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Introduction This real-world study investigated glycaemic control and quality of life (QoL) in insulin-experienced Japanese patients with type 2 diabetes (T2D) who switched to insulin degludec/insulin aspart (IDegAsp). Methods This was a prospective, non-interventional, open-label, single-arm study. Eligible patients were adults (aged ≥ 20 years) with T2D, previously treated with insulin glargine 100 or 300 units/mL (glargine U100/U300) with or without prandial insulin, who switched to IDegAsp as part of routine practice. Change from baseline to end of study (EOS; 26 weeks after initiation or IDegAsp discontinuation) in the following endpoints was assessed by adjusted mixed models for repeated measures: glycated haemoglobin (HbA1c; primary endpoint), fasting plasma glucose (FPG), insulin dose and total Diabetes Therapy-Related Quality of Life (DTR-QoL) score. Non-severe hypoglycaemia was assessed in the 4-week period prior to initiating IDegAsp and in the 4-week period before EOS or discontinuation using negative binomial regression. Results The full analysis set included 236 patients from 29 centres in Japan with mean (± SD) age 63.2 years (± 12.3), HbA1c 7.7% (± 1.0) and diabetes duration 14.9 (± 9.3) years. After 26 weeks with IDegAsp, HbA1c (estimated change − 0.1% [− 0.2; 0.0]95% confidence interval (CI), p = 0.3036) and FPG (− 7.5 mg/dL [− 23.5; 8.5]95% CI, p = 0.3477) were maintained; there were significant reductions in basal and total insulin dose: estimated change of − 3.4 units/day [− 3.8; − 3.0]95% CI and − 1.0 units/day [− 1.9; − 0.1]95% CI, respectively (both p

Aims/Introduction We investigated the potential use of canagliflozin, in comparison with liraglutide, as an alternative to bolus insulin in patients with well‐controlled type 2 diabetes mellitus receiving multiple daily insulin injection therapy. Materials and Methods In 40 patients, with glycated hemoglobin (HbA1c) levels, In patients with well‐controlled type 2 diabetes mellitus, under the support of basal insulin, complex insulin regimens can be simplified by replacing all bolus insulin with once‐daily canagliflozin or liraglutide, which improves patients' quality of life.

Aims/Introduction Hyperglycemia impairs energy substrate oxidation as a result of glucotoxicity. We examined whether the reduction of plasma glucose using a sodium–glucose cotransporter 2 inhibitor, in inpatient diabetes management, has any effect on: (i) treatment period and basal–bolus dosage of insulin that achieve euglycemia; (ii) fasting/postprandial energy expenditure (EE); and (iii) energy substrate oxidation. Materials and Methods This was a randomized, open‐label, 7‐day prospective study. Participants were type 2 diabetes patients with hyperglycemia, aged >20 years, with glycated hemoglobin >10%, daily mean preprandial blood glucose >11 mmol/L (200 mg/dL) and no previous antidiabetic medication. A total of 18 type 2 diabetes patients were randomized (1:1) to basal–bolus insulin titration algorithm (INS) alone or INS + dapagliflozin 5 mg/day (INS/DAPA). The main outcome measures were total daily insulin dose to achieve euglycemia, as well as EE and respiratory quotient during fasting and postprandial states, measured by indirect calorimetry. Results The rate of euglycemia was higher in the INS/DAPA compared with INS group (100 vs 55.6%, P = 0.04), whereas the total daily dose of insulin was 19% lower and was accompanied by a decreased basal–bolus ratio (P = 0.02). Fasting and postprandial EE elevation were similar in both groups. The post‐treatment fasting respiratory quotient significantly increased in the INS/DAPA group (0.72 ± 0.05 vs 0.79 ± 0.08, P = 0.04), and the postprandial respiratory quotient elevation was abolished; the opposite trend was observed in the INS group (P

Introduction Ectopic fat accumulation has been found to play a pathophysiological role in insulin resistance, type 2 diabetes (T2DM), and coronary artery diseases. Findings from a number of previous studies suggest that sodium glucose cotransporter 2 (SGLT2) inhibitors reduce lipid accumulation, including myocardial and pericardial fat, while dipeptidyl peptidase 4 (DPP4) inhibitors suppress ectopic lipid accumulation and improve cardiac function. However, a clinical study that precisely explains and compares the efficacy of SGLT2 inhibitors and DPP4 inhibitors on cardiac fat accumulation has not been performed. Moreover, the association between cardiac fat accumulation and cardiac function or metabolic changes, such as tissue-specific insulin resistance, remains unclear. It is our intention to conduct the first study to assess the effects of empagliflozin compared to sitagliptin in reducing ectopic fat accumulation, specifically pericardial fat, and its association with improvement in cardiac function and tissue-specific insulin sensitivity. Methods We have designed a prospective, randomized open-label, and blinded-endpoint study with the intention to enroll 44 Japanese patients with T2DM. The patients are to be divided them into two groups, an empagliflozin group and an sitagliptin group, with the former to be supplemented with empagliflozin 10 mg and the latter to be supplemented with sitagliptin 100 mg, both groups for 12 weeks. The primary endpoint of the study is the change in the amount of pericardial fat. The secondary endpoints are the changes in the amount of intracellular fat in the myocardium, cardiac function, tissue-specific insulin sensitivity, fatty acid metabolism in myocardial tissue, assessed by parameters of iodine-123-β-methyl-iodophenyl pentadecanoic acid myocardial scintigraphy, blood and urine biomarkers, and lifestyle evaluation. Planned Outcomes The results of this study will be available in 2020. The aim of this study is to provide an effective treatment strategy for patients with T2DM by considering cardiac fat accumulation, cardiac function, and insulin resistance. Funding Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance. Trial Registration University Hospital Medical Information Network Clinical Trial Registry: UMIN000026340.

AIM: Diabetes and aging are both well-established risk factors for insomnia. Therefore, we investigated the changes in subjective sleep quality in relation to clinical backgrounds and age in patients with type 2 diabetes mellitus (T2DM). METHODS: This cross-sectional study included 380 participants with T2DM who were between 18 and 79 years of age from our outpatient clinics. Individuals with any symptoms and medical histories associated with obstructive sleep apnea (OSA) were excluded from the interview and analyses. Data were collected using self-administered questionnaires, namely the Pittsburgh Sleep Quality Index (PSQI) and the Morning-Evening Questionnaire (MEQ), as well as medical records and blood samples. We performed stratified analyses according to age decades. RESULTS: The number of patients in the age groups (in years) was as follows

Background While the cardioprotective benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors have been established in patients with cardiovascular disease (CVD), their advantages over other anti-diabetic drugs at earlier stages remain unclear. We compared the cardioprotective effects of empagliflozin, an SGLT2 inhibitor, with those of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, focusing on cardiac fat accumulation, cardiac function, and cardiac metabolism in patients with early-stage type 2 diabetes mellitus (T2DM) without CVD complications. Methods This was a prospective, randomized, open-label, blinded-endpoint, parallel-group trial that enrolled 44 Japanese patients with T2DM. The patients were randomized for 12-week administration of empagliflozin or sitagliptin. Pericardial fat accumulation and myocardial triglyceride content were evaluated by magnetic resonance imaging and proton magnetic resonance spectroscopy, respectively. Echocardiography, 123I-β-methyl-iodophenyl pentadecanoic acid myocardial scintigraphy, and laboratory tests were performed at baseline and after the 12-week treatment period. Results The patients were middle-aged (50.3 ± 10.7 years, mean ± standard deviation) and overweight (body mass index 29.3 ± 4.9 kg/m2). They had a short diabetes duration (3.5 ± 3.2 years), HbA1c levels of 7.1 ± 0.8%, and preserved cardiac function (ejection fraction 73.8 ± 5.0%) with no vascular complications, except for one baseline case each of diabetic nephropathy and peripheral arterial disease. After the 12-week treatment, no differences from baseline were observed between the two groups regarding changes in pericardial, epicardial, and paracardial fat content; myocardial triglyceride content; cardiac function and mass; and cardiac fatty acid metabolism. However, considering cardiometabolic biomarkers, high-density lipoprotein cholesterol and ketone bodies, including β-hydroxybutyric acid, were significantly increased, whereas uric acid, plasma glucose, plasma insulin, and homeostasis model assessment of insulin resistance were significantly lower in the empagliflozin group than in the sitagliptin group (p Conclusions Although the effects on cardiac fat and function were not statistically different between the two groups, empagliflozin exhibited superior effects on cardiometabolic biomarkers, such as uric acid, high-density lipoprotein cholesterol, ketone bodies, and insulin sensitivity. Therefore, when considering the primary preventive strategies for CVD, early supplementation with SGLT2 inhibitors may be more beneficial than DPP-4 inhibitors, even in patients with early-stage T2DM without current CVD complications. Clinical Trial Registration: UMIN000026340; registered on February 28, 2017. https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000030257

Additional file 1. Additional patient parameters (physical and biochemical parameters that showed no significant differences between the empagliflozin and sitagliptin groups).

Additional file 2. Adverse events (list of observed adverse events).

Background: Ectopic fat accumulation is the major pathogenesis of insulin resistance, type 2 diabetes mellitus (T2DM), and cardiovascular diseases. To date, no prospective study compared the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors on ectopic fat accumulation and tissue-specific insulin sensitivity. Methods: This is the prospective, randomized, open-label, and blind-endpoint study in 44 Japanese patients with T2DM. Patients (HbA1c: 7.2±0.9%, known duration: 3.9±4.0 years, BMI: 29.1±4.8 kg/m2) were randomized to empagliflozin (Empa) add-on group or sitagliptin (Sita) add-on group, and treated for 12 weeks. The primary endpoint was the change of pericardial fat content estimated by magnetic resonance imaging. The secondary endpoints were the changes in the amount of intrahepatic, intra- and extra-myocellular lipid content estimated by proton magnetic resonance spectroscopy, and tissue-specific insulin sensitivity assessed by hyperinsulinemic-euglycemic clamp tests using stable isotope. Results: There was no difference in pericardial fat content between the groups. Interestingly, intrahepatic lipid content (IHL) was reduced significantly from baseline in Empa group compared to Sita (-23.0±26.3 vs. -3.9±19.8%, respectively, p Conclusion: This is the first study that compared Empa and Sita on ectopic fat content and tissue-specific insulin sensitivity. Empa significantly reduced IHL and increased insulin sensitivity in muscle compared to Sita. SGLT2i might be preferable in treatment of T2DM with hepatic steatosis. Disclosure S. Hiruma: None. F. Shigiyama: None. S. Hisatake: None. S. Mizumura: None. N. Shiraga: None. M. Hori: None. T. Ikeda: None. T. Hirose: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; AstraZeneca, Lilly Diabetes, Novo Nordisk Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd. N. Kumashiro: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker’s Bureau; Self; Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Nippon Boehringer Ingelheim Co., Ltd. (1245-0162)

Background Few prospective studies have compared the cardiovascular benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors. We aimed to clarify the efficacy of dapagliflozin versus sitagliptin for modulating cardiometabolic risk factors including high glycated hemoglobin (HbA1c) levels, hypoglycemia, and body weight. Methods This prospective, randomized, open-label, blinded-endpoint, parallel-group trial enrolled 340 Japanese patients with early-stage type 2 diabetes receiving metformin alone or no glucose-lowering agents, who were randomized to receive dapagliflozin or sitagliptin for 24 weeks. The primary endpoint was the proportion of patients who achieved the composite endpoint of HbA1c level maintenance Results Clinical characteristics of patients were age, 58.1 ± 12.2 years; known duration of diabetes, 5.8 ± 6.1 years; body weight, 74.7 ± 14.2 kg; body mass index, 27.9 ± 4.1 kg/m2; and HbA1c level, 7.8 ± 0.8% at baseline. The achievement ratio of primary endpoint was significantly higher in the dapagliflozin group than in the sitagliptin group (24.4% vs. 13.8%, P P Conclusions Compared to sitagliptin, dapagliflozin was significantly more effective at improving cardiometabolic risk factors, suggesting that SGLT2 inhibitors might be more suitable than DPP-4 inhibitors for preventing cardiovascular events in patients with early-stage but inadequately controlled type 2 diabetes. Trial registration Trial number, UMIN000028014; registered on June 30, 2017

Additional file 2: Table S1. Adjusted risk of endpoints that affect the incidence of cardiovascular events.

Sleep deprivation is associated with increased risk for type 2 diabetes mellitus. However, the underlying mechanisms of sleep deprivation-induced glucose intolerance remain elusive. The aim of this study was to investigate the mechanisms of sleep deprivation-induced glucose intolerance in mice with a special focus on the liver. We established a mouse model of sleep deprivation-induced glucose intolerance using C57BL/6J male mice. A single 6-h sleep deprivation by the gentle handling method under fasting condition induced glucose intolerance. Hepatic glucose production assessed by a pyruvate challenge test was significantly increased, as was hepatic triglyceride content (by 67.9%) in the sleep deprivation group, compared with freely sleeping control mice. Metabolome and microarray analyses were used to evaluate hepatic metabolites and gene expression levels and to determine the molecular mechanisms of sleep deprivation-induced hepatic steatosis. Hepatic metabolites, such as acetyl coenzyme A, 3β-hydroxybutyric acid, and certain acylcarnitines, were significantly increased in the sleep deprivation group, suggesting increased lipid oxidation in the liver. In contrast, fasted sleep-deprived mice showed that hepatic gene expression levels of elongation of very long chain fatty acids-like 3, lipin 1, perilipin 4, perilipin 5, and acyl-CoA thioesterase 1, which are known to play lipogenic roles, were 2.7, 4.5, 3.7, 2.9, and 2.8 times, respectively, those of the fasted sleeping control group, as assessed by quantitative RT-PCR. Sleep deprivation-induced hepatic steatosis and hepatic insulin resistance seem to be mediated through upregulation of hepatic lipogenic enzymes.

Nonalcoholic fatty liver disease (NAFLD) plays a crucial role in type 2 diabetes and hepatocellular carcinoma. The major underlying pathogenesis is hepatic insulin resistance. The aim of the present study was to characterize patients with NAFLD with paradoxically normal hepatic insulin sensitivity relative to patients with NAFLD with hepatic insulin resistance. We recruited 26 patients with NAFLD and divided them into three groups ranked by the level of hepatic insulin sensitivity (HIS; high-HIS, mid-HIS, low-HIS), as assessed by the hyperinsulinemic-euglycemic clamp studies using stable isotope. Hepatic insulin sensitivity of the high-HIS group was identical to that of the non-NAFLD lean control (clamped percent suppression of endogenous glucose production, 91.1% ± 5.2% versus 91.0% ± 8.5%, respectively) and was significantly higher than that of the low-HIS group (66.6% ± 7.5%; P < 0.01). Adiposity (subcutaneous, visceral, intrahepatic, and muscular lipid content), hepatic histopathology, and expression levels of various genes by using liver biopsies, muscle, and adipose tissue insulin sensitivity, plasma metabolites by metabolomics analysis, putative biomarkers, and lifestyles were assessed and compared between the high-HIS and low-HIS groups. Among these, adipose tissue insulin sensitivity assessed by clamped percent suppression of free fatty acid, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites, such as citric acid and cis-aconitic acid, were significantly higher in the high-HIS group compared to the low-HIS group. In contrast, there were no differences in adiposity, including intrahepatic lipid content assessed by proton magnetic resonance spectroscopy (28.3% ± 16.1% versus 20.4% ± 9.9%, respectively), hepatic histopathology, other putative biomarkers, and lifestyles. Conclusion: High levels of adipose tissue insulin sensitivity, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites are unique characteristics that define patients with hepatic insulin-sensitive NAFLD regardless of intrahepatic lipid content. (Hepatology Communications 2017;1:634-647).

Background Recent studies reported that sodium glucose cotransporter 2 (SGLT2) inhibitors can potentially reduce the risk of cardiovascular mortality in patients with type 2 diabetes mellitus (T2DM). However, there is little or no information on the therapeutic effects of SGLT2 inhibitors on the progression of atherosclerosis. This dapagliflozin effectiveness on vascular endothelial function and glycemic control (DEFENCE) study was designed to determine the effects of dapagliflozin, a SGLT2 inhibitor, on endothelial function in patients with early-stage T2DM. Methods DEFENCE is a prospective, randomized, open-label, blinded-endpoint, parallel-group, comparative clinical trial. Between October 2015 and August 2016, 80 T2DM patients treated with 750 mg of metformin (hemoglobin A1c ≥6.0 and Results Although FMD tended to improve only in the dapagliflozin group, ΔFMD was comparable between the two groups. Analysis of patients with HbA1c >7.0% showed significant improvement of FMD in the dapagliflozin group than metformin group (P Conclusions Dapagliflozin add-on therapy to metformin for 16 weeks improved endothelial function, as assessed by FMD, in patients with inadequately controlled early-stage T2DM. Improvement in oxidative stress may contribute to the improvement in FMD. Trial registration University Hospital Medical Information Network Clinical Trial Registry (UMIN000018754)

Background: Sodium glucose cotransporter 2 inhibitors (SGLT2i) have attracted attention by the recently reported improved cardiovascular (CV) outcomes in patients with T2DM. In contrast, dipeptidyl peptidase 4 inhibitors (DPP-4i) were reported neutral on CV outcomes. However, there are few prospective studies that have compared the efficacy of SGLT2i and DPP-4i on the prevention of CV disease risks. Therefore, we planned this prospective, randomized, parallel-group trial aimed to compare the therapeutic benefits of dapagliflozin (Dapa) and sitagliptin (Sita) on CV disease risks, with special focus on HbA1c, body weight (BW), and hypoglycemia. Methods: A total of 340 T2DM patients treated with metformin alone or with no glucose-lowering agents (20-80 years of age, HbA1c ≥ 7.1% and < 10.0%) were equally randomized to Dapa 5 mg/day or Sita 50 mg/day add-on group, and treated for 24 weeks. After the 8 weeks, if HbA1c is 7.0% or higher, Dapa and Sita were increased to 10 mg/day and 100 mg/day, respectively. The primary endpoint was the ratio of achieving composite endpoints of the following all 3 items; 1) HbA1c below 7.0%; 2) 3.0% BW loss from baseline; 3) avoidance of hypoglycemia {< 3.0 mmol/L (< 54 mg/dL)}. Hypoglycemia was monitored by flash glucose monitoring system. Results: The achievement ratio of HbA1c below 7.0% was comparable between the groups (49.4 vs. 50.0%, p=1.00, Dapa vs. Sita, respectively). However, 3.0% BW loss was preferably achieved in Dapa group (54.4 vs. 19.6%, p In summary, Dapa treatment for 24 weeks improved CV risk factors in patients with inadequately controlled T2DM. This study provides the evidence on ideal therapeutic choice for preventing CV events in T2DM. Disclosure A. Fuchigami: None. F. Shigiyama: None. T. Kitazawa: Speaker’s Bureau; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Y. Okada: None. T. Ichijo: None. M. Higa: None. T. Hiyoshi: Other Relationship; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly Japan K.K., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. I. Inoue: None. K. Iso: Research Support; Spouse/Partner; AstraZeneca. H. Yoshii: None. T. Hirose: None. N. Kumashiro: Speaker’s Bureau; Self; Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. Funding AstraZeneca K.K.

Hepatic insulin resistance (H-IR) is a major pathogenesis of type 2 diabetes mellitus (T2DM) with nonalcoholic fatty liver disease (NAFLD). Due to pandemic obesity, in addition to reducing toxic lipids in the liver, searching for other factors that may regulate hepatic insulin sensitivity (H-IS) is inevitable in humans with NAFLD. To find such factors, we performed comprehensive assessment in the patients with NAFLD (n=36) aged 47.4±12.3, BMI 29.4±4.7 kg/m2, DM/non-DM 23/13, HbA1c 6.7±1.0% (mean±SD). We assessed putative biomarkers in blood and urine, body composition, tissue lipid content by 1H-MRS, tissue IS by hyperinsulinemic euglycemic clamp, hepatic histological scores and gene expressions using biopsies, and life styles. Furthermore, we developed a new magnetic resonance imaging analytic method that can exactly evaluate the whole liver volume, whole hepatic lipid volume, and whole hepatic lean volume. We performed single regression analysis between H-IS assessed by clamped % suppression of endogenous glucose production and all evaluated indices. As results, existence of diabetes, fasting plasma glucose, and HbA1c showed significant negative correlation with H-IS, while plasma adiponectin, muscle IS and adipose tissue IS showed significant positive correlation with H-IS. Interestingly, whole liver volume (cm3/m2) and lean hepatic volume (cm3/m2) corrected by body surface area showed negative correlation with H-IS (β=-0.02, -0.03 and p Conclusion: Through comprehensive assessment including our new whole hepatic volume evaluation, we first demonstrated that lean hepatic volume strongly associates with H-IR specifically in patients with T2DM. Not only hepatic volume control but quality control supported by adiponectin or other insulin-targeted organs is necessary for H-IS in humans with NAFLD. Disclosure H. Igarashi: None. F. Shigiyama: None. S. Hiruma: None. T. Hirose: None. N. Kumashiro: Speaker's Bureau; Self; Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. Funding Japan Society for the Promotion of Science (26702032, JP17H02180)

Objective: Immune checkpoint inhibitors (ICIs) are novel anticancer agents, also generate peculiar dysimmune toxicities, related to immune-related adverse events (irAEs) that might potentially prolong the survival rate. Our aim was to evaluate diabetes prior to ICIs has any effect on mortality rate, associated with irAEs, to the response in patients inappropriate to operation lung cancer. Methods: Subjects diagnosed during Sep 1, 2015 to Jul 31, 2018 were retrospectively enrolled and followed until Jan 20, 2018, using Toho University NEPTUNE database. Hazard ratios were estimated using Cox regression weighted for propensity scores. Odds ratios (ORs [95% CI]) were calculated with logistic regression and adjusted for imbalanced variables (standardized difference more than 0.2). The Kaplan-Meier method was used to overall survival, and the generalized Wilcoxon test was used to compare median survivals. Results: A total of 88 patients participated, of whom 22 (25.0%) had pre-ICIs diabetes (DM) and 57 (75.0%) were not pre-ICIs diabetes (nonDM). The irAEs was observed in 12.2% of DM and 9.1% of nonDM (p=0.33). Both nonDM and DM has not been associated to irAE’s status for baseline characteristics (age, sex, clinical stage, thyroid status, and renal function) and propensity score matching. Multiple logistic regression analyses revealed that the risk of overall survival was significantly lower in subjects with male than those with female (OR = 0.11, 95% CI = 0.01-0.94, p = 0.044). During a mean follow-up of 21.1 months (adherence rate, 88%), overall 37-month post-ICIs survival was significantly lower in the DM group (Kaplan-Meier estimates 77% vs. 66%; p=0 043), resulting in a 38% reduction in the mortality hazard ratio (0 62 [95% CI 0 40-0 95]). Conclusion: Pre-ICIs treatment diabetes per se, diminish mortality rate in inappropriate to operation lung cancer patients, independently to irAEs on immune-check point inhibitor. Disclosure K. Hisanaga: None. H. Uchino: None. F. Yoshikawa: None. F. Shigiyama: None. N. Kumashiro: Speaker's Bureau; Self; Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. T. Hirose: None. Y. Ando: None. M. Miyagi: None. K. Isobe: None. S. Homma: None.

Introduction This multi-center, prospective, controlled, open, and randomized three-arm parallel study was designed to compare the effects of linagliptin with those of metformin on endothelial function. Materials and Methods Type 2 diabetes patients treated with 750 mg of metformin (hemoglobin A1c ≥6.0% and

Polycystic ovary syndrome (PCOS) is common in obese women with insulin resistant type 2 diabetes for which metformin treatment is getting established in addition to clomiphene. However, lean PCOS patients are sometimes accompanied with type 1 diabetes. It remains unclear whether these patients are insulin resistant and whether metformin is effective for them. A 32-year-old woman, who suffered from acne, hirsutism, and menstrual disorders since age 29, was diagnosed as PCOS by serum high LH levels and polycystic ovary on echography. Interestingly, her body mass index (BMI) had consistently been 21.0 kg/m2 since age 20. She was first treated with clomiphene for one year for infertility but it did not improve her menstrual cycle nor did she get pregnant during that period. She was then assessed with diabetes mellitus and subsequently diagnosed as type 1 diabetes with mild hyperglycemia (HbA1c 6.0%). Since her insulin secretion was still well preserved, to assess insulin sensitivity, hyperinsulinemic-euglycemic clamp test was performed and showed her to be insulin resistant. Low dose insulin and low dose metformin treatment was started without clomiphene. After her ovulation and menstrual cycle were ameliorated only one month later, her treatment was supplemented with clomiphene for the next three months enabling her to at last become pregnant. This report highlights the efficacy of metformin in lean PCOS with type 1 diabetes. Insulin therapy is essential for type 1 diabetes but hyperinsulinemia potentially exacerbates PCOS through hyperandrogenism. Metformin is therefore recommended for treatment of lean PCOS with type 1 diabetes as well as common obese PCOS with type 2 diabetes.

Sleep is an important life style component and its deprivation is a risk for type 2 diabetes. However, the underlying mechanisms and the therapeutic target of sleep deprivation induced glucose intolerance are unclear. The aim of this study was to investigate the mechanisms of sleep deprivation induced glucose intolerance focusing on liver. We established a mouse model of sleep deprivation induced glucose intolerance using C57BL/6J male mice. Single 6 hours sleep deprivation by gentle handling method in fasted condition induced glucose intolerance. Interestingly, hepatic glucose production assessed by pyruvate challenge test was significantly increased, and hepatic triglyceride content was also increased in 67% in the sleep deprivation mice compared to freely sleeping control mice. To explore the molecular mechanisms of sleep deprivation induced hepatic steatosis, hepatic metabolites and gene expressions were comprehensively evaluated using metabolome and microarray analyses. Hepatic metabolites such as acetyl CoA, 3β-hydroxybutyric acid, and some acylcarnitines were significantly increased in sleep deprivation group, suggesting increased lipid oxidation in the liver. In contrast, hepatic gene expressions of Elovl3, Lpin1, Plin4, Plin5 and Acot1 that play a lipogenic role were significantly increased 2.7, 4.5, 3.7, 2.9, and 2.8 times respectively in sleep deprivation group compared to control group, confirmed by quantitative RT-PCR. The increased lipogenic gene expressions may partly explain the sleep deprivation induced hepatic steatosis. Conclusion: Single 6 hours sleep deprivation caused hepatic steatosis and hepatic insulin resistance in fasted C57BL/6J mice. Increased hepatic lipogenic enzymes raised above may be potential therapeutic targets for the sleep deprivation induced hepatic steatosis and hepatic insulin resistance. Disclosure F. Shigiyama: None. N. Kumashiro: Speaker's Bureau; Self; Novo Nordisk Inc.. F. Yoshikawa: None. Y. Tsuneoka: None. H. Funato: None. T. Hirose: Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Research Support; Self; Bayer Yakuhin, Ltd., Novartis Pharma K.K.. Speaker's Bureau; Self; Novartis Pharma K.K.. Research Support; Self; Takeda Development Center Asia, Pte. Ltd.. Speaker's Bureau; Self; Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Ono Pharmaceutical Co., Ltd., Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; MSD K.K.. Speaker's Bureau; Self; MSD K.K.. Research Support; Self; Sanofi K.K.. Speaker's Bureau; Self; Sanofi K.K.. Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Research Support; Self; Daiichi Sankyo Company, Limited. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Sumitomo Dainippon Pharma Co., Ltd.. Speaker's Bureau; Self; Sumitomo Dainippon Pharma Co., Ltd.. Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc..

Background Recent studies reported that sodium glucose cotransporter 2 (SGLT2) inhibitors reduced the cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus (T2DM) compared to placebo in contrast to no reduction with dipeptidyl peptidase 4 (DPP4) inhibitors. However, there are no comparative studies on the effects of SGLT2 inhibitors and DPP4 inhibitors on HbA1c, body weight and hypoglycemia as risk factors of cardiovascular diseases. The aim of the present ongoing study is to compare the effects of dapagliflozin, a SGLT2 inhibitor, with those of sitagliptin, a DPP4 inhibitor, on cardiovascular risk factors in T2DM patients with inadequate glycemic control. Methods The study of dapagliflozin versus sitagliptin treatment efficacy on prevention of cardiovascular risk factors in T2DM patients (DIVERSITY-CVR study) is a prospective, randomized, open-label, blinded-endpoint, parallel-group, comparative study. A total of 340 T2DM patients treated with metformin alone or with no glucose-lowering agents (hemoglobin A1c ≥ 7.0 and Conclusions There is lack of solid information on differences in the therapeutic effects of SGLT2 inhibitors and DPP4 inhibitors on multiple risk factors for cardiovascular diseases. It is anticipated that the results of the DIVERSITY-CVR study provides useful clinical data on the management of patients with T2DM, including reducing the risk of CVD. The results of this study will become available in 2019. Trial registration University Hospital Medical Information Network Clinical Trial Registry (UMIN000028014). Registered 30 June 2017

Additional file 1. List of 62 medical institutions participating in the study.

Additional file 1. Table S1. Changes in body weight and BMI.

Polycystic ovary syndrome (PCOS) is common in obese women with insulin resistant type 2 diabetes for which metformin treatment is getting established in addition to clomiphene. However, lean PCOS patients are sometimes accompanied with type 1 diabetes. It remains unclear whether these patients are insulin resistant and whether metformin is effective for them. A 32-year-old woman, who suffered from acne, hirsutism, and menstrual disorders since age 29, was diagnosed as PCOS by serum high LH levels and polycystic ovary on echography. Interestingly, her body mass index (BMI) had consistently been 21.0 kg/m2 since age 20. She was first treated with clomiphene for one year for infertility but it did not improve her menstrual cycle nor did she get pregnant during that period. She was then assessed with diabetes mellitus and subsequently diagnosed as type 1 diabetes with mild hyperglycemia (HbA1c 6.0%). Since her insulin secretion was still well preserved, to assess insulin sensitivity, hyperinsulinemic-euglycemic clamp test was performed and showed her to be insulin resistant. Low dose insulin and low dose metformin treatment was started without clomiphene. After her ovulation and menstrual cycle were ameliorated only one month later, her treatment was supplemented with clomiphene for the next three months enabling her to at last become pregnant. This report highlights the efficacy of metformin in lean PCOS with type 1 diabetes. Insulin therapy is essential for type 1 diabetes but hyperinsulinemia potentially exacerbates PCOS through hyperandrogenism. Metformin is therefore recommended for treatment of lean PCOS with type 1 diabetes as well as common obese PCOS with type 2 diabetes.