bluuebunny/crossref_metadata_2025_split huggingface dataset:
734-P: Cellular Internalization and Localization of Once-Weekly Basal Insulin Fc (BIF)
Authors: VOLK CATHERINE , ZHANG CHEN , MOYERS JULIE S. 
Published: June 2021

Basal Insulin Fc (BIF, LY3209590) is an insulin Fc-fusion protein in clinical testing as a once weekly treatment for diabetes mellitus. BIF is comprised of a human single-chain insulin fused to a human IgG2 Fc domain through a peptide linker. The cellular internalization characteristics of BIF compared to native insulin using U2OS cells expressing human insulin receptor (hIR) are reported in this work. Internalization and sub-cellular localization were visualized by immuno-fluorescent confocal microscopy in U2OS cells expressing human insulin receptor. Internalization of BIF was observed, and the insulin and Fc moieties remained co-localized. Co-localization studies using an antibody to the early endosomal marker Early Endosome Antigen 1 (EEA1) showed that human insulin and BIF (insulin and Fc moieties) were rapidly internalized and co-localized with EEA1. During ligand washout, the remaining insulin and Fc moieties of BIF remained largely co-localized with EEA1 and a concomitant loss of immunostaining was observed, similar to human insulin. Studies using an antibody to the lysosomal marker Lysosomal Associated Membrane Protein-1 (LAMP-1) revealed a low level of lysosomal localization for human insulin and BIF (insulin and Fc moieties), indicating a similar intracellular trafficking pattern of human insulin and BIF to the lysosomal degradative pathway. The co-localization of remaining ligand decreased over time. IR internalization and transport to early endosomes was measured using an enzyme complementation assay. The EC50 for BIF was 4.7 ± 2.1 nM (n = 3), and the EC50 for human insulin was 0.06 ± 0.01 nM (n = 3).
In summary, BIF stimulated IR internalization to a similar maximum level; however, with decreased potency versus human insulin. The subcellular trafficking pattern of BIF is similar to human insulin. BIF undergoes rapid internalization and transport to early endosomes with limited transport to the lysosomes and undergoes loss of cellular immunostaining during ligand washout.

Disclosure
C. Volk: None. C. Zhang: Employee; Self; Eli Lilly and Company. J. S. Moyers: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company.

Funding
Eli Lilly and Company
771-P: The Effect of Adding Acarbose to Insulin Therapy in Type 1 Diabetes Mellitus: A Systematic Review and Meta-analysis
Authors: LIU ZHIGU , YANG DAIZHI , XU WEN , LV JING , LIN HUIMIN , LIU ZIYU , DENG HONGRONG , YAN JINHUA , YAO BIN 
Published: June 2021

Objective: Acarbose is proved to improve glucose control and glucose variability in T2DM. However, few studies focused on the effect of acarbose in T1DM. We hereby evaluated the efficacy and safety of adding acarbose to insulin in T1DM.
Methods: A literature search on PubMed/Medline, Web of Science, Cochrane Library, Embase, Clinicaltrails.gov, CNKI, Wanfang Database and VIP Database for articles published before November 30, 2020 was performed to identify randomized controlled trials (RCTs) that investigated the efficacy of acarbose adding to insulin therapy among T1DM patients. Statistical analyses were performed by using Revman 5.3.
Results: A total of 7 RCTs with 517 patients were included. The age of participants was 18 to 65 years, and the intervention duration ranged from 7 to 24 weeks. Compared with placebo, the addition of acarbose resulted in decreased HbA1c (SMD= -0.27%, 95% CI: -1.17%~ -0.63%), mean blood glucose (SMD= -1.88 mmol/L, 95% CI: -2.75~ -1.01 mmol/L), fasting plasma blood glucose (FBG, SMD= -0.98 mmol/L, 95% CI: -3.32~ -0.63 mmol/L), 2h postprandial blood glucose (PPG, SMD= -2.65 mmol/L, 95% CI: -3.58~ -1.71 mmol/L), total daily insulin dose (SMD= -0.34 U, 95% CI: -0.52~ -0.15 U), and improved glucose variability parameters including MAGE (SMD= -1.42 mmol/L, 95% CI: -2.27~ -0.57 mmol/L) and the LAGE (SMD= -1.36 mmol/L, 95% CI: -2.41~ -0.30 mmol/L). The change of body weight and lipid profiles were similar between the two groups. In terms of adverse events, acarbose increased the risk of gastrointestinal complaints (OR= 1.80, 95% CI: 1.52~ 2.13), while the occurrence of hypoglycemia was similar (SMD= -0.93, 95% CI: -2.60~0.74).
Conclusion: The addition of acarbose to insulin could improve overall glucose control in T1DM patients, including HbA1c, mean blood glucose, FBG, PPG, and glucose variability as well. However, gastrointestinal adverse effects should be considered although acarbose did not increase the risk of hypoglycemia in this population.

Disclosure
Z. Liu: None. D. Yang: None. W. Xu: None. J. Lv: None. H. Lin: None. Z. Liu: None. H. Deng: None. J. Yan: None. B. Yao: None.

Funding
National Key Research and Development Project of China (2017YFC1309602)
777-P: Efficacy of SGLT2 Inhibitors and GLP1-Receptor Agonists in Asians with Type 2 Diabetes: A Systemic Review and Meta-analysis
Authors: JOHNSON RYAN , FRANCO MELISSA , STAAB ERIN M. , KNITTER ALEXANDRA C. , WAN WEN , ALEXANDER JASON , LAITEERAPONG NEDA 
Published: June 2021

Background: Clinical trials of SGLT2Is and GLP1RAs have shown improved outcomes in patients with type 2 diabetes, but comprehensive data of their effectiveness in the Asian subpopulation are lacking. A systematic review and meta-analysis of clinical trials evaluating SGLT2Is and GLP1RAs was conducted to assess their efficacy in Asians with type 2 diabetes.
Methods: PubMed, Scopus, and clinicaltrials.gov were searched from inception to July 2019 for randomized controlled trials (≥52 weeks) that enrolled Asians with type 2 diabetes and reported outcome data for SGLT2Is or GLP1RAs compared to placebo or other diabetic medications. Using random effect models, binary outcomes were evaluated with relative risks (RR) and continuous outcomes were evaluated with standardized mean differences (MD).
Results: The analysis included 9 trials for SGLT2Is and 11 trials for GLP1RAs. Compared to placebo, SGLT2Is reduced HbA1c (MD: -0.70%, 95% CI: -1.29% to -0.10%) and weight (MD: -1.52 kg, -2.08 to -0.96 kg); compared to other diabetic medications, SGLT2Is reduced systolic blood pressure (MD: -6.42 mmHg, -9.43 to -3.41 mmHg). Compared to placebo, SGLT2Is increased the risk of genital infection (RR: 2.51, 1.01 to 6.21) but reduced the risk for renal events (RR: 0.69, 0.57 to 0.84). GLP1RAs were associated with lower HbA1c (MD: -0.65%, -1.07% to -0.22%) and weight (MD: -2.06 kg, -3.20 to -0.93 kg) when compared to other diabetic medications. GLP1RAs also reduced major cardiovascular events compared to placebo (RR: 0.72, 0.59 to 0.89). Data were not available for comparisons between GLP1RAs and placebo for other outcomes. Neither SGLT2Is or GLP1RAs had sufficient evidence to suggest their use was associated with a change in all-cause mortality.
Conclusion: In the Asian subpopulation, clinical trials provide evidence for a reduction in cardiovascular risk factors and some diabetes-related adverse events by SGLT2Is and GLP1RAs.

Disclosure
R. Johnson: None. M. Franco: None. E. M. Staab: None. A. C. Knitter: None. W. Wan: None. J. Alexander: None. N. Laiteerapong: Other Relationship; Self; American Diabetes Association.

Funding
American Diabetes Association (1-18-JDF-037 to N.L.)
781-P: Beyond Glucosuria: Urine Metabolome Signature Associated with Dapagliflozin in Wild-Type Mice
Authors: ILAIWY AMRO , MINCEY ADAM , BAIN JAMES R. , MUEHLBAUER MICHAEL , CAMPBELL JONATHAN , D’ALESSIO DAVID A. 
Published: June 2021

Background: Glucosuria is a hallmark feature of diabetes. When blood glucose exceeds 200 mg/dl, the amounts reaching the renal tubule overwhelm the capacity of glucose transport and cause glucosuria. SGLT2 inhibitors (SGLT2i) prevent reclamation of glucose from the renal filtrate, leading to glucosuria as well. While SGLT2i promote weight loss and provide cardiovascular protection, those effects are not explained by their glycosuric effect.
Hypothesis:Factors initiated by SGLT-2 blockade lead to excretion of substrates other than glucose, thus creating a unique signature of urine metabolome in SGLT2i-treated mice that may help identify renal responses to SGLT2 inhibition and correspond with system-wide beneficial effects.
Methods: To study SGLT2i effects on the urine metabolome, we used C57BL/6 age-matched male mice. Mice were fasted for three hours and then given either Dapagliflozin (Dapa) or PBS via oral gavage. Capillary glucose was checked prior to gavage. Five hours later, capillary glucose levels were checked again and urine samples were collected for untargeted metabolomics.
Results: Dapa reduced post-gavage glucose by an average Δ of 62.5 mg/dl (p=0.0001). No significant reduction was noted in glucose in the PBS group (Δ=9.2 mg/dl, p=0.52). Glucose was present in the urine of all mice treated with Dapa. Dapa treatment was associated with a unique signature of urine metabolome, with 17 metabolites significantly altered compared to control (P&lt;0.05). While hyperoxaluria has been linked to progression of CKD, mice treated with Dapa had lower level of Oxaluria. Enrichment analysis identified metabolism of Phenylalanine and unsaturated fatty acids to be most affected.
Conclusion: Dapa is associated with excretion of metabolites other than glucose that generates a unique signature of urinary metabolome. Identification of renal response to SGLT2i may help further understand mechanisms of cardiovascular protection and weight loss mediated by SGLT2i.

Disclosure
A. Ilaiwy: None. A. Mincey: None. J. R. Bain: None. M. Muehlbauer: None. J. Campbell: None. D. A. D'alessio: Advisory Panel; Self; Eli Lilly and Company, Sun Pharmaceutical Industries Ltd., Research Support; Self; Eli Lilly and Company, Merck & Co., Inc.

Funding
Endocrine Fellows Foundation (5T32DK007012); National Institute of Diabetes and Digestive and Kidney Diseases
784-P: Does Sacubitril/Valsartan Combination Therapy Provide Additional Renal Benefits in Type 2 Diabetes Mellitus Receiving Canagliflozin?
Authors: GUPTA VISHAL , TELI VAISHALI 
Published: June 2021

Aim: Study the effect of Sacubitril/valsartan (SV) combination therapy on renal functions in T2DM receiving canagliflozin (C).
Methodology: Between July and Sept 2018, T2DM patients aged 18-75 yrs, irrespective of baseline A1c, receiving SVC or C were retrospectively identified. The use of angiotensin receptor blockers (ARB) was 28.6% in SVC gr and 57% in C gr. Propensity score 1:1 matching was done for gr receiving SVC (49 patients) with C (49 patients) for variables to minimise confounding. Patients were evaluated 3 mthly for cardio-renal biomarkers (BMI, A1c, SBP, DBP, Lipid profile (TC, LDL, TG, HDL), Hs-CRP, Nt-ProBNP, creatinine (Cr), eGFR and microalbumin/creatinine ratio {UACR}) for 1 yr. T2DM with H/O IHD, revasularisation, major surgery, K+&gt;5.5Meq/L and eGFR&lt;45 were excluded. Baseline characteristics were analysed using descriptive statistics. Continuous variables were analysed using paired and unpaired t-test expressed as mean ± standard error. For interaction between drug class, ANOVA was used and p value &lt;0.05 was considered significant (S).
Results: Baseline (B) characters: well matched except for age-yrs (SVC 61.27+9.43 and C 56+9.68, p-0.024) and NT-proBNP-pg/ml (SVC 438.68+758.13 vs. C 58.43+53.475, p-0.001). SVC, B-12mnths - S change in SBP, Hba1c, TC, LDL, TG, UACR and hs-CRP. C, B-12mnths - S change in BMI, SBP, DBP, HbA1c, TC, LDL, TG. SVC Versus C at 12mnths - No S difference seen for BMI-kg/m2 (SVC 0.381+0.297 vs. C 0.934+0.215, P-0.136), S-BP-mm (SVC 8.51+2.62 vs. C 6.429+2.349, p-0.556), D-BP-mm (SVC 2.143+1.582 vs. C 2.959+1.457, p-0.705), A1c-% (SVC 0.644+0.143 vs. C 0.677+0.190, p-0.88), Cr-mg% (SVC -0.009+0.025 vs. C 0.0067+0.0225, p-0.638), eGFR (SVC 1.307+2.388 vs. C 1.554+3.177, p-0.953), UACR mg/gm (SVC 52.876+22.684 vs. C 49.517+39.943, p-0.920), hs-CRP mg/L and Lipid Profile. There was no interaction with use of ARB for eGFR (p-0.074) and UACR (p-0.056).
Conclusion: SV does not provide additional renal benefits in T2DM receiving C.

Disclosure
V. Gupta: None. V. Teli: None.
787-P: Individualized Estimated GFR Slope Analysis Is Needed to Preserve Renal Function by SGLT2 Inhibitors in Patients with DKD
Authors: KASHIMA KOJI , SHIMIZU HIROYUKI , YAMADA MASANOBU 
Published: June 2021

Objective: SGLT2 inhibitor (SGLT2i) should be considered for patients with type 2 diabetes (T2D) with CKD. Since eGFR declining speed is different in each patient, we assessed renal protective effects by individual eGFR slope analysis.
Methods: A total of 75 patients with T2D with advanced CKD stage 3-4, treated by SGLT2i (empagliflozin 65% and others) were analyzed. The duration of diabetes at the time of recruitment were as follows: stage 3a (n=29); 11.9±5.4 yrs, stage 3b (n=28); 19.9±12.1 yrs, and stage 4 (n=18); 13.8±8.5 yrs. The mean of age was 70.3±12.2 yrs old. GLP-1RA (Liraglutide; n=36, Duraglutide; n=1) was used in 41%, 64% and 44% respectively. Most rapid baseline slopes were calculated from 46±20 months before using SGLT2i, and slopes after adding SGLT2i were calculated from 31±9 months.
Results: 1) In total, the initiation of SGLT2i decreased eGFR from 46.1±14.1 to 43.6±13.5ml/min/1.73m2 (P&lt;0.001) on first month. 2) Individualized most rapid slopes were improved from -6.4±9.1 to -1.6±3.3ml/min/1.73m2/year (P&lt;0.001). 3) Slopes were improved in all stages, stage 3a: -4.1±3.7 to -1.1±3.4 (P&lt;0.001) and stage 3b; -4.9±3.7 to -1.6±2.9 (P&lt;0.001), and stage 4; -12.4±16.3 to -2.2±3.7ml/min/1.73m2/year (P&lt;0.03). 3) The proportion of responders (defined as their ratios of slopes are reduced &lt; 1.0 after addition of SGLT2i) in each stage were as follows: stage 3a; (22/29), stage 3b; (22/28), stage 4; (16/18). Slopes in responders (61/75) were improved as follows, -7.4±9.8 to -1.0±2.9ml/min/1.73m2/year (P&lt;0.0001). Slopes in non-responders (14/75) were worsened as follows, -2.0±2.0 to -4.1±3.5ml/min/1.73m2/year (P&lt;0.001). 4) Slopes in rapid decliners (13/75) were remarkably improved from -18.9±16.4 to -1.5±3.6ml/min/1.73m2/year (P&lt;0.01) with combined use of GLP-1RA (11/13), who had macro-albuminuria (9/13) and nephrosis (7/13).
Conclusion: To pursuit the renal benefits of SGLT2i, individualized slope analysis is needed for patient-centered care.

Disclosure
K. Kashima: None. H. Shimizu: None. M. Yamada: None.
794-P: Predictors of Hemoglobin (Hb) and Its Changes Focusing on Anemia and Polycythemia after Administration of the SGLT2 Inhibitor Tofogliflozin
Authors: MATSUBAYASHI YASUHIRO , YOSHIDA AKIHIRO , SUGANAMI HIDEKI , KAKU KOHEI , SONE HIROHITO 
Published: June 2021

SGLT2 inhibitors (SGLT2is) increase hematocrit (Ht) and Hb, which may contribute to correcting anemia but also might cause secondary polycythemia. We investigated predictors of Hb after short- and long-term therapy with tofogliflozin (TOFO), a SGLT2i, and explored its impact on Hb in relation to anemia and polycythemia in type 2 diabetes mellitus (T2DM). Analyzed were 774 T2DM patients (66% male) who received TOFO for 52 weeks in two phase 3 studies. Mean baseline characteristics were age 59 y, HbA1c 8%, BMI 26 kg/m2, hemoglobin 15 g/dL and eGFR 84 mL/min/1.73m2. Participants were divided into the Anemia group (baseline Hb &lt;13 g/dL in men and &lt;12 g/dL in women, mean baseline Hb 11.8 g/dL) and Polycythemia group (&gt;16.5 g/dL in men and &gt;16 g/dL in women, mean baseline Hb 17.2 g/dL). Paired t-tests analyzed differences from baseline to weeks 4 and 52. Generalized linear model explored predictors of Hb at weeks 4 and 52. Correlation analysis was performed by Spearman’s product-moment correlation coefficients. Hb was significantly increased at week 4 [mean, +0.14g/dL*; *p&lt;0.05 vs. baseline] and week 52 (+0.34g/dL*). Higher baseline brain natriuretic peptide and lower Ht and triglycerides (TG) were independently correlated with greater increases in Hb at week 4. Lower baseline Hb and TG were significantly correlated with greater increases in Hb at week 52. Higher baseline TG levels and proportion of fatty liver as a comorbidity were observed with higher baseline Hb values. Hb had significantly changed at week 52 in Anemia (+0.94*) and Polythycemia groups (-0.29*). Change in Hb was significantly correlated with change in TG at week 52 (Rho=0.42, p&lt;0.05) in Polycythemia but not Anemia. Increased Hb after short-term TOFO therapy may be due to hemoconcentration while Hb may be corrected according to baseline Hb levels after long-term TOFO therapy. Lower TG in relation to improved fatty liver may be related to correction of higher Hb levels.

Disclosure
Y. Matsubayashi: None. A. Yoshida: Employee; Self; Kowa Company, Ltd. H. Suganami: Employee; Self; Kowa Company, Ltd. K. Kaku: Advisory Panel; Self; Novo Nordisk Pharma Ltd., Consultant; Self; Sanwa Kagaku Kenkyusho, Research Support; Self; Taisho Pharmaceutical Co., Ltd., Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Eli Lilly Japan K. K., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co. H. Sone: Research Support; Self; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.
8-OR: Depression and Diabetes Distress in African American and Latino Parents of Children with Type 1 Diabetes (T1D)
Authors: CARREON SAMANTHA A. , JONES JASMINE N. , GARCIA ARIADNE REYES , PETERS KEYISHI S. , CHRISTOPHER KRYSTAL K. , HILLIARD MARISA E. , BUTLER ASHLEY 
Published: June 2021

Introduction: Parents of young children experience high levels of depression and diabetes distress immediately post-diagnosis. However, there is a limited understanding of these factors later in the disease course, especially among parents from racial/ethnic minority groups who face management difficulties and persistent T1D health disparities (i.e., higher HA1c). This study described parental depressive symptoms, diabetes distress and adherence among African American and Latino parents of children with T1D duration &gt; 1 year.
Methods: African American (n = 39) and Latino (n = 26) parents of children age 5-10 years (M 9.0 ± 1.7 yrs; M HA1c = 9.0 ± 1.9; M T1D duration = 3.7±2.2 yrs) were enrolled in a behavioral intervention trial. At baseline they reported on demographics, treatment adherence (Diabetes Self-Management Questionnaire, DSMQ), diabetes distress (Problem Areas in Diabetes Revised for parents, PAID-PR), and depressive symptoms (Center for Epidemiological Studies-Depression, CES-D). HA1c was extracted from the medical record.
Results: Over one-quarter (27%) of African American (M CES-D = 13.6 ± 9.5) and 42% of Latino (M CES-D = 14.1 ± 8.8) parents reported moderate/severe depressive symptoms. Nearly half (49%) of African American (M PAID-PR = 56.7 ± 19.7) and 38% of Latino (M PAID-PR = 50.2 ± 17.8) parents reported diabetes distress above a clinical cutoff. Both African American and Latino parents reported high levels of adherence (M DSMQ = 25.9 ± 4.7 and 26.7 ± 4.3, respectively, out of 35).
Conclusions: Substantial proportions of African American and Latino parents of school-aged children who have been managing T1D for at least 1 year experience serious mood concerns, both diabetes-specific and general. High levels of T1D adherence indicate resilience in the face of such challenges. Supporting parental psychosocial functioning should be a high priority for diabetes care providers, especially among minority families who may be experiencing elevated challenges.

Disclosure
S. A. Carreon: None. J. N. Jones: None. A. Reyes garcia: None. K. S. Peters: None. K. K. Christopher: None. M. E. Hilliard: None. A. Butler: None.

Funding
National Institutes of Health (1DP3DK113236)
801-P: SGLT2 Inhibitor, Luseogliflozin, Prevent Sarcopenia by Improving Extracellular Lipidome
Authors: BAMBA RYO , OKAMURA TAKURO , HASHIMOTO YOSHITAKA , SENMARU TAKAFUMI , HAMAGUCHI MASAHIDE , FUKUI MICHIAKI 
Published: June 2021

Aims: It has been reported that there is a close relationship between sarcopenia obesity and metabolic disorder such as lipid metabolism. Here we investigated the effect on lipid metabolism of the sodium glucose cotransporter-2 inhibitor (SGLT-2i) luseogliflozin in skeletal muscle. We preformed microarray analysis of mRNA in skeletal muscle and investigated the lipid profile in skeletal muscle and serum.
Methods: Eight-week-old mice were fed a standard diet or a standard diet supplemented with luseogliflozin (0.01% w/w chow) for 8 weeks. Mice were divided into the following three genotype/diet groups: Db/m mice without (w/o) SGLT-2i, Db/Db w/o SGLT-2i, and Db/Db with SGLT-2i. After 8 weeks of diet, in each group, body weight, glucose tolerance, muscle weight and cross-sectional area, free fatty acid concentration, muscle and gene expression in serum were investigated.
Results: The ratio of soleus muscle to body weight and the cross-sectional area of soleus muscle were significantly higher in Db/Db mice with SGLT-2i than in Db/Db mice w/o SGLT-2i. In addition, the concentration of saturated fatty acids in skeletal muscle and serum of Db/Db mice with SGLT-2i was significantly lower than that w/o SGLT2i, and the expression of Fasn, Elovl6, and Scd1, which are involved in fatty acid synthesis, in skeletal muscle was significantly increased in Db/Db w/o SGLT-2i compared to Db/m mice with SGLT-2i, and significantly decreased in Db/Db with SGLT-2i compared to mice w/o SGLT-2i. Furthermore, in cell experiments using C2C12 myotube cells, the administration of saturated fatty acid increased the expression of muscle atrophy-related genes.
Conclusion: The administration of luseogliflozin suppressed skeletal muscle atrophy and reduced the concentration of saturated fatty acids in skeletal muscle. Based on these findings, we hypothesized that secondary effects, other than the hypoglycemic effects of SGLT2i, might lead to the alleviation of obesity-dependent sarcopenia.

Disclosure
R. Bamba: None. T. Okamura: None. Y. Hashimoto: None. T. Senmaru: None. M. Hamaguchi: Research Support; Spouse/Partner; AstraZeneca K. K. M. Fukui: None.