetween Aug 4, 2014, and Sept 3, 2015, we randomly assigned 1089 participants to treatment; the mITT population consisted of 362 participants assigned to 0·5 mg semaglutide, 360 to 1·0 mg semaglutide, and 360 to insulin glargine. 49 (14%) participants assigned to 0·5 mg semaglutide discontinued treatment prematurely, compared with 55 (15%) assigned to 1·0 mg semaglutide, and 26 (7%) assigned to insulin glargine. Most discontinuations were due to adverse events-mostly gastrointestinal with semaglutide, and others such as skin and subcutaneous tissue disorders (eg, rash, pruritus, and urticaria) with insulin glargine. From a mean baseline HbACompared with insulin glargine, semaglutide resulted in greater reductions in HbANovo Nordisk A/S.

To examine the effects of luseogliflozin, a sodium–glucose cotransporter 2 inhibitor, on pancreatic beta cell mass in db/db mice of different ages. db/db mice aged 6, 10, 14 and 24 weeks old were fed either standard chow (control group) or standard chow containing 0.01% luseogliflozin (luseo group). After 4 weeks, immunohistochemistry and gene expression tests were conducted. In 6-week-old db/db mice, immunohistochemistry revealed a significant increase in beta cell mass in the luseo group compared with the control group after 4 weeks of treatment. Gene expression profiling of isolated islets showed upregulation Mafa, Pdx1, Ki67 and Ccnd2 in the luseo group. Beta cell mass decreased with age in db/db mice in the control group. Beta cell mass in the luseo group significantly increased compared with the control group regardless of age, although beta cell mass in the 28-week-old luseo group (4 weeks of treatment in 24-week-old db/db mice) was significantly lower than in the 10-week-old luseo group (4 weeks of treatment in 6-week-old db/db mice). Luseogliflozin preserved beta cell mass in db/db mice. The protective effect was more evident in the earlier phase of diabetes.

Objective: The aim of this study was to examine the fluctuations in CD4+ T cells, CD8+ T cells, and natural CD4+CD25+FoxP3+T-regulatory (Treg) cells following an oral glucose tolerance test (OGTT) in participants with and those without type 2 diabetes. Methods: Nineteen Japanese participants with type 2 diabetes (DM group) and 21 participants without diabetes (non-DM group) were recruited and underwent a 75-g OGTT. The cell numbers of leucocytes, lymphocytes, and the T cell compartment, such as CD4+, CD8+, and Treg, were calculated for blood samples obtained after an overnight 12-h fast and during a 75-g OGTT at 60 and 120 min. Results: Before glucose loading, no differences in the cell numbers of leucocytes, lymphocytes, CD4+, CD8+, and Treg were observed between the DM group and the non-DM group. The proportion of CD8+ was significantly reduced, whereas the proportion of CD4+ was significantly increased, after 120 min of glucose loading in both groups. The proportion of Treg was not affected. Furthermore, a significant positive correlation was observed between the AUC0-120 min of CD8+ and the change in the free fatty acid level following the OGTT (ρ = 0.39, P < 0.05), but not that of glucose or insulin. Conclusions: The proportion of CD4+ T cells was increased and that of CD8+ T cells was reduced after glucose loading in both subjects with and without diabetes. These findings suggest that glucose loading dynamically affects the balance of the circulating T lymphocyte subset, regardless of glucose tolerance.

Chronic low-grade inflammation in the pancreatic islets is observed in individuals with type 2 diabetes, and macrophage levels are elevated in the islets of these individuals. However, the molecular mechanisms underlying the interactions between the pancreatic β cells and macrophages and their involvement in inflammation are not fully understood. Here, we investigated the role of S100 calcium-binding protein A8 (S100A8), a member of the damage-associated molecular pattern molecules (DAMPs), in β-cell inflammation. Co-cultivation of pancreatic islets with unstimulated peritoneal macrophages in the presence of palmitate (to induce lipotoxicity) and high glucose (to induce glucotoxicity) synergistically increased the expression and release of islet-produced S100A8 in a Toll-like receptor 4 (TLR4)-independent manner. Consistently, a significant increase in the expression of the S100a8 gene was observed in the islets of diabetic db/db mice. Furthermore, the islet-derived S100A8 induced TLR4-mediated inflammatory cytokine production by migrating macrophages. When human islet cells were co-cultured with U937 human monocyte cells, the palmitate treatment up-regulated S100A8 expression. This S100A8-mediated interaction between islets and macrophages evoked β-cell apoptosis, which was ameliorated by TLR4 inhibition in the macrophages or S100A8 neutralization in the pancreatic islets. Of note, both glucotoxicity and lipotoxicity triggered S100A8 secretion from the pancreatic islets, which in turn promoted macrophage infiltration of the islets. Taken together, a positive feedback loop between islet-derived S100A8 and macrophages drives β-cell apoptosis and pancreatic islet inflammation. We conclude that developing therapeutic approaches to inhibit S100A8 may serve to prevent β-cell loss in patients with diabetes.

Objective: Obesity-associated diabetes causes aging-like changes to skin physiology in animal models, but there have been no clinical studies focusing on human obese diabetic patients. The purpose of this study was to examine the hypothesis that obesity-associated diabetes accelerates aging-like skin changes in Japanese people. Methods: This cross-sectional study enrolled obese-diabetes patients (body mass index ≥ 25 kg m−2) and healthy volunteers (body mass index −2) as controls. Skin physiology parameters relating to aging (stratum corneum hydration, transepidermal water loss, skin pH, advanced glycation end-products, and dermal collagen density) were evaluated in the two groups. Results: About 37 subjects participated (16 in a control group and 21 in an obese-diabetes group). Age was not significantly different between the groups. The stratum corneum hydration level was significantly lower in the obese-diabetes group. Transepidermal water loss and levels of advanced glycation end-products were significantly higher in this group. Skin pH was not significantly different between groups. Dermal collagen density decreased in the obese-diabetes group. Conclusion: We showed that obese-diabetes patients have decreased stratum corneum hydration, increased transepidermal water loss, higher skin advanced glycation end-products and decreased dermal collagen fiber density compared with normal-weight subjects. These results indicate that the ordinary age-related physiological skin changes seen in the elderly can also occur in obese-diabetes patients aged in their 40s.

Objectives Excessively short and long sleep durations are associated with type 2 diabetes, but there is limited information about the association between sleep quality and diabetes. Accordingly, the present study was performed to investigate this relationship. Materials and methods The subjects were 3249 patients with type 2 diabetes aged 20 years or older. Sleep quality was assessed by using the Pittsburgh Sleep Quality Index (PSQI). A higher global PSQI score indicates worse sleep quality, and a global PSQI score >5 differentiates poor sleepers from good sleepers. Results The mean global PSQI score was 5.94 ± 3.33, and 47.6% of the patients had a score of 6 or higher. Regarding the components of the PSQI, the score was highest for sleep duration, followed by subjective sleep quality and then sleep latency in decreasing order. When the patients were assigned to HbA1c quartiles (≤ 6.5%, 6.6–7.0%, 7.1–7.8%, and ≥ 7.9%), the top quartile had a significantly higher global PSQI score than the other quartiles. The top HbA1c quartile had a sleep duration of only 6.23 ± 1.42 hours, which was significantly shorter than in the other quartiles. Also, sleep latency was 25.3 ± 31.8 minutes in the top quartile, which was significantly longer (by approximately 20 minutes) than in the other quartiles. When analysis was performed with adjustment for age, gender, BMI, smoking, and other confounders, the global PSQI score was still significantly higher and sleep duration was shorter in the top HbA1c quartile (HbA1c ≥ 7.9%). Conclusions Japanese patients with type 2 diabetes were found to have poor subjective sleep quality independently of potential confounders, especially those with inadequate glycemic control. Impairment of sleep quality was associated with both increased sleep latency and a shorter duration of sleep.

Type 2 diabetes is a metabolic disorder that is characterized by an impaired capacity to secrete insulin, insulin resistance, or both. Dehydroepiandrosterone (DHEA), a steroid hormone produced by the adrenal cortex, has been reported to have beneficial effects on diabetes mellitus and obesity in animal models. DHEA and DHEA-sulfate (DHEA-S) have been reported to increase not only insulin secretion of the pancreas but also insulin sensitivity of the liver, adipose tissue, and muscle. We investigated the effects of DHEA on glucose metabolism in animal models and reported decrease of liver gluconeogenesis. Recently, we reported the effect of DHEA on the liver and muscle by using insulin-stimulated insulin receptor substrate 1 and 2 (IRS1 and IRS2)-deficient mice. DHEA increased Akt phosphorylation in the liver of C57BL6 IRS1- and IRS2-deficient mice fed with a high-fat diet (HFD), which suggests that the increase in DHEA-induced Akt signaling is sufficient in the presence of IRS1 or IRS2. In addition, other studies have also reported the effect of DHEA on diabetes mellitus in the liver, muscle, adipose tissue, and pancreatic β-cell and its effect on obesity in animal models. A meta-analysis in elderly men and women has found that DHEA supplementation has no effects on blood glucose levels. However, DHEA supplementation to patients with type 2 diabetes has not been fully elucidated. Therefore, further studies are needed to provide greater insight into the effect of DHEA on diabetes and obesity in animal and human models.

Background: Ipragliflozin is a sodium-glucose co-transporter 2 inhibitor that can improve glycemic control and reduce body weight and blood pressure in patients with type 2 diabetes mellitus (T2DM). We evaluated the efficacy and safety of ipragliflozin in the real-world clinical setting, with a focus on the changes of body composition up to 3 months of treatment. Methods: This was a prospective multicenter interventional trial. We investigated changes of the blood pressure, body composition, blood glucose, hemoglobin A1c (HbA1c), ketone bodies, lipids, and insulin after treatment with ipragliflozin (50 - 100 mg/day) for 12 weeks in Japanese patients with T2DM who showed poor glycemic control despite receiving diet and exercise therapy with or without oral antidiabetic drugs for more than 12 weeks. Results: Two hundred and fifty-seven subjects were included in the efficacy analysis up to 12 weeks of treatment and 301 subjects were included in the safety analysis. From baseline to 12 weeks, HbA1c showed a change of -0.68% (95% confidence interval (CI): -0.83, -0.53) and fasting blood glucose showed a change of -23.9 mg/dL (95% CI: -30.5, -17.2), with both parameters displaying a significant reduction (P < 0.001). The difference of body weight from baseline was -1.82 kg (95% CI: -2.14, -1.50), and it also showed significant reduction (P < 0.001). Analysis of body composition revealed that body fat changed by -1.46 kg (95% CI: -1.79, -1.14, P < 0.001) and body water changed by -0.37 kg (95% CI: -0.60, -0.14, P < 0.01). Laboratory tests demonstrated improvement of liver function and the lipid profile. Adverse events (AEs) occurred in 22.6% of the subjects, with frequent events being vulvovaginal candidiasis in 2.7% and cystitis in 2.0%. Serious AEs occurred in three subjects. Conclusions: In patients with T2DM, ipragliflozin improved glycemic control after 1 month of treatment and caused weight loss by reducing body fat more than body water. J Clin Med Res. 2016;8(2):116-125 doi: http://dx.doi.org/10.14740/jocmr2417w Correction in J Clin Med Res. 2016;8(3):267-267, doi: http://dx.doi.org/10.14740/jocmr2417wc1

Aims To evaluate the efficacy and tolerability of sitagliptin in subjects with impaired glucose tolerance (IGT). Methods In a double-blind, parallel-group study, 242 Japanese subjects with IGT, determined by a 75-g oral glucose tolerance test (OGTT) at week −1, were randomized (1 : 1 : 1) to placebo (n = 83), sitagliptin 25 mg (n = 82) or 50 mg (n = 77) once daily for 8 weeks. Glycaemic variables were assessed using another OGTT at week 7 and meal tolerance tests (MTTs) at weeks 0 and 8. Primary and secondary endpoints were percent change from baseline in glucose total area under the curve 0–2 h (AUC0–2 h) during the MTT and OGTT, respectively. Results Least squares mean percent change from baseline in glucose AUC0–2 h during the MTT were −2.4, −9.5 and −11.5%, and during the OGTT were −3.7, −21.4 and −20.1% with placebo, sitagliptin 25 mg once daily, and 50 mg once daily, respectively (p

The mechanism responsible for the lipid-lowering effect of dipeptidyl peptidase-4 (DPP-4) inhibitors remains unknown in humans. We evaluated the effect of anagliptin on serum lipid profiles, including cholesterol synthesis and absorption markers, in Japanese patients with type 2 diabetes.Thirty patients with type 2 diabetes (20 - 70 years old, low-density lipoprotein cholesterol (LDL-C) level over 120 mg/dl, and no history of treatment with antidiabetic or antihyperlipidemic drugs) were enrolled. One hundred milligrams of anagliptin were administered twice a day for a month.After treatment of anagliptin, the LDL-C and total cholesterol (TC) levels did not decrease overall, but the TC level decreased significantly in 28 patients whose HbA1c levels decreased. Lathosterol decreased significantly, whereas no changes in campesterol, sitosterol or cholestanol were observed.These results of our study show no significant change in LDL-C, a tendency of decrease in TC and non-high-density lipoprotein cholesterol (non-HDL-C) after treatment of anagliptin for 1 month. Anagliptin therapy decreased the cholesterol synthesis marker lathosterol without changing cholesterol absorption markers.

Background: It is unclear whether dipeptidyl peptidase-4 inhibitors decrease hemoglobin A 1c (HbA 1c ) in a glucose-dependent manner in patients on insulin therapy who have impaired insulin secretion. This study investigated factors influencing the efficacy of sitagliptin when used concomitantly with insulin to treat type 2 diabetes mellitus (T2DM) in the real-world setting. Methods: A retrospective study was conducted of 1,004 T2DM patients at 36 Japanese clinics associated with the Diabetes Task Force of the Kanagawa Physicians Association. Eligible patients had been on insulin for at least 6 months, with a baseline HbA 1c of 7.0% (53 mmol/mol) or higher. Baseline characteristics and laboratory data from 495 patients were subjected to multiple regression analysis to identify factors influencing the change of HbA 1c . Results: Most patients (n = 809) received sitagliptin at a dose of 50 mg. In the 1,004 patients, HbA 1c decreased by 0.74% (6 mmol/mol) and body weight increased by 0.1 kg after 6 months of combination therapy. Multiple regression analysis showed that a higher baseline HbA 1c , older age, and lower body mass index influenced the change of HbA 1c after 6 months. Hypoglycemic symptoms occurred in 7.4%, but none were severe. Conclusions: These results emphasize the importance of a higher HbA 1c at the commencement of sitagliptin therapy in patients on insulin. Glucose-dependent suppression of glucagon secretion by sitagliptin may be useful in patients with impaired insulin secretion. Sitagliptin can be used concomitantly with insulin irrespective of the insulin regimen, duration of insulin treatment, and concomitant medications. J Clin Med Res. 2015;7(8):607-612 doi: http://dx.doi.org/10.14740/jocmr2149w

The aim of this randomized, double-blind, parallel-group study was to investigate the safety and efficacy of empagliflozin monotherapy for 52 weeks in Japanese patients with type 2 diabetes (T2DM). In a 12-week dose-finding period, patients [N = 547; mean baseline glycosylated hemoglobin (HbA1c) 7.92–8.02%] received empagliflozin (5, 10, 25, or 50 mg) or placebo. In a 40-week extension period, patients on empagliflozin 10 or 25 mg continued the same treatment and patients on other doses were reallocated to empagliflozin 10 or 25 mg. Outcomes at week 52 included changes from baseline in HbA1c, fasting plasma glucose (FPG), weight and blood pressure (BP) in patients who received empagliflozin 10 or 25 mg in both the initial 12 weeks and the extension and safety in patients treated with ≥1 dose of empagliflozin 10 or 25 mg. Adjusted mean ± SE changes in HbA1c from baseline at week 52 were –0.67 ± 0.09% and −0.86 ± 0.09%, in FPG were −24.7 ± 3.2 mg/dL and −31.3 ± 3.4 mg/dL, and in body weight were −3.1 ± 0.4 kg and −3.1 ± 0.4 kg, with empagliflozin 10 and 25 mg, respectively. Both doses reduced systolic and diastolic BP. Adverse events were reported in 70.8% and 66.8% of patients on empagliflozin 10 and 25 mg, respectively. Confirmed hypoglycemic adverse events (plasma glucose ≤70 mg/dL and/or requiring assistance) were reported in one patient per group. Empagliflozin monotherapy for 52 weeks led to sustained reductions in HbA1c, FPG, weight and BP and was well tolerated in Japanese patients with T2DM. Boehringer Ingelheim and Eli Lilly and Company.

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

Adaptive β-cell replication occurs in response to increased metabolic demand during insulin resistance. The intracellular mediators of this compensatory response are poorly defined and their identification could provide significant targets for β-cell regeneration therapies. Here we show that glucose and insulin in vitro and insulin resistance in vivo activate protein kinase C ζ (PKCζ) in pancreatic islets and β-cells. PKCζ is required for glucose- and glucokinase activator-induced proliferation of rodent and human β-cells in vitro. Furthermore, either kinase-dead PKCζ expression (KD-PKCζ) or disruption of PKCζ in mouse β-cells blocks compensatory β-cell replication when acute hyperglycemia/hyperinsulinemia is induced. Importantly, KD-PKCζ inhibits insulin resistance-mediated mammalian target of rapamycin (mTOR) activation and cyclin-D2 upregulation independent of Akt activation. In summary, PKCζ activation is key for early compensatory β-cell replication in insulin resistance by regulating the downstream signals mTOR and cyclin-D2. This suggests that alterations in PKCζ expression or activity might contribute to inadequate β-cell mass expansion and β-cell failure leading to type 2 diabetes.

Objective The aim of this study was to examine the fluctuations in CD4+ T cells, CD8+ T cells, and natural CD4+CD25+FoxP3+T-regulatory (Treg) cells following an oral glucose tolerance test (OGTT) in participants with and those without type 2 diabetes (T2DM). Methods 19 Japanese participants with T2DM (DM group) and 21 participants without diabetes (non-DM group) were recruited and underwent a 75-g OGTT. The cell numbers of leukocytes, lymphocytes, and the T cell compartment, such as CD4+, CD8+, and Treg, were calculated for blood samples obtained after an overnight 12 h fast and during a 75-g OGTT at 60 and 120 min. Results Before glucose loading, no differences in the cell numbers of leukocytes, lymphocytes, CD4+, CD8+, and Treg were observed between the DM group and the non-DM group. The proportion of CD8+ was significantly reduced, whereas the proportion of CD4+ was significantly increased, after 120 min of glucose loading in both groups. The proportion of Treg was not affected. Furthermore, a significant positive correlation was observed between the AUC0–120 min of CD8+ and the change in the free fatty acid level following the OGTT (ρ = 0.39, P