bluuebunny/crossref_metadata_2025 huggingface dataset:
1080-P: A Prospective, Multicenter, Randomized, Open-Label, Parallel-Group Clinical Trial Comparing Patient Satisfaction and Compliance with a Needle-Free Insulin Injector vs. Conventional Insulin Pen Injections in Chinese Patients with Type 2 Diabetes Mellitus
Authors: WANG YANGANG , JI LINONG , GUO LIXIN , RAN XINGWU , CHEN LIMING , MA ZHONGSHU , SUN ZILIN , SHAN ZHONGYAN , XU XIANGJIN , WANG GUIXIA
Published: June 2019

Background: The proportion of patients with type 2 diabetes (T2DM) using insulin is still very low and often is initiated relatively late. The needle-free insulin injector is designed for diabetic patients who fear injections or are reluctant to initiate insulin therapy when it is clearly indicated.

Objective: To evaluate patient satisfaction and compliance with a needle-free insulin injector versus conventional insulin pen injections in patients with T2DM treated for 16 weeks.

Methods: A total of 427 patients with T2DM were enrolled in a multicenter, prospective, randomized, open-label study, and were randomized 1:1 to receive basal insulin or premixed insulin via a needle-free injector or via conventional insulin pen injections. Patients’ quality-of-life (determined by the SF-36 questionnaire), the insulin dose administered, compliance with insulin therapy (as evaluated by missing injections), and patients’ satisfaction with their injection device (scored on a scale of 0 to 10) were evaluated.

Results: In the 412 patients who completed the study, mean SF-36 questionnaire scores were increased significantly in both the needle-free injector and conventional insulin pen groups (123.21 ± 16.64 vs. 122.11 ± 16.82, respectively), with no significant difference between the 2 groups. There was also no significant difference between the groups in compliance. However, subjects in the needle-free injector group showed significantly higher treatment satisfaction scores than those in the conventional insulin pen group after 16 weeks of treatment (mean scores, 8.17 ± 1.78 vs. 7.21 ± 2.22, respectively; P < 0.0001).

Conclusions: The needle-free injector improved the quality-of-life of T2DM patients and significantly enhanced their satisfaction with insulin treatment compared with conventional insulin pen injections.

Disclosure

Y. Wang: None. L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Roche Pharma, Sanofi. L. Guo: None. X. Ran: None. L. Chen: Research Support; Self; Becton, Dickinson and Company. Z. Ma: None. Z. Sun: None. Z. Shan: None. X. Xu: None. G. Wang: None.
1085-P: Dance 501 Inhaled Human Insulin (INH): Linear Dose Response, Earlier Onset of Action, and Higher Early Effect than s.c. Insulin Lispro (LIS)
Authors: ZIJLSTRA ERIC , PLUM-MOERSCHEL LEONA , ERMER MARCEL , KLEIN OLIVER , PORTER LISA , BUECHE BLAINE , KUO MEI-CHANG , LE TRUC , STEDMAN BENJAMIN J. , PATTON JOHN S.
Published: June 2019

Dance 501 is a novel liquid formulation of human insulin for inhalation with the Dance 501 inhaler. This randomized, cross-over trial investigated the pharmacodynamic (PD) action and safety of INH in its final formulation vs. LIS during 10-hour glucose clamps in non-smoking subjects with T2D. LIS was injected s.c. at low (12 U), medium (24 U) and high (48 U) doses, INH was inhaled at equivalent doses, assuming a 13% relative biopotency. Twenty-two subjects completed all 6 single dose administrations. INH and LIS demonstrated a linear dose-response relationship and comparable total PD action (AUC_GIR0-10h). Median relative biopotency of INH was 12.3 to 13.0%. PD profiles (Figure) show a more rapid onset of action for equivalent doses of INH vs. LIS (median differences 6.5 to 20 min, p<0.02) and greater action in the first hour after administration (median differences 19.7 to 48.2 mg/kg, p<0.05). No safety issues and no cough were observed with any inhalation. These results nicely confirm and extend to higher doses the results of a previous PK/PD study in type 2 patients with an earlier version of the Dance 501 device and formulation (Zijlstra et al. Diabetes 2015; 64(Suppl 1): A248).

In conclusion, Dance 501 showed favorable glucodynamic properties vs. LIS and excellent tolerability and may therefore become a clinically meaningful alternative to rapid-acting insulin injectables.

Disclosure

E. Zijlstra: Speaker's Bureau; Self; Novo Nordisk A/S. L. Plum-Moerschel: None. M. Ermer: None. O. Klein: None. L. Porter: Other Relationship; Self; Dance Biopharm Holdings Inc., Eiger BioPharmaceuticals. B. Bueche: Employee; Self; Dance Biopharm Holdings Inc. M. Kuo: Employee; Self; Dance Biopharm Holdings Inc. T. Le: None. B.J. Stedman: None. J.S. Patton: Other Relationship; Self; Dance Biopharm Holdings Inc.

Funding

Dance Biopharm Holdings Inc.
1086-P: Preclinical Development of an Ultralong-Acting Insulin for Once-Weekly Dosing
Authors: HOWARD VICTOR G. , CHURCH CHRISTOPHER D. , OLDHAM STEPHANIE , HORNIGOLD DAVID C. , TREVASKIS JAMES , BAKER DAVID , RHODES CHRISTOPHER J. , ROSSI ALESSANDRA , NAYLOR JACQUELINE , DHILLON JATINDER , BUCHANAN ANDREW , LIANG LIHUAN
Published: June 2019

Basal insulin analogues have been designed to mimic endogenous insulin secretion for maintaining normoglycaemia. Current insulin therapy for type 2 diabetes (T2D) requires at least daily dosing for patients. However, such daily injections can have poor patient compliance. An insulin analogue with longer duration requiring less frequent administration could improve compliance and maintain better glycaemic control. To achieve extended insulin action pharmacology, a panel of recombinant native single chain (SC) insulin molecules, consisting of B chain to A chain-linker variants, were fused to an antibody fragment crystallizable region (Fc). Characterization of the single chain insulin-Fc (SC-Insulin-Fc) variants were conducted in insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) luminescence-linked reporter assays, and with primary rodent and human hepatocyte assays for phosphorylated AKT. SC-Insulin-Fc-1 and -2 retained potency at the human IR within 6-fold of human insulin, without specificity over IGF1R binding, and induced Akt phosphorylation within a range of endogenous insulin. SC-Insulin-Fc variants lowered blood glucose levels in DIO and db/db mice by more than 50% vs. vehicle controls (p<0.05) for 5 days following a single dose, significantly superior to a standard insulin bolus. Continuous glucose monitoring (CGM) telemetry to profile 24 h control of blood glucose in diabetic ZDF rats was also applied. CGM telemetry revealed enhanced basal and postprandial glucose control in both light and dark cycles (p<0.05 vs. vehicle) up to 10 days following a single administration (90 nmol/kg). Repeat dosing of SC-Insulin-Fc variants (10/30/60 nmol/kg, Q1W) over 5 weeks resulted in dose-dependent improvements of glycaemic control (p≤0.05 vs. vehicle) with a long term readout towards decreasing %HbA1c. This dramatic shift in time spent away from hyperglycaemia toward normoglycaemia suggests once-weekly insulin as a novel viable option to treat human T2D.

Disclosure

V.G. Howard: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. C.D. Church: Employee; Self; AstraZeneca, MedImmune. S. Oldham: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. D.C. Hornigold: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. J. Trevaskis: Employee; Self; Gilead Sciences, Inc., MedImmune. Stock/Shareholder; Self; AstraZeneca. D. Baker: Stock/Shareholder; Self; AstraZeneca. C.J. Rhodes: Employee; Self; AstraZeneca, MedImmune. A. Rossi: Employee; Self; MedImmune. J. Naylor: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. J. Dhillon: Employee; Self; MedImmune. A. Buchanan: Employee; Self; MedImmune. L. Liang: None.
1094-P: A Major Source of Hypoglycemia in Patients with Type 2 Diabetes Using Insulin
Authors: BISGAIER STANLEY G. , ISAMAN DEANNA J. , BASHAN ERAN , HODISH ISRAEL
Published: June 2019

Insulin requirement is highly dynamic, causing unpredictable reductions in insulin needs. Therefore, frequent dosage titration is needed to achieve and maintain therapy goals. Hypoglycemia is the primary risk in insulin management. We sought to determine if reductions in insulin requirements are associated with hypoglycemia frequency, by using data from a technology-based insulin titration service. To keep glycemia stable, the service adjusts insulin dosage at least weekly. Therefore, insulin dosage reacts quickly to both hyper- and hypo- glycemia, and as a result closely tracks insulin requirement. Outcome was defined as events of considerable and persistent decrease in insulin requirements as identified by reductions in daily dose ≥25%. Patients (N=246) were followed for 2.8±0.9 years. Insulin titrations occurred every 6.4±1.9 days. Considerable decrease in insulin requirement was experienced by 70.3% of the patients, every 15.0±7.5 months, lasted 10.0±7.7 weeks, and insulin requirements declined by 39.9%±12.6%. Hypoglycemia (<54mg/dl) occurred 6.0±7.2 times per year, and was 6.5 times more prevalent during reductions in insulin needs (Figure). In total, 39.9% of hypoglycemic events occurred during the 10.5% of time when insulin requirements declined. Substantial reduction in insulin needs explains a significant part of the hypoglycemic burden, which demands frequent titration to preserve treatment safety.

Disclosure

S.G. Bisgaier: Employee; Self; Hygieia. D.J. Isaman: Consultant; Self; Hygieia. E. Bashan: Employee; Self; Hygieia. I. Hodish: Stock/Shareholder; Self; Hygieia.
11-OR: What Has Contributed to the Increase in the National Spending on Antidiabetic Drugs: 2005-2016?
Authors: ZHOU XILIN , SHRESTHA SUNDAR , SHAO HUI , ZHANG PING
Published: June 2019

Spending on antidiabetic drugs is the fastest growing component of the medical cost of diabetes in the U.S. What factors have contributed to the increase remains unclear. Using Medical Expenditure Panel Survey, we (1) estimated the increase in the national spending on antidiabetic drugs from 2005 to 2016; (2) examined magnitudes of contributing factors to the increase using a full decomposition method. The contributing factors were first grouped into insulin verse non-insulin, the former was grouped into human, analog, and premixed insulin and later was grouped into metformin, older drugs (sulfonylurea, thiazolidinediones, alpha-glucosidase inhibitor, and meglitinides), newer drugs (dipeptidyl peptidase-4 inhibitor, amylin analog, glucagon-like peptide-1, and sodium-glucose contransporter-2), and combinations. Spending on insulin and non-insulin was also decomposed into number of users and expenditure per user. National spending increased by $38.7 billion from 2005 to 2016 (Figure). Most of the increase was due to insulin, mainly analog insulin. Increases in noninsulin was a net effect of an increase in newer drugs and a fall in older drugs. Higher spending per user was the main driver for insulin and both more users and lower expenditure per user led to the increase on noninsulin. Understanding the driving factors can help identify ways to slow down the growth in antidiabetic drug expenditures.

Disclosure

X. Zhou: None. S. Shrestha: None. H. Shao: None. P. Zhang: None.
1103-P: Glucose-Responsive Insulin: An Unprecedented Cleavable Linker Concept
Authors: MANNERSTEDT KARIN , ENGHOLM EBBE , MISHRA NARENDRA KUMAR , LUNDH MORTEN , BUCH-MÅNSON NINA , FINK LISBETH N. , PEDERSEN SØREN LJUNGBERG , PEDERSEN PHILIP J. , LE-HUU PRISKA , LAI JOHNATHAN , JENSEN KNUD J. , FOSGERAU KELD
Published: June 2019

Achieving the optimal combination of multiple glucose measurements and insulin injections provides a complex daily situation for most insulin-dependent diabetes patients with currently available insulin products. To date, several fast-acting and long-acting insulins have been developed. However, while the pharmacokinetic profiles have been optimized, it has remained an elusive goal for decades to develop a Glucose Responsive Insulin (GRI), which can be responsive to the fluctuations in blood glucose concentrations during the day. Here we present an unprecedented GRI concept. The concept is based on the hydrolysis of a cleavable linker that is covalently bound to insulin. The chemical nature of this central linker is designed to rapidly release active insulin when glucose rises above euglycemia (5 mM), and this release of active insulin will increase with increasing blood glucose concentration. The second element of the concept is an albumin-mediated inactivation of the GRI by lipidation. After injection, the GRI will bind to albumin and circulate as a depot, resulting in a slow release of insulin like seen with other basal insulins such as insulin Detemir. At the linker level, we have tested three concentrations of glucose, and glucose responsiveness was demonstrated by a decrease in reaction time with increasing glucose concentration. Moreover, fully conjugated GRI molecules were tested in 90% pancreatectomized rats, a model of type 1 diabetes, demonstrating significant and long-lasting glucose lowering effect as compared to control. Overall, we have demonstrated the feasibility of providing a GRI approach, which combines the properties of a basal insulin with that of a bolus insulin. With the circulating depot approach the concept also holds a promise for liver preference. Ultimately our approach could provide a safe insulin for the treatment of insulin-dependent diabetes with very low risk of side effects.

Disclosure

K. Mannerstedt: Employee; Self; Gubra. E. Engholm: Employee; Self; Gubra. N.K. Mishra: Employee; Self; Gubra. M. Lundh: Employee; Self; Gubra. N. Buch-Månson: None. L.N. Fink: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S. S.L. Pedersen: None. P.J. Pedersen: Employee; Self; Gubra. P. Le-Huu: Employee; Self; Gubra, Novo Nordisk A/S. Employee; Spouse/Partner; Novo Nordisk A/S. J. Lai: Employee; Self; Gubra. K.J. Jensen: Consultant; Self; Gubra. Stock/Shareholder; Self; Gubra. K. Fosgerau: Stock/Shareholder; Self; Gubra.
111-LB: Oral Semaglutide vs. Sitagliptin: Efficacy by Baseline HbA1c and Background OAD in PIONEER 3
Authors: ROSENSTOCK JULIO , ALLISON DALE C. , BIRKENFELD ANDREAS L. , BLICHER THALIA MARIE , DEENADAYALAN SRIKANTH , KOUSHOLT ASTRID , DAVIES MELANIE J.
Published: June 2019

Exploratory analyses of PIONEER 3 (NCT02607865) assessed the efficacy (HbA1c change from baseline [BL], achievement of HbA1c <7.0%) of oral semaglutide (sema; 3, 7, or 14 mg), a novel oral GLP-1 receptor agonist, vs. sitagliptin (sita) 100 mg at week 26 by BL HbA1c and background OAD in pts with T2D uncontrolled on metformin ± sulfonylurea.

HbA1c was reduced across all BL HbA1c and OAD groups in all treatment arms; reductions were greater with higher BL HbA1c. HbA1c reductions were significantly greater with oral sema 7 and 14 mg vs. sita in all groups, except for 7 mg in the HbA1c ≤8.0% group (Figure 1). Achievement of HbA1c <7.0% was greater with oral sema 7 and 14 mg vs. sita in all groups (Figure 2).

In conclusion, oral sema 7 and 14 mg significantly improved glycemic control vs. sita across most HbA1c groups, and irrespective of background OAD use.

Disclosure

J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Melior Pharmaceuticals, Inc., Bukwang Pharm. Co., Ltd., Merck & Co., Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc. Other Relationship; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. D.C. Allison: Advisory Panel; Self; Novo Nordisk Inc. Research Support; Self; Bayer US, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Kowa Pharmaceutical Europe Co. Ltd., Sanofi. A.L. Birkenfeld: None. T.M. Blicher: Employee; Self; Novo Nordisk A/S. S. Deenadayalan: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. A. Kousholt: Employee; Self; Novo Nordisk A/S. M.J. Davies: Advisory Panel; Self; Eli Lilly and Company, Janssen Global Services, LLC., Novo Nordisk A/S, Sanofi-Aventis, Servier. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk Foundation. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited.

Funding

Novo Nordisk A/S
1111-P: The Qualitative and Quantitative Effect of IDegLira Compared with the Nonfixed Administration of Degludec and Liraglutide
Authors: KOUTSOVASILIS ANASTASIOS , SOTIROPOULOS ALEXIOS , ANTONIOU ANASTASIA , PAPPA MARIA , BOUSBOULAS STAVROS , PEPPAS THEODOROS
Published: June 2019

Background: The efficacy and safety of IDegLira and the benefits of its complementary mode of action have been examined in the large global DUAL clinical trial program.

Aim: The aim of this study is to examine the effect of the IDegLira on the glycemic control and the cardiometabolic risk factors compared to the non-fixed adiministration of degludec and liraglutide.

Material and Methods: 473 patients with type 2 diabetes mellitus (T2DM) were included in the study. 158 patients on oral antidiabetic drugs (OADs) switched to OADs and IDegLira (Group A), 163 under OADs and liraglutide treatment added degludec to their regimen (Group B) and in 152 patients using degludec and OADs, liraglutide was added (Group C). Follow-up period was 52 ±2 weeks and changes in HbA1c, cardiometabolic risk factors and treatment adherence (with the 8-item Morisky Medication Adherence Scale (MMAS-8)) were recorded.

Results: There was no difference at baseline between the three groups as to age (61.88 ± 9.98 years, p =0.212), diabetes duration (12.08 ± 5.83, p = 0.332), HbA1c (mean HbA1c: 8.59± 1.13, p = 0.118) καιΒΜΙ (BMI 32.08 ± 3.22, p = 0.144). Mean HbA1c levels after the follow-up period was 6.79 ± 0.77, 7.14 ± 1.19, 7.18 ± 1.07 (p = 0.033) for Group A, B and C, respectively. Most of patients in Group A reached the treatment target for HbA1c (p = 0.041). Weight change was -3.2 ± 1.2 kg for Group A, -1.2 ± 1.1 kg for Group B and -4.3 ± 1.7 kg for Group C (p < 0.001). There was no difference in the hypoglycemic episodes between the groups (p = 0.251). The highest levels of adherence were noticed in Group A compared to Group B and C (7.58 ± 1.08, 6.38 ± 1.28 and 6.44 ± 1.16, p = 0.031, respectively) while total insulin dose was lower for Group A compared to the other groups (p=0.041).

Conclusion: Uncontrolled patients on oral antidiabetic drugs when switched to an IDegLira regimen achieved a significant improvement in their glycemic control and a more significant adherence compared the non-fixed combination of degludec and liraglutide.

Disclosure

A. Koutsovasilis: None. A. Sotiropoulos: None. A. Antoniou: None. M. Pappa: None. S. Bousboulas: None. T. Peppas: None.
1113-P: Six Months Comparative Evaluation of Efficacy and Safety of Wockhardt’s Biosimilar Insulin Glargine (Glaritus®) with Reference Insulin Glargine (Lantus®) in Type 2 Diabetes Mellitus in India
Authors: SHARMA SURENDRA , AJMANI AJAY KUMAR , KHOSLA POOJA , MUKHOPADHAYAY PRADIP , BHATIA GIRISH , KG PRAKASH , CHHAYA GAURAV , SUPE PRAVIN , PAVITHRAN VINODKUMAR , BORA HRISHIKESH , SHAH AGAM , INGOLE SHAHU ASHOK , JAIN RISHI
Published: June 2019

Introduction: Glaritus® has been found comparable to reference insulin glargine in physico-chemical characteristics, pre-clinical studies and treatment of type 1 diabetes mellitus (DM).

Objective: To compare the immunogenicity, HbA1c reduction and safety of Glaritus® to Lantus® over 6 months treatment in type 2 DM.

Methods: This is an ongoing prospective, open-label, randomized, multicentre Phase IV study. Total 180 patients of type 2 DM, who were inadequately controlled on oral antidiabetic drugs, were randomized in 1:1 ratio to Glaritus® and reference insulin glargine treatment. Analysis of 144 patients, who completed 6 month comparative phase, is presented herewith.

Results: Baseline characteristics of both the treatment arms were comparable in terms of age, gender distribution and body mass index. Over the treatment period, mean anti-insulin antibody titre increased marginally, mean HbA1c reduced significantly and substantial percentage of patients attained HbA1c value <7% within each treatment arm. However, both arms were comparable (P>0.05) in terms of these changes. Both glargine treatments were found to be safe in terms of hypoglycemic events.

Conclusion: Glaritus® was found to be equally effective and safe in patients with inadequately controlled T2DM compared to reference insulin glargine.

Disclosure

S. Sharma: None. A. Ajmani: None. P. Khosla: None. P. Mukhopadhayay: None. G. Bhatia: None. P. Kg: None. G. Chhaya: None. P. Supe: None. V. Pavithran: None. H. Bora: None. A. Shah: Employee; Self; Wockhardt. S.A. Ingole: Employee; Self; Wockhardt. R. Jain: Employee; Self; Wockhardt.

Funding

Wockhardt Pharmaceuticals Ltd.
1114-P: Feasibility Study of a Novel Way to Initiate Insulin Treatment in Persons with Type 2 Diabetes
Authors: ARADÓTTIR TINNA , BENGTSSON HENRIK , JENSEN MORTEN L. , POULSEN NIELS KJØLSTAD , BOIROUX DIMITRI , SCHMIDT SIGNE , NØRGAARD KIRSTEN
Published: June 2019

Introduction: Insulin initiation in type 2 diabetes (T2D) can be a complex process. In U.S., more than 60% of T2Ds treated with insulin do not reach recommended glycemic targets.

Aim: To investigate the feasibility of using a simple dose response model for predicting the basal insulin dose needed to reach glycemic target for a person with T2D.

Methods: To support initiation of a long acting insulin (insulin Degludec), we used CGM and injection data during insulin initiation to create an individual dose response model. Insulin naïve persons with T2D were included. Patients wore a CGM until the glycemic target was reached. CGM data from the first two weeks were used to identify the lowest glucose value of a day. The estimated safe and effective insulin dose (the 2-week dose estimates) were obtained by combining these lowest daily glucose periods with corresponding insulin doses, and extrapolating to a target range of 4-6 mmol/L. At end of study, the 2-week dose estimate was compared to the actual dose needed for glycemic control to assess how safe and effective the initial estimate would have been.

Results: Of the first 7 of 10 patients who completed the study, 5 were males of average age 60.3 (9.1) years, BMI 30.5 (4.1) kg/m2 and diabetes duration 15.8 (8.8) years. The observed actual dose for reaching the glycemic target was 49.9 (31.4) IU, and the 2-week dose prediction for reaching 4 and 6 mmol/L was 31.4 (12.6) IU and 45.5 (17.7) IU, respectively. At the end of study, a dose range for reaching the 4-6 mmol/L range was estimated using all the collected data, and all estimates were within or below this range.

Conclusion: Preliminary results from this feasibility study show that the insulin Degludec dose predicted two weeks after initiation was within or below the dose range needed for optimal control, thus the prediction errors were on the safe side in all cases. The results indicate that linear glucose and insulin extrapolation can be a safe and effective way to support initiation of insulin Degludec for people with T2D.

Disclosure

T. Aradóttir: None. H. Bengtsson: None. M.L. Jensen: Employee; Self; Novo Nordisk A/S. N.K. Poulsen: None. D. Boiroux: None. S. Schmidt: Speaker's Bureau; Self; Novo Nordisk A/S. K. Nørgaard: Advisory Panel; Self; Abbott, Medtronic, Novo Nordisk A/S. Speaker's Bureau; Self; Bayer US, Medtronic, Roche Diabetes Care, Rubin Medical, Sanofi, Zealand Pharma A/S. Stock/Shareholder; Self; Novo Nordisk A/S.

Funding

Novo Nordisk A/S; Innovation Fund Denmark (5189-00033B); Novo Nordisk Foundation
112-LB: Melatonin and DPP-IV Inhibitor: A Novel Combinatorial Approach for ß-Cell Regeneration
Authors: PATEL ROMA , PRAMANIK SAYANTANI , RATHWA NIRALI NANDUBHAI , PARMAR NISHANT R. , DHIMMAR HEMANGINI , PANCHOLI DHARA ASHWINKUMAR , A.V. RAMACHANDRAN , BEGUM RASHEEDUNNISA
Published: June 2019

Progressive deterioration of β-cell function and mass is a central parameter to the development of type-1/2 diabetes (T1/2D). Over the last decade, many studies have explored the potential benefits of incretin-based therapies on β-cell preservation and/or regeneration. In this context, DPP-IV inhibitor is known to improve GLP-1 and GIP longevity besides increasing β-cell mass. Melatonin, a pineal hormone is shown to ameliorate oxidative stress and bring about insulin secretion via MT1 receptor activation. Our aim was to evaluate the additive therapeutic effect of melatonin and DPP-IV inhibitor (sitagliptin) on β-cell regeneration in chemically (streptozotocin) induced T1D young and old mouse models, and on insulin resistance in high-fat diet (HFD)-induced T2D mouse model. Our results on pancreatic β-cell regeneration in T1D young and old mice suggest that the combinatorial treatment significantly increased insulin levels thereby lowering FBG levels and increasing glucose tolerance. In young diabetic mice, sitagliptin and melatonin work in an additive manner by increasing β-cell mass (replication and neogenesis) and decreasing apoptosis thus, ameliorating TID manifestations. However, in old diabetic mice, melatonin treatment alone was not as effective as sitagliptin treatment but a significant additive effect was observed in S+M group on β-cell regeneration. In HFD-induced T2D mice the combination therapy was superior to monotherapies in reducing FBG levels, and increasing glucose tolerance. Further, the combination treatment showed increased glucose metabolism, glycogen synthesis, and insulin sensitivity. There was no significant change in β-cell mass in HFD-induced T2D mice.

In conclusion, combinatorial therapy is able to ameliorate T1D and T2D in mouse models by β-cell regeneration and increasing insulin sensitivity. Melatonin promotes β-cell proliferation whereas sitagliptin promotes β-cell neogenesis and in concert, they enhance β-cell regeneration.

Disclosure

R. Patel: None. S. Pramanik: None. N.N. Rathwa: None. N.R. Parmar: None. H. Dhimmar: None. D.A. Pancholi: None. R. A.v.: None. R. Begum: None.

Funding

Department of Biotechnology, New Delhi, India (BT/PR12584/MED/31/289/2014)
1121-P: Metformin Intolerance, Proton Pump Inhibitors, and OCT1 Variation: A Recruit-by-Genotype, Randomised Controlled Trial (ImpOCT)
Authors: MCCREIGHT LAURA J. , HAPCA SIMONA M. , PEARSON EWAN
Published: June 2019

Aims: Metformin uptake is transporter-dependent. Observational data indicates that reduced-function variants in organic cation transporter 1 (OCT1) and OCT1-inhibiting drugs increase risk of metformin intolerance. The ImpOCT study investigated impact of OCT1 genotype and use of omeprazole (an OCT1-inhibiting drug) on an individual’s metformin tolerance.

Methods: This recruit-by-genotype, double-blind, randomised, placebo-controlled, crossover study recruited 61 nondiabetic individuals with homozygous reduced-function (null) or wild type (WT) OCT1 genotype. During two 4-week treatment periods, participants received metformin and concurrent omeprazole or placebo. Metformin was titrated weekly according to tolerance, assessed by interview and symptom severity scoring. The primary outcome was maximum tolerated dose of metformin (MTD) in each treatment period. Results were analysed using mixed effects modelling, assessing effect of genotype, treatment and gene x drug interaction on MTD.

Results: Participants were well matched for age and gender. Median BMI was higher in OCT1 null (26.3 [IQR 24.1 - 28.1] vs. 29 [IQR 26.5 - 31.8], p<0.001), though these OCT1 variants are not associated with obesity. Frequency of tolerance was comparable (WT 60% vs. null 64.5%, p=0.7). We identified a significant gene x drug interaction (p=0.04) - OCT1 WT individuals have improved MTD whilst taking omeprazole, compared to placebo, p=0.008, whereas OCT1 null individuals show no improvement in MTD with omeprazole compared to placebo, p=0.87. BMI was not significant in the model of MTD, p=0.27.

Conclusions: Reduced function SNPs in OCT1 are relatively common and can affect transporter efficacy. This study identified a gene x drug interaction, between OCT1, metformin and omeprazole. Our data indicates that OCT1 WT individuals may benefit from PPI treatment to improve symptoms of metformin intolerance - this benefit is lost in those with reduced OCT1 function.

Disclosure

L.J. McCreight: None. S.M. Hapca: None. E. Pearson: None.

Funding

UK Wellcome Trust (to E.P.)
1134-P: Efficacy of iGlarLixi in Adults with Type 2 Diabetes Inadequately Controlled on Two or More Oral Antidiabetic Agents
Authors: SKOLNIK NEIL , NIEMOELLER ELISABETH , SOUHAMI ELISABETH , MENEGHINI LUIGI
Published: June 2019

LixiLan-O, a randomized, 30-week, open-label study compared the fixed-ratio combination of insulin glargine/lixisenatide (iGlarLixi) with insulin glargine (iGlar) or lixisenatide in patients inadequately controlled on metformin alone or combined with a second OAD. This exploratory subgroup analysis examines the efficacy and safety of iGlarLixi vs. iGlar in patients with baseline HbA1c ≥8.0% receiving metformin plus a second OAD at screening; the second OAD was a sulfonylurea in 93.8% of patients. Mean age was 59.2 years, mean BMI was 31.5 kg/m2, mean diabetes duration was 10.0 years, and mean duration of second OAD use was 4.5 years. Compared with iGlar alone, the iGlarLixi-treated group demonstrated greater mean reductions from baseline in HbA1c, 2-h PPG, and weight, greater proportions achieving HbA1c <7.0%, or a composite endpoint of HbA1c <7.0% with no weight gain (Table). There were no differences between the groups in change in FPG, or in insulin dose at Week 30 (40.7 vs. 40.2 U/day, respectively; p=0.8664). Incidences of documented symptomatic hypoglycemia (plasma glucose ≤70 mg/dL) were similar between groups (29.0% and 27.9%, respectively). Patients in this difficult-to-treat subgroup with advanced T2D and higher baseline HbA1c achieved better glycemic control without increased risk of hypoglycemia when intensified with iGlarLixi compared with iGlar.

Disclosure

N. Skolnik: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Mylan, Sanofi, Teva Pharmaceutical Industries Ltd. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., GlaxoSmithKline plc., Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. E. Niemoeller: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. E. Souhami: Employee; Self; Sanofi Research & Development. L. Meneghini: Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Sanofi-Aventis. Consultant; Self; Sanofi-Aventis. Other Relationship; Self; American Diabetes Association.

Funding

Sanofi
1144-P: Distribution of Prescribed Dose During the First Year of Metformin Monotherapy in the U.S.
Authors: IGLAY KRISTY , SAWHNEY BAANIE , RAJPATHAK SWAPNIL , CRUTCHLOW MICHAEL , FERNANDES GAIL , KHUNTI KAMLESH
Published: June 2019

International guidelines recommend metformin as initial pharmacotherapy for patients with type 2 diabetes (T2D). Guidelines recommend metformin is up-titrated to a maximally effective (~2000 mg/day) dose based on glycemic control and tolerability; however, the extent to which this dose titration occurs in the real-world setting is unknown. To address this question in a U.S. population, we conducted a retrospective cohort study using the Optum database to evaluate the dose distribution of metformin monotherapy (MM) over 12 months in adult (≥21 years) T2D patients initiating MM during 2013-2016. Of the 30,352 eligible patients, 49% were female and median age was 65 years. The Table describes the distribution of metformin dose over the 12-month follow-up period. The majority (88%) of patients were initiated on MM at ≤1000 mg/day. At 3, 6 and 12 months, 84%, 82% and 80% of MM patients, respectively, were on doses ≤1000 mg/day. At 12 months, only 16% of patients were on a metformin dose >1500 mg/day. Among those who were up-titrated during follow-up (n=5003), the median highest dose of metformin was 1500 mg/d and median time to highest dose was 165 days.

In conclusion, the majority of MM patients were not up-titrated and remained on a sub-maximally effective dose of metformin at 12 months despite international guidelines. Further research will be conducted to examine the relationship between MM dose and glycemic control.

Disclosure

K. Iglay: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. B. Sawhney: Consultant; Self; Merck & Co., Inc. S. Rajpathak: None. M. Crutchlow: Consultant; Spouse/Partner; Crinetics, Novartis Pharmaceuticals Corporation, ProSciento, Soleno Therapeutics, Zealand Pharma A/S. Employee; Self; Merck & Co., Inc. Research Support; Spouse/Partner; Dexcom, Inc. G. Fernandes: None. K. Khunti: Advisory Panel; Self; Amgen Inc., AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Servier, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. Speaker's Bureau; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Menarini Group, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Servier, Takeda Pharmaceutical Company Limited.
115-OR: Epinephrine Contributes to Hypoglycemia-Associated Autonomic Failure (HAAF)
Authors: YIMAGOU ERIC LONTCHI , ALEKSIC SANDRA , UPADHYAY LAXMI , SHARMA SHIKSHA , CAREY MICHELLE , GOYAL AKANKASHA , YOU JEE YOUNG , HULKOWER RAPHAEL , MURTHI SWETHA , MITCHELL WILLIAM G. , SHAMOON HARRY , HAWKINS MEREDITH
Published: June 2019

Recurrent hypoglycemia leads to HAAF, with blunted counterregulatory hormone responses to subsequent hypoglycemic episodes. A recent report suggested inter-individual differences in susceptibility to HAAF (JCEM 102:3571, 2017). Since adrenergic receptor blockade prevents HAAF (Diabetes 60:602, 2011), we investigated to what extent the rises in plasma epinephrine (EPI) associated with hypoglycemia predict the development of HAAF.

Healthy non-diabetic subjects (n=18, age 43±2years, BMI 25±1 kg/m2) underwent two 2-hour hypoglycemic clamp studies (nadir 54mg/dl; 0-2h and 4-6 h) on Day 1 followed by a third 2-hour hypoglycemic clamp on Day 2. Twelve subjects (67%) developed HAAF by the third episode, as defined by at least 20% reductions in peak EPI levels (peak EPI 1st vs. 3rd episode: HAAF subjects 1072±156 vs. 530±87pg/ml, p<0.001). Importantly, peak EPI levels during the 1st hypoglycemic episode were ∼83% higher in the subjects who developed HAAF compared to those who did not (p=0.02).

To specifically define the role of EPI in the pathogenesis of HAAF, we challenged an additional seven non-diabetic subjects (age 32±4 years, BMI 25±1 kg/m2) with two 2-hour infusions of EPI (0.03 μg/kg/min;0-2h and 4-6 h) on Day 1 followed by 200-minute stepped hypoglycemic clamps (90, 80, 70 and 60 mg/dl, each for 50 minutes) on Day 2. Compared to saline, EPI infusion on Day 1 induced 40% and 28% reductions in epinephrine response to hypoglycemia at the 70 and 60 mg/dl glucose steps on Day 2, respectively (all p<0.05). There were parallel reductions in hypoglycemic symptoms (all p<0.05). Furthermore, the rate of glucose infusion was higher at all steps after EPI infusion (all p<0.05), consistent with a trend towards lower endogenous glucose production (6,6-D2-glucose).

Thus, rises in EPI similar to those seen with hypoglycemia reproduce key features of HAAF in non-diabetic subjects. Marked inter-individual variability in EPI levels in response to hypoglycemia may explain why some people are more prone to develop HAAF.

Disclosure

E. Lontchi Yimagou: None. S. Aleksic: None. L. Upadhyay: None. S. Sharma: None. M. Carey: None. A. Goyal: None. J. You: None. R. Hulkower: None. S. Murthi: None. W.G. Mitchell: None. H. Shamoon: None. M. Hawkins: Other Relationship; Self; Novo Nordisk Inc.

Funding

American Diabetes Association (1-18-PMF-024 to E.L.Y.); National Institutes of Health (R01DK079974)
1155-P: Effect of Endoscopic Duodenal-Jejunal Bypass Liner on Parameters of Insulin Sensitivity and Secretion in Subjects with Type 2 Diabetes Mellitus and Obesity
Authors: KUDLACKOVA MICHAELA , MRAZ MILOS , HALUZIK MARTIN , PELIKANOVA TEREZIE , BENES MAREK , LAPESOVA DANUSE , KOBROVA DANA , VLASAKOVA ZUZANA , BRIZOVA OLGA , LACINOVA ZDENKA
Published: June 2019

Duodenal-jejunal by-pass liner (DJBL) is an endoscopically implantable device designed to non-invasively mimic the effects of surgical gastric by-pass. However, the exact mechanisms responsible for improved glucose control associated with DJBL are still unclear. The aim of our study was to assess the effect of DJBL on insulin sensitivity and secretion in subjects with type 2 diabetes mellitus (T2DM) and obesity. Twenty-one obese subjects with T2DM (15 males, age 52.3 ± 11.2 years) underwent the implantation of the EndoBarrier DJBL (GI Dynamics, U.S.). Anthropometric, biochemical and hormonal parameters were measured before and 10 months after the implantation of DJBL. Insulin sensitivity was assessed using euglycemic-hyperinsulinemic clamp. Standard parameters including glucose disposal rate (M) and metabolic clearance rate of glucose (MCG) were calculated based on clamp results. Over 10 months the implantation of DJBL decreased body weight (body mass index 41.6 ± 6.1 vs. 37.5 ± 4.2 kg/m2, p<0.001) and improved glucose control (fasting blood glucose 10.5 ± 2.5 vs. 8.4 ± 2.4 mmol/l, p<0.001; HbA1C 74.7 ± 17.8 vs. 55.6 ± 12.4 mmol/mol, p<0.001). These improvements were accompanied by a marked increase in insulin sensitivity as shown by the results of the euglycemic-hyperinsulinemic clamp (M 1.5 ± 0.8 vs. 2.6 ± 1.0 mg.kg-1.min-1, p<0.001; MCG 1.4 ± 0.7 vs. 2.6 ± 0.2 mg.kg-1.min-1, p<0.001). In contrast, insulin secretion was not affected by DJBL (fasting insulin 21.8 ± 13.0 vs. 18.5 ± 9.5 mIU/l, p=0.312; C-peptide 2.7 ± 1.1 vs. 2.4 ± 1.1 nmol/l, p=0.172). To conclude the improvement in glucose control associated with the implantation of Endobarrier DJBL is primarily caused by increased insulin sensitivity rather than augmented insulin secretion.

Disclosure

M. Kudlackova: None. M. Mraz: None. M. Haluzik: None. T. Pelikanova: None. M. Benes: None. D. Lapesova: None. D. Kobrova: None. Z. Vlasakova: None. O. Brizova: None. Z. Lacinova: None.

Funding

Institute for Clinical and Experimental Medicine (IN00023001)
1158-P: Type 2 Diabetes Patients Subtype Analysis: Unbiased Machine Learning for Future Personalized T2D Care
Authors: CHEN LI , FENG LINGGE , TANG CUI , ZHANG YI
Published: June 2019

Dorzagliatin (HMS5552) that achieved POC in a recent Ph II trial, demonstrated its potential to treat type 2 diabetes (T2D) patients through a personalized medicine approach in a biomarker guided patient selection study. We here by conducted a data-driven unsupervised clustering analysis on the full analysis set (221 patients) of Dorzagliatin Ph II trail using clinically relevant biomarkers, which generated six clusters. An ANOVA test was done for those variables between clusters, and 40 of them are significantly different (P < 0.05). The study showed that each cluster possesses unique characters related to disease stage of T2D and the stage is progressing to one direction which starts from mild to severe loss of pancreas β-cell function accompany with progressively increase of insulin resistance. Cluster 1 shared similar feature as those in previous Ph Ic study, in which, QD dose of Dorzagliatin offered better response rate of 100%, while in Ph II based cluster, the 75mg QD dose group achieved 1.88% reduction in HbA1c from baseline with the 75mg BID offered HbA1c reduction of 0.95%. However, in Cluster 2 and 4, there are clear trends that BID is more effective than QD in glycemic control as well as improving β-cell function and reduction of insulin resistance. In Cluster 4, it is observed FPG reduction of 1.57mmol/L, PPG reduced of 2.73mmol/L, HOMA-β improvement of 12.22, and HbA1c reduction of 1.69% in 75mg BID dose group, with corresponding changes in 75 QD group of 0.35 mmol/L, 1.7mmol/L, 9.24 and 0.26% respectively adjusted by placebo. The results suggested that the AI methodology is able to differentiate T2D patients into different subclass according to the severity of the disease state, and 75mg BID Dorzagliatin seems offered a minimum therapeutic effective dose (MTED) to all patient population, and 75mg QD regiment is a preferred option for the early stage T2D condition.

Disclosure

L. Chen: Employee; Self; Hua Medicine. L. Feng: Employee; Self; Hua Medicine. C. Tang: Employee; Self; Hua Medicine. Y. Zhang: Employee; Self; Hua Medicine.

Funding

Hua Medicine
1159-P: Metformin Monotherapy Changes Gut Microbiota in Newly Diagnosed Type 2 Diabetes
Authors: HUNG WEI CHUN , HUNG WEI-WEN
Published: June 2019

Current clinical guidelines suggest metformin as the first-line therapy to treat type 2 diabetes. Despite its use for over 60 years, the precise mechanisms of metformin are still not fully discovered. Traditionally, liver was thought to be the main target of metformin action. More recently, gut has become the center of attention due to the increasing evidences suggesting the antidiabetic effect of metformin is derived from the gut. We aimed to evaluate the antidiabetic effects of metformin and the changes of gut microbiota in newly-diagnosed and drug-naive type 2 diabetes. We recruited 22 patients with newly-diagnosed and drug-naive type 2 diabetes from the outpatient clinic in a university hospital in southern Taiwan. Before and after metformin monotherapy for three months, we collected the biochemical data and measured fecal microbiota by quantitative real-time PCR with 16S rRNA gene sequencing. At the end of three months, there were totally 14 patients continued on metformin monotherapy and completed the collection of stool samples. Our results discovered that body-mass index, HbA1C, and fasting blood glucose decreased while HDL-C increased significantly after metformin monotherapy for three months. There were no significant changes in cholesterol, triglyceride, LDL-C, and HOMA-IR. Using quantitative real-time PCR with 16S rRNA gene sequencing, we found that Akkermansia and Escherichia increased significantly. The two major phylum of Firmicutes and Bacteroidetes did not have significant changes after three-month metformin monotherapy. We revealed that the antidiabetic effects of metformin associated with the changes of microbiota including Akkermansia and Escherichia. Understanding the interaction between metformin and gut microbiota in newly-diagnosed type 2 diabetes can help to identify important microbiota species related to the antidiabetic effect of metformin. In the future, gut microbiota has the potential to serve as a new therapeutic tool or target in treating type 2 diabetes.

Disclosure

W. Hung: None. W. Hung: None.

Funding

Kaohsiung Medical University
1160-P: The Risk Factors of Bullous Pemphigoid and Associated Risk between Bullous Pemphigoid and Dipeptidyl Peptidase-IV Inhibitors in Patients with Type 2 Diabetes Mellitus: A Retrospective Cohort Study
Authors: GUO JIA-YIN , CHEN HSIN HUNG , YANG YU-CIH , CHEN CHING-CHU
Published: June 2019

Objective: Bullous pemphigoid (BP) is the most common autoimmune blistering skin disorder with unclear etiology. Previous reports showed that BP may be associated with the use of some drugs. This study aimed to evaluate the risk factors for the development of BP and the relationship of BP with the administration of DPP-4i in patients with type 2 diabetes mellitus (T2DM).

Research Design and Methods: Using the National Health Insurance Research Database (NHIRD) from 2009 to 2013, there were 87,029 patients with T2DM. We excluded patients with T2DM without taking any antidiabetic agents and the development of BP before the use of DPP-4i or before they were selected. We identified individuals with T2DM and the use of DPP-4i 84 days or greater as a DPP-4i cohort and subjects never use DPP-4i as a control cohort. They were frequency matched on gender and age within 5 years at a ratio of 1:2.

Results: We identified 14,178 individuals taking DPP-4i and 28,374 matched cohorts without taking DPP-4i. There were 17 BP events in control cohort and 15 BP events in DPP-4i cohort. The incidence of BP was higher in DPP-4i cohort than in control cohort (1.41 vs. 0.59 per 1000 person-years; adjusted HR 2.14, 95% CI = 1.02-4.50). Patients with dementia had a higher associated risk to develop BP (adjusted HR 3.55, 95% CI = 1.30-9.66). The associated risk was lower in patients taking metformin (adjusted HR 0.38, 95% CI = 0.18-0.79) and higher in patients taking spironolactone (adjusted HR 3.06, 95% CI = 1.25-7.51). The cumulative incidence of BP in DPP-4i cohort was higher than in control cohort (log-rank test, p = 0.01).

Conclusion: DPP-4 inhibitors were associated with an increased risk of the development of BP in patients with T2DM. Patients with dementia and taking spironolactone had a higher associated risk. The development of BP in metformin users is significantly lower than in metformin non-user.

Disclosure

J. Guo: None. H. Chen: None. Y. Yang: None. C. Chen: None.
1162-P: DA-1241, a Novel GPR119 Agonist, Improves Hyperglycaemia by Inhibiting Hepatic Gluconeogenesis and Enhancing Insulin Secretion via Stimulation of GLP-1 Secretion
Authors: KIM JIN HEE , KIM YOUJIN , KIM RYEONG-HYEON , KIM MI-KYUNG , PARK HYUNKI , LEE MINYOUNG , CHO YONGIN , BAE JAEHYUN , LEE SANG BAE , LEE INKUK , LEE HYANGKYU , KIM CHUL HOON , KANG EUN SEOK
Published: June 2019

Unlike other G protein-coupled receptor (GPR)119 agonists, DA-1241 has shown long-term beneficial effects on glucose and lipid metabolism in previous studies. In this study, we investigated the antidiabetic effects of DA-1241 in vitro and in vivo. The efficacy of DA-1241 was evaluated by assessing the changes in glucagon-like peptide-1 (GLP-1) levels, gluconeogenesis, and hepatic autophagy. DA-1241 was administrated to high-fat diet (HFD)-fed C57BL/6J mice for 12 weeks (n=34), and serum insulin and GLP-1 levels were measured by oral glucose tolerance tests at week 8. The effects of DA-1241 on gluconeogenic enzyme expression and autophagic flow were evaluated in HepG2 cells and livers isolated from LC3-GFP-transgenic mice. DA-1241 improved oral glucose tolerance (no significant effect on intraperitoneal glucose tolerance test) with an increase in serum GLP-1 and insulin levels. Fasting blood glucose level decreased, and the insulinogenic index was improved after DA-1241 treatment in HFD-fed mice. However, no significant increase in insulin secretion in INS1E cells and isolated mouse islet with DA1241 treatment. DA-1241 reduced gluconeogenic enzyme expression and blocked autophagic flow in HepG2 cells. Additionally, DA1241 induced GFP fragmentation in liver from LC3-GFP-transgenic mice. These findings suggested that DA-1241 augmented glucose-dependent insulin release via improvement in GLP-1 secretion, and reduced hepatic gluconeogenesis, which might be associated with autophagic blockage, leading to improved glycaemic control.

Disclosure

J. Kim: None. Y. Kim: None. R. Kim: None. M. Kim: None. H. Park: None. M. Lee: None. Y. Cho: None. J. Bae: None. S. Lee: None. I. Lee: None. H. Lee: None. C. Kim: None. E. Kang: None.