bluuebunny/crossref_metadata_2025 huggingface dataset:
357-OR: Continuous Glucose Monitoring in Diabetes Patients with Cognitive Impairment
Authors: KOTECHA PAREETA , CHEN WEI-HAN , LI YUJIA , DONAHOO WILLIAM T. , BIAN JIANG , GUO JINGCHUAN
Published: June 2023

Objective: Continuous glucose monitoring (CGM) is beneficial in individuals at high risk of hypoglycemia or hypoglycemic events. Cognitive impairment can affect diabetes management and lead to poor health outcomes. We aimed to (1) assess the association between CGM use and all-cause mortality among diabetes patients with cognitive impairment and dementia, and (2) determine disparities in the use of CGM in this population.

Methods: We used 2016-2020 electronic health records data from the University of Florida Health System and identified patients who (1) had diagnoses of both diabetes and cognitive impairment (i.e., mild cognitive impairment or Alzheimer's disease and related dementias) and (2) were insulin users. We examined CGM use by race/ethnicity and insurance status; and applied multiple logistic regression to examine the association of CGM use with all-cause mortality.

Results: Of 1995 eligible patients (mean age 70.5±9.9 years, 56.9% non-Hispanic White (NHW), 37.5% non-Hispanic Black (NHB), and 5.6% others), 51 (2.6%) were CGM users and 566 (28.9%) died in a median follow up of 697 days. Black patients were less likely to use CGM compared to White patients (29.4% vs. 37.7% were Black among CGM users vs. non-users, respectively). Medicaid/uninsured patients were less likely to use CGM compared to Medicare/private insurance patients (1.9% vs. 11% were Medicaid/uninsured patients among CGM users vs. non-users, respectively). After adjusting for demographic and clinical characteristics in insulin users, CGM users were associated with a significantly lower risk of all-cause mortality compared to non-CGM users (adjusted OR (95% CI):0.2 (0.1-0.6)).

Conclusion: The use of CGM was associated with improved survival among diabetes patients who were insulin users and had cognitive impairment. However, racial and socioeconomic disparities in the use of CGM were observed, which may exacerbate existing inequities in diabetes care and outcomes.

Disclosure

P.Kotecha: Employee; Novo Nordisk Global Business Services. W.Chen: None. Y.Li: None. W.T.Donahoo: None. J.Bian: None. J.Guo: Consultant; Pfizer Inc., Research Support; PhRMA Foundation, NIH - National Institutes of Health.
358-OR: Better Adherence to Real-Time Continuous Glucose Monitoring (rtCGM) than to Intermittently Scanned CGM (isCGM) among People with Type 2 Diabetes (PWT2D) on Intensive Insulin Therapy (IIT)
Authors: NEMLEKAR POORVA , HANNAH KATIA , NORMAN GREGORY J.
Published: June 2023

Background: For PWT2D, medication regimen adherence is associated with improved glycemic control and reduced health care utilization. However, little is known about CGM adherence for managing T2D, and how it varies by type of CGM.

Materials and Methods: A retrospective analysis of Merative’s MarketScan® US healthcare claims data was conducted. The cohort included CGM-naïve PWT2D on IIT who initiated rtCGM or isCGM between 1/1/2017 through 12/31/2020 (index date=earliest observed pharmacy claim). Adherence was defined as having ≥80% proportion of days covered (PDC) by pharmacy claims. Inclusion criteria were adults ≥30 years of age with T2D, using bolus insulin, with continuous health plan enrollment coverage 12 months before (baseline) and 12 months after the index date (follow-up), and no evidence of prior CGM use. The association between CGM adherence and change in A1C was examined in a subset of 663 patients with 6-month baseline and 6-month follow-up laboratory values.

Results: The rtCGM group (n=2,349) was [mean (SD)] 49.2 (8.0) years of age and 48% female, while the isCGM group (n=8,881) was 50.4 (8.0) years of age and 48% female. Average PDC was 85% (26%) for the rtCGM group and 68% (32%) for the isCGM group. A total of 76.2% of the rtCGM group and 50.6% of the isCGM group met the ≥80% PDC level of adherence. A multivariate logistic regression model showed the odds of adherence were three times greater for rtCGM compared to isCGM (OR=3.2, 95% CI 2.8-3.5, p<0.001). Those adherent to CGM, regardless of device type, had a greater decrease in A1C (-0.94%) compared to those who did not meet the adherence criterion (-0.54%) (p<0.001).

Conclusions: These findings indicate that for PWT2D on IIT, adherence to rtCGM is higher than to isCGM. The association between adherence and reduced A1C suggests patients can improve glycemic control with consistent use of CGM.

Disclosure

P.Nemlekar: Employee; Dexcom, Inc. K.Hannah: Employee; Dexcom, Inc. G.J.Norman: Employee; Dexcom, Inc.

Funding

Dexcom, Inc.
36-LB: Dulce Digital-Me—A Randomized Comparative Effectiveness Trial of Static vs. Adaptive Digital Interventions for Hispanic Adults with Diabetes
Authors: PHILIS-TSIMIKAS ATHENA , FORTMANN ADDIE L. , CLARK TAYLOR , SPIERLING BAGSIC SAMANTHA R. , FARCAS EMILIA , ROESCH SCOTT , SCHULTZ JAMES H. , GILMER TODD P. , GODINO JOB G. , SAVIN KIMBERLY L. , JONES JENNIFER A. , CHICHMARENKO MARIYA , SANDOVAL HALEY , GALLO LINDA
Published: June 2023

We compared the effectiveness of Dulce Digital (DD), a diabetes education text messaging program, versus Dulce Digital-Me (DD-Me), which included DD text messaging plus algorithm-driven, personalized goal-setting and feedback, in improving diabetes outcomes in Hispanic adults with type 2 diabetes (T2D). In this open-label comparative effectiveness trial, Hispanic adults with T2D were randomized (1:1:1) to receive DD, or the more personalized DD-Me approach delivered via automated, algorithm-driven text messaging (DD-Me_Auto) or telephonic communication from a health coach (DD-Me_Tel) across 6-months as part of existing primary care. Changes in clinical (HbA1c—primary) and patient reported outcomes were examined over 12 months. We enrolled N=310 Hispanic participants (69.7% female; M=52.1±10.2 years; 93.2% Spanish preferred; HbA1c M= 9.3±1.6 %) to receive DD (n=107), DD-Me_Auto (n=106) or DD-Me_Tel (n=97). Mixed models revealed no difference between DD and DD-Me (combined Auto+Tel) in rate of HbA1c change across 6- or 12-months, ps>0.05. All groups showed clinically and statistically significant improvements in HbA1c across 6-months [DD ∆ = -0.17% per month post baseline (95% CI -0.22,-0.10); DD-Me_Auto ∆= -0.20% (95% CI -0.26,-0.14); DD-Me_Tel ∆ = -0.15% (95% CI -0.20,-0.10), ps<.001]. Effect sizes were slightly attenuated, but remained statistically significant at 12-months (∆ HbA1c= -0.08% to -0.05% per month; ps < 0.001). Self-management behaviors and diabetes distress improved across 12-months in all groups. DD-Me (combined) showed greater improvement in medication adherence versus DD over time (Bint=-0.20, 95% CI -0.33,-0.01, p< 0.01). Two low-cost digital interventions for Hispanic adults with low income and T2D had similar and clinically significant effects on HbA1c across 12 months. Simple digital approaches can be integrated within primary care-based chronic care models to reduce diabetes disparities.

Disclosure

A. Philis-tsimikas: Advisory Panel; Dexcom, Inc., Novo Nordisk A/S, Sanofi, Other Relationship; Medtronic, Research Support; Novo Nordisk A/S, Lilly, Viking Therapeutics, NIH - National Institutes of Health. K. L. Savin: None. J. A. Jones: None. M. Chichmarenko: None. H. Sandoval: None. L. Gallo: None. A. L. Fortmann: Employee; Dexcom, Inc. T. Clark: None. S. R. Spierling bagsic: None. E. Farcas: None. S. Roesch: None. J. H. Schultz: None. T. P. Gilmer: None. J. G. Godino: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK1123221UL1, TR002550)
360-OR: Continuous Glucose Monitoring–Guided Insulin Administration in Subjects with Type 2 Diabetes in Long-Term Care Facilities—A Randomized Clinical Trial
Authors: IDREES THAER , CASTRO-REVOREDO IRIS A. , OH HYUNGSEOK , GAVALLER MONICA D. , ZABALA ZOHYRA , MORENO EMMELIN M. , MOAZZAMI BOBAK , GALINDO RODOLFO J. , CABB ELENA , JOHNSON THEODORE M. , PENG LIMIN , UMPIERREZ GUILLERMO
Published: June 2023

The efficacy of real-time continuous glucose monitoring (rt-CGM) in adjusting insulin therapy in long-term care facilities (LTCF) has not been evaluated. Accordingly, we randomized 100 insulin-treated subjects with T2D in LTCF. All subjects underwent point-of-care (POC) capillary glucose testing before meals and bedtime. Patients in the standard of care (POC group) wore a blinded Dexcom G6 CGM with treatment adjusted based on POC results; while in the rt-CGM group (Dexcom G6), treatment adjustment was based on daily CGM profile. Treatment adjustment was performed by the LTC medical team, with a target glucose of 140-180 mg/dL, and a duration of intervention up to 60 days. Primary endpoint was difference between groups in time in range (TIR, 70-180 mg/dL). Results: There were no significant differences in TIR (53.38%±30.16 vs 48.81%±28.03, p=0.40), mean daily glucose (185±44 vs 191 ±47 mg/dL, p=0.72), patients with % CGM values <54 mg/dL (0.23±0.8% vs 0.56±2.2 %, p=0.88), with a trend in reducing time below range (TBR <70 mg/dL) (0.83±2.6 % vs 1.18±3.5%, p= 0.51), between CGM and POC group. Conclusion: The results of this pilot randomized study indicate that the use of Dexcom G6 rtCGM is safe and effective in guiding diabetes therapy in long-term care facilities, resulting in a similar improvement in glycemic control (TIR) without differences in hypoglycemia.

Disclosure

T.Idrees: None. T.M.Johnson: Consultant; Astellas Pharma Inc., Research Support; Dexcom, Inc. L.Peng: None. G.Umpierrez: Research Support; Abbott, Dexcom, Inc., Baxter. I.A.Castro-revoredo: None. H.Oh: None. M.D.Gavaller: None. Z.Zabala: None. E.M.Moreno: None. B.Moazzami: None. R.J.Galindo: Consultant; Novo Nordisk, Eli Lilly and Company, Sanofi, Pfizer Inc., Bayer Inc., WW (Weight Watchers), Research Support; Novo Nordisk, Eli Lilly and Company, Dexcom, Inc. E.Cabb: None.

Funding

Dexcom, Inc. (IIS-2020-119_6X)
364-OR: Unsupervised Approach Systematically Analyzes the Multiomics Profiles Associated with T2D Insulin Insensitivity—An IMI-RHAPSODY Study
Authors: LI SHIYING , IBBERSON MARK , RUTTER GUY A. , PEARSON EWAN , SLIEKER RODERICK , BEULENS JOLINE , HANSEN MICHAEL K. , KUZNETSOV DMITRY , GERL MATHIAS J. , DRAGAN IULIAN J. , SIMONS KAI , DONNELLY LOUISE A. , TRAN VAN DU T. , MEHL FLORENCE , 'T HART LEEN M.
Published: June 2023

Considerable heterogeneity exists in Type 2 diabetes disease onset and subsequent outcomes. Multi-omics analysis may provide a means to better assess inter-patient variations and design personalised approaches. Previous T2D biomarker discovery mainly focused on associating biomarkers with clinical pre-assigned patients. Here, we attempt to group T2D patients with similar multi-omics profiles using a multi-omics integrating clustering approach, Similarity Network Fusion (SNF). Each T2D subgroup’s unique omics profiles were then associated with T2D progression. In both cohorts, 180 and 1195 circulating lipids and proteins from a total of 1,134 subjects in DCS and GoDARTS cohorts group patients into two subgroups. Two subgroups are likely to represent the different stages of T2D insulin insensitivity with differences at HOMA2 (p=0.0008;4.2e-11;1.1e-09, -B, -IR and -S, DCS), C-peptide (p=3.7e-11;2.5e-06) and overall disease progression (HR=0.6;0.7). This is the first study solely relying on integrated lipidomics and proteomics to capture the stages of T2D insulin insensitivity, allowing potential novel biomarker discovery which may be masked by traditional approaches. In both cohorts, a number of discriminative omics features can be observed. Immune proteins, such as IL-18R, CLP, IL-1R and COD antigen showed strong but differing associations with insulin insensitivity, which may be related to the inflammation associated with T2D. Moreover, growth factors such as GHR and IGFs also exhibit strong associations with the present study. For lipids, patients with less severe insulin insensitivity exhibit elevated levels of sphingomyelins. In conclusion, we systematically analysed the multi-omics profiles associated with T2D insulin insensitivity. The molecular signatures may be used to investigate molecular mechanisms underpinning progression and provide insights for precision medicine.

Disclosure

S.Li: None. I.J.Dragan: None. K.Simons: Other Relationship; Lipotype, I have no there compoanz. L.A.Donnelly: None. V.T.Tran: None. F.Mehl: None. L.M.'t hart: Research Support; European Union. M.Ibberson: Consultant; Novo Nordisk Foundation. G.A.Rutter: Consultant; Sun Pharmaceutical Industries Ltd. E.Pearson: Speaker's Bureau; Novo Nordisk, Lilly, Illumina. R.Slieker: None. J.Beulens: None. M.K.Hansen: None. D.Kuznetsov: None. M.J.Gerl: Employee; Lipotype GmbH.
367-OR: E-cigarette Vaping Exposure Increases Adipose 11ß-HSD1 Expression and Disturbs Glucose Homeostasis in Mice
Authors: WANG JIAN , LIU JENNY , WANG YING , KIM SAMUEL C.J. , ESPINAL ELIZABETH , YANG RONG , ZHONG HUI , SHAO XUESI M. , LUTFY KABIRULLAH , FRIEDMAN THEODORE , JIANG MEISHENG , LIU YANJUN
Published: June 2023

Electronic cigarette (E-cigs) use may increase the prediabetic risk, but the underlying mechanisms remain underexplored. Pre-receptor activation of glucocorticoids (GCs) via 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in adipose tissues has been identified as an important mediator of insulin resistance and type 2 diabetes. However, little is known about the effects of E-cig vaping on 11β-HSD1 and glucose homeostasis. To address this issue, we conducted animal model studies with mice exposed to aerosolized PBS, nicotine-free or nicotine-containing E-cigs, with concurrent exposure to either vehicle or the GC receptor (GR) antagonist RU486. We observed that exposure of E-cig vaping nicotine for 4 weeks increased 11β-HSD1 expression and induced lipase HSL and ATGL abundance within the adipose tissues with induction of hypercortisolemia in response to elevated plasma nicotine levels in mice compared with those of aerosolized E-cig vaping vehicle or PBS controls. Induction of adipose 11β-HSD1 was correlated with elevated the expression of hepatic gluconeogenic enzymes PEPCK and G6Pase and corresponded to the elevated fasting glucose levels. Moreover, E-cig vaping nicotine also increased glucose intolerance, but decreased the glucose-lowing effects of insulin and elevated plasma FFA levels in mice compared with PBS controls. However, E-cig vapor without nicotine did not affect these metabolic parameters. Furthermore, RU486 treatment attenuated E-cig vaping nicotine-induced adipose 11β-HSD1 and lipase expression. In addition, RU486 also attenuated the E-cig-mediated activation of hepatic PEPCK and G6Pase and decreased plasma FFA levels, but did not change the elevated plasma corticosterone levels in mice on E-cig vaping nicotine. These data indicate that E-cig vapor exposure harmfully affects glucose homeostasis and these effects may arise, in part, from aerosol nicotine-induced adipose 11β-HSD1 and GR expression.

Disclosure

J.Wang: None. T.Friedman: None. M.Jiang: None. Y.Liu: None. J.Liu: None. Y.Wang: None. S.C.J.Kim: None. E.Espinal: None. R.Yang: None. H.Zhong: None. X.M.Shao: None. K.Lutfy: None.

Funding

Tobacco-Related Disease Research Program (T31IR1603)
368-OR: Life Expectancy and Causes of Death after Bariatric Surgery or Usual Care in Patients Stratified by Baseline Type 2 Diabetes in the Swedish Obese Subjects Study
Authors: SJÖHOLM KAJSA , ANDERSSON ASSARSSON JOHANNA C. , TAUBE MAGDALENA , CARLSSON EKANDER LENA
Published: June 2023

Introduction: Patients with and without type 2 diabetes (T2D) differ in terms of metabolic disturbances and cardiovascular risk factors. Thus, it is possible that the increased survival after surgical obesity treatment is due to reduction of different causes of death. Here, we determined mortality and causes of death after bariatric surgery in relation to baseline T2D status in the prospective controlled Swedish Obese Subjects (SOS) study.

Methods: Deaths after bariatric surgery or usual care were determined in subgroups defined by baseline T2D (n=697) or non-T2D (n=3335) during a median follow-up of 26 years. The Swedish Cause of Death Register, case sheets and autopsy reports were assessed to determine the direct cause of death. Analyses were adjusted for preselected risk factors (age, sex, BMI and smoking at baseline, and year of inclusion in the study).

Results In T2D and non-T2D subgroups, bariatric surgery was associated with increased life expectancy (2.1, 95% confidence interval (95% CI) 0.2-4.0 and 1.6, 0.5-2.7 years, respectively) and lower overall mortality (adjusted hazard ratio (adjHR)=0.77, 95% CI 0.61-0.97; and 0.82, 0.72-0.94, respectively), and the treatment benefit was similar (p for interaction 0.615). Bariatric surgery was associated with reduced cardiovascular mortality in both subgroups (adjHR=0.65, 95% CI 0.46-0.91; and 0.70, 0.55-0.88, respectively (p for interaction 0.516)).

Conclusions: Bariatric surgery is associated with similar reduction of overall and cardiovascular mortality and increased life expectancy regardless of baseline diabetes status.

Disclosure

K.Sjöholm: None. J.C.Andersson assarsson: None. M.Taube: None. L.Carlsson ekander: None.

Funding

Swedish Research Council; Swedish State; Swedish Heart and Lung Foundation; Swedish Diabetes Foundation; Adlerbert Research Foundation
37-LB: Impacts and Influencing Factors of an Internet-Supported Diabetes Management Program in Beijing
Authors: WU YIMING
Published: June 2023

Purpose: The aim of the study is to examine the impact of an Internet supported diabetes management program and to analyze the influencing factors of the improvement.

Methods: The Internet Diabetes Shared Care Program (IDSC) in Peking University Shougang Hospital was an application of DSMES (Diabetes Self-Management Education and Support) with Internet technologies. Interdisciplinary care team including diabetologist, nurses, dietitians and diabetes educators provide individualized consultation in hospital every 3 months, and continuous online lifestyle coaching via smartphone applications. Change of (HbA1c), BP, LDL-c, BMI at baseline and at last visit were compared. Multiple linear regression analysis were applied to analyze the data.

Results: Total of 349 patients (female 51%) were enrolled from 2018 to 2022 with average age 56.98±10.61 years, duration of DM 9.59±8.23 years. Patients were followed in the IDSC program for 1.78±0.90 years. At baseline, 41.8% used insulin. After the program. the HbA1c decreased 1.29±2.22%(8.41±2.23% vs 7.12±1.30%, t=10.32, P=0.000), BMI decreased 0.43±2.50 kg/m2(25.98±3.99kg/m2 vs 25.56±3.83 kg/m2, t=3.10, P=0.002). Multiple linear regression found and patient age (β=-0.036, P=0.001), followed duration (β=-0.349, P=0.004), baseline HbA1c achieved ≤7% (β=-2.477, P=0.000) and weekly communication with diabetes educators (β=0.828, P=0.013)were the impact factors for glycemic improvement.

Conclusion: The Internet supported diabetes management program significantly improved the glycemic control of DM patients, in which age, weekly communication and continuous care are essential factors for glycemic improvements.

Disclosure

Y. Wu: None.
372-OR: Long-Term Outcomes of Metabolic Surgery vs. Medical/Lifestyle Therapy on Nonalcoholic Fatty Liver Disease in Adults with Obesity and Type 2 Diabetes
Authors: LUNDHOLM MICHELLE D. , HU BO , KIRWAN JOHN P. , PATTI MARY-ELIZABETH , CUMMINGS DAVID E. , KASHYAP SANGEETA , CONSORTIUM ARMMS-T2D
Published: June 2023

Introduction: Data are lacking on the long-term effects of metabolic surgery vs medical intervention on NAFLD in patients with obesity and T2D.

Methods: A multi-center, prospective, observational study was performed with adults enrolled in the Alliance of Randomized trials of Medicine vs Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D) consortium. Patients with BMI 27-45 kg/m2 were randomized to medical therapy or surgery with gastric sleeve (GS), gastric band (GB), or Roux-en-Y gastric bypass (RYGB). The hepatic steatosis index (HSI), FIB-4 index, and AST-to-platelet ratio index (APRI) were calculated at baseline and follow-up at 6-15 years then compared by intention-to-treat analysis.

Results: We enrolled 262 patients, 49.9±8.3 yrs, 68.3% female, 67.2% white, HbA1c 8.5±1.5%, BMI 36.4±3.5 kg/m2. Liver steatosis was 100% positive by HSI. Fibrosis was rare by FIB-4 (<1% advanced, 16.7% at-risk) and APRI (5.0% significant or severe). Steatosis and fibrosis rates did not differ between patients when randomized to medical (N=96) or surgical (N=166) therapies (GB N=36, GS N=41, RYGB N=89). At latest follow-up, the surgical group had greater decrease in weight (-20.1 vs -11.2 kg, p<0.001), HbA1c (-1.10% vs -0.50%, p<0.001), and greater diabetes remission (16.8% vs 2.2%, p<0.001). Steatosis scores improved in both groups but to a greater extent after surgery (-8.5 vs -4.9, p<0.001). Fibrosis scores were stable even though patients were 6-15 years older and values did not differ between surgical vs medical groups (FIB-4 -0.01 vs -0.02, p=0.77; APRI -0.04 vs -0.01, p=0.60).

Conclusion: Hepatic steatosis scores improved more in patients with T2D randomized to metabolic surgery vs medical management. Fibrosis scores did not worsen as would be expected with aging, suggesting a protective effect of both surgical and medical interventions. These results support a continued role for weight loss interventions to prevent and treat NAFLD.

Disclosure

M.D.Lundholm: None. B.Hu: None. J.P.Kirwan: None. M.Patti: Consultant; MBX Biosciences, AstraZeneca, Hanmi Pharm. Co., Ltd., Other Relationship; Fractyl Health, Inc. D.E.Cummings: None. S.Kashyap: Consultant; GI Dynamics, Research Support; Fractyl Health, Inc., Stock/Shareholder; Gila therapuetics. Armms-t2d consortium: n/a.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (U01DK114156)
373-OR: Repetitive Transcranial Magnetic Stimulation—A Potential Antiobesity Approach for Long-Term Maintenance of Weight Loss
Authors: FERRULLI ANNA , MASSARINI STEFANO , MACRÌ CONCETTA , SENESI PAMELA , TERRUZZI ILEANA , CANNAVARO DANIELE , LUZI LIVIO
Published: June 2023

Current anti-obesity interventions result in early rapid weight loss, but long-term maintenance of lost weight is much more challenging. Initial weight loss is typically followed by a weight plateau and progressive regain. We demonstrated the efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) in inducing long-term weight loss (up to 1 year) in individuals with obesity by modulating the brain dopaminergic system and the prefrontal cortex. In a post-hoc analysis, we re-evaluated body weight loss up to 3 years after, in 44 individuals treated with a 5-week high frequency rTMS or sham stimulation, for obesity. Out of 44 subjects, 30 individuals (21 F/9 M, BMI 35.3±2.8, age 49.9±9.3) did not undergo any further weight loss treatments (except diet), 9 subjects (5 F/4 M, BMI 40.4±4.7, age 44.7±.6.1) underwent bariatric surgery, and 5 patients were treated for persistent obesity with a GLP-1 receptor agonist (GLP1-RA) (5 F/0 M, BMI 36.8±6.5, age 53.2±13.9). Out of 30 subject who did not undergo any further weight loss intervention, the 16 patients who received real rTMS (10 F/6 M, BMI 34.6±3.2, age 49.2±7.5) reported a significant body weight loss compared to the Sham group (11 F/3M, BMI 36.1±2.0, age 50.7±2.0) at the end of the 5-week intervention (BMI:-4.5±1.7% vs -1.6±1.8%, p=0.0001). Crucially, they continued to lose body weight compared to the Sham even 3 years after the end of intervention (BMI: -9.5±7.6% vs -3.6±8.4%, p=0.056). As expected, during the 3-year follow-up, bariatric surgery was more effective in promoting weight loss compared to the rTMS and the GLP1-RA (p=0.0001), but rTMS has not been shown to be less effective than GLP1-RA in maintaining lost weight (p=0.621). This preliminary evidence of efficacy of rTMS in promoting long-term weight loss (over one year) may be explained via neuronal neuroplasticity. TMS alone or in combination with other anti-obesity approaches may open new ways to sustain the efficacy of weight control interventions.

Disclosure

A.Ferrulli: None. S.Massarini: None. C.Macrì: None. P.Senesi: None. I.Terruzzi: None. D.Cannavaro: None. L.Luzi: Advisory Panel; Eli Lilly and Company, Medtronic, Research Support; Gelesis, Speaker's Bureau; A. Menarini Diagnostics, Amgen Inc., Boehringer Ingelheim and Eli Lilly Alliance, Eli Lilly and Company, Novo Nordisk, Novartis.

Funding

IRCCS MultiMedica (Ricerca Corrente)
374-OR: Exercise Training Decreases ß-Cell Senescence in Mice and Humans
Authors: CARAPETO PRISCILA , KAHNG JIHO , ALVES WAGNER ANA BARBARA T. , MIDDELBEEK ROELAND J.W. , HIRSHMAN MICHAEL F. , RUTTER GUY A. , GOODYEAR LAURIE , AGUAYO-MAZZUCATO CRISTINA
Published: June 2023

Increased β-cell senescence contributes to the development of type 2 diabetes (T2D). Exercise is critical in the treatment of T2D and can attenuate aging-associated cellular changes, but exercise effects on β-cell senescence are unknown. We tested the effects of treadmill running (1h/day for 10 days) on two insulin resistance models: high-fat diet and insulin receptor antagonist (S961). Exercise improved glucose responsiveness and decreased senescence markers (SA-βGal activity, p21Cip1 and p16Ink4a mRNA and protein levels). RNAseq from pancreatic islets of exercised mice revealed decreased expression of senescence effector genes and senescence associated secretory phenotype factors. Exercise increased AMPK activity in islets as assessed by alpha catalytic subunit phosphorylation. Islets from sedentary mice cultured for 2 days with serum from exercised mice showed decreased senescence, suggesting a circulatory factor was responsible for these effects. Pathway analysis of RNASeq revealed that exercise upregulated glucagon type ligand receptors. Glucagon treatment of mouse and human islets activated AMPK and decreased senescence in β-cells, an affect attenuated by an AMPK inhibitor (compound C). Exercised mice treated with a glucagon antagonist (adomeglivant) blocked AMPK phosphorylation and increased p21Cip1 and p16Ink4. Exercise increased nuclear translocation of the AMPK substrate NRF2 in mouse islets while downregulation of Nrf2 with siRNA in MIN6 cells increased transcription of p16Ink4a, suggesting a potential mechanism linking exercise, AMPK activation and downregulation of β-cell senescence. Treatment of human donor islets with serum obtained pre- and post-exercise training for 10 weeks in people with T2D showed that training activated AMPK and decreased senescence markers. These findings demonstrate that exercise training decreases β-cell senescence and suggest that this important response to exercise occurs through circulating factors mediating an AMPK-dependent pathway.

Disclosure

P.Carapeto: None. J.Kahng: None. A.T.Alves wagner: None. R.J.W.Middelbeek: Research Support; Novo Nordisk. M.F.Hirshman: Stock/Shareholder; Abbott, AbbVie Inc., Amgen Inc., Colgate-Palmolive, Eli Lilly and Company, Medtronic. G.A.Rutter: Consultant; Sun Pharmaceutical Industries Ltd. L.Goodyear: None. C.Aguayo-mazzucato: None.

Funding

Joslin Diabetes Center (to C.A-M.); Richard and Susan Smith Family Foundation; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (001)
375-OR: Epigenetic Control of Beta-Cell Stress Response and Senescence
Authors: VARGHESE SNEHA S. , PARVEEN NAZIA , WANG JEAN K. , HERNANDEZ-DE LA PENA ALESSANDRO G. , DHAWAN SANGEETA
Published: June 2023

Both type 1 and type 2 diabetes (T1D and T2D) result from chronic insulin insufficiency due to progressive dysfunction and loss of beta cells, driven by cellular stress. Beta cell failure in both forms of diabetes involves defective stress-response and the onset of premature senescence, an irreversible form of cell-cycle arrest induced by chronic stress. However, the mechanisms by which cellular stress triggers beta cell senescence are not clear. We now show that CTCF, a stress-sensitive epigenetic regulator, controls the beta cell stress-response and senescence programs during beta cell maturation process along with the cohesin Smc3. Chromatin immunoprecipitation data suggest that CTCF and Smc3 differentially occupy genes associated with stress and DNA damage responses, functional maturation, and senescence in neonatal versus adult beta cells. Our data show that CTCF and cohesin Smc3 dependent control protects replicating beta cells from DNA damage, and is especially critical during the neonatal growth phase marked by high rates of replication. Beta cell specific loss of CTCF triggers a p53/p21 dependent senescence program, followed by beta cell dysfunction and eventual beta cell failure with advancing age. We further demonstrate that reduced CTCF levels in beta cells lead to adaptive failure in response to a high fat diet challenge, and recapitulate a neonatal beta cell like epigenetic landscape. Notably, CTCF levels are reduced in beta cells in T1D and T2D in mice and humans, and lead to reduced occupancy of CTCF and Smc3 at genes involved in senescence, DNA damage response, and beta cell function. Our data show that CTCF and cohesin collectively protect against senescence and govern beta cell function and fitness through a program established in the neonatal maturation phase.

Disclosure

S.S.Varghese: None. N.Parveen: None. J.K.Wang: Employee; Pfizer Inc., Johnson & Johnson. A.G.Hernandez-de la pena: None. S.Dhawan: None.

Funding

National Institutes of Health (R01DK120253)
377-OR: Stabilizing 14-3-3 and ChREBP Cytoplasmic Interaction to Rescue ß-Cells from Glucolipotoxicity
Authors: KATZ LIORA S. , TSE ISABELLE L. , VISSER EMIRA , BAUMEL-ALTERZON SHARON , KAISER MARKUS , BRUNSVELD LUC M. , PENNINGS MARLOES , OTTMANN CHRISTIAN , SCOTT DONALD
Published: June 2023

Carbohydrate response element binding protein (ChREBP) is a glucose-responsive transcription factor with two splice isoforms (α and β). ChREBPα remains cytoplasmic by binding to 14-3-3. Increased glucose metabolism allows ChREBPα to enter the nucleus and induce ChREBPβ, a hyperactive isoform that is a key mediator of glucolipotoxicity. Using structure-guided stabilizer optimization, we have developed novel drugs that stabilize the protein-protein interaction between ChREBPα and 14-3-3, with a goal to prevent ChREBPα nuclear translocation, induction of ChREBPβ, and glucolipotoxicity. One hit compound, K391, has an EC50 of 0.3±0.1μM by fluorescent polarization assay and a Kd of 0.12μM by isotitration calorimetry. Using dual label analysis of the kinetics of cell growth and cell death, we found that K391 significantly reduced β-cell death by 31.8±3% and enabled proliferation in glucolipotoxic conditions in INS-1 cells (20mM glucose and 1mM palmitate). In response to glucose, 76.4±3.5 % of the cells stained for nuclear ChREBP. In the presence of K391, 39.75±5.3 % fewer cells displayed nuclear ChREBP in high glucose concentrations and 65.7±1.6% less in glucolipotoxic conditions, indicating that K391 retains ChREBPα in the cytoplasm and prevents transcription of ChREBPβ. Time course with an antibody against ChREBPα showed that ChREBPα transiently translocated to the nucleus at 30 min and then cleared out of the nucleus in high glucose, an effect blocked by K391 (N=3). In glucolipotoxic conditions, ChREBPα remained nuclear over time, an effect significantly attenuated by K391 (N=3). Txnip is an important mediator of glucose toxicity and a target gene of ChREBPβ. Importantly, K391 blocked the glucose response of the human Txnip promoter in a luciferase assay by 2±0.2 folds. We conclude that the K391 retains ChREBPα in the cytoplasm in high glucose and in glucolipotoxic conditions by stabilizing the ChREBPα and 14-3-3 interaction and thereby rescues β-cells from glucolipotoxicity.

Disclosure

L.S.Katz: None. I.L.Tse: None. E.Visser: None. S.Baumel-alterzon: None. M.Kaiser: None. L.M.Brunsveld: Consultant; Novartis, Ambagon Therapeutics, Research Support; Roche Diagnostics. M.Pennings: None. C.Ottmann: None. D.Scott: None.

Funding

National Institutes of Health (R01DK130300)
38-LB: Ex Vivo Immune Cell Function Analysis in Patients with CKD Undergoing Dialysis Treatment Monitors Exercise Treatment Effects on Immunosurveillance
Authors: HOFMANN SUSANNA M. , DINGES SOPHIA M. , WALTER MARC , VONKORN PIA , VONGERSDORFF GERO D. , ANDING-ROST KIRSTEN , HALLE MARTIN
Published: June 2023

Chronic kidney disease (CKD) is marked by a pre-aging and dysfunctional immune system and chronic inflammation. Recent research indicates that chronic physical exercise training (ET) increases regulatory monocytes and T-cells thus modulating the inflammatory status associated with cardio-metabolic diseases. In particular, ET primes monocytes and T-cells towards a less inflammatory phenotype. We hypothesized that intradialytic ET is beneficial to patients with CKD by improving certain immune cell features and decreasing systemic inflammation. We isolated PBMCs from a subset of 18 patients with CKD (58-90 years, 38 % females) enrolled in the prospective intervention trial DiaTT (Dialysis Training Therapy; ClinicalTrials.gov: NCT03885102) at the beginning and after a 12-months intradialytic ET intervention (aerobic endurance + resistance training). Circulating immune cell populations were characterized by FACS. Ex-vivo basal and PMA-induced T-cell activation was determined by cell surface expression analysis of CD69. We found that ET reversed the shift towards intermediate monocytes, a known marker for CKD morbidity and mortality, and nonclassical monocytes in patients with CKD undergoing dialysis treatment. We observed an increase in naïve T-cells and Recent Thymic Emigrants (RTE) indicating an improvement of T-cell function. On T-cells, basal CD69 expression was significantly enhanced and PMA-induced CD69 expression was severely impaired in patients with CKD compared to healthy control subjects (n= 7). When patients with CKD underwent ET this specific T-cell function was restored to normal levels. Here, we show that even in these severely sick patients certain circulating immune cell functions can be regained potentially leading to an enhanced immunosurveillance. Our ex-vivo immune cell characterization and function analysis can be used to monitor exercise treatment effects on systemic inflammation.

Disclosure

S. M. Hofmann: None. S. M. Dinges: None. M. Walter: None. P. Vonkorn: None. G. D. Vongersdorff: None. K. Anding-rost: None. M. Halle: Advisory Panel; Abbott, Speaker's Bureau; Boehringer Ingelheim (Canada) Ltd., Daiichi Sankyo, Amgen Inc., BMS.
383-P: Intranasal (IN) Naloxone as a Novel Therapy to Preserve Hypoglycemia Counterregulatory (CR) Response after Exercise in Type 1 Diabetes (T1D)
Authors: MOHEET AMIR , EBERLY LYNN E. , INKOLLU SINDHURA , KUMAR ANJALI , ALVEAR ALISON C. , ZHANG YUAN , COLES LISA , EVANOFF NICHOLAS , DENGEL DONALD R. , SEAQUIST ELIZABETH R.
Published: June 2023

Hypoglycemia (HG) is common after exercise in people with T1D. Antecedent exercise leads to attenuation of CR response during subsequent HG. In healthy humans, IV administration of naloxone during exercise preserved CR response to HG the following day. We tested the hypothesis that IN administration of naloxone during exercise will preserve CR response to HG in people with T1D with intact awareness of HG. We performed a single-blind randomized cross over trial to compare the impact of IN naloxone vs. IN saline administered during exercise on day 1 (D1) on the symptoms and epinephrine (Epi) response to HG on day 2 (D2). On D1, participants underwent two 90-min hyperinsulinemic-euglycemic clamps during exercise at 60% VO2max with IN naloxone (4 mg at start and +45 min each exercise period) or IN saline exposure; on D2 a HG clamp (target 50 mg/dl) was performed. 27 subjects (10F, age 29 ± 8 yrs) participated in the protocol. Outcomes included D2 average symptom scores (SS) and peak Epi level over HG clamp’s last 30 min. A general linear mixed model for each of SS and Epi with effects for naloxone vs. saline, treatment order (naloxone 1st vs. 2nd), and time (Part 1 vs. Part 2) was performed. SS and Epi response on D2 were not different following IN naloxone compared to placebo. In people with T1D, administration of IN naloxone during exercise did not alter symptom or EPI response to subsequent HG.

Disclosure

A.Moheet: None. E.R.Seaquist: Consultant; Zucara Therapeutics. L.E.Eberly: None. S.Inkollu: None. A.Kumar: None. A.C.Alvear: None. Y.Zhang: None. L.Coles: None. N.Evanoff: None. D.R.Dengel: None.

Funding

JDRF
384-P: Inadequate Follow-up and Intervention after Severe Hypoglycemia Treated by Emergency Medical Services (EMS)
Authors: RODE MATTHEW , BOGGUST BRETT , MANGGAARD JENNIFER M. , SWANSON KRISTI , MCCOY ROZALINA G.
Published: June 2023

Severe hypoglycemia incurs substantial morbidity and distress in patients with diabetes. Prior studies found that clinicians fail to screen for hypoglycemia and deintensify therapy after detected events. Whether patients treated by EMS for hypoglycemia receive follow-up or treatment modification to prevent hypoglycemia recurrence is unknown. We analyzed all 911 calls for hypoglycemia made by adults with diabetes to Mayo Clinic Ambulance Service (serving a large geographic area across Minnesota and Wisconsin) between 1/1/2013-12/31/2019, manually linked to Mayo Clinic electronic health records. Encounters within 7 days of the hypoglycemic event were analyzed for type of encounter, provider, discussion of hypoglycemia, prescription of glucagon, change of diabetes medications, and referral to a diabetes provider. Hypoglycemia was addressed more often with escalating levels of care (Figure). In-patient endocrinologists addressed hypoglycemia most often (96% discussion, 83% med changes), followed by hospitalists (87% discussion, 50% med changes). Primary care providers (74% discussion, 25% med changes) and emergency medicine providers (88% discussion, 14% med changes) addressed hypoglycemia less often. Results did not change when patients had experienced previous ED visits/hospitalization for hypoglycemia. Such therapeutic inertia hinders hypoglycemia prevention.

Disclosure

M.Rode: None. B.Boggust: None. J.M.Manggaard: None. K.Swanson: None. R.G.Mccoy: Consultant; Emmi.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (K23DK114497)
387-P: High Incidences of Level 3 Severe Hypoglycemia Reported by T2DM Secretagogue-Users (iNPHORM, USA)
Authors: RATZKI-LEEWING ALEXANDRIA , BLACK JASON E. , ZOU GUANGYONG , RYAN BRIDGET L. , HARRIS STEWART B.
Published: June 2023

In the US, >90% of people with T2DM on oral antihyperglycemics use secretagogues. The present analysis is the first to quantify the real-world, US frequency of Level 3 severe hypoglycaemia (SH) in this population. Longitudinal, prospective data were leveraged from the iNPHORM study. Adults (≥18 years old) with secretagogue-treated T2DM (not on insulin) were recruited from a US-wide, probability-based internet panel. Data on participant characteristics and Level 3 SH occurrence were captured across a screener, baseline and 12 monthly follow-ups. Multivariable negative binomial regression with cluster bootstrapping for repeated measures modelled the annualized rate of SH for individuals completing ≥1 follow-up(s). A repeated lasso regression ‘voting’ procedure selected all risk factors. Multiple imputation addressed missingness. Of the 353 respondents (male: 51.1%; age: 54.6 [SD: 13.2] years; diabetes duration: 10 [IQR: 12] years; retention rate: 84.4%), the incidence proportion of SH over follow-up was 21.8 (95% CI: 17.8-26.3)%, and the rate was 3.8 (95% CI: 2.5-5.7) events per person-year. Our final model included age, continuous/flash glucose monitoring use, corticosteroid use, number of healthcare visits, fear of hypoglycemia, number of past-year SH requiring hospital care, retinopathy, and other diabetes complications. The rate of annualized Level 3 SH statistically increased with younger age, more frequent healthcare visits, greater fear of hypoglycemia, higher number of past-year healthcare-related SH, and presence of retinopathy. Our results indicate disturbingly high incidences of Level 3 SH among secretagogue users. Whenever logical and feasible, clinicians should prioritize one of the many other available antihyperglycemics that confer little to no hypoglycemia risk. Else, other hypoglycemia prevention strategies—risk-tailored to this ubiquitous T2DM population—are urgently warranted.

Disclosure

A.Ratzki-leewing: Consultant; Novo Nordisk, Eli Lilly and Company, Research Support; Sanofi. J.E.Black: None. G.Zou: None. B.L.Ryan: None. S.B.Harris: Advisory Panel; Bayer Inc., AstraZeneca, Eli Lilly and Company, Dexcom, Inc., Novo Nordisk A/S, Novo Nordisk Canada Inc., Sanofi, Consultant; Abbott Diabetes, Janssen Pharmaceuticals, Inc., Other Relationship; American Diabetes Association, Research Support; Abvance Therapeutics, Canadian Institutes of Health Research.

Funding

Sanofi Global
39-LB: The Greater the Increase in Physical Activity and Exercise after Metabolic Bariatric Surgery, the Greater the Loss of Fat Mass in Obese Korean Subjects
Authors: NA JANG HAN , SUK PARK YOUNG , HO MOON JOON , CHOI SUNGHEE , MIN CHO YOUNG , CHUL JANG HAK , JUNG OH TAE
Published: June 2023

Object: Exercise after metabolic bariatric surgery (MBS) is known to be more effective in reducing weight, maintaining muscle strength, and improving insulin sensitivity than MBS alone. In this study, we investigated the influence of increment in physical activity and exercise on clinical outcomes after MBS in obese Korean subjects.

Method: We recruited 94 patients who underwent MBS from April 2019 to December 2021 prospectively. The levels of physical activity and exercise were collected with self-report questionnaires before and 1 year after MBS. Physical activity- and exercise-related energy expenditure (MET-min/week) was calculated by multiplying the frequency, intensity, and duration of the activities. Patients were classified into non-improved and improved groups according to changes in energy expenditure relative to before surgery.

Result: The mean age was 41.4 ± 10.4 years, 38 (40.4%) were male, BMI was 36.9 [32.6, 40.6] kg/m2, and energy expenditure was 438.0 [87.0, 1105.3] MET-min/week at baseline. The improved group had significantly higher BMI (38.0 [34.4, 41.1] vs 33.2 [32.1, 38.8], P = 0.031) and lower MET-min/week (369.8 [174.0, 601.1] vs 761.3 [65.3, 1414.5] METS-min/week, P = 0.045) before surgery. The reduction of BMI and fat mass was significantly greater in the improved group compared with the non-improved group (BMI, 10.2 [8.6, 13.2] vs 9.0 [6.7, 10.9] kg/m2, P = 0.030; fat mass, 25.9 ± 11.1 vs 20.3 ± 9.6 kg, P = 0.016). However, the change in muscle mass was not different between the groups. A greater increase in MET-min/week after MBS was associated with a greater reduction in fat mass after MBS (β = -0.217, P = 0.007), but not with the change in muscle mass.

Conclusion: Patients with higher BMI and lower degree of physical activity and exercise were likely to increase their physical activity after MBS. This improvement in physical activity and exercise was associated with more fat mass loss while maintaining muscle mass.

Disclosure

H. Jang: None. Y. Park: None. J. Moon: None. S. Choi: None. Y. Cho: Consultant; LG Chem. H. Jang: None. T. Oh: None.
393-P: Acute Hypoglycemia Alters Serum Immune Mediators Associated with Macrophage and T-Cell Activation in Type 2 Diabetes
Authors: MOIN ABU S. , SATHYAPALAN THOZHUKAT , ATKIN STEPHEN , BUTLER ALEXANDRA E.
Published: June 2023

Objective: Hypoglycemia complicates intensive glycemia regimens in type 2 diabetes (T2D). Hyperglycemia induces macrophage priming and dysregulates T-cell activation/function. Immune cell response to acute hypoglycemia has not been investigated in T2D. Thus, immune mediators associated with macrophage/T-cell activation in response to insulin-induced hypoglycemia were studied.

Methods: Hypoglycaemia (<2.2mmol/l; <40mg/dl) was achieved in T2D (n=23) and controls (n=23) by intravenous insulin infusion. Somalogic analysis of plasma proteins related to macrophage/T-cell activation was performed at baseline, hypoglycemia and post-hypoglycemia to 24 hours.

Results: IL-4 and IL-13 (promotors of alternative macrophage activation (M2 macrophages)) decreased 2hours post-hypoglycemia in T2D (p<0.05). Co-stimulatory molecules of T-cell activation expressed in antigen presenting cells (APCs), CD80 and CD86, were decreased at 2h post-hypoglycemia (CD86 in T2D, p<0.05; CD80 in controls and T2D, p<0.05). Hypoglycemia did not affect ligands of co-stimulatory molecules, CTLA4 (ligand of CD80, expressed in APCs) and CD40LG (ligand of CD40, expressed in dendritic cells). The negative regulator of T-cell activation, IL-10, was decreased at 2h (p<0.001) and increased at 4h post-hypoglycemia (p<0.01). Elevation of CD80 (p<0.05) and CD86 (p<0.05), with increased T-cell proliferator IL-6 (p<0.05) was seen in T2D at 4h post-hypoglycemia. Positive correlations of IL10 with IL6, IL4, were observed at 2h post-hypoglycemia in T2D, suggesting a role for IL10 in altering immune cell activation mediators following hypoglycemia in T2D. No correlations with glucagon suggest changes are independent of glucose counter-regulation.

Conclusion: Induced hypoglycemia is associated with decreases in macrophage and T-cell activation mediators (cytokines) in T2D. Thus, this study reveals a novel link between hypoglycemia and inefficient immune system activation.

Disclosure

A.S.Moin: None. T.Sathyapalan: Other Relationship; Novo Nordisk, Abbott Diabetes, Research Support; Abbott Diabetes, Novo Nordisk, Eli Lilly and Company. S.Atkin: None. A.E.Butler: None.