Nippon Boehringer Ingelheim Research Articles

Efficacy and Safety of Faster Aspart Compared with Insulin Aspart Both with Insulin Degludec in Adults with T1D

Fast-acting insulin aspart (FA) can improve glycemic control in subjects with T1D. To further assess the effect and safety of FA, a multicenter, treat-to-target, 26-week trial (onset 8) randomized subjects with T1D to double-blind mealtime FA (n=342), or insulin aspart (IAsp; n=342), or open-label post-meal FA (n=341), each with insulin degludec. All available information regardless of treatment discontinuation was used for the evaluation of effect. Non-inferiority for the primary endpoint, change from baseline in A1C, was confirmed for mealtime and post-meal FA vs. IAsp (Figure). Mealtime FA was superior to IAsp for 1-h PPG increment using a standard meal test (ETD: -0.90 [-1.36;-0.45] mmol/L; -16.24 [-24.42;-8.05] mg/dL). Self-measured 1 hour PPG increment favored FA at breakfast (ETD: -0.58 [-0.99;-0.17] mmol/L; -10.43 [-17.85;-3.02] mg/dL) and across all meals (ETD: -0.48 [-0.74;-0.21] mmol/L; -8.58 [-13.35;-3.81] mg/dL). No significant differences were observed in treatment-emergent adverse events or overall rate of severe or confirmed hypoglycemic episodes (PG <3.1 mmol/L [56 mg/dL]), but significantly less hypoglycemia was seen 3 to 4 h after meals with mealtime FA. In summary, mealtime FA provided superior PPG control to IAsp with a similar overall improvement in A1C and no increased safety risk. These findings were consistent with those previously reported in subjects with T1D. Disclosure J.B. Buse: Other Relationship; Self; ADOCIA, AstraZeneca, Dexcom, Inc., Elcelyx Therapeutics, Inc., Eli Lilly and Company, Fractyl Laboratories, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Metavention, NovaTarg, Novo Nordisk A/S, Sanofi, VTV Therapeutics. Research Support; Self; Boehringer Ingelheim GmbH, Johnson & Johnson Services, Inc., Theracos, Inc.. Other Relationship; Self; Shenzhen Hightide Biopharmaceutical, Ltd.. Research Support; Self; National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences. Other Relationship; Self; National Institute of Diabetes and Digestive and Kidney Diseases, American Diabetes Association. Research Support; Self; Patient-Centered Outcomes Research Institute. Other Relationship; Self; National Institute of Environmental Health Sciences. A. Carlson: Advisory Panel; Self; Sanofi, Insulet Corporation. Consultant; Self; Merck & Co., Inc.. Research Support; Self; Medtronic, Novo Nordisk A/S. M. Komatsu: Research Support; Self; Nippon Boehringer Ingelheim Co. Ltd., Sanofi K.K., Ono Pharmaceutical Co., Ltd., MSD K.K., Takeda Pharmaceutical Co Ltd., Mitsubishi Tanabe Pharma Corporation, Astellas Pharma US, Inc., Sumitomo Dainippon Pharma Co., Ltd., Teijin Pharma Limited, Novo Nordisk A/S, Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Daiichi Sankyo Company, Limited, Fujifilm Pharma Co Ltd, Eli Lilly Japan K.K., Taisho Pharmaceutical Co., Ltd., Novartis Pharma K.K., Kowa Pharmaceutical Co. Ltd.. Speaker's Bureau; Self; Nippon Boehringer Ingelheim Co. Ltd., Sanofi K.K., Ono Pharmaceutical Co., Ltd., MSD K.K., Takeda Pharmaceutical Co Ltd., Mitsubishi Tanabe Pharma Corporation, Astellas Pharma US, Inc., Sumitomo Dainippon Pharma Co., Ltd., Teijin Pharma Limited, Novo Nordisk A/S, Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Terumo Medical Corporation, Daiichi Sankyo Company, Limited, Fujifilm Pharma Co Ltd, Eli Lilly Japan K.K., Taisho Pharmaceutical Co., Ltd., Novartis Pharma K.K., Bayer Yakuhin, Ltd., Medtronic Japan Co. Ltd., Maruho Co. Ltd., Kowa Pharmaceutical Co. Ltd. O. Mosenzon: Advisory Panel; Self; Novo Nordisk A/S, Sanofi, Merck Sharp & Dohme Corp., Boehringer Ingelheim GmbH, AstraZeneca. Consultant; Self; Novo Nordisk A/S, Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Novo Nordisk A/S, AstraZeneca. Speaker's Bureau; Self; Novo Nordisk A/S, Sanofi, Merck Sharp & Dohme Corp., Boehringer Ingelheim GmbH, AstraZeneca, Eli Lilly and Company, Novartis AG. L. Rose: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Member of Association of Statutory Health Insurance Physicians. B. Liang: Employee; Self; Novo Nordisk A/S. Employee; Spouse/Partner; Pfizer ApS, H. Lundbeck A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Pfizer Inc. H. Horio: Employee; Self; Novo Nordisk Pharma Ltd.. Employee; Spouse/Partner; Chugai Clinical Research Center Co., Ltd. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.

Nonalcoholic Fatty Liver Disease Is Associated with Type 2 Diabetes Mellitus Only in Individuals with Visceral Obesity

Nonalcoholic fatty liver disease (NAFLD) is considered to be a risk factor for the onset of type 2 diabetes mellitus (T2D), but no studies have considered the role of visceral fat (VF), which is strongly linked to both NAFLD and T2D, as a potential confounder. Therefore, it is not fully understood how NAFLD and T2D are associated. We previously reported that the risk of T2D onset and NAFLD were associated via VF accumulation. In this study, we further investigated the association between liver fat accumulation or NAFLD and T2D comorbidity, focusing on the presence or absence of visceral obesity (VO). The subjects were 367 individuals (179 men, 48.8%; mean age, 56.3 years), who received health check-ups at our medical examination center, MedCity21. In all subjects, quantitative live fat accumulation was evaluated by controlled attenuation parameter (CAP) value using Fibroscan®, and VF area at umbilical level (VFA) by abdominal CT scan as an index of VF accumulation. Those who habitually drank > 30 g/day of alcohol and those with confirmed liver diseases were excluded. CAP value ≥ 236 dB/m was defined as NAFLD, and VFA > 100 cm2 as VO. The association of CAP values or existence of NAFLD with T2D comorbidity was examined in the subgroups with and without VO (n = 101 and n = 266, respectively) by multivariate logistic analysis, with other factors adjusted. NAFLD was found 33.8% of subjects in non-VO group and 75.2% in VO group, respectively. In non-VO group, neither CAP value nor NAFLD showed significant association with T2D. In contrast, in VO group, the odds of T2D comorbidity were higher by 12.7% for each 10 dB/m higher CAP value, and NAFLD raised the odds of T2D comorbidity 5.2 times compared to non-NAFLD. These findings suggest that liver fat accumulation is associated with T2D via interaction with VF accumulation. In conclusion, both liver fat accumulation and NAFLD are associated with T2D comorbidity only in individuals with VO. Disclosure S. Fukumoto: Speaker's Bureau; Self; Astellas Pharma US, Inc.. Research Support; Self; Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Novo Nordisk Inc., Sanofi K.K.. Research Support; Self; Takeda Pharmaceuticals U.S.A., Inc., Taisho Toyama Pharmaceutical Co., Ltd. M. Emoto: Speaker's Bureau; Self; Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Sumitomo Dainippon Pharma Co., Ltd.. Research Support; Self; Astellas Pharma Inc, Ono Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceutical Company Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation. K. Motoyama: None. T. Morioka: Consultant; Self; Ono Pharmaceutical Co., Ltd.. Research Support; Self; Novartis Pharma K.K., MSD K.K., Eli Lilly and Company, Sanofi K.K., Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Takeda Pharmaceuticals U.S.A., Inc., Novo Nordisk Inc., Kowa Pharmaceuticals America, Inc., Astellas Pharma US, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Sumitomo Dainippon Pharma Co., Ltd. T. Shoji: Speaker's Bureau; Self; Astellas Pharma Inc, Bayer Yakuhin Ltd. Research Support; Self; Bayer Yakuhin Ltd. Speaker's Bureau; Self; Kowa Pharamaceutical Co Ltd, Daiichi Sankyo Company, Limited, MSD K.K., Chugai Pharmaceutical Co., Ltd.. Research Support; Self; Chugai Pharmaceutical Co., Ltd.. Speaker's Bureau; Self; Kyowa Hakko Kirin Co., Ltd., Kissei Pharmaceutical Co., Ltd. K. Hirata: Speaker's Bureau; Self; AstraZeneca, Astellas Pharma Inc., Eisai Co., Ltd., KYORIN Pharmaceutical Co.,Ltd., Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., TAIHO PHARMACEUTICAL Co.,Ltd., Chugai Pharmaceutical Co., Ltd., TEIJIN HOME HEALTHCARE LIMITED, Eli Lilly Japan K.K, Nippon Shinyaku Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Pfizer Japan Inc.. Research Support; Self; KYORIN Pharmaceutical Co.,Ltd., Daiichi Sankyo Company, Limited, Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., MSD K.K.. Other Relationship; Self; AstraZeneca, GlaxoSmithKline K.K., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Santen Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Eli Lilly Japan K.K. M. Inaba: None.

Genotype–Phenotype Correlations and Structural Basis of INSR and IGF1R Mutations Causing Severe Insulin/IGF-1 Resistance

Mutations of the insulin receptor (INSR) gene cause severe insulin resistance, resulting in several syndromes with various abnormal phenotypes associated with variable severity of INSR dysfunction. As a member of the insulin receptor family, the IGF-I receptor (IGF1R) shows the same domain structure as INSR containing the fibronectin type III (FnIII) domains where there are an α-β cleavage site and a part of the ligand binding site. Mutations of IGF1R can cause intrauterine and postnatal growth retardation. We compiled 3 mutations of the FnIII-2 and FnIII-3 domains in IGF1R registered in HGMD, ClinVar and UniProt databases as causing growth retardation as well as the SNP with >1% allele frequency in IGF1R from the 1000 Genomes Project data, ESP6500, HGVD and 3.5KJPN, a reference panel of Japanese individuals. We conducted in silico structural analysis of the mutations of the FnIII domains in IGF1R which revealed that the pathogenic mutations were predicted to severely impair stability of the FnIII domains and hydrophobic core formation or affect processing site, while the SNP was predicted not to affect folding of the domains. In addition, IGF-1 proreceptor processing was impaired in cells expressing mutations of FnIII compared to cells expressing WT form. Previously, we performed structural analysis of mutations of the FnIII domains in INSR, which revealed that missense mutations causing the most severe Donohue syndrome were predicted to severely impair hydrophobic core formation and stability of the FnIII domains, while those causing less severe Rabson-Mendenhall syndrome were predicted to lead to localized destabilization and not to affect folding of the FnIII domains. Genotype-structure-phenotype correlations of variants of the FnIII domains in INSR and IGF1R identified in these analyses will enable early diagnosis of pathogenic mutations in INSR and IGF1R and provide a valuable insight into the molecular mechanism of severe insulin or IGF-1 resistance. Disclosure J. Hosoe: None. H. Kadowaki: None. F. Miya: None. M. Takakura: None. T. Tsunoda: None. N. Shojima: None. T. Yamauchi: Research Support; Self; Novo Nordisk Inc., Daiichi Sankyo Company, Limited, Sanofi, Takeda, Tanabe-Mitsubishi. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.

Tofogliflozin Suppresses the Progression of Atherosclerosis and Reduces Inflammation in Macrophages of STZ-Diabetic ApoE KO Mice due to Improvement of Glucose Tolerance

Background: Selective sodium-glucose cotransporter 2 inhibitor (SGLT2i) has become widely used for treatment of diabetes. Recently, EMPA-REG OUTCOME and CANVAS Program showed that SGLT2i reduce cardiovascular events in patients with type 2 diabetes, but the mechanism still remains uncertain. We investigated the mechanisms of vascular protection of Tofogliflozin (Tofo), one of the SGLT2i. Method: 1) Streptozotocin (STZ)-diabetic apolipoprotein-E-deficient (ApoE KO) mice were separated into two groups, one group were fed normal chow and the other were fed normal chow containing 0.005% Tofo for ad libitum. After 6weeks, all mice were administered thioglycolate intraperitoneally, and 4 days later, peritoneal macrophages were collected to investigate the expressions of inflammatory cytokines of peritoneal macrophages by real-time PCR. Histological analyses were carried out by Sudan IV, Oil Red O, and MOMA-2 staining. 2) The same experiment targeted were carried out towards nondiabetic ApoE KO mice. Results: 1) Tofo increased food and water intake and decreased blood glucose, but there were no significant changes in body weight, serum levels of free fatty acid, triglyceride and total cholesterol between two groups. The legions of atherosclerosis and macrophages accumulations were significantly suppressed in Tofo group. Moreover, the expression levels of TNF-α, IL-β were significantly suppressed in macrophages from Tofo group. 2) Nondiabetic ApoE KO mice showed similar increase in food and water intake, but failed to exhibit differences in blood glucose, Sudan IV staining, and expressions of inflammatory cytokines in macrophages, as observed in diabetic ApoE KO mice. Conclusion: Tofogliflozin suppresses the progression of atherosclerosis and reduces inflammation in macrophages of STZ- diabetic ApoE KO mice. These beneficial effects may be exerted due to improvement of glucose tolerance. Disclosure M. Iwamoto: None. N. Kubota: None. T. Kubota: None. Y. Sakurai: None. N. Wada: None. I. Takamoto: None. S. Shioda: None. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.

The Prevalence of Gastrointestinal Symptoms Depends on Disease Duration and Gastrointestinal Tract Region in Patients with Type 2 Diabetes

Background/Aims: We aimed to unravel how symptoms related to gastrointestinal (GI) dysfunction impair quality of life (QoL) in patients with diabetes mellitus (DM). Methods: We enrolled 134 outpatients with type 2 DM and 16 non-DM. In DM patients, mean age was 64.7 years, mean body mass index (BMI) 24.7 kg/m2, mean glycated hemoglobin (HbA1c) 7.1%, and mean DM duration 13.7 years. In non-DM, mean age was 66.6 years and mean BMI was 25.2 kg/m2. GI symptom-related QoL was determined using the Izumo scale, based on five factors, i.e., heartburn, gastralgia, postprandial fullness, constipation and diarrhea. The sum of scores obtained for the three questions in each domain was calculated, and subjects with a score of 5 or higher were considered to be symptomatic with impaired QoL. JMP Clinical version 5.0 was used for all statistical analyses. Results: In DM patients, constipation was much greater than non-DM, diarrhea was somewhat higher, other symptoms did not increase significantly. In DM, lower abdominal symptoms were found to be more frequent than those affecting the upper abdomen. Diabetic duration and medications showed associations with GI symptoms. We identified differences in peak prevalences of the five symptoms. Gastralgia and total GI symptoms peaked at a diabetes duration of 15-19 years. Heartburn and postprandial fullness tended to increase with disease duration. Constipation and diarrhea showed bimodal peaks, with the first early and the second late in the disease course. Finally, GI symptoms showed clustering that reflected the region of the GI tract affected, i.e., constipation and diarrhea had similar frequencies. Conclusions: Our study highlights the importance of questioning patients about QoL impairment due to abdominal symptoms, especially in the early and the late periods of diabetes. The heterogeneous nature of the underlying GI symptoms, including medication usage, should be taken into consideration when managing patients with T2DM. Disclosure M. Fujishiro: Research Support; Self; Johnson & Johnson Services, Inc. A. Kushiyama: Research Support; Self; Teijin Pharma Limited, Sanwa Kagaku Kenkyusho Co., Ltd., Kowa Pharmaceutical Co., Ltd, StaGen. Consultant; Self; RIZAP. H. Yamazaki: None. T. Yamamotoya: None. T. Kikuchi: None. H. Sakoda: None. R. Suzuki: Research Support; Self; Daiichi Sankyo Company, Limited, Kyowa Hakko Kirin Co., Ltd.. Other Relationship; Self; MSD K.K., Novo Nordisk Pharma Ltd., Daiichi Sankyo Company, Limited, Eli Lilly Japan K.K. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.

Lack of Brain Insulin Receptor Substrate-1 (IRS1) Causes Growth Retardation via Growth Hormone Releasing Hormone

Background and Purpose: We previously revealed that systemic Irs1 deficient mice showed growth retardation, indicating that Irs1 plays an important role in growth. Irs1 is main substrate of not only insulin receptor (IR) but also IGF-1 receptor (IGF-1R) tyrosine kinase. Recently, brain specific IGF-1 receptor knockout mice were reported to become growth impairment. We hypothesized that brain Irs1 may regulate growth via IGF-1. Methods: We generated NIrs1KO mice and analyzed growth related parameter and immunohistochemistry (IHC) study. Result: The body weight of NIrs1KO mice was significantly smaller than control mice. NIrs1KO mice also showed shorter body length and bone length. On the other hand food intake and gene expression of appetite-related neuropeptides (POMC, AgRP and NPY) were not different between two groups. We next confirmed that plasma IGF-1 and growth hormone (GH) levels of NIrs1KO mice were lower than control mice. Hypothalamic GHRH mRNA expression levels of NIrs1KO mice were also lower than those of control mice although hypothalamic somatostatin mRNA expression was not different between two groups. These data strongly suggest that lack of brain Irs1 causes growth retardation via GHRH. IHC study indicated that Irs1 colocalized with GHRH neuron in hypothalamus. We next investigated the IGF-1-induced proliferation in hypothalamic neural cells by using siIrs1. Downregulation of Irs1 significantly inhibited IGF-1-induced neural cell proliferation. Conclusion: Our results suggest that IGF-1-Irs1 pathway promotes the proliferation of GHRH neurons and regulate growth. Disclosure T. Hayashi: None. N. Kubota: None. T. Kubota: None. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.

Impairment of M2a-Subtype Macrophage Activation by Il-4-Irs2 Pathway in Obesity

Introduction: M2a-subtype macrophage activation is known to be impaired in obesity, although the underlying mechanisms remain poorly understood. Methods: We found that the phosphorylation levels of Irs2 by IL-4 were significantly reduced along with decreased Irs2 expression in macrophages of high-fat (HF) diet-fed mice. To investigate the role of Irs2 in the macrophages, we then generated myeloid cell-specific Irs2-deficient (MIrs2KO) mice. Results: HF diet-fed MIrs2KO mice showed impairment of IL-4-induced M2a-subtype macrophage activation, resulting in insulin resistance. Expressions of the maker genes for M2a-subtype macrophages were downregulated by stabilization of the FoxO1/HDAC3/NCoR1 corepressor complex via impairment of the IL-4/Irs2 pathway. Furthermore, Irs2 expression was significantly suppressed by insulin treatment in macrophages, suggesting that chronic hyperinsulinemia downregulates macrophage Irs2 expression via insulin receptor (IR). Indeed, in myeloid cell-specific IR-deficient mice, the IL-4-Irs2 pathway was preserved in the macrophages due to the lack of IR-mediated downregulation of Irs2, resulting in a reduced degree of inflammation and insulin resistance. Conclusion: These data suggest that in obesity, downregulation of macrophage Irs2 is induced by hyperinsulinemia, resulting in impaired IL-4-induced M2a-subtype macrophage activation, and insulin resistance. Disclosure T. Kubota: None. M. Inoue: None. N. Kubota: None. I. Takamoto: None. K. Ueki: Speaker's Bureau; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., MSD K.K., Novo Nordisk Inc., Mitsubishi Tanabe Pharma Corporation, Kyowa Hakko Kirin Co., Ltd., Takeda. Research Support; Self; Takeda, Astellas, Novo Nordisk Inc. T. Yamauchi: Research Support; Self; Novo Nordisk Inc., Daiichi Sankyo Company, Limited, Sanofi, Takeda, Tanabe-Mitsubishi. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.

Distinct Phenotypes of Islet Antigen-Specific CD4+ T Cells among the Three Subtypes of Type 1 Diabetes

Type 1 diabetes (T1D) is classified into three subtypes in Japan based on the manner of disease progression: acute onset (AT1D), slowly progressive (SP1D), and fulminant (FT1D). While cellular immunity is considered to play a major role in pancreatic β cell destruction in T1D, the phenotypes of autoreactive T cells in each subtype remain largely unknown. In this study, we performed an integrated assay that permits the determination of ex-vivo cellular immune responses and T cell repertoires specific for islet antigens. Briefly, peripheral blood mononuclear cells obtained from 20 AT1D, 17 SP1D, 18 FT1D patients, and 17 nondiabetics (ND) were stimulated for 48 h with GAD65, preproinsulin (PPI), IGRP, and ZnT8 peptide clusters, after which cytokine/chemokine secretion was measured (ex-vivo assay). Subsequently, peptide-reactive T cells were further expanded with IL-2 to identify CD4+ T cell subsets based on intracellular cytokine staining (ICS assay). In the ex-vivo assay, GAD65-specific IL-6 and IP-10 responses, and PPI-specific IP-10 responses were significantly upregulated in AT1D as compared to ND. Furthermore, GAD65-specific IL-1β and G-CSF, and PPI-specific G-CSF responses were significantly upregulated in FT1D when compared to ND. The ICS assay further revealed that GAD65- and PPI-specific CD4+ T cells were skewed towards Th1 cells in AT1D (P = 0.007 and P = 0.004, respectively), whereas GAD65- and IGRP-specific Th2 cells were more prevalent in SP1D (P = 0.01 and P = 0.03, respectively) than in ND. Interestingly, GAD65-specific Th1 cells were more abundant in SP1D with HLA-DR9 than in those without DR9 (P = 0.03). Of note, FT1D displayed significantly less Tr1 cells specific for all four antigens and GAD65-specific Th2 cells than ND. In conclusion, the phenotypes of islet antigen-specific CD4+ T cells differ among the three T1D subtypes. These distinct phenotypes of pathogenic T cells may be associated with the manner of progression of β cell destruction. Disclosure D. Chujo: Research Support; Self; Mitsubishi Tanabe Pharma Corporation, Sanofi K.K., Kyowa Hakko Kirin Co., Ltd.. A. Kawabe: None. N. Takahashi: None. M. Matsushita: None. C. Tsutsumi: Research Support; Self; MSD K.K.. F. Haseda: None. A. Imagawa: Research Support; Self; Kowa Pharmaceutical, Sanwa Kagaku Kenkyusho Co., Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Eli Lilly and Company, MSD K.K., Mitsubishi Tanabe Pharma Corporation, Shionogi & Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Sanofi K.K., Novo Nordisk A/S, Mitsubishi Tanabe Pharma Corporation, Daiichi Sankyo Company, Limited, Nipro, Eli Lilly and Company, AstraZeneca, Nippon Boehringer Ingelheim Co. Ltd., Taisho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Terumo Medical Corporation. T. Hanafusa: Speaker's Bureau; Self; Novo Nordisk Inc.. K. Yagi: None. M. Shimoda: None. K. Ueki: Speaker's Bureau; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., MSD K.K., Novo Nordisk Inc., Mitsubishi Tanabe Pharma Corporation, Kyowa Hakko Kirin Co., Ltd., Takeda. Research Support; Self; Takeda, Astellas, Novo Nordisk Inc.. H. Kajio: None.

Factors Responsible for Progression of Microalbuminuria in Japanese Patients with Type 2 Diabetes-Retrospective Analysis

Aim: This study was designed to investigate factors associated with progression or remission of microalbuminuria (MA) in Japanese type 2 diabetes (T2D). Subjects and Methods: T2D patients with MA, defined as urinary albumin/Cre ratio (UACR) 30-299 mg/gCre, were retrospectively screened from medical records of 65,323 patients who visited Kansai Electric Power Hospital between 20and 2009 (baseline period); and their status of MA was re-evaluated between 2014 and 2017 (evaluation period) using mean values of multiple measurements of UACR or urinary protein/Cre ratio (UPCR). Data were analyzed using χ2 test, ANOVA and logistic regression analysis. Result: T2D patients with MA identified in the baseline period (n=155) had 3 different outcomes in the evaluation period: Group A (n=26; UACR <30 mg/gCre), group B (n=106; UACR 30-299 mg/gCre) and group C (n=23; UACR >300 mg/gCre or UPCR >500 mg/gCre). Mean and standard deviation (SD) of HbA1c during the observation period differ significantly among different groups in the evaluation period (Table 1), despite of the similar baseline age, BMI, T2D duration and HbA1c. Mean and SD HbA1c also associated with MA (Mean OR 2.18 (95% CI; 1.23-3.88), SD OR 9.91 (95% CI: 2.57-38.2)). Conclusion: Sustained glycemic control is the critical to prevent MA progression in Japanese T2D.Table 1. Glycemic control and use of drugs during the observation period.GroupABCP valuen(M/F)26(20/6)106(76/30)23(16/7)Mean HbA1c(%)7.44±0.117.39±0.067.88±0.130.014Standard deviation of HbA1c during total observation period(%)0.51±0.050.58±0.020.77±0.070.013Antihypertensive drug use (%)73.170.895.70.043Lipid-lowering drug use (%)73.178.369.6n.s.Antiplatelet drug use (%)19.232.129.6n.s. Disclosure S. Kubota: None. H. Kuwata: None. D. Yabe: Speaker's Bureau; Self; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd.. Research Support; Self; Nippon Boehringer Ingelheim Co. Ltd., Eli Lilly and Company, MSD K.K., Ono Pharmaceutical Co., Ltd., Arkray, Inc., Taisho Toyama Pharmaceutical Co., Ltd., Novo Vordisk Pharma Ltd., Takeda Pharamaceutical Co., Ltd.. K. Murotani: None. Y. Hamamoto: None. T. Kurose: Consultant; Self; Sanofi, Ono Pharmaceutical Co., Ltd.. Other Relationship; Self; Abbott. Consultant; Self; Taisho Pharmaceutical Co., Ltd.. Other Relationship; Self; Takeda Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Novartis Pharma K.K. Y. Seino: Speaker's Bureau; Self; MSD K.K., Kao Corporation, Taisho Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Taisho Toyama Pharamceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Nippon Becton Dickinson Co., Ltd., Novo Nordisk Pharma Ltd.. Research Support; Self; Terumo Medical Corporation, Bayer Yakuhin, Ltd., Boehringer Ingelheim GmbH, Arkray, Inc., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Novo Nordisk Pharma Ltd..

Macrophages React to Postprandial Signals and Regulate the Response to Feeding through Akt-mTOR–Dependent Production of IL-10

We explored the role of the serine/threonine protein kinase Akt in macrophages, using conditional knockout models. Myeloid specific Akt1 Akt2 double knockout mice (MAktDKO mice), fed a normal chow diet, showed higher plasma glucose levels in the fed state. Among the various responses to feeding, the liver of MAktDKO mice did not show the repressed gluconeogenic gene expression in response to feeding. As this was also mimicked in mice treated with multiple antibiotics to eradicate the intestinal flora, lipopolysaccharide (LPS), which increases in the blood after feeding may play a role in this context. Among genes Akt dependently induced by LPS, IL-10 was induced in 72 hours when stimulated by LPS alone, but this induction was markedly shortened to 3 hours when also stimulated by insulin. Elevations of plasma concentrations of IL-10 could be detected in the portal vein after feeding, and such concentrations of IL-10 augmented suppression of gluconeogenic gene expression in primary hepatocytes by physiologically detected levels of insulin. Deficient suppression of gluconeogenic gene expression in these mice was rescued when mTOR signaling was strengthened by deletion of TSC2, implicating an important role of Akt-mTOR signaling in the feeding response. Moreover, mice injected with adenovirus expressing short hairpin RNA targeting the IL-10 receptor showed deficient suppression of post prandial gluconeogenic gene expression, in support of a model in which macrophages respond to postprandial signals, regulating glucose homeostasis in the liver by expressing IL-10 in an Akt-mTOR dependent process. Disclosure G. Toda: None. N. Kamei: None. K. Soeda: None. Y. Masuda: None. Y. Izumida: None. N. Kobayashi: None. T. Sasako: None. K. Tobe: Research Support; Self; Bristol-Myers Squibb Company, Takeda Pharmaceutical Company, Teijin Pharma Limited, Japan Diabetes Society, Eli Lilly and Company, MSD K.K., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Astellas Parma Inc, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Tsumura Co., Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., Sumitomo Dainippon Pharma Co. M.J. Birnbaum: None. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S. K. Ueki: Speaker's Bureau; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., MSD K.K., Novo Nordisk Inc., Mitsubishi Tanabe Pharma Corporation, Kyowa Hakko Kirin Co., Ltd., Takeda. Research Support; Self; Takeda, Astellas, Novo Nordisk Inc..

Effects of Dietary Instructions Including Meal-Sequence for Prediabetes Subjects—Comparison with Conventional Approach

Aims: In addition to total energy intake and nutritional balance, meal-sequence is an emerging focus in dietary instructions for individuals with diabetes. However, the effectiveness of dietary instructions including meal-sequence among prediabetes subjects awaits investigation. Methods: The experiment was a multi-center, open label, cluster randomized trial. Prediabetes subjects received conventional dietary instructions (Group A) or dietary instructions including meal-sequence (Group B) after randomization and were monitored for their observance of the designated dietary instructions by public nurses through e-mail every month. Before and 6 months after dietary instructions, the subjects received physical and blood examinations as well as food frequency questionnaires. Results: A total of 29 prediabetes subjects completed the study. Bodyweight was reduced in Group B, along with reduced total energy and fat intake 6 months after dietary instructions. Visceral fat was reduced in both groups, while FPG was reduced only in Group B. HbA1c and 1, 5-anhydroglucitol were largely unchanged in both groups. Conclusion: The current findings show that dietary instructions including meal-sequence are more effective than conventional instructions in reducing bodyweight among prediabetes subjects.Changes of selected outcome measures (*, p<0.05 vs. Group A; #, p<0.05 vs. 0 month)Group A (n=11)Group B (n=18)0 month6 monthDelta0 month6 monthDeltaBMI (kg/m2)25.6±0.3925.9±0.500.32±0.1626.1±0.5926.0±0.74-0.17±0.15*Bodyweight (Kg)75.7±1.576.6±1.60.90±0.4879.7±2.279.2±2.1-0.53±0.48*Visceral fat area (cm2)153.5±5.5140.9±9.0-12.6±5.4#159.2±7.0149.5±5.8-9.7±4.1#Fasting plasma glucose (mg/dL)111.0±4.9107.4±5.5-3.6±2.4115.6±2.3109.3±2.9-6.3±1.9#HbA1c (%)6.00±0.176.07±0.150.07±0.075.94±0.085.99±0.080.05±0.041, 5-anhydroglucitol (µg/mL)21.84±2.8320.71±2.74-1.13±0.5220.59±2.2020.42±2.29-0.17±0.34 Disclosure D. Yabe: Speaker's Bureau; Self; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd.. Research Support; Self; Nippon Boehringer Ingelheim Co. Ltd., Eli Lilly and Company, MSD K.K., Ono Pharmaceutical Co., Ltd., Arkray, Inc., Taisho Toyama Pharmaceutical Co., Ltd., Novo Vordisk Pharma Ltd., Takeda Pharamaceutical Co., Ltd.. H. Kuwata: None. Y. Fujiwara: None. K. Murotani: None. S. Ito: None. H. Asano: None. H. Mishima: Employee; Self; Kansai Electric Power Co.,Inc. H. Takase: Employee; Self; Kao Corporation. N. Oota: Employee; Self; Kao Corporation. Y. Seino: None. Y. Hamamoto: None. T. Kurose: Consultant; Self; Sanofi, Ono Pharmaceutical Co., Ltd.. Other Relationship; Self; Abbott. Consultant; Self; Taisho Pharmaceutical Co., Ltd.. Other Relationship; Self; Takeda Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Novartis Pharma K.K. Y. Seino: Speaker's Bureau; Self; MSD K.K., Kao Corporation, Taisho Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Taisho Toyama Pharamceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Nippon Becton Dickinson Co., Ltd., Novo Nordisk Pharma Ltd.. Research Support; Self; Terumo Medical Corporation, Bayer Yakuhin, Ltd., Boehringer Ingelheim GmbH, Arkray, Inc., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Novo Nordisk Pharma Ltd..

Deterioration of HbA1c-Lowering Effects in Dipeptidyl-Peptidase Inhibitor and Dietary Habits in Japanese Type 2 Diabetes—Comparison with That of Metformin

Aims: This study was designed to assess the possible relationship between deterioration of HbA1c-lowering effects with dipeptidyl peptidase-4 inhibitor (DPP-4i) or metformin (MET) treatment and macronutrient intake among patients with type 2 diabetes. Methods: Medical records of individuals visiting Kansai Electric Power Hospital during the period between September 20and June 2017 were retrospectively analyzed, based on predefined criteria, for initiation and continuation of DPP-4i or MET without any prescription change as well as HbA1c, bodyweight and macro-nutrient intake. Identified patients were stratified into two groups based on changes in HbA1c from 0.5 to 1 year (δHbA1c [1-0.5 year]) as previously described: Group A, patients whose HbA1c was maintained 1 year after initiation of DPP-4i or MET (δHbA1c [1-0.5 year] <0.4%), and group B, patients whose HbA1c was increased (δHbA1c [1-0.5 year] ≥0.4%). Results: Screening of 65,323 individuals’ medical records identified 63 DPP-4i patients (Groups A and B: n=53 and 10; age 65.2±1.6 and 58.2±4.2 years; BMI 24.6±1.6 and 25.3±1.2 kg/m2) and 35 MET patients (Groups A and B: n=27 and 8; age 52.6±11.7 and 53.9±2.4 years; BMI 30.7±7.4 and 30.2±2.7 kg/m2). In the DPP-4i patients, group B had significantly higher total energy intake and fat intake while the two groups had similar carbohydrate and protein intake. Group B also had significantly higher intake of saturated and monounsaturated fats but not polyunsaturated fats. A stepwise multiple regression analysis showed that δHbA1c (1-0.5 year) was independently correlated with saturated fat intake (B=0.032, SE=0.010, p< 0.01). In the MET patients, the two groups had similar intake of total energy, carbohydrate, protein and fat. Conclusion: The current findings show a novel association between deterioration of the HbA1c-lowering effects in DPP-4i-treated, but not in MET-treated patients, and dietary saturated fat intake. Disclosure S. Okamoto: None. H. Kuwata: None. D. Yabe: Speaker's Bureau; Self; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd.. Research Support; Self; Nippon Boehringer Ingelheim Co. Ltd., Eli Lilly and Company, MSD K.K., Ono Pharmaceutical Co., Ltd., Arkray, Inc., Taisho Toyama Pharmaceutical Co., Ltd., Novo Vordisk Pharma Ltd., Takeda Pharamaceutical Co., Ltd.. K. Murotani: None. Y. Seino: None. R. Usui: None. H. Tatsuoka: None. Y. Hamamoto: None. T. Kurose: Consultant; Self; Sanofi, Ono Pharmaceutical Co., Ltd.. Other Relationship; Self; Abbott. Consultant; Self; Taisho Pharmaceutical Co., Ltd.. Other Relationship; Self; Takeda Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Novartis Pharma K.K. Y. Seino: Speaker's Bureau; Self; MSD K.K., Kao Corporation, Taisho Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Taisho Toyama Pharamceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Nippon Becton Dickinson Co., Ltd., Novo Nordisk Pharma Ltd.. Research Support; Self; Terumo Medical Corporation, Bayer Yakuhin, Ltd., Boehringer Ingelheim GmbH, Arkray, Inc., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Novo Nordisk Pharma Ltd..

Ipragliflozin, a SGLT2 Inhibitor, Reduced Body Weight and Fat Mass but Not Muscle Mass in Japanese Type 2 Diabetic Patients Treated with Insulin—A Randomized Clinical Trial

Objective: Weight gain is a common problem in the insulin treatment. SGLT2 inhibitors are expected to reduce body weight (BW) due to negative energy balance. Previous reports suggested that BW reduction is achieved mainly by loss of body fat, and ∼20% of reduction is by lean mass. However, the efficacy of SGLT2 inhibitor on BW and body composition remains unclear. We examined these in the Japanese T2DM treated with insulin. Methods: The study was an open label randomized controlled trial. Primary endpoint was the change in BW from baseline to week 24 between the two groups. Fifty overweight patients (BMI > 23) who had inadequate glycemic control with insulin treatment were randomly assigned to ipragliflozin (Ipra) or standard treatment (Con) and followed for 24 weeks. Body composition was assessed by DEXA and impedance method. Results: The change in BW was significantly larger in Ipra compared to Con. Ipra showed significant larger reduction of HbA1c. Total fat mass was reduced in the Ipra compared to Con mainly due to lower limb fat and trunk fat. Total muscle mass was maintained at lower limbs and trunk but tended to be reduced at arm in Ipra. Conclusion: Ipragliflozin treatment for 24 weeks resulted in reduction of BW mainly due to fat mass at lower limb and trunk. Reduction of the muscle mass at lower limb may be protected by anti-gravity effect. Disclosure K. Morino: Research Support; Self; Astellas Pharma US, Inc., AstraZeneca, Sunstar Inc., CMIC Pharmascience, Kowa Pharmaceutical. H. Inoue: None. K. Fuse: None. S. Tanaka: None. K. Kondo: None. H. Arima: Advisory Panel; Self; Kyowa Kirin. Speaker's Bureau; Self; Takeda Japan, Daiichi Sankyo Company, Limited. K. Miura: None. D. Sato: None. N. Ohashi: None. S. Ida: None. I. Miyazawa: None. O. Sekine: None. S. Ugi: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., MSD K.K. H. Maegawa: Speaker's Bureau; Self; Astellas Pharma US, Inc.. Research Support; Self; Astellas Pharma US, Inc.. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Nippon Boehringer Ingelheim Co. Ltd.. Research Support; Self; Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Daiichi Sankyo Company, Limited, Takeda Pharmaceutical Company. Speaker's Bureau; Self; Takeda Pharmaceutical Company, Novo Nordisk A/S, Eli Lilly and Company.

Sodium-Glucose Cotransporter 2 Inhibitors for Type 1 Diabetes Mellitus—Systematic Review and Meta-analysis

Additional treatment for type 1 diabetes is an unmet need. We investigated the efficacy and safety of adding Sodium-glucose co-transporter 2 inhibitors (SGLT2is) to insulin in patients with type 1 diabetes mellitus by performing meta-analysis. Prospective randomized, placebo-controlled trials investigating insulin and SGLT2is in adults with type 1 diabetes were assessed. We searched electronic databases up to November 2017. Meta-analysis was performed by a random effects model. Two reviewers independently extracted information and evaluated study quality with the Cochrane risk-of-bias tool. Among about 1300 studies identified, 14 studies were investigated (N=4,591). Meta-analysis revealed that SGLT2i therapy significantly reduced HbA1c by 0.4% (95% confidence interval [CI]: 0.35, 0.46; P<0.001; I2=0%), fasting plasma glucose by 1.14 mmol/l (0.8,1.47), body weight by 2.68 kg (2.0, 3.36), and systolic blood pressure by 3.37 mmHg (1.46, 5.28). In addition, the total daily insulin dose decreased by 6.0 units (4.9, 7.1), bolus insulin decreased by 3.6 units/day (2.0, 5.3), and basal insulin decreased by 4.2 units/day (2.2, 6.3). There was no significant increase of hypoglycemia or severe hypoglycemia. However, SGLT2i therapy increased diabetic ketoacidosis [OR: 3.38 (1.74, 6.56)] and genital tract infection [OR: 3.44 (2.34, 5.07)]. In summary, SGLT2i therapy might be advantageous for type 1 diabetes. However, use of this combination should be considered carefully. Disclosure T. Yamada: None. J. Hosoe: None. N. Shojima: None. T. Yamauchi: Research Support; Self; Novo Nordisk Inc., Daiichi Sankyo Company, Limited, Sanofi, Takeda, Tanabe-Mitsubishi. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.

NFIA Colocalizes with PPARgamma and Activates the Cell-Type–Specific Enhancers to Control the Brown Fat Gene Program

Brown fat dissipates energy as heat by means of the uncoupling protein-1 (UCP1) on the mitochondrial inner membrane. Brown fat activity is inversely correlated with body mass index in humans, and pilot studies have shown that interventions such as chronic cold exposure successfully recruit human brown fat and increase systemic energy expenditure. Therefore, stimulating development and/or function of brown fat would be a novel strategy for the treatment of obesity and its complications. Here, we identified nuclear factor I-A (NFIA) as a transcriptional regulator of brown fat by a genome-wide open chromatin analysis of murine brown and white fat followed by motif analysis of the brown-fat-specific open chromatin regions. Introduction of NFIA into myoblasts results in brown adipocyte differentiation. Conversely, the brown fat of NFIA knockout mice displays impaired expression of the brown-fat-specific genes and reciprocal elevation of muscle genes. In human brown fat, expression of NFIA and the brown-fat-specific genes including UCP1 is positively correlated. Mechanistically, NFIA co-localizes with the master transcriptional regulator of adipogenesis, PPARgamma, selectively at the brown-fat-specific enhancers. Moreover, the binding of NFIA precedes and facilitates the binding of PPARgamma, leading to increased chromatin accessibility and active transcription. Most recently, we performed mass spectrometry analysis of NFIA protein complex to identify and characterize the crucial partner of NFIA-dependent brown-fat-specific chromatin regulation. Collectively, these results indicate that NFIA is a key transcription factor that activates the cell-type-specific enhancers and facilitates the binding of PPARgamma for controlling the brown fat gene program. Disclosure Y. Hiraike: Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S, Mitsubishi Tanabe Pharma Corporation. H. Waki: Research Support; Self; MSD K.K., Novartis Pharma K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi K.K., Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Takeda PHarmaceutical Co., Ltd.. S. Tsutsumi: None. H. Aburatani: None. T. Yamauchi: Research Support; Self; Novo Nordisk Inc., Daiichi Sankyo Company, Limited, Sanofi, Takeda, Tanabe-Mitsubishi. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.

Total Energy Expenditure Evaluated by Doubly Labeled Water Method in Japanese Patients with Diabetes Mellitus—Clinical Evaluation of Energy Requirements in Patients with Diabetes Mellitus (CLEVER-DM) Study

Background and Aim: Assessment of total energy expenditure (TEE) is essential for recommendations for dietary intakes and physical activity in patients with diabetes mellitus as well as healthy people. However, few reports have shown TEE in patients with diabetes, particularly in Asian countries. Therefore, we evaluated accurate TEE by doubly labeled water (DLW) and physical activity level (PAL) in Japanese patients with diabetes mellitus. Methods: We planned to recruit sixty patients with type 2 diabetes and sex- and age-matched twenty nondiabetic subjects as the CLEVER-DM Study at a single university hospital. The current presentation is a part of this study with forty-one patients with type 2 diabetes (DM, 69.9 years, men/women: 23/18) and nine patients without DM (non-DM, 67.2 years, men/women: 2/7). TEE was measured over 14 days by DLW method and PAL was calculated as TEE divided by resting energy expenditure assessed by indirect calorimetry. Results: The numbers of DM patients treated with insulin, oral hypoglycemic agents, and diet/exercise were 13 (31.7%), 20 (48.8%), and 8 (19.5%), respectively. Mean (standard deviation [SD]) level of HbA1c was 6.9 (0.8)% for DM and 5.5 (0.4)% for non-DM (p<0.001). Mean (SD) body mass index was 23.2 (2.9) kg/m2 for DM and 23.1 (1.9) kg/m2 for non-DM. After adjusted for sex, age, fat-free mass, and fat mass, mean TEE was 2150 kcal/day for DM, and 2067 kcal/day for non-DM, and there was no significant difference between two groups, although DM tended to have a higher value (mean difference: 83 kcal/day, 95% confidential interval [CI]: -101 to 267 kcal/day). Mean PAL adjusted for sex and age was 1.68 for DM and 1.63 for non-DM, showing no statistical differences (mean difference: 0.04, 95% CI: -0.07 to 0.15). Conclusion: TEE was comparable between DM and non-DM groups among Japanese. Disclosure K. Kondo: None. K. Morino: Research Support; Self; Astellas Pharma US, Inc., AstraZeneca, Sunstar Inc., CMIC Pharmascience, Kowa Pharmaceutical. S. Tanaka: None. K. Fuse: None. A. Ohi: None. M. Kurihara: None. M. Sasaki: Other Relationship; Spouse/Partner; Terumo, Nestle Japan. F. Katsukawa: Speaker's Bureau; Self; Merck Sharp & Dohme Corp., Sanofi, Astellas Pharma US, Inc. H. Maegawa: Speaker's Bureau; Self; Astellas Pharma US, Inc.. Research Support; Self; Astellas Pharma US, Inc.. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Nippon Boehringer Ingelheim Co. Ltd.. Research Support; Self; Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Daiichi Sankyo Company, Limited, Takeda Pharmaceutical Company. Speaker's Bureau; Self; Takeda Pharmaceutical Company, Novo Nordisk A/S, Eli Lilly and Company.

Human Brown Adipose Tissue Density Assessed by Near-Infrared Time-Resolved Spectroscopy Inversely Correlates with the Body Mass Index in Patients with Type 2 Diabetes

Background: Near-infrared time-resolved spectroscopy is a non-invasive method that facilitates analysis of human brown adipose tissue (BAT) density. We measured BAT density in middle-aged patients who had type 2 diabetes by this method and examined the relationship using clinical parameters. Methods: We studied 33 Japanese middle-aged diabetic patients (30 male and 3 female, age 53.8±10.1 years, BMI 25.4±4.5, and HbA1c 7.2±1.1%). Tissue hemoglobin concentration (tHb) of the supraclavicular region was measured using near-infrared time-resolved spectroscopy, and normalized by subcutaneous fat thickness at the measurement sites. Results: The average tHb concentration was 51.1±17.7 μM and lower than 77.8 μM—the value equivalent to the detection threshold of BAT by standard FDG-PET in young adults. Univariate regression analysis showed that the tHb of the supraclavicular region was inversely correlated with BMI (r = −0.55, p=0.0009), but the tHb of the deltoid region was not (r = 0.04, p = 0.31). Other parameters showing significant correlations with BAT mass included systolic blood pressure (r = −0.47, p = 0.01) and insulin treatment (r=0.45, p=0.01). Multivariate regression analysis suggested that BMI (β=−0.42, p=0.005), systolic blood pressure (β=−0.29, p=0.042), and insulin treatment (β=0.34, p=0.015) independently account for BAT density. Conclusion: Our findings suggest that BAT density in middle-aged diabetic patients may relate to obesity more closely than previously thought. Disclosure H. Waki: Research Support; Self; MSD K.K., Novartis Pharma K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi K.K., Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Takeda PHarmaceutical Co., Ltd.. N. Watanabe: None. S. Fuse: None. Y. Kurosawa: None. T. Yamauchi: Research Support; Self; Novo Nordisk Inc., Daiichi Sankyo Company, Limited, Sanofi, Takeda, Tanabe-Mitsubishi. R. Kime: None. T. Hamaoka: None. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.

The Ratio of Liver to Spleen (L/S Ratio) for CT Attenuation Value Is Associated with the Onset of Diabetes Mellitus in a Community-Based Sample of Japanese Men—The Shiga Epidemiological Study of Subclinical Atherosclerosis (SESSA)

Background and Aim: Fatty liver is reported to be associated with type 2 diabetes mellitus. Most of the previous studies are cross-sectional and liver fat was evaluated using ultrasound echography or plasma levels of liver enzyme. We assessed liver fat content in a semi-quantitative method using computed tomographic (CT) images and verified the hypothesis that the L/S ratio for CT attenuation value was associated with the onset of diabetes in longitudinal observational cohort study of Japanese men. Methods: Participants were randomly selected men from Kusatsu City, Japan. We analyzed 622 participants (63.5±9.9 years) without diabetes at baseline. We calculated odds ratio (OR) and 95% confidence interval (CI) of the presence of fatty liver (defined by L/S ratio<1.0) and per 1 standard deviation (SD) decrease in L/S ratio for the development of diabetes, using logistic regression model. Adjustments were age, family history of diabetes, smoking pack year, alcohol consumption, step count and BMI. We added stratified analysis at BMI 25 kg/m². Diabetes was diagnosed as follows; HbA1c ≥6.5% or fasting plasma glucose ≥126 mg/dL or taking diabetes medication. Results: During 5.1±1.4 years of follow-up period, 36 participants (5.8%) developed diabetes. Although the presence of fatty liver was not significantly associated with the development of diabetes (OR 1.77, 95% CI 0.81-3.85), OR for those of per 1 SD (0.18) decrease in L/S ratio was 1.40 (95% CI 1.02-1.92). We still found the significant results that L/S ratio was associated with the development of diabetes in the stratified analysis. Conclusions: The ratio of liver to spleen for CT attenuation value was associated with the development of diabetes during 5 years regardless of BMI in Japanese community-based study. Disclosure K. Fuse: None. A. Kadota: None. K. Kondo: None. A. Fujiyoshi: None. T. Hisamatsu: None. S. Kadowaki: None. I. Miyazawa: None. K. Morino: Research Support; Self; Astellas Pharma US, Inc., AstraZeneca, Sunstar Inc., CMIC Pharmascience, Kowa Pharmaceutical. O. Sekine: None. S. Ugi: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., MSD K.K. H. Maegawa: Speaker's Bureau; Self; Astellas Pharma US, Inc.. Research Support; Self; Astellas Pharma US, Inc.. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Nippon Boehringer Ingelheim Co. Ltd.. Research Support; Self; Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Daiichi Sankyo Company, Limited, Takeda Pharmaceutical Company. Speaker's Bureau; Self; Takeda Pharmaceutical Company, Novo Nordisk A/S, Eli Lilly and Company. K. Miura: None. H. Ueshima: None.

MiR-494 Regulates Mitochondrial Biogenesis and Thermogenesis through PGC1-α Signaling in Beige Adipocytes

Background: Mitochondria play an essential role in the heat generation in beige adipocytes. Their number and function are regulated in response to external stimuli such as cold exposure and beta-3 adrenergic receptor (β3-AR) agonist. Previously, we have reported that miR-494 regulates mitochondrial biogenesis in the skeletal muscle. However, this remains unknown in beige adipocytes. Aim: We investigated the role of miR-494 on mitochondrial biogenesis during adipogenesis and browning. Result: C57BL/6J mice were subjected to intermittent mild cold exposure. The expression levels of peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC1-α) and mitochondrial proteins including mitochondrial transcription factor A (TFAM), pyruvate dehydrogenase (PDH), mitochondrially encoded cytochrome c oxidase (MTCO1) and uncoupling protein 1 (Ucp1) were strongly increased in inguinal white adipose tissue (iWAT). On the contrary, that of miR-494 resulted in 27% reduction (p < 0.05) in iWAT following 12°C cold exposure for 6 hours. Furthermore, β3-AR stimulation potently reduced miR-494 expression in 3T3-L1 beige cells. Overexpression of miR-494 substantially reduced the protein expression of PGC1-α and its downstream targets such asTFAM and MTCO1 (p < 0.05). In contrast, antisense of miR-494 significantly increased the expression of TFAM, MTCO1 and PDH (p < 0.05). Overexpression of miR-494 strongly decreased the oxygen consumption rate in 3T3-L1 beige cells and protein expression of PGC1-α and Ucp1 (p < 0.05) in primary beige adipocytes. Finally, we explored the direct target of miR-494 and found that 3`UTR region of PGC1-α is a direct target of miR-494 by luciferase assay. Conclusion: These findings demonstrate that miR-494 directly inhibits the expression of PGC1-α in adipose tissue. The decreased miR-494 expression during adipocyte differentiation removes its inhibitory effect, leading to stimulation of Ucp1 expression and mitochondrial biogenesis. Disclosure M. Lemecha: None. K. Morino: Research Support; Self; Astellas Pharma US, Inc., AstraZeneca, Sunstar Inc., CMIC Pharmascience, Kowa Pharmaceutical. T. Imamura: None. H. Iwasaki: None. N. Ohashi: None. H. Yamamoto: None. S. Ugi: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., MSD K.K. H. Maegawa: Speaker's Bureau; Self; Astellas Pharma US, Inc.. Research Support; Self; Astellas Pharma US, Inc.. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Nippon Boehringer Ingelheim Co. Ltd.. Research Support; Self; Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Daiichi Sankyo Company, Limited, Takeda Pharmaceutical Company. Speaker's Bureau; Self; Takeda Pharmaceutical Company, Novo Nordisk A/S, Eli Lilly and Company.

Study of the Correlation between Tear Glucose Concentrations and Blood Glucose Concentrations

To achieve intensive glucose control for avoiding diabetic complications, it is necessary for diabetic patients to measure their blood glucose levels frequently. However, all currently available methods for blood glucose monitoring, including the finger prick method, are invasive. One of the possible noninvasive glucose monitoring approaches is tear glucose monitoring. Previous studies have showed the correlations between blood and tear glucose concentrations. But these correlations were not accurate sufficiently because the methods for tear sample collection were not standardized. For clinical development of tear glucose monitoring as a tool for predicting the blood glucose concentrations, we recruited 10 nondiabetic subjects and 20 diabetic subjects, observed the daily blood and tear glucose dynamics using samples collected under the standardized method, and determined the correlation between the blood and tear glucose concentrations. Preprandial blood glucose levels of diabetic subjects were significantly higher than those of nondiabetic subjects (p < 0.001), and preprandial tear glucose levels of diabetic subjects had a higher tendency than those of nondiabetic subjects (p = 0.051). Two hours postprandial blood and tear glucose levels of diabetic subjects were significantly higher than those of nondiabetic subjects (p < 0.001, p < 0.05, respectively). The blood and tear glucose dynamics showed that the behavior of the tear glucose concentrations paralleled that of the blood glucose concentrations. A linear mixed model for diabetic subjects revealed the existence of a significant association between the blood glucose concentrations and tear glucose concentrations (p < 0.001), and the association consisted even after adjusting for HbA1c levels and conditions of meals. In conclusion, tear glucose monitoring would be a tool for predicting the blood glucose levels noninvasively for various diabetic patients. Disclosure M. Aihara: None. N. Kubota: None. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.