bluuebunny/crossref_metadata_2025 huggingface dataset:
556-P: Early Results of Expanded Options for Demonstrating Risk Reduction in the National Diabetes Prevention Program (National DPP)
Authors: LANDAU ERIN O. , ELY ELIZABETH
Published: June 2023

In 2012, CDC’s Diabetes Prevention Recognition Program (DPRP) released the first version of the DPRP Standards and Operating Procedures, which defined risk reduction as a minimum 5% mean weight loss for participants who completed the National DPP lifestyle change program (LCP). The most recent version of the Standards, implemented in May 2021, established 3 metrics to show risk reduction: a minimum 5% weight loss; or a minimum 4% weight loss plus a weekly mean of 150+ physical activity minutes; or a 0.2% reduction in HbA1c. As of October 2022, the DPRP has received data from 4,200+ organizations on 650,000+ participants ever enrolled in the LCP. This analysis is limited to 29,352 participants who completed the program after the 2021 Standards were implemented. This study focuses on the 765 participants who provided a pre-intervention HbA1c result within the prediabetes range (5.7%-6.4%), and a post-intervention HbA1c in months 9-12 of the yearlong program. Of those, 211 demonstrated a 0.2% reduction in HbA1c; 53 had a 0.1% reduction in HbA1c; 456 showed no change; and 45 had an increase in HbA1c. The median weight loss for participants who demonstrated a 0.2% reduction in HbA1c was 6.0%, and their median reported physical activity minutes per week was 182.6. This is compared to a 4.5% median weight loss and 156.9 median reported physical activity minutes per week among those who did not demonstrate a 0.2% HbA1c reduction. Those who provided a pre-intervention HbA1c in the prediabetes range (5.7%-6.4%), regardless of whether they provided a post-intervention HbA1c, had a median weight loss of 5.0% compared to those who did not provide a pre-intervention result (4.5% median weight loss). The DPRP has received data on an additional 9,295 participants who have provided a pre-intervention HbA1c but have not yet concluded the program. As a result, those achieving a 0.2% HbA1c reduction may increase over the next 12 months and will provide the opportunity for deeper analysis.

Disclosure

E.O.Landau: None. E.Ely: None.
568-P: Study of the Effect of PPARß/δ Activation on Diabetic Cardiomyopathy
Authors: ROSTAMI ADEL
Published: June 2023

Diabetic cardiomyopathy (DC), the leading cause of death among people with diabetes, is definedas the occurrence of myocardial dysfunction in diabetic patients that is not directly attributableto coronary artery disease, hypertension, or valve disease. No specific drugs have yet beenapproved for treating DC and the use of Peroxisome Proliferator-Activated Receptor (PPAR)β/δagonists for the treatment of this disease show promise. Here, we examined as to whethertreatment with a PPARβ/δ agonist can prevent or ameliorate this pathology and as to whetherstreptozotozin (STZ)-induced DC is exacerbated in PPARβ/δ-deficient mice. In the STZ-induced mouse model of DC, an increase in cardiac fibrosis and an impairment inglucose and fatty acid metabolism was observed. Treatment with the PPARβ/δ agonist GW0742partially reduced the STZ-induced fibrosis, inflammation and metabolic disturbances, suggestingthat PPARβ/δ activation might be a potential target to prevent this disease suggesting a closerelation between inflammation and fibrosis in cardiac dysfunction of DC. In addition, we showthat PPARβ/δ suppression exacerbated hyperglycemia-induced DC and that PPARβ/δ activationthrough administration of agonists like GW501516 prevented the induction of some of themolecular mechanisms involved in the development of DC in these cells. Overall, these findingsdemonstrate the implication of PPARβ/δ in DC and suggest that its activation might be aneffective therapeutic tool for preventing or treating DC.

Disclosure

A.Rostami: None.
578-P: Effect of Two Timings for Postprandial Exercise Onset on Hypoglycemic Risk in Adults Living with Type 1 Diabetes
Authors: MOLVEAU JOSÉPHINE , MYETTE-CÔTÉ ÉTIENNE , TAGOUGUI SEMAH , TALEB NADINE , HEYMAN ELSA , SUPPERE CORINNE , RABASA-LHORET RÉMI
Published: June 2023

Introduction: To limit hypoglycemic risk of during postprandial aerobic exercise the importance of reducing prandial insulin dose have been established with exercise starting 90-min after the meal. People with type 1 diabetes also exercise closer or further away of their mealtime and hypoglycemic risk associated with those timings may be different.

Objective: We aimed to evaluate the effect of two different timings for exercise onset (60-min vs. 120-min post-meal) during moderate intensity exercise.

Methods: 37 participants (25 M/ 12 F; HbA1c: 7.4 ± 0.9%) received an ultra-rapid insulin dose reduced by 50% and performed 1 hour of continuous moderate intensity exercise (at 60% of VO2peak) started either 60-min (EX60min) or 120-min (EX120min) after breakfast. Venous blood glucose was measured every 10-min during exercise.

Results: Decrease in blood glucose between exercise onset and nadir (lowest point during exercise) was more important with EX120min (-68.5 ± 43.2 mg/dL, EX60min vs. -75.7 ± 39.6 mg/dL, EX120min, p=0.015). The number of hypoglycemic events during exercise and during recovery (90-min post-exercise) were similar between EX60min and EX120min (3 vs. 4 and 3 vs. 0, respectively). Postprandial glucose excursion before exercise onset was reduced with Ex60min compared to Ex120min.

Conclusion: For postprandial aerobic exercise, with a reduced insulin meal bolus, hypoglycemic risk is comparable if exercise is started at 60 or 120min after the meal. Guidelines established with exercise starting 90min after the meal can probably be used for earlier or later timing.

Disclosure

J.Molveau: None. É.Myette-côté: None. S.Tagougui: None. N.Taleb: Consultant; Viatris Inc. E.Heyman: None. C.Suppere: None. R.Rabasa-lhoret: Consultant; Dexcom, Inc., Abbott, Janssen Pharmaceuticals, Inc., Novo Nordisk Canada Inc., Sanofi, Lilly, Tandem Diabetes Care, Inc., Insulet Corporation.
634-P: Autoantibody Screening Attitudes and Experiences in People Affected by Type 1 Diabetes
Authors: KELLY CAITLIN S. , CHAPMAN KATHERINE S.M. , DUNNE JESSICA L. , CORNELIUS EMILEE M. , PETER MEGAN , PAGAN INDOE ELLEN , WOLF WENDY
Published: June 2023

Screening for type 1 diabetes (T1D) autoantibodies provides risk information before the onset of symptoms. Yet few individuals undergo screening. We aimed to understand knowledge, attitudes, and experiences regarding autoantibody screening in people affected by T1D. We recruited adults (aged 18+) from the T1D Exchange Online Registry who fell exclusively into one group: persons with T1D (‘PwD’) with a biological child without T1D or plans for a child; caregivers to a biological child with T1D and at least one without (‘caregivers’); and biological children or siblings to a person with T1D (‘relatives’). Eligible participants completed an online survey. As shown in Table 1, participants reported knowledge about autoantibody screening between ‘a little’ and ‘somewhat’ across groups. Perceptions of screening both in general and for their child [themselves] were generally positive, but most participants had not screened. PwD and caregivers reported feeling somewhat confident to independently understand results and explain results to their child. Relatives reported slightly less independence in self-efficacy to understand results. Results suggest more work needs to be done to increase awareness and knowledge about autoantibody screening. Moreover, while perceptions about screening are positive, screening remains underutilized even in a sample of people who are experienced with T1D.

Disclosure

C.S.Kelly: None. K.S.M.Chapman: None. J.L.Dunne: Employee; Janssen Research & Development, LLC. E.M.Cornelius: None. M.Peter: None. E.Pagan indoe: Other Relationship; Johnson & Johnson. W.Wolf: None.
64-LB: Cognitive and Somatic Symptoms of Depression Are Uniquely Related to HbA1c and Suicide Attempt History
Authors: GETTINGS JULIE M. , PANTESCO ELIZABETH J. , ANDORKO NICOLE , WILLI STEVEN M.
Published: June 2023

Screening for depression and suicide risk is an essential part of care for adolescents and young adults (AYA) with type 1 diabetes (T1D), as increased depression symptoms and suicide attempt history are independently associated with elevated Hba1c. As symptoms of depression and prolonged hyperglycemia may coexist, further insight may be gained from an understanding of how somatic versus cognitive symptoms may uniquely relate to clinical outcomes in AYA with T1D. This study examined the independent relationships between HbA1c and suicide attempt history with cognitive and somatic symptoms on the Patient Health Questionnaire-9 Adolescent Version (PHQ-9) for AYA with T1D. The PHQ-9 was electronically administered (n = 2,491) at routine outpatient medical visits, and PHQ-9 scores, relevant background variables (age, sex, race, ethnicity, diabetes duration), and HbA1c values were obtained via chart review. AYA with T1D were 15.7 years old and had diabetes for 6.2 years, on average. After adjusting for covariates, somatic (B = .08, p <0.001), but not cognitive symptoms (B = .02, p = 0.3), predicted HbA1c levels. Follow up analyses showed this relationship varied by sex, with somatic symptoms and HbA1c related in females (B = .10, p = .002) but not males (B = .05, p = .14), and by race, with somatic symptoms and HbA1c related in those who identify as African American (B = .13, p = .009) but not White (B = .03, p = .32). Logistic regression analyses controlling for relevant background variables showed cognitive symptoms (B = .46, p < 0.001), but not somatic symptoms (B = .06, p = 0.39), were related to suicide attempt history. Findings demonstrate the value of independently monitoring cognitive and somatic symptoms of depression for AYA with T1D. Somatic symptoms are more strongly related to glycemic control, particularly for AYA with T1D who are female and identify as African American, respectively, whereas cognitive symptoms are significantly related to suicide attempt history.

Disclosure

J. M. Gettings: None. E. J. Pantesco: None. N. Andorko: None. S. M. Willi: Advisory Panel; Boehringer Ingelheim International GmbH, Medtronic.
645-P: Experiences of Managing Comorbid Obstructive Sleep Apnea and Type 2 Diabetes among Veterans
Authors: SONG YEONSU , CHOI SARAH E. , PAPAZYAN ANNA , MACEY PAUL M. , ALESSI CATHY , FUNG CONSTANCE H. , MARTIN JENNIFER
Published: June 2023

Obstructive sleep apnea (OSA) is highly prevalent in patients with type 2 diabetes (T2DM), more so in veterans compared to non-veterans. Positive airway pressure (PAP) is the recommended first-line treatment for OSA. However, adherence to both PAP and to diabetes management regimens can be challenging to older adults. This study describes older veterans’ experiences managing comorbid OSA and T2DM, and the types of support they receive from family and friends.

Methods: We conducted a postal survey of 900 randomly selected veterans (aged ≥50 years with medical diagnoses of OSA and T2DM) from one VA healthcare system. Questions included the Diabetes Patient Behavior Checklist and perceived benefits of and assistance with PAP use. Results: Of the 145 respondents (97% men, 51% White, 21% Black, mean age 72 years), 43% received help for diabetes from family or a friend, including preparing healthy food (91%), providing encouragement for diabetes self-care (89%), and eating at the same time (89%). Almost two thirds of the respondents were current PAP users. Among the respondents, 27% received help using PAP from a household member, including putting on the mask (68%), filling the water reservoir (59%), and cleaning the device (59%). Current PAP users had significantly lower levels of hemoglobin A1c than nonusers (6.7 ± 1.1 vs. 7.3± 1.6 %, respectively, p=0.008). Current PAP users also reported significantly higher perceived benefits of PAP use on improving sleep quality, sleep apnea, diabetes, and general health than nonusers. Married or non-White respondents thought it would be more helpful for a family member or friend to receive education on treatment of both OSA and T2DM.

Conclusion: Future studies should investigate feasible strategies for addressing adherence to PAP use as part of diabetes self-management to improve glycemic control and overall health outcomes among patients with T2DM and comorbid OSA. Family support and social/demographic factors should be considered.

Disclosure

Y.Song: None. S.E.Choi: None. A.Papazyan: None. P.M.Macey: None. C.Alessi: None. C.H.Fung: None. J.Martin: None.

Funding

National Institutes of Health (K23AG055668); University of California, Los Angeles Clinical and Translational Science Institute School of Nursing
687-P: Risk Patterns for Suicide Attempts among People with Diabetes Using Association Rules Mining
Authors: NARINDRARANGKURA PLOYPUN , ALAFAIREET PATRICIA , KHAN UZMA Z. , KIM MIN
Published: June 2023

Prevalence of suicide attempts among people with diabetes was approximately 10%, higher than the general population (<5%). This is the first study using association rules mining to discover the risk patterns for suicide attempts in people with diabetes using large multi-centered EHR data. We retrieved data on 3,265,041 diabetes patients from 2010-2020, and 0.2% had a record of suicide attempts. Figure 1 shows the visualization of the top ten association rules. The first rule, {benzodiazepines, no. antidepressants ≥2} ≤ {suicide=Yes}, Support=0.19, Confidence=0.87, means “19% of patients had a record of benzodiazepines, the number of antidepressants ≥2 and suicide attempts together.” In addition, “87% of patients with benzodiazepines and the number of antidepressants ≥2 also had a record of suicide attempts.” We found new findings related to suicide attempts in people with diabetes, including the use of benzodiazepines, atypical antipsychotic agents, two and more antidepressants, none or one diabetes medication, and white in the race. Further studies are needed to validate the results and investigate the causality of suicide attempts and diabetes. Our results can be explainable and practically used by providers during outpatient clinic visits.

Figure 1. Visualization of the top ten association rules represented by circles. Darker color denotes higher confidence, and a larger circle means greater support.

Disclosure

P.Narindrarangkura: None. P.Alafaireet: None. U.Z.Khan: None. M.Kim: None.
694-P: Differences in Diabetes-Related Stigma by Demographic Group and Intensity of Diabetes Management
Authors: ZENG ALISON , LIN EMILY , COX EVELYN , XU EMILY , BELL TREVOR , BRISTOW TRACY L.
Published: June 2023

The social stigma surrounding diabetes refers to the negative attitudes, discrimination, or prejudice someone may face due to their diabetes. For many people with diabetes (PWD), stigma is a major challenge and often results in significant negative consequences, such as poor psychological well-being and worse clinical outcomes. This study aimed to identify groups who may be at greater risk of experiencing stigma. From October-December 2022, 10,338 adults living with diabetes in the United States, Canada, France, Germany, Italy, Netherlands, Sweden, and United Kingdom took an online survey assessing stigma associated with diabetes. Stigma was measured using four items about concealing or difficulty disclosing one's diabetes as well as diabetes-related embarrassment and isolation. These four items were averaged to create a composite variable on degree of stigma experienced (α = 0.87, M = 1.82, SD = 0.89). Subsequent responses were analyzed by various demographic factors and diabetes management strategies using SPSS. Stigma levels differ by intensity of diabetes management; respondents with more demanding diabetes management regimens experience greater levels of stigma. CGM users (p<0.001) and insulin users (p<0.001) experience more stigma than non-users, and PWD taking multiple daily injections experience more stigma than pump users (p=0.027). Stigma also varies across several demographic factors. French respondents report the highest stigma score, while German respondents report the lowest. Further, people with T1D experience more stigma than those with T2D (p<0.001). This research reveals differences in diabetes-related stigma by country and diabetes type and suggests that stigma becomes more prevalent with more intensive diabetes management. Additional research is needed to further explore experiences of stigma and identify methods of support, especially for at-risk groups.

Disclosure

A.Zeng: Employee; dQ&A. E.Lin: Employee; dQ&A. E.Cox: Employee; dQ&A. E.Xu: Employee; dQ&A. T.Bell: Employee; dQ&A. T.L.Bristow: Employee; dQ&A.
72-LB: DD01, a Novel Once-Weekly Dual GLP-1/Glucagon Receptor Agonist, Improves Metabolic Health and Achieves Rapid, Clinically Significant Reductions in Hepatic Steatosis following Only Four Weeks of Treatment and without the Need for Significant Weight Loss in Overweight/Diabetic Subjects with NAFLD
Authors: TO DENNIS , SHIN JAEHEE , KARANTH SUBBU , LIN YEN-HUEI , SOSNOVTSEVA SVETLANA , BELL ADAM C.
Published: June 2023

DD01 is a dual GLP-1/glucagon receptor agonist acting through two independent pathways to provide rapid resolution of hepatic steatosis, improve glucose control, an reduce body weight in subjects with type 2 diabetes who are obese/overweight and have NAFLD. In a recently completed Phase 1 single and repeat dose safety and pharmacology study, DD01 was well tolerated and improved fasting and fed glucose while providing significant reductions in liver fat as measured by MRI-PDFF. Following only 4 weeks of once-weekly treatment, up to 100% of patients achieved ≥30% reduction in MRI-PDFF. In the high dose group, all subjects achieved at least a 40% reduction in liver fat with a mean reduction of 52% whereas the change from baseline liver fat in the placebo group was only 2.8%. Meaningful and rapid improvements in steatosis were observed at well-tolerated doses that did not cause significant weight loss, thus uncoupling the need for weight loss to precede or coincide with significant improvements in liver health.

Disclosure

D. To: Employee; Neuraly Inc. J. Shin: Employee; D&D Pharmatech. S. Karanth: None. Y. Lin: None. S. Sosnovtseva: None. A. C. Bell: None.
75-LB: CT-388, a Novel Once-Weekly Dual GLP-1 and GIP Receptor Modulator, Is Safe, Well-Tolerated, and Produces More than 8% Weight Loss in Four Weeks in Overweight and Obese Adults
Authors: CHAKRAVARTHY MANU , ARGÜELLES-TELLO FEDERICO A. , SUN ANA LIZA A. , ELLIOTT MICHAEL , ACOSTA LUIS , RANKIN JONATHON E. , HANSEN STIG K.
Published: June 2023

GLP-1 and GIP can deliver complementary pharmacology when combined. CT-388 is a biased dual GLP-1 and GIP receptor modulator that exhibits no to minimal β-arrestin coupling at either receptor, designed for once-weekly subcutaneous dosing. A Phase 1, randomized, placebo-controlled, double-blind study was conducted where single ascending doses (0.5-7.5 mg) and multiple ascending doses (MAD; doses 5-12 mg via titration in 3 cohorts) for 4 weeks were administered to overweight/obese adults. Primary objective was to investigate safety and tolerability of CT-388. Total of 64 participants (men/women: 28/36; median age/BMI: 34 years/33 kg/m2) received at least 1 dose of CT-388 or placebo. PK profile was investigated over a wide dose range (0.5-12 mg) and supports once-weekly administration. Percent change in body weight from baseline at Day 29 was dose responsive and significantly greater in CT-388 treated participants versus placebo (p <0.0001) across the 3 MAD cohorts with Least Square Mean difference [95% CI] of -4.8% [-6.3, -3.3], -6.4% [-7.8, -5.0], and -8.5% [-10.4, -6.7]. Mean percent decrease from baseline at Day 23 in fasting glucose (↓8-10%), insulin (↓20-26%), HOMA-IR (↓26-33%), AUC0-120min glucose (↓26-28%) and AUC0-120min insulin (↓33-58%) during oGTT were seen in cohorts dosed up to 12 mg CT-388, suggestive of improved insulin sensitivity. Over the 4-week treatment period, CT-388 was generally well tolerated with no treatment-related discontinuations. The most frequent side effects reported were gastrointestinal (decreased appetite, nausea, vomiting, diarrhea), which were mostly mild in severity.

In summary, CT-388 delivers clinically meaningful weight loss and metabolic control with a favorable tolerability profile. These data warrant further clinical evaluation of CT-388, possibly with minimal to no titration, for the treatment of obesity, T2DM, and other weight-related comorbidities.

Disclosure

M. Chakravarthy: Employee; Carmot Therapeutics, Inc. F. A. Argüelles-Tello: Research Support; Carmot Therapeutics, Inc. A. A. Sun: None. M. Elliott: Employee; Carmot Therapeutics, Inc. L. Acosta: None. J. E. Rankin: None. S. K. Hansen: Board Member; Carmot Therapeutics, Inc.
753-P: Tirzepatide Improves HRQoL Compared with Insulin Lispro in Poorly Controlled Basal Insulin–Treated Adults with Long-Standing T2D (SURPASS-6)
Authors: BOYE KRISTINA , SAPIN HELENE , LING POON JIAT , FERNANDEZ LANDO LAURA , HUH RUTH , WANG MIANBO , PATEL HIREN
Published: June 2023

Tirzepatide, a first-in-class GIP/GLP-1 receptor agonist, resulted in significant improvements in HbA1c and body weight compared to insulin lispro (iLispro) at 52 weeks in the SURPASS-6 study. We compared the HRQoL of participants with T2D treated with tirzepatide (all doses pooled) versus iLispro, both added to basal insulin, in SURPASS-6.

Adults with T2D and inadequate glycemic control were randomized (1:1:1:3) to tirzepatide 5, 10, or 15 mg QW, or iLispro TID, as add-on to optimized insulin glargine, with or without metformin, for 52 weeks in this open-label, multicenter, Phase 3b study. HRQoL was measured at baseline and endpoint (Week 52) using the SF-36v2 acute form comprised of 8 domains and 2 component summary scores.

Overall, 1428 participants with mean baseline age 59 y, T2D duration 14 y, HbA1c 8.8% and BMI 33.1 kg/m2 were randomized. At endpoint, tirzepatide-treated participants had statistically significantly improved scores across all SF-36v2 domains and component summaries compared to iLispro-treated participants, with the largest differences observed in the General health (LS mean [SE] change 3.0 [0.31] vs. -0.1 [0.32]) and Vitality (1.5 [0.31] vs. -1.1 [0.32]) domains (Table).

Tirzepatide treatment resulted in greater improvements across multiple domains of HRQoL than iLispro in adults with long standing T2D already treated with basal insulin.

Disclosure

K.Boye: Employee; Eli Lilly and Company. H.Sapin: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.Poon: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. L.Fernandez lando: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. R.Huh: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. M.Wang: None. H.Patel: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.

Funding

Eli Lilly and Company
754-P: A First-in-Human Single Ascending Dose Study of GSBR-1290, a Novel Small Molecule GLP-1 Receptor Agonist, in Healthy Volunteers
Authors: COLL BLAI , ZHANG JINQIANG J. , JACOBER SCOTT J. , ARGENT CHRISTOPHER , IBARRA LANI , SNYDER MARGO , BACH MARK A.
Published: June 2023

Introduction: Type 2 Diabetes Mellitus (T2DM) and obesity incidences are rising globally. The risk:benefit ratio of peptide GLP-1 receptor agonists (RAs) has been established; however, new therapeutic options are still needed. We report the results of a single ascending dose (SAD) study with GSBR-1290, a highly potent, orally bioavailable, fully biased small molecule GLP-1 RA.

Methods: The study enrolled 48 healthy volunteers in 6 Cohorts, randomized 3:1 to receive GSBR-1290 (1, 10, 15, 30, 60, and 90 mg) or placebo, under fasting conditions. The safety, tolerability, and pharmacokinetics (PK) of a single dose of GSBR-1290 were investigated. The food effect on PK was also assessed in the 15 mg cohort.

Results: Participants were well-balanced across the treatment groups: female (60%), white (66%), mean age (SD) 30 (8) years, and BMI (SD) 24.5 (3.0). All randomized subjects completed the study and there were no deaths or serious adverse events. Treatment-emergent adverse events (TEAEs) were reported for 32/36 participants (89%) following fasted administration of GSBR-1290 and for 7/12 participants (58%) following administration of placebo. The majority (94%) were mild or moderate in severity. As expected, the most common TEAEs were gastrointestinal-related and included nausea, vomiting, decreased appetite and diarrhea, consistent with other drugs in this class. No clinically significant changes in laboratory safety parameters were reported. PK (Cmax and AUC) of GSBR-1290 increased with dose, and a high fat meal was associated with a 20% decrease in the geometric mean AUC and a 36% decrease in Cmax.

Conclusion: GSBR-1290 is a promising orally available GLP-1 RA and was well-tolerated in this SAD study in healthy volunteers. These data support further clinical development in a multiple ascending dose study in individuals with T2DM and obesity.

Disclosure

B.Coll: Employee; Amgen Inc., ShouTi Pharma Inc. J.J.Zhang: Employee; Structure Therapeutics Inc. S.J.Jacober: Consultant; Structure Therapeutics, Inc., Adocia, Employee; Sanofi-Aventis U.S., Applied Therapeutics Inc., Other Relationship; Eli Lilly and Company. C.Argent: None. L.Ibarra: Employee; Structure Therapeutics. M.Snyder: None. M.A.Bach: Employee; Structure Therapeutics, Stock/Shareholder; Johnson & Johnson.

Funding

Structure Therapeutics Inc.
77-OR: Targeting JunB Induces a Shift from Low- to High-Thermogenic Adipocytes and Ameliorates Diet-Induced Insulin Resistance
Authors: ZHANG XING , WANG CHUNQING , LIU MEILIAN
Published: June 2023

The coexistence of brown adipocytes with low and high thermogenic activity is a fundamental feature of brown adipose tissue (BAT) heterogeneity and plasticity. However, the mechanisms that govern thermogenic adipocyte heterogeneity and its significance in obesity and metabolic disease remain poorly understood. In the current study, we identified a population of JunB-enriched adipocytes (JunB+ adipocytes) within the brown fat depot that exhibits lower thermogenic capacity and fewer and smaller lipid droplets compared to high-thermogenic adipocytes. This population of JunB+ adipocytes exhibited marked expansion during obesity, in part through induction of pro-inflammatory cytokines TNFα and IL-6. Depletion of JunB in adipocytes or UCP1+ adipocytes increased the fraction of adipocytes exhibiting high mitochondrial content and thermogenic capacity, leading to enhanced basal and cold-induced energy expenditure and protection against diet-induced obesity and insulin resistance. Mechanistically, JunB directly binds to the promoter of estrogen-related receptor α (Errα), a downstream effector of PGC1α, and suppresses its transcriptional function. JunB antagonizes the stimulatory effects of PGC1α-ERRα on mitochondrial biogenesis and high-thermogenic adipocyte development. Taken together, our studies uncover a novel mechanism involving JunB that shapes thermogenic adipocyte heterogeneity and serves a critical role in maintaining systemic metabolic health.

Disclosure

X.Zhang: None. C.Wang: None. M.Liu: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (DK110439); American Heart Association (20POST35120020)
777-P: Early Weight Loss and Late Metabolic Outcomes in Tirzepatide-Treated Participants with Type 2 Diabetes
Authors: LINGVAY ILDIKO , GIORGINO FRANCESCO , VAN GAAL LUC , LIU MINZHI , RODRÍGUEZ ÁNGEL , TORCELLO-GOMEZ AMELIA , KILJANSKI JACEK I.
Published: June 2023

Tirzepatide (TZP), a novel, once-weekly GIP/GLP-1 receptor agonist, significantly improved glycemic control with robust weight loss vs comparators in the SURPASS 1-5 trials. The aim of this analysis was to assess whether the magnitude of early weight loss with TZP (<5% or ≥5% at Week 8) would be associated with different clinical response in terms of HbA1c and weight at Week 40/42 across the SURPASS 1-5 trials.

These phase 3 trials included participants with type 2 diabetes receiving TZP as monotherapy or add-on to background antihyperglycemic medications. This post-hoc analysis used pooled data from all TZP arms (5, 10, and 15 mg) across trials.

Participants achieving ≥5% early weight loss at Week 8 had lower HbA1c and weight at baseline, and experienced greater reductions in HbA1c and weight at Week 40/42 vs those achieving <5% early weight loss (Table). Among participants achieving ≥5% early weight loss, greater proportions met HbA1c <7% and ≤6.5%, ≥10% weight loss, and the composite endpoint of HbA1c <7% and ≥10% weight loss.

Early weight loss with TZP predicts greater reductions of HbA1c and weight at Week 40/42. However, even the one third of participants achieving <5% weight loss early in the course of therapy are likely to meet the ADA/EASD dual treatment goals of HbA1c <7% and ≥10% weight loss.

Disclosure

I.Lingvay: Advisory Panel; Novo Nordisk A/S, Lilly Diabetes, Boehringer-Ingelheim, Sanofi, Consultant; Carmot Therapeutics, Inc., Merck Sharp & Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc., Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer, Research Support; Novo Nordisk A/S, Boehringer-Ingelheim. F.Giorgino: Advisory Panel; Boehringer-Ingelheim, Amarin Corporation, Medtronic, Roche Diabetes Care, Sanofi, Bayer Inc., Novo Nordisk, Consultant; Novo Nordisk, Lilly, Research Support; Lilly, Roche Diabetes Care, AlfaSigma, Speaker's Bureau; Abbott, Boehringer-Ingelheim, Lilly, Sanofi, Medscape. L.Van gaal: Advisory Panel; Merck Sharp & Dohme Corp., Speaker's Bureau; Boehringer Ingelheim Pharma GmbH&Co.KG, Eli Lilly and Company, Novo Nordisk. M.Liu: Consultant; Eli Lilly and Company. Á.Rodríguez: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A.Torcello-gomez: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.I.Kiljanski: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.

Funding

Eli Lilly and Company
810-P: Do People Living with T1D Use the Dosing Flexibility of Degludec and Does This Depend on Patient Characteristics?
Authors: WINHOFER YVONNE , KAAS ANNE , KNUDSEN NIKOLINE N. , MARTINY JOHANNES H.J. , MATHIEU CHANTAL
Published: June 2023

Flexibility in insulin degludec injection timing of 8-40 hrs between doses allows people with diabetes to adapt their treatment around daily life. This real-world multinational study explored flexible dosing (≥6hr difference in time of day [clock-time] between consecutive doses) in terms of prevalence and associated characteristics in 1136 people with T1D (mean [SD] age 31.3 [17.7] years, 54% male, median observation period 124 days [IQR 41, 234]) who were administering insulin degludec with smart pens. Of these participants, 14.4% regularly flexed dosing time (≥1 time every month). The probability of having ≥1 flexible dose in a given 2-week period was shown by a generalized linear mixed model (log link) with participant ID as a random effect and individual characteristics as fixed effects. Estimated LS-mean probability of ≥1 flexible dose in a given 2-week period was 25.0% (95% CI: 21.5%, 28.9%), with higher probability for young adults (aged 18-25), those who usually inject 9am-6pm, and those with a higher (>30 U/day) basal dose (all p<0.01). Probability decreased with time from smart pen initiation (p<0.01). In the subgroup of 455 adults with CGM data, flexibility in dosing time did not affect glycemic control. Overall, a group of people with T1D used the degludec dosing flexibility; these were most often young adults aged 18-25, those injecting 9am-6pm, and those requiring higher degludec doses.

Disclosure

Y.Winhofer: Speaker's Bureau; Abbott Diabetes, Amgen Inc., Boehringer-Ingelheim, Eli Lilly and Company, Novartis, Novo Nordisk, Medtronic, Sanofi-Aventis Deutschland GmbH, Daiichi Sankyo. A.Kaas: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. N.N.Knudsen: Employee; Novo Nordisk. J.H.J.Martiny: Employee; Novo Nordisk. C.Mathieu: Advisory Panel; Novo Nordisk A/S, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated, Roche Diabetes Care, Imcyse, Speaker's Bureau; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated.

Funding

Novo Nordisk A/S
820-P: The Proposed Insulin Lispro Biosimilar GN1101DP Shows Pharmacokinetic (PK) and Pharmacodynamic (PD) Bioequivalence to Humalog in Caucasian and Chinese Healthy Subjects
Authors: HEISE TIM , ZIJLSTRA ERIC , ANDERSEN GRIT , SELKER STEFFEN B. , SHEN CHUN , WANG YUN
Published: June 2023

This randomized, double-blind, cross-over study compared PK/PD-properties of Humalog and GN1101DP, a proposed insulin lispro (INS) biosimilar with an identical primary structure and high physicochemical and bio-functional similarity to Humalog. Thirty-five Caucasian and 13 Chinese healthy subjects completed the study and received a single dose of 0.3 U/kg of GN1101DP and Humalog under euglycemic automated glucose clamp conditions (ClampArt®, plasma glucose (PG) target 81 mg/dL, clamp duration 12 hours post-dose, wash-out period 2-14 days between the two dosings). Plasma INS concentrations were determined by tandem ultra performance liquid chromatography-mass spectrometry. GN1101DP demonstrated both PK- and PD-bioequivalence to Humalog with superimposable INS concentration and glucose infusion rate (GIR) profiles, point estimates close to 100%, and 90% confidence intervals were within the pre-defined similarity range of 80-125%. Bioequivalence was observed in all and also separately in Caucasian and Chinese subjects (Figure). Clamp quality was high (mean PG-variations of ~5% and deviations from target <0.6 mg/dL). Both lispro formulations were well tolerated. No injection site reactions occurred. In conclusion, GN1101DP demonstrated PK- and PD-bioequivalence to Humalog in Caucasian and Chinese subjects.

Disclosure

T.Heise: Advisory Panel; Novo Nordisk, Consultant; Gan & Lee Pharmaceuticals, Research Support; Adocia, AstraZeneca, Biocon, Crinetics Pharmaceuticals, Inc., Eli Lilly and Company, Genova, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker's Bureau; Eli Lilly and Company, Novo Nordisk. E.Zijlstra: Other Relationship; Eli Lilly and Company, Speaker's Bureau; Gan & Lee Pharmaceuticals, Novo Nordisk A/S. G.Andersen: None. S.B.Selker: None. C.Shen: None. Y.Wang: None.

Funding

Genova Biotech Pvt. Ltd.
888-P: Urinary Albumin Levels Prior to SGLT2 Inhibitors Initiation Predict Increased TIR after 12 Months in Patients with Type 1 Diabetes on Sensor-Augmented Pump Therapy
Authors: SUGANUMA YUKA , TAKAHASHI HIROSHI , OHNO TAKAYUKI , NISHIMURA RIMEI
Published: June 2023

Purpose: SGLT2 inhibitors (SGLT2i) have been shown to improve glycemic control in patients with type 1 diabetes (T1D). Predictors of SGLT2i efficacy in patients with T1D on sensor-augmented pump (SAP) therapy were investigated.

Methods: Patients with T1D on SAP therapy attending our hospital who were newly initiated on SGLT2i between 2019-2020 and followed for at least one year, were included in the study. Data on BMI, blood tests, and continuous glucose monitors were compared before and 12 months after SGLT2i initiation. The predictors of time in range (TIR) change (ΔTIR) were determined by multiple regression analysis. The cutoff values for predictors of ΔTIR above the median at the end of the study were determined using ROC curve analysis.

Results: 17 patients (70.6% females, median age 44.0 years) were included in the analysis, except for three patients who discontinued SGLT2i due to side effects. Median BMI and eGFR decreased significantly from 25.3 kg/m2, and 79.0 ml/min/1.73m2 at baseline to 23.9 kg/m2, and 73.0 ml/min/1.73m2 (p = 0.013, p = 0.002, respectively), while total daily dose of insulin, basal-to-total insulin ratio, and urinary albumin-to-creatinine ratio (UACR) showed no significant change (40.1 vs 41.0 units [p = 0.084], 40.1 vs 38.5% [p = 0.266], 7.0 vs 2.0 mg/g [p = 0.285], respectively). HbA1c, TIR, and TAR improved significantly (8.2 vs 7.8% [p = 0.004], 53.0 vs 61.0% [p = 0.003], and 47.0 vs 36.0% [p = 0.003], respectively), while TBR showed no significant change (0.4 vs 0.8% [p = 0.309]). Predictors of increased ΔTIR were overweight and high UACR at baseline (p = 0.026) and the cutoff value for UACR that predicted ΔTIR above the median was 28.0 mg/g (AUC = 0.82 [95%CI, 0.61-1.03]; p = 0.003).

Conclusion: SGLT2i improved glycemic control of patients with T1D on SAP therapy without increasing TBR. It was also suggested that patients with UACR above 28.0 mg/g could have greater impact on TIR improvement after 12 months.

Disclosure

Y.Suganuma: None. H.Takahashi: Speaker's Bureau; Eli Lilly Japan K.K., Boehringer Ingelheim Japan, Inc., Medtronic, Novo Nordisk. T.Ohno: None. R.Nishimura: Speaker's Bureau; Sanofi K.K., Medicure Inc., Boehringer Ingelheim Inc., Takeda Pharmaceutical Company Limited, Kissei Pharmaceutical Co., Ltd., Novartis Pharma K.K., Eli Lilly Japan K.K., Novo Nordisk, Merck & Co., Inc., Abbott Japan Co., Ltd., Astellas Pharma Inc., Teijin Pharma Limited, Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., AstraZeneca.
89-LB: Oral Delivery of a GLP-1 Agonist with High Bioavailability in Dogs and Humans
Authors: VO APRIL T. , YAMAGUCHI ALYSON , DHALLA ARVINDER , HORLEN KYLE , FUNG LEONARD , SYED BABER , IMRAN MIR , HASHIM MIR
Published: June 2023

GLP-1 mimetics, which are highly efficacious as antidiabetic agents, are also proving to be effective for weight loss, albeit at higher doses. While most require injections due to poor oral bioavailability, Rybelsus® (semaglutide) is orally effective for glycemic control, however, its 1% bioavailability and high dose requirement limits its viability as an effective oral weight-loss medication. Here, we demonstrate high oral bioavailability of the GLP-1 agonist, exenatide, A) in canines using an orally ingestible robotic pill (RP) which painlessly injects drug transenterically in the proximal small bowel and B) in humans using an endoscopically guided transenteric injection which mimics RP delivery. Awake dogs received 10 µg of exenatide orally via RP (RT-104, N=4) or SC injection (Byetta®, N=5), while 5 healthy human volunteers received 10 µg of Byetta® via an endoscopic, transenteric injection and, after a 3-day washout, via a SC injection. Exenatide concentrations, determined via ELISA in serially collected plasma samples, yielded similar PK curves in both species (Figure) with oral bioavailability via RP or endoscopic injection calculated to be 79% in dogs and 81% in humans, respectively, compared to SC injections. These data provide the basis for further development of an orally ingestible GLP-1 mimetic (RT-104) which would provide the higher, efficacious exposures needed for both weight loss and glycemic control.

Disclosure

A. T. Vo: None. A. Yamaguchi: None. A. Dhalla: Employee; Rani Therapeutics. K. Horlen: Employee; Rani Therapeutics. L. Fung: None. B. Syed: None. M. Imran: Board Member; Neptune Medical, Other Relationship; InCube Ventures, Modulus, Inc. M. Hashim: None.
92-OR: The Survival and Function of Whole or Dissociated Islet Transplants Are Improved by Immunomodulatory Microporous Annealed Particle (MAP) Gel
Authors: MA MINGYANG , ROOSA COLLEEN A. , GRIFFIN DONALD R. , BRAYMAN KENNETH L. , CHHABRA PREETI
Published: June 2023

The aim was to investigate if MAP gel can support the function of whole islets or dissociated islet cells, and improve transplantation under kidney capsule or within the epididymal fat pad. A) Whole or dissociated BL/6 islets were transplanted into syngeneic diabetic recipients in the presence or absence of MAP gel. 100 islets were transplanted under the kidney capsule (n=6/group). Mice receiving transplant within the fat pad were divided into 6 groups (n=2/group): 300 whole islets; 400 dissociated islets; MAP gel alone; and 200, 300 or 400 dissociated islets with MAP gel. Blood glucose (BG) was measured daily. B) MAP gel or NP gel was transplanted within the fat pad of NOD mice (n=4/group) to analyze the immune response. Graft-containing fat pad was excised 6 weeks post-transplantation and analyzed for cytokines by flow cytometry. Our results indicated that transplantation of dissociated islets and MAP gel under the kidney capsule permanently restored normoglycemia within 18 days. In contrast, uncoated dissociated islet cells failed to reverse diabetes. Treatment efficacy continued 40 days post-transplantation, the entire period of observation. At Day 30, average BG was 163±38mg/dL. Diabetic mice transplanted with dissociated islet cells without MAP gel remained hyperglycemic. Transplantation of 400 dissociated islet cells with MAP gel within the fat pad also achieved normal BG levels that continued 44 days post-transplantation, the period of observation. In contrast, transplantation of MAP gel, or 300 whole islets, or dissociated islets alone into the fat pad, failed to reverse diabetes. An upregulation of IL-10 and downregulation of IL-6 was observed only in the graft microenvironment of the MAP gel group, validating the immunomodulating capacity of MAP gel. To conclude, MAP gel can promote transplantation outcomes under the kidney capsule or within the fat pad by improving the survival and function of both, whole and dissociated islets.

Disclosure

M.Ma: None. C.A.Roosa: None. D.R.Griffin: Board Member; Tempo Therapeutics. K.L.Brayman: None. P.Chhabra: None.

Funding

LaunchPad for Diabetes Innovation Fund (GF004946); LaunchPad for Diabetes Ignite Program (169098)
920-P: Effects of Hybrid Closed-Loop System on Glycemic Control and Psychological Aspects in Persons with Type 1 Diabetes Treated with Sensor-Augmented Pump—A Prospective Single-Center Observational Study
Authors: AKIYAMA TOMOAKI , ORIME KAZUKI , YAMAKAWA TADASHI
Published: June 2023

Introduction Since the Medtronic 770G hybrid closed-loop (HCL) system was approved in Japan in 2022, we evaluated the effects of the HCL system on glycemic control and psychological aspects in persons with type 1 diabetes mellitus (T1DM) treated with the Medtronic 640G predictive low glucose suspend (PLGS) system. Materials and Methods In a 3-month prospective observational study, 21 people with T1DM (mean age: 48.7 years; male: 5 people) treated with PLGS system were enrolled. The participants switched to the 770G system, where the algorithm maintains glucose levels at 120 mg/dl, and in 3 months the percentage of time in blood glucose range (TIR) 70-180 mg/dl and glycated hemoglobin level (HbA1c) were evaluated. Self-reported questionnaires were administered at baseline and in 3 months to assess their satisfaction, emotional distress, and quality of life (QoL), using Diabetes treatment satisfaction questionnaire status (DTSQs), Problem area in diabetes scale (PAID), and Diabetes therapy-related QoL (DTR-QoL), respectively. Results In 3 months, TIR increased from 63.2 ± 13.7% to 72.7 ± 11.1% (mean ± standard deviation) (P < 0.0005), whereas time above blood glucose range (TAR) 181-250 mg/dl decreased from 26.9 ± 9.1% to 19.7 ± 7.2 % (P < 0.0005). TAR > 250 mg/dl, time below blood glucose range (TBR) 54-69 mg/dl and TBR < 54 mg/dl did not differ significantly. HbA1c decreased from 7.7 ± 1.0% to 7.2 ± 0.8% (P = 0.0013). There were no significant changes in DTSQs, PAID, and DTR-QOL in 3 months (DTSQs 26.7 ± 6.0 compared with baseline 26.9 ± 4.0, P = 0.87, PAID 52.3 ± 17.9 compared with baseline 54.0 ± 16.3, P = 0.48, DTR-QoL 50.1 ± 19.0 compared with baseline 47.0 ± 16.9, P = 0.38). Conclusion HCL system could increase TIR, compared with PLGS system, without worsening treatment satisfaction, emotional distress, and QoL. This study suggested HCL system is useful for Japanese people with T1DM.

Disclosure

T. Akiyama: None. K. Orime: None. T. Yamakawa: None.
923-P: CamAPS FX Hybrid Closed-Loop with Ultra-Rapid Insulin Lispro Increases Time in Range Compared with Standard Insulin Lispro in Adults with Type 1 Diabetes—A Double-Blind, Randomized, Crossover Study
Authors: NWOKOLO MUNACHISO , LAKSHMAN RAMA , BOUGHTON CHARLOTTE K. , WARE JULIA , ALLEN JANET M. , WILINSKA MALGORZATA E. , ALWAN HEBA , EVANS MARK , HOVORKA ROMAN
Published: June 2023

Aim: To evaluate hybrid closed-loop with ultra-rapid insulin lispro (Lyumjev) in adults with type 1 diabetes (T1D).

Methods: In a double-blind, randomized, crossover study, 28 adults with T1D (mean±SD; age 44.5±10.7 years, HbA1c 7.1±0.9% [54±10mmol/mol]) underwent two 8-week periods comparing hybrid closed-loop with Lyumjev and hybrid closed-loop with standard insulin lispro in random order. CamAPS FX closed-loop system was used in both periods.

Results: In an intention-to-treat analysis, proportion of time sensor glucose was in target range (70 to 180mg/dL; primary endpoint) was greater with Lyumjev compared with standard insulin lispro (mean±SD; 78.7±9.8% vs. 76.2±9.6%; mean difference 2.5 percentage points [95%CI 0.8 to 4.2]; p=0.005). Mean sensor glucose was lower with Lyumjev compared with standard insulin lispro (142±14mg/dL vs. 146±16mg/dL; p=0.048). Proportion of time with sensor glucose <70mg/dL was similar between interventions (median[IQR] Lyumjev 2.3% [1.3-2.7%] vs. standard insulin lispro 2.1% [1.4-3.3%]; p=0.33). No severe hypoglycemia or ketoacidosis occurred.

Conclusions: The use of Lyumjev with CamAPS FX hybrid closed-loop increases time in range and reduces mean glucose with no difference in hypoglycemia compared with standard insulin lispro in adults with T1D.

Disclosure

M.Nwokolo: None. R.Lakshman: None. C.K.Boughton: Consultant; CamDiab Ltd., Speaker's Bureau; Ypsomed AG. J.Ware: Other Relationship; Ypsomed AG. J.M.Allen: Research Support; CamDiab Ltd. M.E.Wilinska: Consultant; CamDiab Ltd. H.Alwan: None. M.Evans: Advisory Panel; Zucara Therapeutics, Pila Pharma, Dexcom, Inc., Other Relationship; Novo Nordisk, AstraZeneca, Abbott Diabetes, Speaker's Bureau; Eli Lilly and Company. R.Hovorka: Advisory Panel; Ypsomed AG, Consultant; Abbott Diabetes, B.Braun, Speaker's Bureau; Eli Lilly and Company, Stock/Shareholder; CamDiab Ltd.

Funding

National Institute for Health and Care Research; Cambridge Biomedical Research Centre (BRC-1215-20014)