Nippon Boehringer Ingelheim Research Articles

878-P: Absolute Amount of Urinary Glucose Excretion, Not the Change, Is the Measure Determinant for the Effects of SGLT2 inhibitors

SGLT2 inhibitors exhibit hypoglycemic effect via increased urinary glucose excretion (UGE) by inhibiting glucose reabsorption in the kidney. Although the effects of SGLT2 inhibitors are theoretically dependent on UGE, clinical trials have shown renoprotective effect even in severely impaired kidney function. Thus, we aimed to investigate the relationship between UGE and various parameters before and after the administration of SGLT2 inhibitors. The patients newly administered SGLT2 inhibitors and measured 24-hour UGE before and after the administration during hospitalization for diabetes education were included. Body weight (BW), blood ketone levels, hematocrit (Ht), eGFR, and 7-point SMBG (DBG) were measured, and the correlations between the parameters before(b-), after (a-) and the change (Δ-) were analyzed by simple linear regression. A total of 32 patients (age 59.3±10.9 years, 19 males) were included (empagliflozin 5, tohogliflozin 6, dapagliflozin 2, canagliflozin 4, luseogliflozin 15). The mean A1C and BW were 8.8±1.2% and 77.7±11.5kg, and mean UGE, average of DBG at baseline were 15.4 ± 27.5g/day and 10.3±2.0mM/L, respectively. As shown in table, ΔDBG showed correlation only with UGE before and after administration but not with ΔUGE. In conclusion, hypoglycemic effect of SGLT2 inhibitors is dependent on absolute amount of UGE but not on ΔUGE after administration. Disclosure Y.Hamamoto: None. Y.Yamada: Speaker's Bureau; Novo Nordisk Pharma Ltd., Teijin Pharma Limited, Ono Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd. Y.Seino: Research Support; Terumo Corporation, Nippon Boehringer Ingelheim, Arkray Marketing, Taisho Pharmaceutical Holdings Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Speaker's Bureau; Merck & Co., Inc., Nippon Boehringer Ingelheim, Arkray Marketing, Taisho Pharmaceutical Holdings Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd.

631-P: Development of Noninvasive Diabetes Management Method Using Glycated Albumin in Tears

Aims/Background: Several clinical trials have demonstrated that strict glycemic control is important to minimize the risk of diabetic complications. Although frequent measurement of blood glucose levels by the invasive finger prick method is useful to achieve strict glycemic control, this method is invasive and burdensome to the patients. Glycated albumin (GA) is a biomarker which reflects the glycemic control status over the previous 2 weeks. We demonstrated GA levels in tears correlated those in blood. We hypothesized that regular GA tests in tears caused behavior change and improved glycemic control. Methods: Participants with type 2 diabetes were recruited and randomly divided to two groups. One group (intervention group) was performed tear GA tests every 2 weeks and reported the results, while the other group (control group) was not. After 8 weeks of intervention, the two groups were compared. GA levels in tears were measured by Liquid Chromatography / Mass Spectrometry. Results: We enrolled 56 participants to the study. Compared with the control group, the intervention group showed improvement in fasting blood glucose, HbA1c, GA, non-HDL cholesterol. Conclusions: Levels of GA, as a diabetes-related biomarker, in tears can be measured noninvasively. Regular measurement of the GA levels in tears could allow smoother management of diabetes mellitus and reduce the risk of complications noninvasively. Disclosure M.Aihara: None. N.Kubota: None. T.Yamauchi: Other Relationship; Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited, Novo Nordisk, Astellas Pharma Inc., AstraZeneca, Ono Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim, Kyowa Kirin Co., Ltd., Kowa Company, Ltd., Merck & Co., Inc., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Daiichi Sankyo, Taiho Pharmaceutical Co. Ltd., Tosoh Corporation, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., NTT Docomo Inc., Aero Switch, Asahi Mutual Life Insurance Company, NIPRO Medical Corporation, Abbott Japan Co., Ltd., Bayer Inc., Kyorin Pharmaceutical Company, Limited.

462-P: DPP-4 Deficiency Suppresses the Progression of Atherosclerosis via Inducing M2 Macrophage Polarization

Background: Dipeptidyl peptidase-4 (DPP4) inhibitors suppressed progression of atherosclerosis in atherosclerotic mouse models. However, the role of DPP4 on the progression of atherosclerosis is not clear. We investigated the effect of DPP4 deficiency on the progression of atherosclerosis in DPP4 and apolipoprotein-E double knockout (DPP4/ApoE-DKO) mice. Methods: Both ApoE-KO mice and DPP4/ApoE-DKO mice were fed with normal chow until 20 weeks of age. Whole aorta and aortic sinus were stained with Oil red O. Bone marrow-derived macrophages (mφ) from wildtype or DPP4-KO mice were used in in vitro study. Expression of iNOS, MCP-1, TNF-α and IL-1β (M1 markers), and arginase-1, Mgl2 and Ym1 (M2 markers) mRNA were evaluated by real-time RT-PCR, and mφ polarization was evaluated by flowcytometry. Results: There were no differences on food intake, body weight, lipid profiles and the blood glucose levels by insulin tolerance test between each group, but the blood glucose levels by glucose tolerance test were significantly decreased in DPP4/ApoE-DKO mice. Oil-Red-O staining demonstrated that the size of atherosclerotic lesions was significantly smaller in DPP4/ApoE-DKO mice. In in vitro assay, LPS+IFNγ induced the mRNA expression of M1 markers and there was no difference between wildtype mφ and DPP4-KO mφ. On the other hand, the mRNA expression of M2 markers were significantly increased in DPP4-KO mφ. Flowcytometry revealed that the number of iNOS (M1 marker)-positive cells were increased by LPS+IFNγ, which was comparable between wildtype mφ and DPP4-KO mφ. On the other hand, the number of CD206 (M2 marker)-positive cells was higher in DPP4-KO mφ than that in wildtype mφ. Conclusion: This study suggests that DPP4 deficiency suppresses the progression of atherosclerosis in apoE-KO mice. Moreover, DPP4 deficiency increases the polarization of M2 mφ. These findings may indicate the involvement of DPP4 at least in part on the development of diabetic macrovascular complications. Disclosure Y.Zhou: None. T.Matsumura: Research Support; Shimadzu Corporation, Speaker's Bureau; Eli Lilly Japan K.K., Boehringer Ingelheim Japan, Inc. Y.Yagi: None. T.Yoshinaga: None. T.Senokuchi: None. N.Ishii: None. T.Kondo: None. E.Araki: Research Support; Eli Lilly Japan K.K., Nippon Boehringer Ingelheim, Mitsubishi Tanabe Pharma Corporation, Speaker's Bureau; AstraZeneca, Merck & Co., Inc., Ono Pharmaceutical Co., Ltd., Kowa Company, Ltd., Sumitomo Pharma Co., Ltd., Daiichi Sankyo, Novo Nordisk Pharma Ltd.

1382-P: Relationship between Diabetes Diet–Related Quality of Life and Dietary Fiber Intake among People with Type 2 Diabetes—A Cross-Sectional Study

Introduction: This cross-sectional study investigated the association between diabetes diet-related quality of life (QoL) and diet intake in people with type 2 diabetes (T2D) (67.5±10.7 years and 62.2% men). Methods: Diabetes diet-related QoL and nutritional intake were evaluated using the DDRQoL-R-9, including satisfaction with diet, perceived merits of diet therapy, and burden of diet therapy, and brief-type self-administered diet history questionnaire. Results: Table shows that perceived merits of diet therapy were positively correlated with glycemic control, although burden of diet therapy was negatively correlated with glycemic control and that dietary fiber intake was negatively correlated with burden of diet therapy, although positively correlated with perceived merits of diet therapy. Dietary fiber intake was associated with perceived merits of diet therapy (β = 0.390, p < 0.001), burden of diet therapy (β = −0.215, p = 0.013), and satisfaction with diet (β = 0.177, p = 0.036), after adjusting for covariates. Discussion: People who have poor glycemic control despite diet therapy may have been overburdened by the diet therapy. High dietary fiber intake may affect increased burden of diet therapy although the perceived benefits of the diet therapy. Conclusion: Dietary fiber intake is associated with diabetes diet-related QoL in people with T2D. Disclosure F. Takahashi: None. Y. Hashimoto: Speaker's Bureau; Takeda Pharmaceutical Co., Ltd., Sanofi K.K., Kowa Company, Ltd., Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd., Nippon Boehringer Ingelheim. Y. Kondo: None. M. Hamaguchi: Research Support; Yamada Bee Company, Inc. M. Yamazaki: None. M. Fukui: None.

1465-P: Metabolic Remodeling in Pancreatic Beta Cells in Japanese Patients with Type 2 Diabetes

Background and Aims: It has been shown that metabolic remodeling from oxidative phosphorylation to glycolysis via activation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) occurs in pancreatic beta cells in non-Asians with diabetes, resulting in impaired beta cell function. We used multiple autopsy pancreatic sections to investigate whether such changes occur in Japanese patients with type 2 diabetes (T2D) , and if so, which clinical and pathological features of islets relate to this remodeling. Methods: Autopsy pancreatic sections from patients with T2D and non-diabetic donors (ND) were stained with antibodies against PFKFB3, insulin, and glucagon. The PFKFB3-positive ratio of pancreatic beta cells and alpha cells between T2D and ND were compared. Next, the relationships between PFKFB3-postive beta cell ratio, patient background factors and pathological features of the islets were explored. Results: In total, 36 cases (18 cases each for T2D and ND) were enrolled and 50-100 islets/case were evaluated. Mean age was 70.6 ± 7.7 vs. 64.3 ± 12.8 years and body mass index (BMI) 22.4 ± 4.2 vs. 23.3 ± 4.5 kg/m2, respectively. T2D duration was 9.8 ± 9.9 years. The PFKFB3-positive beta cell ratio was significantly higher in T2D (29.7 ± 18.6% vs. 11.1 ± 8.7%, p<0.05) , whereas the PFKFB3-positive alpha cell ratio did not differ between groups. A negative correlation between PFKFB3-positive beta cell ratio and BMI was found only in the T2D group (r=-0.65, p<0.05) . No correlation was observed between PFKFB3-positive beta cell ratio and age/disease duration in the T2D group. Thioflavin T staining revealed a positive correlation between amyloid deposition in the islets of T2D and PFKFB3 positivity in beta cells (r=0.67, p<0.05) . Conclusion: Our results indicate that intracellular metabolic remodeling mediated by upregulation of PFKFB3 occurs in pancreatic beta cells of Japanese patients with T2D. Low BMI and amyloid deposition may affect PFKFB3 expression in beta cells from patients with T2D. Disclosure R.Izumihara: None. H.Nomoto: None. K.Chiba: Research Support; Grant for Young Researcher from Japan Association for Diabetes Education and Care, Japan Diabetes Society Junior Scientist Development Grant, Japan Society for the Promotion of Science , MSD Life Science Foundation, Promotion for Young Research Talent and Network, The Akiyama Life Science Foundation, The Uehara Memorial Foundation. H.Kameda: None. K.Cho: None. A.Nakamura: Research Support; Kissei Pharmaceutical Co., Ltd., MSD, Nippon Boehringer Ingelheim, Taisho Pharmaceutical Holdings Co., Ltd. H.Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Speaker's Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. H.Mizukami: None. T.Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL & BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc., Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Speaker's Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc. Funding JSPS KAKENHI Grant Number JP20281167.Japan Diabetes Society Junior Scientist Development Grant.MSD Life Science Foundation, Public Interest Incorporated Foundation.

686-P: Unstable Glucose Variability in Type 2 Diabetes Patients with Small Abdominal Visceral Fat Area and Impaired Endogenous Insulin Secretion

Background: Impaired endogenous insulin secretion was related to instability of glucose variability (GV) in patients with type 2 diabetes (T2DM) in our previous studies. However, some patients, including those with fasting serum C-peptide (CPR) ≤2 ng/mL, did not show this relationship. Given these findings, the present study aimed to identify other factors that affect GV in T2DM patients with impaired endogenous insulin secretion. Methods: Data were obtained from our prospective observational study, comprising 2Japanese outpatients with T2DM who underwent continuous glucose monitoring (CGM) , fasting blood sample collection, and a computed tomography scan of their abdominal visceral and subcutaneous fat. Fasting CPR was used as a marker of endogenous insulin secretion and the coefficient of variation (CV) for the CGM data was used as a measure of GV. Background characteristics related to unstable GV were identified by multivariate logistic regression analysis after we extracted the data for patients with T2DM and CPR ≤2 ng/mL. All tests were two-sided. P<0.was considered to indicate statistical significance. Results: In the total cohort, mean age was 67.0 (IQR 58.0, 74.8) years, mean HbA1c 7.1% (IQR 6.6%, 7.7%) , and mean body mass index (BMI) 25.0 (IQR 23.0, 28.4) kg/m2. In patients with low CPR (≤2 ng/mL; n=119) , small visceral fat area (VFA) was an independent risk factor for CV above the median CV (OR 0.98, 95% CI 0.97-0.99, P=0.0443) , while subcutaneous fat area (SFA) and BMI were equally distributed. In patients with high CPR (>2 ng/mL; n=85) , VFA, SFA, and BMI were equally distributed between patients with CV above or below the median CV. Conclusions: GV is unstable in T2DM patients with impaired endogenous insulin secretion, particularly in patients with small VFA. The present findings suggest that visceral fat is related to the stability of GV. Disclosure A.Miya: None. A.Nakamura: Research Support; Kissei Pharmaceutical Co., Ltd., MSD, Nippon Boehringer Ingelheim, Taisho Pharmaceutical Holdings Co., Ltd. H.Nomoto: None. H.Kameda: None. K.Cho: None. S.Nagai: Other Relationship; Eli Lilly and Company. Y.M.Ito: None. H.Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Speaker’s Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. T.Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL & BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc., Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Speaker’s Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc.

116-OR: Changes in Glucose Tolerance and Related Factors after Renal Transplantation in Recipients with Impaired Glucose Tolerance

Background and Aims: Our previous study revealed that more than half of patients with impaired glucose tolerance (IGT) before renal transplantation improved to normal glucose tolerance after transplantation. However, the mechanism was not clear. This study aimed to investigate whether changes in glucose tolerance were associated with insulin secretion and resistance in Japanese renal transplant recipients diagnosed with IGT before transplantation. Materials and Methods: We analyzed data for 179 patients ≥20 years of age who received their first renal transplantation in our hospital from April 2005-October 20 and had no history of diabetes before transplantation. A total of 54 recipients who received the oral glucose tolerance test (OGTT) before and 1 year after transplantation and were diagnosed with IGT before transplantation. Patients were divided into two groups according to negative or positive changes in area under the blood glucose curves from 0-120 min after ingestion: improved group and non-improved group, respectively. Insulin secretion was estimated by the insulin secretion sensitivity index-2 (ISSI-2) and insulin sensitivity was estimated by the Matsuda index (MI) and homeostasis model assessment of insulin resistance (HOMA-IR) . Results: Thirty and 24 patients were in the improved and non-improved groups, respectively. ISSI-2 significantly increased from 1.67±0.44 to 2.00±0.60 (P<0.01) after transplantation in the improved group, but not in the non-improved group. ΔISSI-2 was significantly associated with the 60-min blood glucose level of the OGTT and ISSI-2 level before transplantation (β=0.01, P<0. and β=−0.59, P<0.01, respectively) . There were no differences in MI or HOMA-IR before and after transplantation between these two groups. Conclusion: Improvement of glucose tolerance after renal transplantation in patients diagnosed with IGT before transplantation is related to improvement of insulin secretion. Disclosure M. Kusumi: None. A. Nakamura: Research Support; Kissei Pharmaceutical Co., Ltd., MSD, Nippon Boehringer Ingelheim, Taisho Pharmaceutical Holdings Co., Ltd. H. Nomoto: None. H. Kameda: None. K. Cho: None. H. Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. Speaker's Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. T. Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL & BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc. Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc.

670-P: Iron-Deficiency Anemia Case Report Showing the Clinical Relevance of RBC-Lifespan–Adjusted A1C

Laboratory A1C does not precisely reflect glycemic control in those with altered RBC lifespan and our aim was to evaluate an adjusted A1C, a glycemic measure that adjusts A1C to a reference RBC lifespan. By removing the individual RBC lifespan variation, adjusted A1C better reflects intracellular glucose exposure in RBCs and perhaps other organs susceptible to complications. Iron-deficiency anemia and treatment is known to affect RBC lifespan and therefore provides opportunity to evaluate the model. The patient was a 53-year-old woman with iron-deficiency anemia and type 1 diabetes utilizing sensor-augmented pump therapy. Longitudinal A1C and CGM were evaluated with a novel kinetic model to estimate RBC lifespan and glucose uptake rate. During the six months before iron therapy, the RBC lifespan was estimated at 151 days and 93% of a reference glucose uptake. During six months of iron therapy, the RBC lifespan decreased to 122 days, while the RBC glucose uptake increased slightly to 101% of reference value. The RBC lifespan change explains the observed laboratory A1C change (Figure) and can be attribute to the iron therapy and supported by Hb, RDW and Ferritin data. The adjusted A1C based on these two different RBC lifespans agree with the stable CGM mean glucose of this patient. In this case study, we confirmed the clinical relevance of adjusted A1C to account for variations in RBC lifespan. Disclosure Y.Hirota: Speaker's Bureau; Abbott Japan Co., Ltd., Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Kirin Co., Ltd., Lilly, Medtronic, Mochida Pharmaceutical Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Terumo Corporation. Y.Xu: Employee; Abbott Diabetes. A.Yamamoto: None. A.Matsuoka: None. T.Dunn: Employee; Abbott. W.Ogawa: Advisory Panel; Abbott Japan Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk, Other Relationship; Abbott Japan Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Research Support; Abbott, Astellas Pharma Inc., Eli Lilly and Company, Kowa Company, Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Funding Abbott Diabetes Care

446-P: Lipid Droplet Protein PLIN1 Regulates Inflammatory Polarity in Human Macrophages and Is Involved in Atherosclerotic Plaque Development by Promoting Stable Lipid Storage

Background: Lipid droplet (LD) proteins play important roles in lipid accumulation and maturation in adipocytes. The relationship among PLIN family proteins and macrophage polarization in atherosclerosis has not been elucidated. Methods: The experiments used human artery tissues from 65 patients who had undergone a carotid endarterectomy. Cultured macrophages generated from healthy human peripheral blood mononuclear cells are utilized as well. Results: Plaque immunohistochemistry demonstrated co-expression of PLIN1 and PLIN2 in both symptomatic (n=31) and asymptomatic patients (n=34) . PLIN2 mRNA expression increased 3.38-fold in the symptomatic group compared with those from asymptomatic. PLIN1 was not expressed on small LDs at a shorter incubation (24 h) but was on large LDs at longer incubation (7 days) with oxidized LDL and VLDL, while PLIN2 was observed after 24 h and increased with a longer incubation in cultured M1 macrophage. In M2 macrophages, PLIN1 was seen as early as 24 h following incubation with VLDL, and LD size increased with longer incubation. PLIN1 overexpression increased the size of LDs in M1 macrophages, even after a short incubation, and reduced the RNA expression of TNFA, MMP2, ABCA1, and ABCG1 versus the M1 control. Conversely, silencing of PLIN1 in M2 macrophages had the contrary effects on LD size and RNA expression. Conclusion: There was a relationship among macrophage polarity, cytosolic LD size, and PLIN1/PLIN2 expression levels. PLIN2 was mainly expressed in arterial plaques in symptomatic stroke patients, and associated with the inflammatory phenotype of human macrophages, while PLIN1 expression is closely associated with plaque stability and the anti-inflammatory phenotype. Disclosure K.Cho: None. H.Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Speaker's Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. A.Nakamura: Research Support; Kissei Pharmaceutical Co., Ltd., MSD, Nippon Boehringer Ingelheim, Taisho Pharmaceutical Holdings Co., Ltd. T.Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL & BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc., Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Speaker's Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc.

120-OR: Hepatic Steatosis Is Inversely Associated with Improvement of Pancreatic Beta-Cell Function after Vertical Sleeve Gastrectomy in Patients with Type 2 Diabetes

Background: Improvement of beta-cell function is reportedly involved in the improvement of glucose tolerance and remission of diabetes after bariatric and metabolic surgery. However, the impact of this surgery on beta-cell function in Japanese patients is not clear. The objective of this study was to investigate the effect of this surgery on beta-cell function and the characteristics and factors related to changes in beta-cell function. Methods: We conducted a prospective study of patients with type 2 diabetes who underwent vertical sleeve gastrectomy. A 75-g OGTT was performed before and 1 year after this surgery. Glucose tolerance was evaluated using the area under the blood glucose curve (AUCglu) during the OGTT. Insulin secretion was evaluated by the insulin secretion-sensitivity index-2 (ISSI-2) and disposition index (DI) , and insulin sensitivity was estimated using the Matsuda index (MI) and HOMA-IR. Visceral fat and subcutaneous fat area were quantified by abdominal CT examination, and hepatic fat content was quantified using the MRI proton density fat fraction. Results: The mean age of 15 patients (6 females) was 41.9 ± 8.8 years. After 1 year of the surgery, BMI (Before 42.0±8.2 kg/m2, After 32.7±7.2 kg/m2; P < 0.01) , HbA1c, and AUCglu were significantly reduced. ISSI-2 and DI were significantly increased, with no significant changes in the MI or HOMA-IR. Changes in ISSI-2 and DI were inversely associated with hepatic fat content before the surgery (ISSI-2: r = -0.63, P < 0.05; DI: r = -0.59, P < 0.05) , but not with age, BMI, visceral fat area, AUCglu, ISSI-2, DI, MI or HOMA-IR before the surgery. Conclusion: Our results showed that beta-cell function was improved by vertical sleeve gastrectomy even in Japanese obese patients with type 2 diabetes. The degree of improvement in beta-cell function was associated with the degree of preoperative hepatic steatosis, suggesting that a hepatic-pancreatic association may exist. Disclosure A. Nakamura: Research Support; Kissei Pharmaceutical Co., Ltd., MSD, Nippon Boehringer Ingelheim, Taisho Pharmaceutical Holdings Co., Ltd. Y. Oe: None. M. Kusumi: None. H. Nomoto: None. H. Kameda: None. K. Cho: None. K. Ogawa: None. Y. Ebihara: None. T. Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL & BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc. Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc. H. Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. Speaker's Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd.

1424-P: Impact of Laparoscopic Sleeve Gastrectomy on Nonalcoholic Fatty Liver Disease in Obese Patients with Type 2 Diabetes: Prospective Observational Study

Background: Bariatric/metabolic surgery is a valid treatment option for patients with obesity, type 2 diabetes (T2DM) and nonalcoholic fatty liver disease (NAFLD) . Although magnetic resonance imaging (MRI) is more accurate, the evaluation of NAFLD is generally limited to ultrasonography and various scoring systems. Here, we show a therapeutic effect of laparoscopic sleeve gastrectomy (LSG) on NAFLD in Japanese patients with T2DM using MRI. Methods: We conducted a prospective observational study of Japanese patients with obesity, T2DM, and NAFLD over 1 year (UMIN000034667) . The participants were 20 surgically (LSG group) and 20 medically (control group) treated patients. We compared various parameters at baseline and 1 year later in the two groups. The primary outcome was the change in the MRI proton density fat fraction and elasticity of the liver. The secondary outcomes were changes in metabolic parameters, including body mass index (BMI) , HbA1c, and diabetic remission rate. Results: To date, 28 patients (LSG 15, control 13) have completed the study. Their baseline BMIs were LSG 39.5 [35.5, 45.1] kg/m2 and control 35.9 [32.6, 43.6] kg/m2 (P=0.12) . One year after surgery, the index of hepatic steatosis, MRI proton density fat fraction (LSG −13.3±8.4%, control −0.8±5.5%, P<0.01) , was significantly lower in the LSG group. A second index, stiffness on MRI elastography (LSG −0.2 [−0.3, 0.1] kPa, control −0.[−0.35, 0.4] kPa, P=0.60) tended to be lower. In addition, BMI (LSG −9.5±3.2 kg/m2, control −0.1±0.6 kg/m2; P<0.01) and HbA1c (LSG −1.4±1.0%, control 0.3±0.8 kg/m2; P<0.01) were significantly lower. The postoperative diabetic remission rate was 86.7%. Conclusion: We have shown that LSG causes marked weight loss and diabetic remission in many patients. NAFLD was also markedly ameliorated, especially hepatic steatosis, although a longer study may be required to detect an improvement in fibrosis. Disclosure Y.Oe: None. T.Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL & BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc., Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Speaker's Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc. H.Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Speaker's Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. T.Takase: None. K.Cho: None. K.Ogawa: None. Y.Ebihara: None. A.Miya: None. H.Nomoto: None. H.Kameda: None. A.Nakamura: Research Support; Kissei Pharmaceutical Co., Ltd., MSD, Nippon Boehringer Ingelheim, Taisho Pharmaceutical Holdings Co., Ltd.

1462-P: Effect of Energy Restriction on the Intracellular Metabolism of Rodent Pancreatic ß-Cells In Vitro and Obese Mice

Background: In pancreatic β-cells under diabetic conditions, metabolic stressors cause mitochondrial dysfunction and reduce oxidative phosphorylation, resulting in impaired intracellular metabolism. It has been suggested that aberrant activation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) plays a role in this impairment. However, it is not clear whether the defect in activation of PFKFB3 is reversible. We investigated the effects of energy restriction on PFKFB3 and other metabolic enzymes in pancreatic β-cells. Methods: INS-1 832/13 cells and islets from C57BL/6J mice were cultured in medium containing a low (5.5 mM; low-G) or a high (22 mM: high-G) glucose concentration for 48 hours, or high-G for 24 hours followed by low-G for another 24 hours. The protein expression of glycolysis-related enzymes was measured using western blotting (WB) . Next, 6-week-old ob/+ and ob/ob mice were fed a standard chow diet ad lib or the same diet restricted to 2 g/day for 4 weeks. The body mass, blood glucose concentration, glucose tolerance, and insulin resistance of the mice were compared. The expression of glycolytic enzymes in the pancreatic islets was evaluated using WB and immunohistochemical staining. Results: In both INS-1 832/13 cells and isolated islets, higher expression of PKFFB3 was observed in the high-G group than in the low-G group. However, this was normalized by changing from a high-G to a low-G environment. Ad lib-fed ob/ob mice showed hyperglycemia and greater weight gain than ob/+ mice. The expression of PFKFB3, isocitrate dehydrogenase, and hexokinase was higher in ad lib-fed ob/ob mice. Restricted feeding suppressed weight gain and improved glucose tolerance versus ad lib-fed ob/ob mice. The high expression of PFKFB3 was ameliorated by restricted feeding. Conclusion: The intracellular metabolic changes in pancreatic β cells that are associated with obesity and diabetes are flexible. Disclosure K. Chiba: Research Support; Grant for Young Researcher from Japan Association for Diabetes Education and Care, Japan Diabetes Society Junior Scientist Development Grant, Japan Society for the Promotion of Science, MSD Life Science Foundation, Promotion for Young Research Talent and Network, The Akiyama Life Science Foundation, The Uehara Memorial Foundation. H. Nomoto: None. R. Izumihara: None. H. Kameda: None. K. Cho: None. H. Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. Speaker's Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. T. Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL & BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc. Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc.

6-OR: Vascular Endothelial ROCK2 Deficiency Promotes Browning and Burning of White Adipose Tissue

The accumulation of visceral fat is associated with multiple coronary risk factors such as glucose intolerance, dyslipidemia, and hypertension. We have previously demonstrated that Rho/Rho-associated protein kinase (ROCK) signaling is activated in animal models of diabetes and is involved in the pathogenesis of vascular complications. Specifically, ROCK is implicated in the molecular basis of inflammation- and ischemia-induced tissue damage through the actions on NF-κB dynamics. These findings support the hypothesis that ROCK signaling could be one of the important therapeutic targets for preventing cardiorenal events. However, isoform-specific roles of ROCKs have not been clarified yet. In this study, we aimed to determine the tissue-intrinsic roles of ROCK2 in the setting of obesity. To this end, we generated vascular endothelium-specific ROCK2 knockout mice (ER2KO) by crossing ROCK2 floxed mice with VE-Cadherin-Cre mice. ER2KO mice were fertile and had the same lifespan as wild type mice. Notably, ER2KO gained weight at a slower rate than wild type mice under high-fat diet feeding. Fat composition, as assessed by magnetic resonance imaging, was significantly lower in ER2KO, even though ER2KO displayed increased food intake. The gene expression analysis revealed increased expression of PPARα, a browning-inducing factor, and its downstream components, CIDEA, IL-4, and IL-10, in white adipose tissue obtained from ER2KO mice. ER2KO mice also showed an elevation in body temperature after fasting, suggesting that endothelial ROCK2 may negatively regulate fat browning. In summary, vascular endothelial ROCK2 negatively regulates fat accumulation through the mechanism of browning inhibition. Disclosure Y. Takeda: None. K. Matoba: None. R. Ukichi: None. Y. Nagai: None. Y. Kanazawa: None. K. Utsunomiya: None. R. Nishimura: Speaker's Bureau; Abbott Diabetes, Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck & Co., Inc., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi, Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Terumo Corporation. Funding a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science, the MSD Life Science Foundation, the Takeda Science Foundation, the Suzuken Memorial Foundation, Sanofi KK, Tanabe Pharma, and Takeda Pharmaceutical., Kazunori Utsunomiya has received research support from Terumo, Novo Nordisk Pharma, Taisho Pharmaceutical, Böehringer Ingelheim, Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, and OPharmaceutical as, Rimei Nishimura has received speaker honoraria from Astellas Pharma, Nippon Boehringer Ingelheim, Eli Lilly Japan KK, Kissei Pharmaceutical, Medtronic Japan, MSD, Novartis Pharma KK, Novo Nordisk Phar.

1038-P: Exposures to Hyperglycemia in the Embryonic Period and to Breast Milk from Mothers with Hyperglycemia Affect Glucose Tolerance with Higher Glucagon-Like Peptide-1 Secretion

Exposure to hyperglycemia during pregnancy results in diabetes in offspring. However, its underlying mechanisms are unclear. We therefore focused on the glucose metabolism of the offspring who were exposed to hyperglycemia in uterus or who were breast-fed from mothers with hyperglycemia. ICR female mice received single intraperitoneal injection (i.p.) of streptozotocin at six weeks old as the model of mother with diabetes (MD) . An additional group of mice received citric acid buffer injection, instead, as the model of mother with normal glycemia (MNG) . We established the model exposed to hyperglycemia in the uterus (EHU) by switching offspring from MD to MNG right after birth. As the model exposed to the breast milk of mothers with hyperglycemia (EBM) , the offspring from MNG were moved to MD right after birth. To eliminate the effects of cross fostering, offspring from MNG were fostered by another MNG as the control group. In intraperitoneal glucose tolerance test (IPGTT) at P60, EHU and EBM didn’t show increase of blood glucose level (BG) nor decrease of plasma insulin level but showed in oral glucose tolerance test (OGTT) at P50 (AUC of BG: p < 0.in EHU, p < 0.00in EBM, AUC of plasma insulin level per BG: <0.00in EHU and EBM) . From these conflicting results, we suspected the participation of glucagon-like peptide-1 (GLP-1) . However, the AUC of plasma total GLP-1 and active GLP-1 levels were higher in OGTT. Since we didn’t observe any difference in beta cell area per whole pancreas section by immunostaining, EHU and EBM might have GLP-1 resistance. Disclosure K.Ishii: None. M.Odawara: Other Relationship; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo, Daiichi Sankyo, Dainippon Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Kowa Company, Ltd., Kyowa Kirin Co., Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk, Omnipod, ONO PHARMACEUTICAL CO., LTD., Sanofi K.K., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Co.,Ltd., Teijin Pharma Limited. R.Suzuki: Consultant; Novo Nordisk A/S, Other Relationship; Daiichi Sankyo, Eli Lilly Japan K.K., MSD K.K., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Research Support; Boehringer Ingelheim Japan, Inc., LifeScan, Mitsubishi Tanabe Pharma Corporation. J.Sasaki: None. K.Sugai: None. M.Ito: None. H.Iwasaki: None. N.Hara: None. M.Aierken: n/a. G.Li: None. H.Suwanai: None.

721-P: Insulin-Sparing Effects of Oral Semaglutide: An Analysis of PIONEER 8

The PIONEER 8 (NCT03021187) trial demonstrated significant glucose-lowering efficacy of oral semaglutide vs. placebo (pbo) in patients (pts) with T2D inadequately controlled with insulin. Additionally, those assigned to oral semaglutide (7 or 14 mg daily) had a lower total daily insulin dose at end of treatment (week 52) relative to baseline, vs. those treated with pbo, suggesting an insulin-sparing effect. This post-hoc analysis of PIONEER 8 aimed to characterize the transition of adding a GLP-1RA to insulin therapy and to quantify reductions in total insulin dose seen with the addition of oral semaglutide. A 20% reduction in total daily insulin dose was recommended at randomization up to week 8. Total daily insulin was not to exceed pre-randomization dose between weeks 8 and 26 but was freely adjustable at the investigator’s discretion from week 26 to 52. For all doses of oral semaglutide, a greater proportion of pts were able to maintain a greater level of insulin dose reduction vs. pbo at week 26 (Figure) . Greater proportions of pts on oral semaglutide 3, 7, and 14 mg achieved ≥20% reductions in insulin vs. those in the pbo group at both weeks 26 and 52 (Treatment policy estimand; 27.5%, 28.9%, 31.2% vs. 12.4% and 19.5%, 25.0%, 32.0% vs 5.7%, respectively; P<0.0 for all) . Addition of oral semaglutide in pts with T2D permits a significant reduction in insulin dose, which may provide benefits (e.g. lower risk of hypoglycemia and weight gain) long-term. Disclosure V.R.Aroda: Consultant; Applied Therapeutics, Fractyl Health, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Other Relationship; Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Research Support; Applied Therapeutics, Fractyl Health, Inc., Novo Nordisk, Sanofi. M.T.Abildlund: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. R.Agesen: Employee; Novo Nordisk A/S. S.B.Harris: Consultant; Abbott, AstraZeneca, Eli Lilly and Company, Novo Nordisk, Sanofi, Other Relationship; Abbott, AstraZeneca, Bayer Inc., Dexcom, Eli Lilly and Company, HLS Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Research Support; Applied Therapeutics Inc., AstraZeneca, Canadian Institutes of Health Research, Juvenile Diabetes Research Foundation (JDRF) , Novo Nordisk, Sanofi, The Lawson Foundation. B.Zahedi: Employee; Novo Nordisk A/S. B.Zinman: Advisory Panel; Abbott Diabetes, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Canada Inc., Sanofi K.K. E.Araki: Other Relationship; Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly and Company, Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk, Sanofi K.K., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Corporation, Speaker's Bureau; Abbott, AstraZeneca, Kyowa Kirin Co., Ltd., Ono Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho. Funding Funded by Novo Nordisk A/S

120O Pembrolizumab (Pembro) with or without lenvatinib (Lenva) in first-line metastatic NSCLC with PD-L1 TPS ≥1% (LEAP-007): A phase III, randomized, double-blind study

120O Pembrolizumab (Pembro) with or without lenvatinib (Lenva) in first-line metastatic NSCLC with PD-L1 TPS ≥1% (LEAP-007): A phase III, randomized, double-blind study

Japanese Society of Neuropsychopharmacology: "Guideline for Pharmacological Therapy of Schizophrenia".

Japanese Society of Neuropsychopharmacology: "Guideline for Pharmacological Therapy of Schizophrenia".

High Expression of MEF2D-Fusion Protein Is Caused By Escaping from the Suppression By miRNA and Leads to Suppress Transcriptional Activity of PAX5

We previously discovered new fusion genes, MEF2D-BCL9 and MEF2D-HNRNPUL1, in 9% of adolescent and young adult B-cell acute lymphoblastic leukemia (ALL; Yasuda T, et al. , Nature Genetics, 2016;48:569-574). Vector driving expression of MEF2D-fusion protein was markedly higher than the expression of wild-type MEF2D (MEF2D W) protein driven by the same expression vector system; however, the mechanism and significance of the high-expression have been yet to be clarified.We first confirmed fusion specific MEF2D high expression was occurred in MEF2D fusion-positive ALL cell lines, Kasumi-7 and Kasumi-9. Protein half-life and the effect of proteasome inhibitor on protein expression were not significantly different between MEF2D W and MEF2D-fusion, suggesting that stability of protein was not different between them. We speculated that MEF2D fusion gene lost the miRNA target that existed in C-terminal half of MEF2D mRNA and that the high-expression of MEF2D fusion protein was caused by escaping from the suppression by miRNA (Figure A). In order to investigate this speculation, we made several expression vectors of MEF2D that express same partial MEF2D protein but transcript different length of mRNA. That is, we introduced a mutation substituting stop codon for D336, the breakpoint of MEF2D-HNRNPUL1 fusion protein, into the expression vector of wild-type MEF2D and designated it as MEF2D (full D336Stop). We deleted C-terminal legion from it with various lengths (Figure B). The protein expression level of MEF2D (1-335) from MEF2D (full D336Stop) vector was similar to that of MEF2D W; however, the protein expression level was markedly increased when DNA region coding amino acid (aa) 377-418 was deleted from the expression vector (Figure C), indicating that protein expression of MEF2D (1-335) was down regulated by miRNA targeting mRNA coding aa 377-418. We identified a candidate of responsible miRNA by database search. Transfection of miRNA mimic of the candidate miRNA decreased the protein expression of MEF2D W but not that of MEF2D fusion. Introduction of mutation at the binding site of the candidate miRNA increased the protein expression of MEF2D W. We examined the effect of MEF2D fusion protein on transcriptional activity of various B cell differentiation regulators and found that MEF2D-fusion protein suppressed transcriptional activity of PAX5 in luciferase assays in dose-dependent manner and that MEF2D W protein did not significantly affect it. These results suggested that the high-expression of MEF2D fusion protein impaired B cell differentiation through the inhibition of PAX5 function. This is the first report that a mutation of a coding gene causes high expression of the protein coded by the gene through escape from suppression by miRNA. These results shed a new insight into the mechanism of leukemia development by MEF2D fusion gene and pathological significance of miRNA-related disorder. [Display omitted] DisclosuresNaoe:Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; Nippon Boehringer Ingelheim Co.: Honoraria, Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Dainippon Sumitomo Pharma Co.,LTD.: Research Funding; Astellas Pharma Inc.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding. Kiyoi:Bristol-Myers Squibb: Honoraria, Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Meiji Seika Pharma Co.,Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; MSD K.K.: Research Funding; Celgene Corporation: Consultancy, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; JCR Pharmaceuticals Co.,Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; ONO Pharmaceutical Co., Ltd.: Research Funding; Phizer Japan Inc.: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding.

607-P: Glycemic Metrics in Japanese Flash Glucose Monitoring Users by Diabetes Type and Therapy

Our aim was to assess differences in glycemic metrics according to diabetes type and therapy in Japan. An optional survey was conducted for users of FreeStyle LibreTM readers in Japan (Jun2020 - Oct2020). Survey responses were linked to glucose data from Jan2017 - Oct2020. Four groups (adults) were used: type 1 diabetes (T1), type 2 on intensive insulin (T2 MDI), T2 on basal or pre-mixed insulin (T2 non-MDI), and T2 not on insulin (T2 non-insulin). A total of 2,434 users in Japan were analyzed: 1,237 T1, 429 T2 MDI, 256 T2 non-MDI, and 512 T2 non-insulin. Glucose control for T2 MDI and T2 non-MDI groups was similar. Mean avg glucose for T1 was similar to T2 insulin users, but TIR was lower and TB70 was higher for T1. The non-insulin group had high engagement (mean 21 scans/day), but tested BG less than once/day prior to the sensor. These patients also largely pay for the device without reimbursement and have more recent diabetes diagnoses than other groups. These data show the variety of users of the FreeStyle Libre system in Japan. The non-insulin group's engagement through high average scan rates despite lack of consistent BG testing before using the sensor demonstrates that patients find value in easier monitoring. High scan rates in all groups indicate that scanning is not a barrier to glucose monitoring. The data selects those users who responded to the optional survey but is comparable to the overall glucose control of all users in Japan.View largeDownload slideView largeDownload slide DisclosureW. Ogawa: Advisory Panel; Self; Abbott Diabetes, Novo Nordisk Pharma Ltd., Research Support; Self; Eli Lilly Japan K. K., Nippon Boehringer Ingelheim Co. Ltd., Takeda Pharmaceutical Co., Speaker's Bureau; Self; Dainippon Sumitomo Pharm, Kowa Company, Ltd., MSD K. K., Novartis Pharma K. K., Ono Pharmaceutical Co., Ltd. T. Urakami: None. T. Kadowaki: Other Relationship; Self; Asahi Mutual Life Insurance Company, MSD Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly Japan K. K., Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD Corporation, Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co., Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly Japan K. K., Kowa Company, Ltd., Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd. K. Kao: Employee; Self; Abbott Diabetes. L. Brandner: Employee; Self; Abbott Diabetes. K. Shimizu: Employee; Self; Abbott Japan Co., Ltd. T. Dunn: Employee; Self; Abbott Diabetes.

780-P: Improved Mitochondrial Function by Luseogliflozin Prevents Pancreatic Beta-Cell Damage

We previously showed a sodium glucose co-transporter 2 (SGLT2) inhibitor, luseogliflozin, increased beta cell mass and improved beta cell function in db/db mice, but the mechanism has remained unclear. The aim of this study is to investigate the mechanism of favorable effects of luseogliflozin on beta cells. Six-week-old db/db mice were fed to standard chow (control group) or standard chow containing 0.01% luseogliflozin (luseo group) for 4 weeks. DNA microarray analysis, real-time PCR analysis, measurement of mitochondrial respiratory capacity and reactive oxygen species (ROS) generation, and metabolome analysis were performed using isolated islets. Immunohistochemistry and electron microscopy were performed using pancreatic tissues. DNA microarray and real-time PCR analysis showed gene expressions of solute carrier family 2 member 2 (Slc2a2) related to glucose uptake, pyruvate carboxylase (Pcx) and enzymes related to the tricarboxylic acid (TCA) cycle, and cytochrome c oxidase subunit 6A2 (Cox6a2) related to electron transport chain were upregulated in the luseo group. The luseo group had a higher mitochondrial complex II-linked oxidative phosphorylation capacity, and had a lower mitochondrial ROS generation compared with the control group. Electron microscopy showed mitochondrial swelling in the control group, while the mitochondrial size was normally maintained in the luseo group. Immunohistochemistry showed the proportion of Nkx6.1 positive cells/beta cells was significantly higher in the luseo group compared with the control group (89.8 ± 1.8% vs. 75.3 ± 3.5%, P < 0.01). In metabolome analysis, the metabolites in the TCA cycle were greater in the luseo group compared with the control group. Relief of glucotoxicity by luseogliflozin may reduce mitochondrial ROS generation and elevate Nkx6.1 expression related to beta cell proliferation. The elevated expression of Nkx6.1 could improve glucose metabolism in the TCA cycle, resulting in protection of beta cells. Disclosure Y. Yamauchi: None. K. Cho: None. T. Anzai: None. S. Tanaka: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Novo Nordisk, Sanofi, Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Speaker’s Bureau; Self; Abbott, Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. H. Miyoshi: Research Support; Self; Abbott Japan Co., Ltd., Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Speaker’s Bureau; Self; Astellas Pharma Inc., Eli Lilly Japan K. K., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd. T. Atsumi: Research Support; Self; Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly Japan K. K., Gilead Sciences, Inc., Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., UCB Japan Co. Ltd., Speaker’s Bureau; Self; AbbVie Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K. K., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Takeda Pharmaceutical Co., UCB Japan Co. Ltd. A. Nakamura: Research Support; Self; Boehringer Ingelheim International GmbH, Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Taisho Pharmaceutical Co., Ltd. T. Yokota: None. K. Takahashi: None. S. Kawata: None. K. Tsuchida: None. K. Omori: None. H. Nomoto: None. H. Kameda: None.