bluuebunny/crossref_metadata_2025 huggingface dataset:
801-P: Short-Acting Exenatide Added Three Times Daily to Insulin Therapy Improves Fatty Liver Index in Type 1 Diabetes
Authors: JOHANSEN NICKLAS , DEJGAARD THOMAS F. , LUND ASGER , NIELSEN CASPER K. , VILSBØLL TINA , KNOP FILIP K.
Published: June 2023

Fatty liver index (FLI), a marker of hepatic fat content, has been reported as an independent risk factor for all-cause mortality and major cardiovascular events in type 1 diabetes. How short-acting glucagon-like peptide 1 receptor agonists (GLP-1RA) influence FLI in type 1 diabetes remains unknown. We analyzed FLI post-hoc in a phase 2, double-blind, randomized (1:1), clinical trial (NCT03017352) that assessed the efficacy of short-acting GLP-1RA exenatide 10 μg added three times daily to insulin therapy as compared with placebo over 26 weeks of treatment in 108 individuals with type 1 diabetes (76/32 men/women, age 50 (14) years (mean (standard deviation)), diabetes duration 21 (12) years, BMI 28 (4) kg/m2, glycated hemoglobin A1c 8.2 (0.7) % / 66 (7) mmol/mol). Exenatide significantly reduced FLI by 23 % (95 % confidence interval -44; -10, P = 0.001) (Table 1) as compared with placebo after 26 weeks’ treatment. In conclusion, short-acting exenatide reduced FLI-assessed hepatic fat content in patients with long-standing type 1 diabetes and inadequate glycemic control, alluding to potential beneficial effects of this GLP-1RA on both morbidity and mortality in type 1 diabetes.

Disclosure

N.Johansen: Other Relationship; AstraZeneca, Novo Nordisk, Research Support; JDRF. T.F.Dejgaard: Advisory Panel; Novo Nordisk, Research Support; Novo Nordisk, Speaker's Bureau; Boehringer-Ingelheim, Novo Nordisk, AstraZeneca. A.Lund: Speaker's Bureau; Novo Nordisk. C.K.Nielsen: None. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck.

Funding

AstraZeneca
809-P: The Effect of Various Degrees of Hepatic Impairment on the Pharmacokinetic Characteristics of Once-Weekly Insulin Icodec
Authors: HAAHR HANNE , CIESLAROVA BLANKA , DONATSKY ANDERS M. , JOSEPH JOSMIN R. , KRISTENSEN NIELS R. , KUPCOVÁ VIERA , HINGST JANNE R.
Published: June 2023

Insulin icodec is a novel basal insulin being developed for once-weekly administration. This study investigated if the pharmacokinetic characteristics of icodec are affected by hepatic impairment. In an open-label, parallel-group trial, 25 individuals (13 females/12 males; mean±SD age 54±9 yrs, BMI 28.3±5.2 kg/m2) were allocated to four groups based on hepatic function: normal hepatic function (n=6), mild (Child-Pugh Classification grade A; n=6), moderate (Child-Pugh grade B; n=6), and severe (Child-Pugh grade C; n=7) hepatic impairment. Icodec was administered as a single s.c. dose (1.5 U/kg) followed by blood sampling for pharmacokinetics until 840 h (35 days) post-dose. Total exposure of icodec (AUC0-∞,SD) was greater for mild (by 13%) and moderate (by 15%) hepatic impairment vs normal hepatic function, while no difference was observed for severe hepatic impairment vs normal hepatic function (Figure). Maximum concentration of icodec was not affected by hepatic impairment after a single dose (Cmax,SD) or at simulated steady state (Cmax,SS). In conclusion, the slightly greater total exposure of icodec for mild and moderate hepatic impairment vs normal hepatic function is considered of limited clinical relevance as icodec should be dosed according to individual need. No specific dose adjustment of icodec is required in individuals with hepatic impairment.

Disclosure

H.Haahr: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk. B.Cieslarova: None. A.M.Donatsky: Employee; Novo Nordisk. J.R.Joseph: None. N.R.Kristensen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. V.Kupcová: None. J.R.Hingst: Employee; Novo Nordisk, Research Support; Pfizer Inc.

Funding

Novo Nordisk
81-LB: Novel Microsphere Technology Reducing Injection Site Reaction in the Development of Long-Acting GLP-1 RA Formulation
Authors: KIM YEJIN , SEOL EUNYOUNG
Published: June 2023

Microspheres are typically used for long-acting injectable formulation, but often the injection site reactions are reported as side effects. This can reduce patient compliance with medication despite the benefit of reducing the number of administrations. Side effects at the injection site are mostly derived from inflammatory reactions. Therefore, it is necessary to minimize inflammatory reactions for the successful development of long-acting diabetes treatments, including GLP-1 receptor agonists. The purpose of this study is to evaluate the injection site reaction in the placebo, semaglutide and tirzepatide microspheres manufactured using the conventional microsphere technology and to investigate the injection site reaction improvement in the placebo, semaglutide and tirzepatide microspheres manufactured using novel technology by adding anti-inflammatory agent, dexamethasone. Skin samples were collected from the injection site of SD rats on days 3 and 8 after the administration of microspheres with or without dexamethasone. The collected skin was stained with H&E to determine infiltration of inflammatory cells, angiogenesis, and fibrosis and was graded. When microspheres manufactured using the conventional method were subcutaneously administered to rats, infiltration of inflammatory cells and fibrous tissue formation occurred on both days 3 and 8. Higher dexamethasone content in the microsphere showed a tendency for the lesser occurrence of inflammation and greater anti-inflammatory effect in the test group. Surprisingly, improvement in the injection site reaction for microspheres containing dexamethasone was observed even at systemic dexamethasone concentrations much lower than the therapeutic level.

In conclusion, this novel microsphere containing a small amount of dexamethasone shows potential for the development of a long-acting GLP-1 microsphere injectable for diabetes treatment with reduced injection site reaction.

Disclosure

Y. Kim: None. E. Seol: None.

Funding

Ministry of Health & Welfare, Republic of Korea (HI21C1732)
814-P: Intensive Insulin Therapy within One Week Can Improve ß-Cell Function in T2D Patients
Authors: JIANG WEI , CHEN XUANRONG , LIU ZHIGU , LIN BEISI , XU WEN , ZENG LONGYI
Published: June 2023

Objective: Short-term intensive insulin therapy (IIT), usually over 2 weeks, can improve β-cell function in T2D. However, whether shorter duration of IIT could also have impact on β-cell function remained unclear. This study was thus designed to explore this question.

Methods: One hundred and ninety-two T2D patients who received continuous subcutaneous insulin infusion within 1 week and underwent comprehensive evaluation of β-cell function before and after IIT were included. β-cell function indices including HOMA-β, insulinogenic index, disposition index (DI), fasting and postprandial C-peptide index (CPI), AUC of insulin and C-peptide were adopted. In a subset patients underwent CGM, the correlation of glucose variability and β-cell function were analyzed.

Results: The patients were 56.2±13.7 (mean±SD) years old, with diabetic duration of 6.0 (12.1) [median (interquartile)] years, HbA1c of 9.3±2.0%. After 3-7 days (median: 5 days) of IIT, insulinogenic index [3.6 (5.3) mU/mmol vs. 2.9 (4.4) mU/mmol, p=0.005], DI [358.3 (398.5) vs. 233.3 (275.5), p<0.001], fasting CPI [1.2 (0.8) nmol/mmol vs. 1.0 (0.8) nmol/mmol, p<0.001], postprandial CPI [1.8 (1.5) nmol/mmol vs. 1.4 (1.2) nmol/mmol, p<0.001] and AUC of C-peptide [113.0 (67.1) nmol∙min/L vs. 103.7 (55.9) nmol∙min/L, p=0.002] were significantly improved compared with baseline. Among these patients, 45 subjects underwent CGM. It was found that changes in DI from baseline (ΔDI) were negatively correlated with TAR (r=-0.417, P=0.004), standard deviation (r=-0.366, P=0.013), MAGE (r=-0.295, P=0.049), glucose coefficient of variation (r=-0.321, P=0.031) and positively correlated with TIR (r=0.359, P=0.004). Multiple linear regression revealed that duration of IIT (β=0.453, P=0.009) and TIR (β=0.527, P=0.006) were independent factors of ΔDI.

Conclusions: IIT within 1 week can also improved β-cell function in T2D patients. Duration of IIT and TIR could be the independent factors responsible for the improvement of β-cell function.

Disclosure

W.Jiang: None. X.Chen: None. Z.Liu: None. B.Lin: None. W.Xu: None. L.Zeng: None.
816-P: Predictors of Adherence and Persistence to Basal Insulin Therapy in Adults with Type 2 Diabetes
Authors: ARODA VANITA R. , NIELSEN NICK F. , MANGLA KAMAL K. , WANG YI , NAMVAR TARLAN , RAJPURA JIGAR R.
Published: June 2023

Objectives: Treatment adherence and persistence lead to gaps in achieving glycemic control in type 2 diabetes (T2D). We sought to identify predictors of adherence and persistence to basal insulin therapy among adults with T2D initiating therapy.

Methods: Commercially insured US adults with T2D initiating basal insulin treatment between January 1, 2016 and December 31, 2018 were identified using IQVIA PharMetrics® Plus claims data. Adherence and persistence were quantified based on basal insulin claims in the one-year follow-up period and established definitions. Logistic regression models were developed to identify predictors of adherence and persistence based on baseline clinical and demographic information.

Results: Among the 64,953 patients sampled, medication adherence and nonadherence (42% and 58%) and medication persistence and non-persistence (57% and 43%) were identified. Older age at baseline, oral and injectable antidiabetic medicine use, and physician office visits were associated with increased persistence and adherence; baseline hospitalization and emergency room visits were associated with decreased levels.

Conclusions: Multiple predictors of adherence and persistence with basal insulin therapy were identified. These findings may help guide therapeutic choices and research priorities to bridge the gap between achievable efficacy of insulin therapy and real-world effectiveness.

Disclosure

V.R.Aroda: Consultant; Applied Therapeutics Inc., Fractyl Health, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Other Relationship; Janssen Pharmaceuticals, Inc., Research Support; Applied Therapeutics Inc., Eli Lilly and Company, Fractyl Health, Inc., Novo Nordisk, Sanofi. N.F.Nielsen: Employee; Novo Nordisk A/S, Coloplast A/S. K.K.Mangla: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. Y.Wang: None. T.Namvar: None. J.R.Rajpura: Employee; Novo Nordisk.
817-P: Late Postprandial Hypoglycemia Is Reduced with Ultrarapid Insulin—An Insulclock Connected Cap-Based Real-World Study
Authors: GOMEZ-PERALTA FERNANDO , VALLEDOR XOÁN , LOPEZ-PICADO AMANDA , ABREU CRISTINA , PUJANTE ALARCÓN PEDRO , FERNÁNDEZ-RUBIO ELSA , GARCÍA ELENA , AZRIEL SHARONA , CORCOY ROSA , CERQUEIRA CRISTINA , PÉREZ JESUS , RUIZ-VALDEPEÑAS LUIS
Published: June 2023

Background: Reaching optimal postprandial glucose dynamics is a daily challenge in T1D people. The study aimed to analyze the postprandial hyperglycemia excursion (PHE) and late postprandial hypoglycemia (LPH) risk according to time and type of insulin.

Methods: Real-world (RW), retrospective study in T1D using multiple daily injection (MDI) insulin. Five hours of paired CGM and automatically tracked insulin injections collected with the connected cap Insulclock®. Meal events were identified using the ROC detection methodology. Postprandial glucometrics and LPH (glucose <70mg/dL 2-5 hours after a meal) were evaluated according to insulin injection time and type: rapid (RI) or ultrarapid analog-Fiasp®- (URI).

Results: Meal glycemic excursions (n= 2488), RI: 1211, 48.7%; UR: 1277, 51.3%, in 82 people. In 63% insulin was injected after the meal started. URI use was associated with lower LPH risk URI vs RI, n(%): Early (-45-15 min): 20 (9,5) vs 11 (8,0); Optimal (-15-0 min): 18 (6,4) vs 29 (8,8); Delayed (0+45 min) 71 (9,1) vs 100 (13,4); (p 0.012). Lower PHE (Glucose peak-baseline; mg/dL) was observed with URI vs RI (mean±SD): Early: 102.23 ±32.19 vs 101.2 ±36.73; Optimal: 96.62 ±29.63 vs 99.89 ±29.93; Delayed 111.6 ±40.2 vs 118.13 ±43.3; (p <0.001).

Conclusion: Ultrarapid analog use reduces postprandial hyper- and hypoglycemia, even in the case of delayed injections.

Disclosure

F.Gomez-peralta: Advisory Panel; Abbott Diabetes, Insulcloud S.L., Speaker's Bureau; A. Menarini Diagnostics, Boehringer Ingelheim and Eli Lilly Alliance, Lilly Diabetes, Novartis, Novo Nordisk. C.Cerqueira: Employee; Insulcloud S.L. J.Pérez: Employee; Insulcloud S.L. L.Ruiz-valdepeñas: Employee; Insulcloud S.L., Stock/Shareholder; Insulcloud S.L. X.Valledor: Employee; Insulcloud S.L. A.Lopez-picado: Employee; Insulcloud S.L.. C.Abreu: Speaker's Bureau; Lilly, Novo Nordisk. P.Pujante alarcón: None. E.Fernández-rubio: Speaker's Bureau; Lilly Diabetes, Novo Nordisk, AstraZeneca. E.García: Advisory Panel; Airliquide, Speaker's Bureau; Abbott Diabetes, Dexcom, Inc., Boehringer Ingelheim and Eli Lilly Alliance, Novo Nordisk, Sanofi, Airliquide. S.Azriel: Advisory Panel; Boehringer-Ingelheim, Novo Nordisk, Medtronic, Speaker's Bureau; Dexcom, Inc., Lilly Diabetes, AstraZeneca, Sanofi. R.Corcoy: Advisory Panel; Novo Nordisk, Other Relationship; Novo Nordisk, Lilly, Sanofi, Abbott, Speaker's Bureau; Sanofi, Roche Diabetes Care.
819-P: Impact of Meal Bolus Timing and Bedtime Snacking on Glycemic Control in Hospitalized Patients
Authors: ALEXANIAN SARA , CHENEY MICHAEL C. , BELLO RAMOS JENNY , SPARTANO NICOLE L. , WOLPERT HOWARD , STEENKAMP DEVIN W.
Published: June 2023

Background: Basal-bolus insulin is the standard of care to treat hyperglycemia in hospitalized patients in the non-ICU setting. Matching insulin with food is a barrier to achieving blood glucose (BG) goals. The glycemic impact of a snack at bedtime without prandial insulin and delayed meal-time bolus in the hospital has not been previously explored.

Methods: The InFi study is an ongoing randomized controlled open-label trial comparing Fiasp vs aspart in hospitalized patients using the Dexcom G6 PRO CGM to assess postmeal glycemic outcomes. We performed an interim analysis of 100 subjects to assess the impact of bedtime snacks on fasting POC glucose (FG) and the impact of delayed meal bolus on postprandial sensor glucose (PPSG) time in range (TIR) 70-180 mg/dL. Meal intake was determined by a CGM heuristic, insulin bolus time by barcoded EMR.

Results: Four hour post-meal TIR was 54% for on-time boluses (n=119) vs 25% with bolus delay of >5 minutes (n=86), p <0.001. Evening snacking (9pm-12am) was associated with higher FG levels, 201 vs 158 mg/dL (N=30, 50), p = 0.03.

Conclusion: Delayed meal-time insulin bolusing is common in hospitalized patients and results in a significant reduction in post-meal TIR. Evening snacking is a significant cause of overnight hyperglycemia. Given the importance of BG control, hospitals should work to optimize meal insulin delivery and develop strategies to address bedtime food intake.

Disclosure

S.Alexanian: Research Support; Novo Nordisk. M.C.Cheney: None. J.Bello ramos: None. N.L.Spartano: Research Support; Novo Nordisk. H.Wolpert: Consultant; Abbott Diabetes, Employee; Eli Lilly and Company. D.W.Steenkamp: Research Support; Abbott Diabetes, Novo Nordisk.

Funding

Novo Nordisk (ISS-001295)
82-OR: NRF2 Regulates Neonatal ß-Cell Mass Expansion
Authors: BAUMEL-ALTERZON SHARON , KATZ LIORA S. , LAMBERTINI LUCA , GARCIA-OCANA ADOLFO , SCOTT DONALD
Published: June 2023

The pediatric population suffers from increased incidence of both major types of diabetes in recent decades, highlighting the urgent need for discovering mechanisms that regulate functional β-cell mass. We found that the master antioxidant regulator, Nrf2, is required for adaptive adult β-cell expansion under hypercaloric conditions via regulation of β-cell proliferation, β-cell survival, and maintenance of β-cell identity. Additionally, we found that Nrf2 expression in β-cells of 7-day-old mice is 15-fold higher of that in adult β-cells (p<0.0001, n=6). Based on these observations, we hypothesized that Nrf2 regulates β-cell proliferation and survival at early stages of life and contributes to the maintenance of normal β-cell mass later in life. To test this, we deleted Nrf2 in β-cells by crossing InsCre with Nrf2lox/lox mice (βNrf2KO). βNrf2KO mice at 28 days of age exhibited a 65% reduction of β-cell mass compared to control mice (p<0.0005, n=6). Importantly, at 7 days of age, βNrf2KO mice displayed a 65% reduction of β-cell proliferation (p<0.0001, n=6), a 22% reduction of nuclear Pdx1 levels (p<0.0001, n=6), a 5.84-fold increase in β-cell death (±0.04, p<0.001, n=6) and a 2.93-fold increase in β-cell oxidative stress (p<0.001, n=6) compared to control mice. Surprisingly, daily administration of antioxidant NAC to 7-day-old βNrf2KO mice only partially restored β-cell proliferation but completely blunted oxidative stress compared to control mice. This suggests that neonatal β-cell proliferation induced by Nrf2 relies on additional mechanisms beyond oxidative stress. Interestingly, RNAseq of isolated islets from 7-day-old βNrf2KO mice showed decreased expression of mitochondrial encoded genes and upregulation of stress-responsive genes. This suggests that Nrf2 controls β-cell proliferation by regulating mitochondrial bioenergetics. We conclude that Nrf2 is required for β-cell mass expansion in neonatal ages by controlling β-cell proliferation, identity, and survival.

Disclosure

S.Baumel-alterzon: None. L.S.Katz: None. L.Lambertini: None. A.Garcia-ocana: Consultant; Sun Pharmaceutical Industries Ltd. D.Scott: None.

Funding

National Institutes of Health (DK128387, DK114338)
828-P: Identification of Novel Protein Biomarkers as Predictors of Type 1 Diabetes Development and Progression, and as Indicators of Treatment Efficacy
Authors: CHHABRA PREETI , MA MINGYANG , BRAYMAN KENNETH L.
Published: June 2023

The aim was to identify novel protein biomarkers as predictors of Type 1 diabetes (T1D) development and progression in NOD mice, and as indicators of treatment efficacy. Heparin plasma was obtained from 6-weeks old NOD mice divided into Control, Prehyperglycemic, Diabetic, and IgM-treated groups. Plasma samples were analyzed using SomaScan Proteomic platform. 7288 somamers were evaluated. Cyclic Loess normalized Log2 signal was used to analyze the ADAT files (Boulder BioConsulting). Linear regression models were fit and ANOVA performed. Extracted pairwise contrasts, coefficients and predictions were used for downstream analysis in R. BH FDR correction was performed for p values. Differentially expressed (DE) somamer selection was based on p value or q value <0.05 and/or >2 absolute fold-change criteria. GSEA v4.2.2 and Cytoscape v3.9.1 EnrichmentMap pipeline v1.1.0 was used for Pathway analysis, and enrichment results mapped as a network of gene sets. Our studies identified four significant DE proteins in the prehyperglycemic stage and seven in diabetes, with an overlap of two. 17 enriched pathways were downregulated and two upregulated with diabetes. IgM group formed a distinct cluster in principal component analysis suggesting a global effect of the treatment. IgM-treated vs. Diabetic contrast found 418 DE proteins, many associated with the treatment itself. IgM-treated vs. Prehyperglycemic + Diabetic contrast identified 386 DE proteins in a second model. IgM-treated vs. healthy controls had 334 DE proteins. 33 DE proteins in the diabetic group were maintained at normal levels with IgM therapy. Venn diagrams comparing contrasts involving IgM-treated samples showed a significant overlap of unique DE proteins. IgM downregulated ~46 pathways. To conclude, novel proteins have been identified with significant clinical potential as predictors for T1D development and progression, and for monitoring treatment efficacy.

Disclosure

P.Chhabra: None. M.Ma: None. K.L.Brayman: None.

Funding

Manning Family Foundation (GF006791)
83-LB: Simplifying Insulin Treatment in Persons with T2 DM over 65 Years—Interim Report of the STOP Study
Authors: MAZZIERI ALESSIO , DE FANO MICHELANTONIO , MANCINETTI FRANCESCA , XENOS DIONYSIOS , BOCCARDI VIRGINIA , FANELLI CARMINE G. , PORCELLATI FRANCESCA
Published: June 2023

This is an interim evaluation of the STOP study, a proof-of-concept observation, whose aim is to test effectiveness and safety of IDegLira in deintensifying diabetes therapy in insulin-treated persons with T2DM aged >65 years. The study, retrospective observational, gathered so far data related to 93 consecutive persons with T2 DM, in whom IDegLira was introduced in therapy, and for whom clinical data were available for at least 6 months after the switch. The 93 persons (42 F, age 76±8 yrs, diabetes duration 20±10 yrs, duration of insulin treatment 13±12 yrs, BMI 28.6±4.9 kg/m2, A1C 7.4±0.9), were for the 75% in basal/bolus insulin therapy. Sixteen % of them, needed caregiver, whereas 53% were in follow up at the Geriatric Clinic for mild/severe cognitive impairment. After 3 months, fasting plasma glucose (PG) decreased (from 138±38 to 117±24 mg/dl, p=0.000036 vs baseline), similarly A1C (from 7.4±0.9 to 7.0±0.6%, p=0.000126). All results showed additional improvement at 6 month (p< 0.005 vs baseline). Rates of hypoglycemia at any time of day (PG <70 mg/dl) were lower after 3 months (0.35±0.94 vs 1.15±2.61, episodes/pt/month, p=0.0057). Episodes with PG <54 mg/dl decreased from 0.56±1.71 to 0.03±0.25, p=0.0093). Accordingly, the proportion of patients with at least one episode of PG <70 mg and 54 mg/dl, felt down from baseline to 3 month (23.7 to 14%;16.1 to 11%, respectively), being zero at 6 months. Rapid acting insulin dose decreased by 80 % at 3, up to 95% at 6 months (from 0.18±0.13 to 0.04±0.06 at 3, and 0.01±0.04 U/kg at 6 months, p< 0.0001). Nearly all patients interrupted it. IDegLira was initiated at a mean dose of 17±5.4 U/die to further increase to 23±9.6 after 6 months. BMI did not change significantly (p=ns). According to our preliminary results, IDegLira seems to offer a relevant option, to more complex insulin regimens, in terms of effectiveness and safety, in a population in whom preventing hypoglycemia and improving quality of life are mandatory and clinical inertia is often present.

Disclosure

A. Mazzieri: None. M. De fano: None. F. Mancinetti: None. D. Xenos: None. V. Boccardi: None. C. G. Fanelli: None. F. Porcellati: Board Member; Lilly Diabetes, Sanofi, Consultant; Novo Nordisk.
83-OR: Defining the Transcriptome and Epitranscriptome of the ß-Cell Compensation to Insulin Resistance
Authors: DE JESUS DARIO F. , ZHANG ZIJIE , WEI JIANGBO , BROWN NATALIE K. , HU JIANG , KAHRAMAN SEVIM , DIRICE ERCUMENT , KULKARNI ROHIT
Published: June 2023

Type 2 diabetes (T2D) is characterized by decreased functional β-cell mass and poor compensation to insulin resistance. Thus, understanding of the mechanism(s) responsible for the physiological adaptation of β-cells to states of high metabolic demand is desirable. We aimed to dissect the transcriptome and m6A mRNA methylation landscape in the β-cell adaptation to insulin resistance. To this end we conducted RNA-sequencing in sorted β-cells and m6A-sequencing in whole islets from three mouse models: a) a dietary model (60% high-fat diet: Control-HF), b) a genetic model (liver-specific insulin receptor KO mouse on chow: LIRKO-C), and c) a superimposed dietary and genetic model of insulin resistance (LIRKO on a high fat diet: LIRKO-HF). These data were compared to littermate controls fed a chow diet (Control-C). Control-HF, LIRKO-C and LIRKO-HF each presented an increase in insulin resistance compared to Control-C. However, LIRKO-C and LIRKO-HF presented a robust insulin secretion capacity and a graded increase in β-cell proliferation and mass compared to Control-C. First, we correlated the transcriptome with surrogates of β-cell adaptation such as insulin secretion, β-cell mass or proliferation. Next, we intersected the genes that positively correlated with β-cell compensation with single-cell RNA seq datasets performed in islets from humans with or without T2D. This bioinformatics analyses identified extracellular matrix (ECM) as the most enriched pathway in the β-cell adaptation to insulin resistance. On the other hand, m6A-sequencing of Control-C, LIRKO-C and LIRKO-HF islets and the intersection of this dataset with the differentially methylated genes in human T2D islets, revealed enrichment in pathways associated with chromatin modifications. Together, these results point to ECM pathways as being important in the transcriptomic remodeling and that m6A acts on chromatin-modifying enzymes in the β-cell compensation to mammalian insulin resistance.

Disclosure

D.F.De jesus: None. Z.Zhang: Research Support; SinoVac. J.Wei: None. N.K.Brown: None. J.Hu: None. S.Kahraman: Employee; Boehringer Ingelheim Pharmaceuticals Inc. E.Dirice: None. R.Kulkarni: Advisory Panel; Novo Nordisk, Inversago, Biomea Fusion, Inc., REDD Pharma, Research Support; Inversago.

Funding

American Diabetes Association (7-21-PDF-140 to D.F.DJ.); National Institutes of Health (R01067536)
837-P: Improved Outcomes across Socioeconomically Advantaged and Disadvantaged Communities—A Real-World Study
Authors: MCKENZIE AMY L. , ATHINARAYANAN SHAMINIE J.
Published: June 2023

Socioeconomic conditions of one's community have been attributed to disparities in diabetes outcomes and management practices. Among a random sample (n=19955) of people with type 2 diabetes receiving care at a nationwide telemedicine clinic utilizing a carbohydrate restricted nutritional approach and continuous remote care model (CR-CRCM), we explored A1c and medication utilization by area deprivation index quintile (Q). Upon enrollment, patients residing in more disadvantaged areas (Q4, Q5) had higher A1c compared to the least disadvantaged area (Q1; 7.8% vs 7.7%, p<0.01), and insulin (INS) and sulfonylureas (SU), but not other medication classes, were prescribed to a greater proportion of patients living in Q5 (25% INS, 23% SU) compared to Q1 (18% INS, 18% SU) and Q2 (21% INS, 19% SU) after accounting for differences in age, sex, baseline BMI, baseline INS use (when appropriate), and race and ethnicity (p<0.05). After one year in clinic, no differences in the prescription of medication classes between Q were observed, except for INS, where greater use remained only in Q5 than Q1 (14% vs 10%, p=0.011); among those remaining on INS, dose was reduced by 49-58% across all Q (p<0.001). Differences in SU use were no longer present; 77-83% fewer SU were prescribed across Q. Differences in A1c between Q4 (6.6%) and Q5 (6.7%) vs Q1 (6.5%) remained (p<0.001), though all groups achieved significant reductions in A1c of 1.1-1.2% (all p<0.001) concurrent with reduced prescription of all diabetes medication (from 1.7-1.8 to 1.1-1.2 medication classes per person). Across all levels of socioeconomic disadvantage, patients achieved clinically and statistically meaningful reductions in A1c and medication. Higher rates of SU use among patients residing in more disadvantaged areas were mitigated through a CR-CRCM to improve glycemia. Further, these data suggest a CR-CRCM may overcome financial barriers to optimal diabetes management through reduced need for medication.

Disclosure

A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. S.J.Athinarayanan: Employee; Virta Health Corp.
84-LB: Intensification of Glucagon-Like Peptide-1 Receptor Agonists Therapy with Glargine 300 U/mL or IDegLira—The RESTORE-G Real-World Study
Authors: CANDIDO RICCARDO , NICOLUCCI ANTONIO , CHIARA ROSSI MARIA , LAROSA MONICA , NAPOLI RAFFAELE , STUDY GROUP RESTORE-G
Published: June 2023

Combined use of basal insulin (BI) and glucagon-like peptide 1 receptor agonist (GLP1-RA) deserves consideration for the synergistic effects on glucose profile. Nevertheless, it is unclear if the addition of BI to the ongoing GLP1-RA therapy in free or fixed combination is associated with different outcomes. Aim of this RESTORE-G sub-study was to perform a propensity-score adjusted comparative effectiveness analysis of the two most innovative BIs for intensifying GLP1-RA therapy (±oral agents), i.e. Glargine 300 U/mL in free combination (Gla-300) vs. the fixed ratio combination of insulin degludec + liraglutide (IDegLira). Table shows sample sizes, patients characteristics and effectiveness results.

Compared to IDegLira, Gla-300 group had older age, worse metabolic control, and higher starting BI doses. After 6 months, statistically significant larger FBG reduction and BI dose increase were found in the free vs. fixed combination group. Trends of larger HbA1c and weight reductions with the free combination were also found, without reaching the statistical significance. In conclusion, higher benefits on FBG control in free vs. fixed combination has been found in people uncontrolled on GLP-1 RA, likely due to a better titration of the components. However, inertia in insulin initiation was documented in both groups.

Disclosure

R. Candido: None. A. Nicolucci: Board Member; AstraZeneca, Research Support; Novo Nordisk, Sanofi, Sobi, Shionogi & Co., Ltd., AlfaSigma, Speaker's Bureau; Boehringer Ingelheim and Eli Lilly Alliance. M. Rossi: Research Support; Sanofi, Novo Nordisk, Shionogi & Co., Ltd., AlfaSigma. M. Larosa: None. R. Napoli: Advisory Panel; Sanofi, Eli Lilly and Company, Novo Nordisk, Research Support; Novo Nordisk, AstraZeneca, Speaker's Bureau; Sanofi, Eli Lilly and Company, Novo Nordisk, AstraZeneca, MSD Life Science Foundation. Restore-g study group: n/a.

Funding

Sanofi
840-P: Dual Amylin and Calcitonin Receptor Agonist Treatment Improves Blood Pressure and Glucose Control in ZSF1 Rats
Authors: MELANDER SIMONE A. , LARSEN ANNA T. , ELHADY MOHAMED KHALED , KARSDAL MORTEN A. , HENRIKSEN KIM
Published: June 2023

Long-acting dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for the treatment of type 2 diabetes and obesity due to their beneficial effects on both body weight, glucose control and insulin action. However, whether DACRAs affect hypertension, and diabetes-related cardiovascular complications remain unknown. In this study, the cardiovascular protective effect of the DACRA KBP-336 was evaluated in obese Zucker diabetic fatty-Spontaneously hypertensive heart failure F1 hybrid (ZSF1) rats. Obese ZSF1 rats were treated for 60 days with the KBP-336 (4.5 nmol/kg Q3D) and treatment efficacy on glucose control and blood pressure measured by tail cuff was evaluated. Furthermore, serum biomarkers of cardiovascular complications were evaluated. KBP-336 treatment significantly lowered fasting blood glucose levels compared to vehicle (P<0.001). This was also illustrated in the HbA1c levels at study end, where KBP-336 resulted in significantly (P<0.001) lower levels than vehicle. Importantly, KBP-336 significantly reduced both systolic (AUC levels reduced by 13.3%, P<0.001) and diastolic (AUC levels reduced by 17.0%, P<0.001) blood pressure compared to vehicle without affecting the heart rate. Notably, the beneficial effects on both glucose control and blood pressure were obtained independent of weight loss as KBP-336 only resulted in a small and transient weight reduction. Furthermore, serum levels of the marker of cardiovascular disease, rPRO-C6 (collagen type VI formation marker) were 6.4% lower in KBP-336 treated rats compared to vehicle, supporting improvement in cardiovascular parameters. In summary, we show for the first time that KBP-336 benefits blood pressure in a metabolic rat model suffering from hypertension. In addition, KBP-336 improved glucose control independent of weight loss. These data highlight KBP-336 as a promising candidate for treating obesity and related comorbidities including type 2 diabetes and hypertension.

Disclosure

S.A.Melander: None. A.T.Larsen: Employee; Nordic Bioscience A/S. K.Mohamed: Employee; Nordic Bioscience. M.A.Karsdal: Speaker's Bureau; Pfizer Inc. K.Henriksen: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S.

Funding

Danish Research Foundation; Innovation Fund Denmark; European Union’s Horizon 2020 Research and Innovation Program (814244)
852-P: Duodenal Recellularization via Electroporation Therapy (ReCET) and GLP-1 RA to Replace Insulin in T2D Patients—EMINENT Study Six-Month Results
Authors: BUSCH CELINE B.E. , MEIRING SUZANNE , VAN BAAR ANNIEKE C.G. , HOLLEMAN FRITS , NIEUWDORP MAX , BERGMAN JACQUES J.
Published: June 2023

Introduction: Re-Cellularization via Electroporation Therapy (ReCET™), a novel endoscopic procedure using electroporation to elicit apoptosis of the duodenal mucosa. In this study we aimed to eliminate insulin in T2D patients using a single ReCET procedure combined with GLP-1RA. Safety, feasibility, and efficacy of ReCET using the Endogenex system were assessed.

Methods: First in human study with 14 T2D patients on basal insulin (BMI 24-40 kg/m2; HbA1c ≤ 8.0%; C-peptide ≥ 0.2 nmol/l). All underwent ReCET after which semaglutide was titrated up to 1mg. Primary endpoints were: feasibility (technical success rate, procedure time [catheter in - out], % GLP-1RA tolerance); safety ((S)AE, hypoglycemic events); efficacy (off insulin at 6 mo; HbA1c ≤ 7.5%).

Results: ReCET showed 100% technical success rate. Procedure time was 58 (IQR 49-79) min. Maximum semaglutide dosage was tolerated by 13 patients. No device related SAEs were observed. One non-severe hypoglycemic event occurred. At 6 mo, 12 patients were off insulin. A significant improvement in several glycemic and metabolic parameters was observed (Table 1); HbA1c decreased (7.2 to 6.6% p=0.003) and TIR increased (72 to 91% p=0.022).

Conclusion: ReCET is safe and feasible. ReCET combined with semaglutide may effectively eliminate insulin in selected T2D patients, while improving glycemic control and metabolic health.

Disclosure

C.B.E.Busch: None. S.Meiring: None. A.C.G.Van baar: None. F.Holleman: None. M.Nieuwdorp: Advisory Panel; caelus health. J.J.Bergman: Consultant; Endogenex, Fractyl Health, Inc., Digma Medical, Research Support; Endogenex, Fractyl Health, Inc., Digma Medical.
856-P: Long-Term Safety and Efficacy Evaluation of Hydroxychloroquine in T2D
Authors: PAREEK ANIL , CHANDURKAR NITIN , NAIDU KUMAR B. , DICHOLKAR PARNIKA
Published: June 2023

This prospective, multicentric, phase 4 study enrolled 747 T2D patients uncontrolled (A1c≥7) on Metformin+SU combination to receive add on HCQ 400 mg/day for 52 weeks. Primary outcome measure was, long term safety of HCQ evaluated in ITT population (n=747). Secondary outcomes were post treatment changes in glycemic, lipids and inflammatory parameters. Total of 191 AEs were reported in 111 patients, most were GI related (26.2%), mild in intensity (85%) and unlikely related (70%) to HCQ. Level 1 hypoglycemia was reported in 6.8% patients and mild NPDR in 11 patients. Of the 9 SAEs reported, 8 were unrelated and 1 (anemia) was probably related to HCQ. In mITTc population, the overall fall in A1c, FBG and PPG at week 12, 24 and 52 was significant from baseline. Additionally, a significant fall in TC, LDL-C, non-HDL-C was reported at week 24 and 52 from baseline. Patients were divided in two subgroups based on their baseline hsCRP levels (≤3 or ≥3). Of the 52% females enrolled, more than 60 % had high inflammatory load at baseline. There was significant fall in A1c, FBG, PPG, LDL-C, TC, and non-HDL-C at week 24 and 52 irrespective of baseline hsCRP. However, fall in A1C was significantly more at week 12 and 24 in patients with higher inflammatory load (hsCRP: ≥3) at baseline (p<0.0001). T2D is characterized by chronic low grade inflammation (meta-inflammation). HCQ has significantly reduced glycemic parameters with added benefits on lipids

Disclosure

A.Pareek: None. N.Chandurkar: None. K.B.Naidu: None. P.Dicholkar: None.
858-P: Recruitment Strategies for a Cellular Therapy Study for Type 1 Diabetes
Authors: BENN LEAH , GOU WENYU , NIETERT PAUL J. , CORNIER MARC-ANDRE , NORTON SUSAN , STRANGE CHARLIE , WANG HONGJUN
Published: June 2023

Mesenchymal stem cells may be a novel T1D treatment based on immunoregulatory and tissue-protective properties. Therefore, an NIDDK sponsored prospective, single center, double blind study of MSCs for new onset T1D (NCT04061746) has generated significant social media interest. This trial is hard to enroll because of a narrow age range (18-30 years) and requirement of a new onset diagnosis (6 months). We evaluated the impact of social media tools, clinicaltrials.gov advertisement, and medical record review (EPIC) to define the optimal screening process for this and future trials. Through clinicaltrials.gov the study piqued the interest of 173 participants. Additionally, the study team has pre-screened 346 patients from an EPIC generated report. Among the 22 patients consented, referrals were received from physicians (N=5), clinicaltrials.gov (N=13), and EPIC reports (N=4). Among those discovered via EPIC list, we depicted the main reasons for study ineligibility (Fig. 1). The study recently launched a social media campaign in December 2022, initially reaching a total of 16,593 viewers. 4,475 viewers (26.97%) interacted with the campaign, and 2 (0.012%) were potentially interested in follow up from the research team. We conclude that clinicaltrials.gov, medical record review, and physician referrals are all critical to screening for new-onset diabetes studies. Other T1D studies might benefit from utilizing these strategies.

Disclosure

L.Benn: None. W.Gou: None. P.J.Nietert: None. M.Cornier: Consultant; Novo Nordisk, Alnylum, Letsgetchecked, Research Support; Novartis Pharmaceuticals Corporation, Amgen Inc., Kaneka. S.Norton: None. C.Strange: None. H.Wang: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK118529, DK120394, DK105183, DK125454); U.S. Department of Veterans Affairs (I01BX004536)
859-P: Study of Oral Antihyperglycemic Agents in the Hospital—A Multinational Perspective
Authors: FAYFMAN MAYA , HOCHBERG IRIT , MAGEE MICHELLE F. , RASHIED AMMAR A. , JAGANNATHAN RAM , BLANCO GERARDO , MARIE MORENO EMMELIN , PASQUEL FRANCISCO J. , UMPIERREZ GUILLERMO
Published: June 2023

Oral antidiabetic drugs (OAD) are commonly used in the hospital setting despite limited safety and efficacy data.

To better understand the safety and efficacy of inpatient use of OAD, we pooled data from three healthcare systems in the US and Israel between from 2008-2018 (N=78,947). Treatment with OAD in the hospital was compared to Insulin (I) and OAD+Insulin (OAD+I). Patients on OAD were slightly older than those on I or OAD+I (67 vs 64 vs 65, respectively), more likely to admitted to surgical services (OAD: 33%; I: 21%, OAD+I: 23%, p<0.0001), and to have lower admission blood glucose (Blood glucose (BG): (161 vs 200 vs 192 mg/dl, p<0.0001). The average length of stay was 4-5 days for all groups. We performed propensity score matching by age, sex, Carlson Comorbidity Index, service (medicine or surgery), admission BG and creatinine to assess glycemic control and outcomes (Table). The primary outcome was good glycemic control with defined as mean hospital BG of 80-180 mg/dL and no hypoglycemia. Compared to I, patients treated with OAD were more likely to have good glycemic control [Odds Ratio (OR): 2.07 (95% CI: 1.85, 2.31)] and less hypoglycemia defined by BG <70mg/dL [OR: 0.63 (95% CI: 0.54, 0.74)]. No differences in rate of lactic acidosis were observed.

In summary, patients treated with OAD had better in-hospital inpatient glycemic control, lower rates of hypoglycemia and no difference in lactic acidosis as compared to Insulin.

Disclosure

M.Fayfman: None. I.Hochberg: Other Relationship; Eli Lilly and Company, Novo Nordisk. M.F.Magee: None. A.A.Rashied: None. R.Jagannathan: None. G.Blanco: None. E.Moreno: None. F.J.Pasquel: Consultant; Dexcom, Inc., Medscape, Research Support; Dexcom, Inc., Ideal Medical Technologies. G.Umpierrez: Research Support; Abbott, Dexcom, Inc., Baxter.
86-OR: Self-Organized Insulin-Producing ß-Cells Differentiated from Human Omentum-Derived Stem Cells
Authors: HWANG YONGSUNG
Published: June 2023

Human omentum-derived mesenchymal stem cells (hO-MSCs) possess a great potential to differentiate into multiple lineages and have self-renewal capacities, allowing them to be utilized as patient-specific cell-based therapeutics. Although various stem cell-derived insulin-producing β-cells have been proposed for the treatment of diabetes mellitus, developing an efficient method to establish highly functionalized insulin-producing β-cells remains a challenging task. Here, we aimed to develop a novel cell culture platform that could regulate important cell-cell/cell-matrix interactions by introducing a fibroblast growth factor 2 (FGF2)-immobilized matrix that can support cell adhesion, proliferation, and differentiation of hO-MSCs into insulin-producing β-cells. Our initial findings demonstrated that cells cultured on an FGF2-immobilized matrix were able to self-organize into insulin-producing β-cell-like progenitors, as evident from the upregulation of pancreatic β-cell-specific markers such as PDX-1, Insulin, and Glut-2. Furthermore, heparan sulfate proteoglycan, gap junction proteins including Cx36 and Cx43, and cell adhesion molecules such as E-cadherin and Ncam1 were significantly upregulated, leading to cell maturation and insulin secretion in the pancreatic niche environment. These results suggest that our novel platform could promote β-cell differentiation and glucose-stimulated insulin secretion from hO-MSCs by enhancing cell-cell junction proteins such as connexins (Cx36, Cx43), E-cadherin, and N-cam. Such a cell culture platform can offer novel strategies to obtain functional pancreatic β-cells from a patient-specific cell sources, ultimately enabling better treatments for diabetes mellitus.

Disclosure

Y.Hwang: None.

Funding

National Research Foundation of Korea (2019R1A5A8083404)
863-P: Effect of Bashan Tea Drink, a Vegetable Plant-Based Compound Tea Drink, on Blood Glucose in Type 2 Diabetic Patients
Authors: NI CHENGMING , SUN ZILIN , ZHOU XIAOYING , YAO SHENGHONG
Published: June 2023

Background: The Bashan drink is a vegetable plant-based compound tea drink combing several pure plant ingredients. Plant-based ingredients are rich in phytochemicals, which can regulate human metabolic enzymes. For instance, catechin-rich green tea can reduce insulin resistance, increase insulin sensitivity and improve postprandial blood glucose.

Objective: To observe the effects of Bashan on blood glucose (BG) in type 2 diabetes (T2DM) patients by a standardized mashed potato meal and continuous BG monitoring.

Methods: A total of 29 patients (23 males, age 49.64±1.71years, HbA1c 8.49±0.42%) with T2DM who were newly diagnosed or failed to achieve glycemic control using antidiabetic monotherapy were included in the study. Subjects were randomized to take either 180ml of Bashan or water 3 times a day directly after meals for 2 weeks, with a 1-week washout period. Before and after the intervention, subjects were detected BG for 240 min after a mashed potato meal (368.5 kcal: 61.4 g carbohydrate, 7.4 g protein and 8.9 g fat). Average blood glucose(ABG) were collected from the continuous glucose monitors. Data are presented as means ± SEM, and P < 0.05 was considered statistically significant.

Results: Four subjects were excluded for not completing the study. Compared with water, drinking Bashan significantly improved the ABG on day 10 to 12 (Bashan vs water: day 10, 7.37 ± 0.40 mmol/L vs 8.03 ± 0.45 mmol/L, P = 0.029; day 11, 7.17 ± 0.36 mmol/L vs 8.12 ± 0.59 mmol/L, P = 0.032; day 12, 6.90 ± 0.36 mmol/L vs 7.86 ± 0.54 mmol/L, P = 0.018). Drinking Bashan decreased HOMA2-IR and increased Homa2-%β, though not of statistical significance. (HOMA2-IR: Bashan day 14: 1.80 ± 0.17, day 1: 1.97 ± 0.19 vs water day 14: 1.83 ± 0.15, day 1: 1.80 ± 0.18, P >0.05; HOMA2-%β: Bashan day 14: 86.26±9.02, day 1: 73.40 ± 8.24 vs water day 14: 74.29 ± 7.46, day 1: 71.42 ± 7.27, P >0.05).

Conclusion: Drinking Bashan continuously can improve ABG, and can potentially improve insulin resistance and β cell function.

Disclosure

C.Ni: None. Z.Sun: None. X.Zhou: None. S.Yao: None.
864-P: Effects on Glycemic Control by Combination Therapy of Gliclazide-Metformin and Insulin in Type 2 Diabetes Mellitus Patients
Authors: SAIFUDDIN MOHAMMAD
Published: June 2023

Background: Diabetes mellitus is most common non-communicable diseases. Purpose of this study was to observe the effects on glycemic control by combination therapy of gliclazide-metformin and insulin in type 2 diabetes mellitus patients according to baseline HbA1c, fasting blood glucose (FBG) and blood glucose 2 hours after breakfast.

Methods: An observational study was conducted at Endocrinology Outpatient Department of Dhaka Medical College Hospital, Dhaka and Outpatient Department of Ibrahim General Hospital, Mirpur, Dhaka over a period of one year (July 2018 to June 2019). Total 110 type 2 diabetic patients were selected purposively. The patients were divided into two groups. In group I, 55 patients treated with gliclazide (80mg) and metformin (500mg) combination therapy twice daily for consecutive 12 weeks and in group II, 55 patients treated with Insulin (premixed 30/70) twice daily for consecutive 12 weeks.

Results: After 12 weeks of treatment HbA1c level reduced from (mean ± SD) 8.94 ± 0.91 to 7.82 ± 1.86 in group I and 10.07 ± 1.28 to 7.90 ± 1.01in group II. FBG level reduced from 10.05 ± 1.57 to 7.96 ± 1.62 in group I and 11.61 ± 2.62 to 7.60 ± 1.23 in group II. Blood glucose 2 hours ABF level reduced from 14.00 ± 2.04 to10.99 ± 1.41 in group I and 16.70 ± 3.61to 10.71 ± 1.52 in group II. In group I, 36.4% patients achieved HbA1c target level, 40% patients achieved FBG target level and 25.5% patients achieved blood glucose 2 hrs ABF target level. In group II, 29.1% patients achieved HbA1c target level, 56.4% patients achieved FBG target level and 29.1% patients achieved blood glucose 2 hrs ABF target level

Conclusion: This study showed improvement in the overall glycemic control (HbA1c, FBG and blood sugar 2hours ABF) during the study period. Both groups of drugs are effective in controlling blood glucose but individual group has unique beneficial effect.

Key words: Type 2 diabetes mellitus, Glycemic control, Glicazide-Metformin

Disclosure

M.Saifuddin: None.