bluuebunny/crossref_metadata_2025 huggingface dataset:
148-OR: Partial Knockout of Skeletal Muscle Dynamin-Related Protein 1 Improves Insulin Sensitivity in Diet-Induced Insulin Resistant Mice, but Not in Normal Control Mice
Authors: KUGLER BENJAMIN A. , LIN NANA , NGUYEN PAUL D. , ALI ABIR , SESAY AMIRA , KALEMBA BABY LENGA , SESAKI HIROMI , ZOU KAI
Published: May 2022

Dynamin-related protein 1 (Drp1) is the key regulator of mitochondrial fission. We and others have reported excessive Drp1 activity in skeletal muscle from both animals and humans with insulin resistance, which is strongly correlated to impaired skeletal muscle insulin sensitivity. To examine whether Drp1 directly regulates skeletal muscle insulin sensitivity and whole-body glucose homeostasis, we generated tamoxifen-inducible skeletal muscle-specific heterozygous Drp1 partial knockout mice (mDrp1+/-) . Male mDrp1+/- and wildtype (WT) mice were fed with either a high-fat diet (HFD) or low-fat diet (LFD) for four weeks, received tamoxifen injections for five consecutive days, and remained on their respective diet for another four weeks. Improvements in whole-body glucose tolerance and insulin sensitivity were observed in HFD-fed mDrp1+/- mice (P<0.05) , but not in LFD-fed mDrp1+/- mice, when compared to their respective WT controls. Further, HFD-induced impairment in skeletal muscle insulin-stimulated Akt Ser473 phosphorylation (P<0.05) was mitigated in HFD-fed mDrp1+/- mice. In contrast, insulin-stimulated Akt Ser473 phosphorylation was reduced in LFD-fed mDrp1+/- mice compared to LFD-fed WT mice (P<0.05) . mDrp1+/- mice exhibited more fused and interconnected mitochondrial networks in skeletal muscle than WT mice. The examination of mitochondrial function revealed no change in mitochondrial respiration but reductions in mitochondrial Complex I and II and pyruvate dehydrogenase derived H2O2 production in HFD-fed mDrp1+/- mice compared to HFD-fed WT mice (P<0.05) .

In conclusion, our data suggest that partial knockout of skeletal muscle Drp1 improves skeletal muscle insulin sensitivity and whole-body glucose homeostasis in diet-induced insulin-resistant mice but not in normal control mice. These improvements are, at least in part, due to reduced mitochondrial-derived H2O2 production.

Disclosure

B.A.Kugler: None. N.Lin: None. P.D.Nguyen: None. A.Ali: None. A.Sesay: None. B.Kalemba: None. H.Sesaki: None. K.Zou: None.

Funding

National Institutes of Health (R15DK131512) Diabetes Action Research and Education Foundation Grant (#505)
150-LB: Diabetes and School Health (DASH) Program—An Innovative School-Based Health Model to Optimize Care for Youth with Type 1 Diabetes
Authors: WOOD AURELIA C.H. , MOFFETT AMY M. , SIMMS KATHRYN , MOORE MATT , SULI ELVIA , IRWIN MARY KAY K. , EDWARDS ELIZABETH , GANDHI KAJAL
Published: May 2022

Objectives: Pediatric type 1 diabetes (T1D) care requires collaboration of families, diabetes team and caregivers. Youth spend most of the time in school so care optimization in school is crucial. There are no evidence-based guidelines for school-based care, and management varies based on local legislation, school district, and staffing. An innovative school-based program provides an opportunity to standardize care, improve outcomes, reduce inequities, and inform guidelines for school T1D care.

Methods: The Nationwide Children's Hospital (NCH) Diabetes and School Health (DASH) program is a novel school-based intervention. The intradisciplinary DASH team provides on-site education to students/staff, addresses medical/psychosocial concerns, coordinates delivery of medications/supplies, and facilitates communication. The pilot aimed to enroll 50 students identified as high risk based on their Diabetes Composite Score, a risk assessment tool developed by NCH. Qualitative and quantitative data was obtained for students, caregivers, and staff, including A1C, acute care utilization, educational mastery, quality of life, psychosocial, and health equity measures.

Results: 50 students over 35 schools enrolled in the pilot. The majority used injections, 50% never used a continuous glucose monitor, and the average baseline A1C was 12%. More than 60% identified as an ethnic minority. Survey data showed over 50% of students felt others did not appreciate the burden of T1D care and endorsed T1D "burn out." Over 50% of caregivers endorsed feeling defeated/discouraged by T1D care, and worry about T1D related complications.

Conclusions: DASH is a novel school-based program that provides support, education, and oversight to students at high risk of T1D complications. The program aims to standardize school-based care, empower school staff, improve self-efficacy, address inequities, decrease T1D complications and provide a framework for school based care.

Disclosure

A. C. H. Wood: None. A. M. Moffett: None. K. Simms: None. M. Moore: None. E. Suli: None. M. K. Irwin: None. E. Edwards: None. K. Gandhi: None.
155-OR: Brown Adipose Tissue Leptin Feedback Regulates Feeding Behavior
Authors: MUNOZ MARCOS D. , IRIZARRY SR., VALERIA C. TORRES , XU PINGWEN , LIEW CHONG WEE
Published: May 2022

Obesity is a consequence of chronic disruption in energy homeostasis. This phenomenon is controlled by systemic and local signals such as leptin, a nutrient-sensitive signal secreted primarily by the white adipose tissue (WAT) . In contrast, interscapular brown adipose tissue (iBAT) has been shown to express undetectable or very low levels of leptin. In this study, unexpectedly, we observed overnight fasting decreased leptin expression in iBAT, and 2-hour refeeding was able to restore the iBAT leptin levels. This nutritional status-dependent fluctuation suggests a vital role of iBAT leptin in the acute regulation of energy homeostasis. Consistently, we found that mice with leptin selectively overexpressed in the UCP1-positive cells of iBAT (LEP-OEiBAT/UCP1) showed reduced fast-induced food intake. This hypophagia phenotype was associated with increased satiation as reflected by decreased meal numbers and increase postmeal interval. Notably, LEP-OEiBAT/UCP1 selectively increased the mRNA expression of leptin in the iBAT without affecting circulating leptin levels, indicating a possible paracrine role of iBAT leptin. In supporting this point of view, we showed that chemical ablation of sensory nerves (SS) in iBAT significantly increased fast-induced food intake, associated with altered meal frequency. Additionally, we also found that iBAT-specific infusion of leptin increased Stat3 phosphorylation (pStat3) in the upstream iBAT-innervating sensory neurons, suggesting leptin-mediated sensory detection. Notably, the increased pStat3 was associated with neural activation in the arcuate nucleus of the hypothalamus in the brain, and chemical ablation of iBAT SS blunted this stimulation. Our results support a model that feeding-induced iBAT leptin modulates iBAT-specific sensory inputs to the brain to regulate food intake and feeding patterns.

Disclosure

M.D.Munoz: None. V.C.Torres irizarry: None. P.Xu: None. C.Liew: None.

Funding

RDK109015A1
157-LB: Scanning Frequency and Glucose Variability in the First Trimester of T1DM Pregnancies Predict Time Spent in Very Low Glucose Range in the Last One—Analysis of Intermittently Scanned Continuous Glucose Monitoring
Authors: BARETIC MAJA , LEKSIC GLORIA , IVANISEVIC MARINA
Published: May 2022

Scanning frequency and glucose variability in the first trimester of T1DM pregnancies predict time spent in very low glucose range in the last one: analysis of intermittently scanned continuous glucose monitoring

Hypoglycemia is inevitable side effect of tight glycemic control in type 1 diabetes mellitus (T1DM) pregnancies. Using technology novel risk factors are revealed. Total of 34 patients (mean age 29.8 ± 6.1 yrs, BMI 23.6± 3.6 kg/m2, disease duration 15.2± 8.9 yrs) having very low glycemia in third trimester (< 3 mmol/L or 55 mg/dL) were included in the study. Patients used intermittently scanned continuous glucose monitoring (isCGM) FreeStyle Libre, Abott for a minimum of 3 months before conception and had glucose data availability > 80% of the time. Data from first trimester showed mean scanning frequency 12.17 ± 6.5 scans/day, estimated average glucose 7.2 ± 1.4 mmol/L, CV% 41.9 ± 6.5, GMI 6.4 ± 0.5, time below range <3.5 mmol/L or 64 mg/dL 10.7 ± 8.0 % and time spent in very low glucose range <3mmol/L or 55 mg/dL 5.4 ± 4.9 %. In last trimester mean scanning frequency was 16.3 ± 7.6 scans/day, estimated average glucose 6.1 ± 0.9 mmol/L, CV% 34.6 ±6.0 , GMI 5.9 ± 0.4 , time below range 11.0 ±9.3 %, time spent in very low glucose range 5.2 ± 4.8 %. Parameters from the first trimester of pregnancy significantly correlating with time spent in very low glucose range in the third trimester were scanning frequency (r −0.365, p 0.37) and CV % (r 0.465, p 0.006) . Linear regression analysis performed for CV% and scanning frequency showed R square 0.434 and p 0.002 in ANOVA. Two isCGM parameters from first trimester of pregnancy that influence on very low glucose rate in the third one are low scanning frequency and higher %CV. Combined they add to 43% of very low glucose occurrence. Patients who scan frequently in the first trimester of pregnancy and have low glucose variability spend less time in very low glucose range in the third trimester. For the others continuous glucose monitoring with hypo alerts should be offered.

Disclosure

M. Baretic: None. G. Leksic: None. M. Ivanisevic: None.
158-OR: Perinatal Hypercaloric Diet Leads to Cardiometabolic Imbalance via Hypothalamic Methylation Events in Male Mice
Authors: ELGAZZAZ MONA , BERDASCO CLARA , LAZARTIGUES ERIC D.
Published: May 2022

Cardiometabolic diseases are among the highest prevalent diseases worldwide. We have reported that perinatal maternal programming through hypercaloric diet (HCD) leads to an elevation in systolic BP and blood glucose levels exclusively in male mice offspring. These findings led us to investigate epigenetic modulations in the brain of the offspring that support the cardiometabolic phenotype. To elucidate the underlying mechanisms, we challenged the programmed offspring with postnatal HCD, speculating that it would exaggerate the cardiometabolic phenotype. C57BL6/J dams were fed on HCD or regular diet (RD) for 1 month then mated with RD-fed males. From weaning, all pups were maintained on HCD for 3 months resulting in RD-HCD and HCD-HCD groups of male mice. Results showed that HCD-HCD mice have higher systolic BP when compared to RD-HCD (125 ±1.9 vs. 115 ±2.8 mmHg) . Surprisingly, a glucose tolerance test showed that HCD-HCD mice were more glucose tolerant when compared with RD-HCD mice (AUC 29632 ±3516 vs. 604±4724, p=0.003, n=6-10/group) . Whole-genome methylation sequencing of the hypothalamus in offspring revealed differentially methylated regions (DMR) in HCD-HCD mice. Pathway analysis showed that DMR are annotated to genes involved in insulin signaling, neurotransmitter binding, and inflammatory pathways. Insulin receptor substrate (Irs1) gene exon was hypomethylated in HCD-HCD mice when compared to RD-HCD (DMR= -0.12, p=0.03) . Protein expression showed an increase in Irs1 protein fold change (FC) levels in both HCD-HCD and RD-HCD (FC=1.45 and 1.33 p=0.005, 0.03 respectively) compared to RD-fed mice. However, serine phosphorylated Irs1 (pSer307-Irs1) , an indicator for disturbed insulin signaling, showed decreased levels only in HCD-HCD mice compared to RD-HCD males (p=0.003) . We conclude that perinatal HCD programming leads to methylation events in the hypothalamus that modulate the expression of key genes regulating cardiometabolic functions.

Disclosure

M.Elgazzaz: None. C.Berdasco: None. E.D.Lazartigues: None.

Funding

American Diabetes Association (1-19-IBS-291) ;
160-LB: Age-Related Adipose Tissue Fibrosis and Neuropathy in the Genetically Diverse HET3 Mouse
Authors: WILLOWS JAKE , MISHRA GARGI , BLASZKIEWICZ MAGDALENA , TOWNSEND KRISTY L.
Published: May 2022

Changes in adipose tissue's extracellular matrix, as with fibrosis, inhibits the tissue's ability to shrink and expand as needed, resulting in sheer stress on adipocytes and chronic inflammation, as well as decreased insulin sensitivity. With aging, a state of metabolic dysregulation and increased incidence of insulin resistance, we have observed a reduction in adipose innervation. This ‘adipose neuropathy' likely poses a physiological challenge for tissue metabolic function and glucose homeostasis, as has been observed in adipose denervation studies. Using second-harmonic generation label-free imaging of adipose collagen and advanced image co-localization techniques, we found that obese adipose tissue exhibits higher co-localization of nerves with collagen fibers, indicating that changes in tissue fibrosis may tie mechanistically with tissue neuropathy. We compared C57BL/6J mice with the more genetically diverse HET3 mouse model that is used by the NIA's intervention testing program, to investigate age-related neuropathy and adipose fibrosis. We found that HET3 mice displayed mitigated neuropathy phenotypes in skin, muscle and adipose, compared to inbred C56BL/6J mice. Tissue fibrosis was significantly increased with age in subcutaneous and visceral white adipose depots of both strains of mice. Using birefringence imaging, we found that the relative distribution of type I / thick filament collagen increased with age while type III / thin filament collagen decreased. Gene expression by qPCR revealed significant increases in collagen genes Col1a1, Col3a1, and Col5a1 in adipose with age. Despite its success as a longevity treatment, the mTOR inhibitor rapamycin had little to no effect on reducing or preventing the onset of neuropathy in HET3 aged mice, and importantly it worsened the fibrotic phenotype with increased type 1 collagen in adipose. Together, we found that rapamycin's longevity effects are uncoupled from healthspan producing effects, with detrimental impacts on adipose fibrosis that may impact age-related insulin resistance.

Disclosure

J. Willows: None. G. Mishra: None. M. Blaszkiewicz: None. K. L. Townsend: Other Relationship; Neuright, Inc.

Funding

American Heart Association (AHA) Collaborative Sciences Award (18CSA34090028)
160-OR: Effects of Bariatric Surgery on Early Postprandial Glucose Turnover Assessed through a Dual Tracer Study
Authors: SCHIAVON MICHELE , TRIPYLA AFRODITI , HERZIG DAVID , THOMAS ANDREAS , BALLY LIA , MAN CHIARA DALLA
Published: May 2022

Postbariatric hypoglycemia (PBH) is a complication of bariatric surgery, mainly Roux-en-Y bypass (GB) . Surgery-induced changes in the gastrointestinal anatomy affect nutrient passage, absorption kinetics and may contribute to PBH. Here we aim to explore early postprandial glucose turnover in GB subjects with confirmed PBH vs. unaffected operated and non-operated controls. A total of 32 subjects (age = 48 [32,53] y, BMI = 29 [25,32] kg/m2; median [IQR]) , belonging to 4 matched (age/BMI/sex) groups (GB with PBH [GB-PBH] and unaffected [GB], sleeve gastrectomy [SG] and non-operated controls [C]) , ingested 15g of labeled [U-13C]-glucose (t=0 min) , 100 min after initiation of a primed constant infusion (30 μg/kg/min) of [6,6-2H2]-glucose. Plasma glucose and enrichments were measured, allowing the calculation of postprandial glucose fluxes, i.e. rates of meal glucose appearance (Rameal) , endogenous glucose production (EGP) and glucose disappearance (Rd) , together with insulin concentration. iAUC (0-20 min) of plasma glucose was significantly higher in both GB groups than C (GB-PBH: 36 [29,38], GB: 38 [31,40], C: 9 [17,19] mmol/L*min; p<0.01) . This was also the case for Rameal normalized to glucose dose (GB-PBH: 39 [34,42], GB: 42 [35,44], C: 20 [16,27] %; p<0.03) and Rd normalized to basal (GB-PBH: 56 [19,83], GB: 65 [54,76], C: -8 [-20,21] %; p<0.03) but not EGP, which was similarly suppressed in all groups. Finally, iAUC (0-20 min) of plasma insulin was significantly higher in GB and SG than C (GB: 657 [534,826], SG: 563 [351,822], C: 265 [192,310] μU/mL*min; p<0.03) while GB-PBH failed to reach significance (477 [384,631] μU/mL; p=0.06) . After a small dose (15g) of oral glucose, early postprandial glucose exposure, Rameal and Rd were faster in GB subjects than C, while insulin exposure was higher in almost all operated groups vs. C. However, no difference between GB groups was observed, underscoring the multifactorial etiology of PBH.

Disclosure

M.Schiavon: None. A.Tripyla: None. D.Herzig: None. A.Thomas: None. L.Bally: None. C.Dalla man: Research Support; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH.

Funding

MIUR (Italian Minister for Education) under the initiative "Departments of Excellence" (Law 232/2016) and Swiss National Science Foundation (SNSF) PCEGP3_186978
168-LB: Presentation of New Onset Diabetes in Youth during the COVID-19 Pandemic
Authors: CITRON KATE , STEIN CHERYL R. , ILKOWITZ JENIECE , GONZALEZ JUANA E. , JOSEPH VANESSA , PAT GALLAGHER MARY
Published: May 2022

Background: Early research suggests during the COVID-19 pandemic there was an increase in new onset diabetes mellitus (DM) and greater severity at presentation. We examined pandemic related trends of new onset DM among patients at a pediatric diabetes center in New York, NY.

Methods: We conducted a retrospective chart review of 168 youth 0-26 years old presenting with new onset DM from January 2019 to October 2021. We used chi-square statistics, t-tests, and ANOVAs to compare aspects of presentation by year of diagnosis, overall and type 2 DM (T2D) versus type 1 DM (T1D) .

Results: The number of patients presenting with new onset DM increased throughout this time, with 43 in 2019, 57 in 2020, and 68 in 2021. This increase was primarily driven by an increase in T2D (8 in 2019, 16 in 2020, 27 in 2021) . Patients with T2D had higher mean BMI percentile at presentation compared to T1D (97.5 vs. 42.9; p<.001) . The mean BMI percentile of all patients increased (p for trend=0.02) and was higher in 2021 (67.8) compared to 2019 (50.1; p=0.02) . These differences, however, were not statistically significant when examined by DM type. There was no significant difference in severity of presentation based on HbA1C, DKA frequency or severity, lowest potassium level, or length of stay (LOS) . For example, among all patients in DKA, the prevalence of severe DKA was 53% in 2019, 62% in 2020, and 55% in 2021 (p=0.89) . Although numbers were small, there was a qualitative increase in LOS and decrease in bicarbonate level in patients with new onset T2D between 2019 and 2021.

Conclusions: In this population, the number of pediatric new onset DM increased during the COVID-19 pandemic. Cases of T2D increased by a greater degree than T1D which may explain the increased mean BMI percentile at diagnosis. There was no change in severity of DM presentation when examining multiple markers of severity. Further research is needed to understand if lifestyle changes during the pandemic may have impacted BMI and how this may relate to new onset pediatric DM, particularly T2D.

Disclosure

K. Citron: None. C. R. Stein: None. J. Ilkowitz: None. J. E. Gonzalez: None. V. Joseph: None. M. Gallagher: None.
169-LB: Structural Echocardiographic Abnormalities in T2D —Mexico Cohort of Take Care of Me Program
Authors: SAHAGUN-SANCHEZ GUILLERMO , GUTIÉRREZ-FAJARDO PEDRO , MEZA-LEDEZMA OMAR , RODRIGUEZ-VALADEZ FLORISA , LAVALLE-GONZALEZ FERNANDO J. , VAZQUEZ-MENDEZ ESTEFANIA
Published: May 2022

Rationale: Due to gaps in detecting subclinical cardiac abnormalities in T2D, we evaluated prevalence and clinical manifestations of early echocardiographic (echo) abnormalities in primary care in Mexico.

Methods: Mexico cohort of the ongoing ‘Take CaRe of Me program’ enrolled 2760 people with T2D (between 7 Dec 2020 - 10 Dec 2021) and no cardiorenal disease per index visit history. We present descriptive data of documented echo performed by cardiologists as routine clinical care (499) in high-risk T2D identified by Systematic Coronary Risk Evaluation (ESC 2019) .

Results: With mean age of 54.2±11.4 years, 55.4% were females and 189 patients (37.9%) had echo abnormalities — left ventricular hypertrophy (21%, 105) , left atrial enlargement (24.2%, 121) , diastolic dysfunction (6.8%, 34) , pulmonary hypertension (5.4%, 27) and valvular disease (4.8%, 24) . Substantial proportion of people with echo abnormalities had high or very high CV risk (Table) . Overall, 23 people had presumptive diagnosis of pre-HF based on symptoms and echo. Per documented data, 18 people had HF with preserved ejection fraction (EF) , 4 had mid-range EF and 1 had reduced EF.

Conclusion: Structural abnormalities are prevalent in 37.9% of people with T2D referred for an echo, even in absence of symptoms. Timely diagnosis of silent structural heart abnormalities in T2D is an opportunity for using novel cardiorenal pharmacotherapy for preventing HF.

Disclosure

G. Sahagun-sanchez: None. P. Gutiérrez-fajardo: None. O. Meza-ledezma: None. F. Rodriguez-valadez: None. F. J. Lavalle-gonzalez: Speaker's Bureau; Abbott Diagnostics, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Servier Laboratories. E. Vazquez-mendez: None.

Funding

TCoM study was funded by AstraZeneca International. We are thankful to the cardiologists at the investigation centers for performing echocardiography and primary care physicians of Clinicas del Azcar for recruiting the patients.
17-LB: Antihyperglycemic Use in Hemodialysis-Dependent Kidney Failure
Authors: KLEIN KLARA , PATE VIRGINIA , ASSIMON MAGDALENE M. , STÜRMER TIL , BUSE JOHN B. , FLYTHE JENNIFER
Published: May 2022

Background: At least two-thirds of people with hemodialysis-dependent kidney failure have comorbid diabetes which associates with higher mortality. Some GLP-1 receptor agonists (RA) do not require renal dosing and could uniquely benefit dialysis patients, individuals with tremendous cardiovascular disease burden.

Methods: Using data from a national surveillance system for kidney failure in the U.S. that includes Medicare Part D prescription drug claims, we: 1) calculated the quarterly prevalence of antihyperglycemic use among diabetic hemodialysis patients from 2012 to 2017 and 2) characterized antihyperglycemic users in October 2017.

Results: Among the 129,865 hemodialysis patients with comorbid diabetes, insulin was the most prescribed agent (33%) , followed by sulfonylureas (SU, 7%) and DPP4 inhibitors (DPP4i, 5%) in October 2017. SU use fell, and DPP4i use rose from 2012 to 2017. Less than 5% of patients received combination therapy (insulin + a 2nd agent; Figure 1) . Disregarding kidney disease as an atherosclerotic cardiovascular disease (ASCVD) risk factor, 64% of patients met American Diabetes Association ASCVD criteria and 98% were at high risk for ASCVD in 2017. GLP-1 RA were prescribed to <1% of patients, 20% of whom had an endocrinology claim in the prior 6 months.

Conclusions: GLP-1 RA use by hemodialysis patients is limited. There is compelling need to establish the safety and efficacy of GLP-1 RA in this high-risk population.

Disclosure

K. Klein: None. V. Pate: None. M. M. Assimon: None. T. Stürmer: Research Support; Novo Nordisk. Stock/Shareholder; Novartis AG, Novo Nordisk, Roche Pharmaceuticals. Other Relationship; AbbVie Inc., Boehringer Ingelheim International GmbH, GlaxoSmithKline plc., Takeda Pharmaceutical Company Limited, UCB, Inc. J. B. Buse: Consultant; Alkahest, Anji, AstraZeneca, Boehringer Ingelheim International GmbH, Cirius Therapeutics, Inc., Eli Lilly and Company, Fortress biotech, GentiBio, Glycadia, Glyscend, Janssen Pharmaceuticals, Inc., Mellitus Health, Moderna, Inc., Pendulum Therapeutics, Praetego, LLC, Stability Health, Valo, Zealand Pharma A/S. Research Support; AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, vTv Therapeutics. Stock/Shareholder; Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Praetego, LLC, Stability Health. Other Relationship; Adocia, AstraZeneca, Eli Lilly and Company, Intarcia Therapeutics, Inc., MannKind Corporation, Novo Nordisk, Sanofi, Senseonics, vTv Therapeutics. J. Flythe: Advisory Panel; Fresenius Medical Care. Consultant; AstraZeneca. Research Support; Fresenius Medical Care.
170-OR: Outcomes of a Digital Health Coaching Program Integrating Food Delivery for a Population of Adults with T2DM at Risk of Food Insecurity
Authors: RUTLAND SARAH , MOORE JASMINE , TRAN VANESSIA T. , ALLISON MATTHEW , BURTON B. STEPHEN , PATEL DHIREN
Published: May 2022

Background: Recent reviews suggest that concurrent Type 2 Diabetes Mellitus (T2DM) and food insecurity contributes to poorer outcomes, including worse glycemic control and increased healthcare use. We present outcomes from a real-world program involving digital health coaching (DHC) and bi-weekly food delivery for individuals with T2DM screened for food insecurity.

Methods: Individuals with T2DM were enrolled in a payor-supported DHC program and screened for food insecurity through social worker, provider, or payor records. A retrospective analysis compared data from baseline to 3-months of enrollment to evaluate T2DM-related outcomes.

Results: Of the 1093 individuals who completed baseline assessments, 75% completed 3 months of DHC. This population was primarily female (74%) , racially/ethnically diverse (38% Black, 54% white, 8% other or multi-racial) , with an average age of 53. At 3 months, there were significant improvements in mean scores on the Diabetes Distress Score (2.76 to 2.09, p<0.001) , HbA1c (8.22 to 7.52, p<0.001) , and USDA Food Security Survey (2.49 to 1.39, p<0.001) among evaluable participants (n=710) .

Conclusions: A DHC program with integrated food delivery demonstrated promising results, suggesting that addressing basic needs such as food security may contribute to improved clinical and quality of life outcomes for individuals with T2DM.

Disclosure

S.Rutland: Employee; Pack Health. J.Moore: None. V.T.Tran: None. M.Allison: None. B.Burton: None. D.Patel: None.
171-LB: Estimating the Immunological Risk for Type 1 Diabetes from a CGM-Based One Week Self-Administered Home Test
Authors: MONTASER ESLAM , VILLARD ORIANNE , FABRIS CHIARA , LOBO BENJAMIN , BROWN SUE A. , DEBOER MARK D. , KOVATCHEV BORIS , FARHY LEON
Published: May 2022

Background and aims: Detection of immunological risk (IR) for type 1 diabetes (T1D) requires testing for presence of islet autoantibodies (AB) . However, who and when to test is challenging. Our goal is to develop a (pre) screening technology to estimate the T1D IR from a simple continuous glucose monitoring (CGM) home test.

Methods: Data from a NIH TrialNet ancillary study with 53 healthy relatives to T1D with (N=35) or without (N=18) AB, mean±SD age of 25.4±10.7, HbA1c of 5.1±0.3%, and BMI of 22.9±5.2 (kg/m2) were used. Subjects wear CGM for a week and consumed 3 caloric drinks (Boost) . Nine glycemia features were extracted from the 75 minutes post-Boost CGM traces and used for IR classification. K-fold cross-validation with eight different classification models (i.e., linear, nonlinear, advanced, etc.) was used to develop an IR classifier. Receiver operating characteristic (ROC) curves, sensitivity, and specificity were used to select the best performing classification model.

Results: IR classifier based on a neural network (NN) model with upsampling and 10-fold cross-validation achieved the best performance between different classification models: an AUC-ROC of 0.93, a sensitivity of 89%, and a specificity of 75%. A random forest model-based classifier performed almost equally well. The Naive Bayes model achieved the best sensitivity of 100%, but had an AUC-ROC of 0.78, and specificity of 32%. On the other hand, the support vector machines models achieved the worst performance with the best being AUC-ROC of 0.63, a sensitivity of 65%, and a specificity of 54%.

Conclusion: We have developed a new methodology, which combines a dedicated one-week CGM home test with a neural network-based classifier that reliably predicts the individual IR in terms of presence or absence of islet AB. The test is self-administered, does not require a visit to a hospital or a lab, and can be used as an alternative or in addition (e.g., for prescreening) to the standard test for presence of islet autoantibodies.

Disclosure

E. Montaser: None. O. Villard: None. C. Fabris: None. B. Lobo: Other Relationship; Dexcom, Inc., Research Support; Dexcom, Inc. S. A. Brown: Research Support; Dexcom, Inc., Insulet Corporation, Roche Diagnostics USA, Tandem Diabetes Care, Inc., Tolerion, Inc. M. D. Deboer: Research Support; Dexcom, Inc., Tandem Diabetes Care, Inc. B. Kovatchev: Other Relationship; Dexcom, Inc., Johnson & Johnson, Novo Nordisk, Sanofi, Research Support; Dexcom, Inc., Novo Nordisk, Tandem Diabetes Care, Inc., Speaker's Bureau; Dexcom, Inc., Tandem Diabetes Care, Inc. L. Farhy: Research Support; Dexcom, Inc., Novo Nordisk.

Funding

NIH DP3DK106907 (TrialNet ancillary study) and CRCF Award MF20-007-LS
173-OR: Associations between Post-Discharge Care (PDC) and Cognitive Impairment-Related Hospital Readmissions for Ketoacidosis and Severe Hypoglycemia in Adults with Diabetes
Authors: WANG YEHUA , ZHANG PING , FANG RUOGU R. , BROWN JOSHUA D. , JIAO TIANZE , GUO JINGCHUAN , SHAO HUI
Published: May 2022

Cognitive Impairment (CI) is associated with an increased risk of ketoacidosis (DKA) and severe hypoglycemia (SH) in persons with diabetes (DM) . Post-discharge Care (PDC) in nursing homes and home care facilities provides continuous medical care after hospital discharges. This study examined whether PDC is associated with lower CI-related hospital readmission for DKA and SH in US adults with DM (age >18) . Our study population includes 43,467 and 166,221 adults admitted for DKA and SH from the 2016-2018 National Readmission Database, among which 1492 (3.43%) and 822 (0.49%) had CI, respectively. Readmission was defined as hospitalization for all causes within 30 days after discharge. CI-related readmission risk was estimated by comparing those with and without CI using a multiple logistic regression model, adjusting for age, sex, primary payer, income level, disease severity, mortality risk at the index discharge, and PDC status. PDC as an effect modulator was tested as an interaction term of PDC and CI. For patients initially admitted for DKA, CI was associated with 62% (adjusted odds ratio (aOR) =1.62, 1.25-2.11) higher odds of readmission among those who were discharged to home. The CI-related increase in readmission risk disappeared if patients received PDC (aOR=1.05, 0.88-1.26) . For patients initially admitted for SH, CI was associated with 34% (aOR=1.34, 95% CI 1.08-1.66) higher odds of readmission among those discharged to home and a 32% lower odds of readmission if patients received PDC (aOR=0.68, 0.59-0.81) . CI was associated with increased readmission risks for SH and DKA among adults with DM discharged to home. This CI-related readmission risk was substantially lower in patients who received PDC, indicating the importance of PDC for people with DM and CI.

Disclosure

Y.Wang: None. P.Zhang: None. R.R.Fang: None. J.D.Brown: None. T.Jiao: None. J.Guo: None. H.Shao: Board Member; BRAVO4HEALTH, LLC.
174-OR: Identify Effect Modulators of Intensive Glucose Control in Preventing Cognitive Function Decline among Individuals with Type 2 Diabetes: A Revisit to the ACCORD MIND Trial
Authors: KIANMEHR HAMED , GUO JINGCHUAN , FONSECA VIVIAN , SHI LIZHENG , SHAO HUI
Published: May 2022

This study aimed to identify patient characteristics associated with the effectiveness of intensive glucose control (i.e., A1c<6.0% vs. A1c 7-8%) in preventing cognitive function decline (CFD) among individuals with type 2 diabetes (T2D) in the ACCORD trial. The Memory in Diabetes (MIND) study was sub trial of the ACCORD study, including 2,977 participants without a history of cognitive impairment or dementia. We applied the causal forest (CF) and causal tree (CT) algorithm to identify participant characteristics that modulate the effectiveness of intensive glucose control in preventing CFD from a list of 58 candidate variables (demographics, disease histories, medications, and biomarkers) at the study baseline. The study outcome was the change of cognitive function from the baseline to the 40th month, assessed through the Digit Symbol Substitution Test (DSST) , Rey Auditory Verbal Learning Test (RAVLT) , Mini-Mental State Examination (MMSE) , and Stroop test. A computer-driven approach identified a close relationship between renal function and the effectiveness of intensive glycemic control in preventing CFD: study participants with the urinary albumin less than 0.4 mg/dl (absolute function change (AFC) : 0.43 in MSSE) or urinary creatinine 120-200 mg/dl (AFC: 0.30 in RAVLT) had slower CFD associated with intensive glycemic control, while participants with GFR<60 (AFC:-0.51 in RVALT) , or GFR<90 (AFC:-1.7 in Stroop) had a faster CFD associated with intensive glycemic control. In addition, only participants with age below 60 years old benefited from the intensive glucose control (AFC:1.23 in DSST) in preventing CFD. All p<0.05. Our study tied renal function to the effectiveness of intensive glycemic control in preventing CFD. Clinicians may consider these individualized characteristics for better-targeted A1c goal setting, especially those at risk for CFD.

Disclosure

H.Kianmehr: None. J.Guo: None. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. L.Shi: None. H.Shao: Board Member; BRAVO4HEALTH, LLC.
175-LB: Patient Determinants of Mortality with Severe DKA and/or HHS during the COVID Pandemic Differ from the Prepandemic
Authors: YANG ALMIRA J. , FIREK MATTHEW A. , MUNIR IQBAL , TRAN ANH , FIREK ANTHONY
Published: May 2022

Background: SARS CoV-2 has been linked to higher mortality rate among DM patients who present with diabetic ketoacidosis (DKA) and/or hyperosmolar hyperglycemic state (HHS) . The Riverside University Health System Medical Center (RUHS-MC) -DKA Outcomes Group initiated a study to determine outcomes and risk factors before and during the pandemic in patients hospitalized at RUHS-MC with DKA and/or HHS.

Methods: This was a retrospective cohort study reviewing medical records of non-pregnant adults age 18 or older admitted to the RUHS-MC for DKA and/or HHS from 03/2020 to 02/2021 (“pandemic”) compared to 3 years before the pandemic (“pre-pandemic”) . Descriptive statistics were used to determine the clinical characteristics. Logistic regression was used to assess the impact of the parameters on the death rate.

Results: The mortality rate of DKA and/or HHS was 9% (30/335) during pandemic vs. 1.8% (15/855) during pre-pandemic. Six out of 30 patients died without COVID-19 infection, consistent with the pre-pandemic mortality rate. Pre-existing myocardial infarction and lower beta-hydroxybutyrate level were associated with increased mortality (Table 1) .

Discussion: At our institution, the mortality rate of DKA and/or HHS during pandemic was significantly higher, specifically associated with COVID-19 infection. Our study suggests concomitant COVID-19 is a highly lethal and independent factor in patients that develop DKA. The gender disparity in mortality is unexplained and requires additional studies.

Disclosure

A. J. Yang: None. M. A. Firek: n/a. I. Munir: None. A. Tran: None. A. Firek: None.
175-OR: Effect of Hyperketonemia on Cardiac Efficiency in Patients with Heart Failure and Type 2 Diabetes
Authors: SOLIS-HERRERA CAROLINA , QIN YUEJUAN , HONKA HENRI , MOODY ALEXANDER , CLARKE GEOFFREY D. , TRIPLITT CURTIS L. , CERSOSIMO EUGENIO , DEFRONZO RALPH A.
Published: May 2022

Mechanism (s) responsible for the cardiac benefits of SGLT2 inhibitors remain unknown.

Aim: To examine the effect of increased ketone concentration (with infusion of beta-hydroxybutyrate [BOHB]) on left ventricular (LV) function and myocardial glucose uptake (MGU) Methods: Two groups (12 per group) of T2DM with HFrEF (<45%) were studied. Group I (Age=60; BMI=32 kg/m2; A1c = 7.7%) received randomly a 6-hr BOHB infusion (Prime =1.5 mg/kg.min, then 0.75 mg/kg.min) or 6-hr HCO3 infusion (control) . Group II (Age=57; BMI=32 kg/m2; A1c=7%) received a 3-hr BOHB infusion at a higher rate. A cardiac MRI was performed before and after each infusion. Additionally, Group I underwent a PET study with 18FDG

Results: Groups I and II achieved plasma ketone levels of 1.2 and 2.6 mmol/L respectively. In both groups, the BOHB infusion significantly (P<0.05) increased CO, stroke volume (SV) , and ejection fraction (EF) ; the increase in EF was greater in Group II vs. Group I (<0.001) (Figure 1) . NaHCO3 infusion had no effect on CO, SV, or EF. Myocardial glucose uptake was not altered by BOHB

Conclusion: In patients with T2DM and HFrEF, increased plasma ketones significantly increases LV function and may be dose-dependent. These findings support the hypothesis that plasma ketones can provide an additional fuel for the heart, without interfering myocardial glucose metabolism and may be used therapeutically to improve cardiac function in HFrEF.

Disclosure

C.Solis-herrera: Speaker's Bureau; Novo Nordisk. Y.Qin: None. H.Honka: None. A.Moody: None. G.D.Clarke: None. C.L.Triplitt: Consultant; Bayer AG, Speaker's Bureau; Eli Lilly and Company, Novo Nordisk. E.Cersosimo: Research Support; AstraZeneca. R.A.Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker's Bureau; AstraZeneca.

Funding

Merck and Co and The Max and Minnie Tomerlin Voelcker Foundation and
18-OR: Discontinuation of Renin Angiotensin System Inhibitor and Cardiovascular-Renal Events in Advanced Diabetic Kidney Disease
Authors: SHI MAI , YANG AIMIN , LAU ERIC S.H. , WU HONGJIANG , ZHANG XINGE , FAN BAOQI , KONG ALICE P. , LUK ANDREA , MA RONALD C. , CHAN JULIANA C. , CHOW ELAINE
Published: May 2022

Introduction: Whether angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) should be discontinued in advanced diabetic kidney disease (DKD) remains controversial. We examined the association of discontinuation of ACEi/ARBs when estimated glomerular filtration rate (eGFR) reached <30 ml/min/1.73m2 with risk of death, major adverse cardiovascular events (MACE) , and end-stage-kidney-disease (ESKD) defined as dialysis and/or eGFR <15/ml/min/1.73m2 in Chinese patients with type 2 diabetes (T2D) .

Methods: We performed a prospective analysis of a register including 11,323 patients stratified by continuation of ACEi/ARBs within 6 months of reaching eGFR <30 ml/min/1.73m2 in 2002-2018 followed up until 2019. We used Cox model with time-dependent exposure and covariates to estimate the hazard ratio (HR) of outcomes in the overlap propensity score weighted cohort.

Results: Of 11,323 ACEi/ARBs users with new-onset eGFR<30 ml/min/1.73m2, 2,055 (18.5%) discontinued ACEi/ARBs within 6 months whereas 9,268 (81.5%) had continuation of ACEi/ARBs. During a mean follow-up of 4.3 years, 13.5% and 28.4% had incident MACE and ESKD respectively, and 36.2% died. Compared to ACEi/ARBs continuation, discontinuation of ACEi/ARBs was associated with higher risk of MACE (HR=1.26, 95% CI: 1.15-1.39) and ESKD (HR=1.26, 95% CI: 1.14-1.40) , and neutral risk of death (HR=0.96, 95% CI: 0.89-1.04) . Results were consistent when modeling ACEi/ARBs as a time-dependent exposure using a marginal structural model.

Conclusions: Discontinuation of ACEi/ARBs was associated with increased risk of cardiovascular-renal events in support of their continued use in patients with advanced DKD.

Disclosure

M.Shi: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. A.Yang: None. E.S.H.Lau: None. H.Wu: None. X.Zhang: None. B.Fan: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. A.Luk: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc.
182-OR: Clinical Effects of SGLT2 Inhibitors in HNF1A-Diabetes (MODY3) : A Case Series
Authors: MAAGENSEN HENRIK , HAEDERSDAL SOFIE , KROGH JESPER , HANSEN TORBEN , KNOP FILIP K. , VILSBØLL TINA
Published: May 2022

Mutations in hepatocyte nuclear factor 1-alpha (HNF1A) cause HNF1A-diabetes (or maturity-onset diabetes of the young type 3 (MODY3)) . Treatment of HNF1A-diabetes is primarily based on sulphonylureas (SU) and secondarily insulins, glucagon-like peptide 1 receptor agonists (GLP1-RA) and dipeptidyl peptidase-4 inhibitors (DPP4i) . Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective glucose-lowering agents, cause body weight loss and protect from chronic kidney disease, heart failure and major adverse cardiovascular events. The utility of SGLT2i in patients with HNF1A-diabetes is unknown. Here, we describe a case series of five patients with HNF1A-diabetes treated with SGLT2i. Patient characteristics (median [range]) : age: 52 [35; 68] years; men/women: n=4/1; diabetes duration: 23 [9; 55] years; age at diabetes onset: 18 [13; 44] years; HbA1c: 6.9 [6.0; 7.4]% (52 [42; 57] mmol/mol) ; body weight: 92.3 [65.5; 95.1] kg; BMI: 25.6 [23.8; 29.4] kg/m2. At baseline, patients were treated with SU (n=5) , insulin (n=3; total daily dose: 15 [6; 25] IE divided into 1-4 injections/day) , DPP-4i (n=3) , GLP1-RA (n=2) , metformin (n=1) . All patients were started on empagliflozin mg QD. Follow-up was 1.5 [0.7; 1.8] years (total 6.2 patient years) . After three to six months of SGLT2i therapy, HbA1c was 6.1 [5.5; 7.5]% (43 [37; 59] mmol/mol) and had decreased in four patients (HbA1c change: -0.5 [-1.3; 0.7]% (-5 [-14; 8] mmol/mol)) , while body weight had decreased in all patients (change: -3.4 [-5.9; -1.5] kg) . During SGLT2i treatment, insulin was fully ceased in two patients and insulin dose was reduced from 15 IE/day to 3 IE/day in one patient. No serious adverse events were reported. Our data suggest that SGLT2i is safe, have glucose-lowering effects and is well-tolerated in HNF1A-diabetes, but randomized controlled trials are needed.

Disclosure

H.Maagensen: None. S.Haedersdal: None. J.Krogh: None. T.Hansen: None. F.K.Knop: Advisory Panel; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, ShouTi, Zucara Therapeutics, Consultant; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pharmacosmos A/S, Sanofi, ShouTi, Zealand Pharma A/S, Zucara Therapeutics, Research Support; AstraZeneca, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Stock/Shareholder; Antag Therapeutics. T.Vilsbøll: Consultant; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk, Sun Pharmaceutical Industries Ltd.
183-OR: Overcoming Immunological Barriers for “Off-the-Shelf” iPSC-Derived Islets
Authors: HU XIAOMENG , WHITE KATHY , OLROYD ARI G. , DEJESUS ROWENA , DOMINGUEZ ANTONIA , DOWDLE WILLIAM E. , CHU ELAINE Y.L. , FRIERA ANNABELLE , YOUNG CHI , WELLS FRANK , MCGILL TREVOR , RUKSTALIS MICHAEL , GATTIS CORIE , BASCO RONALD , MILLMAN JEFFREY R. , SCHREPFER SONJA
Published: May 2022

Improved differentiation protocols allow large-scale generation of induced pluripotent stem cell (iPSC) -derived islets. In order to make allogeneic “off-the-shelf” islets clinically useful and avoid rejection absent immunosuppression (IS) , they need to evade host immune responses, a property we refer to as being “hypoimmune.” Rhesus macaque (NHP) iPSCs were engineered to knock-out function of MHC class I and II and overexpress CD47 (HIP iPSCs) . HIP iPSCs and unedited iPSCs (wt iPSCs) were transduced to express luciferase and transplanted IM into four allogeneic NHPs per group. There was a strong IFN-γ ELISpot T cell response 1 week after wt iPSC transplantation, and increased production of wt-iPSC specifc IgM antibodies (Ab) and IgG Abs. At all time points tested (up to 12 weeks) , PBMCs killed wt iPSCs via direct and Ab-mediated cellular cytotoxicity. Furthermore, serum from NHPs killed wt iPSCs via complement-dependent cytotoxicity. In contrast, NHPs that received HIP iPSCs showed no measurable immune response against HIP iPSCs at all time points. After 6 weeks, NHPs initially receiving wt iPSCs were injected with HIP iPSCs. Although the NHPs maintained their strong immune response against wt iPSCs, they did not mount any response against HIP iPSCs. NHPs receiving HIP iPSCs first developed a strong cellular and Ab-response against the subsequently injected wt iPSCs but continued to have no reactivity against HIP iPSCs. Bioluminescence imaging in vivo revealed rejection of all wt iPSC grafts in both groups within 2-3 weeks after transplantation, while all HIP iPSC grafts survived the study period of 16 weeks. As a step to extending these studies to human iPSCs, we created human HIP iPSCs. We were able to differentiate these human HIP iPSCs into functional HIP islet cells that evaded host immune responses. This work suggests that HIP modifications do not impact islet cell differentiation or function. These data support the development of allogeneic HIP islets for the treatment of patients with T1DM.

Disclosure

X.Hu: None. F.Wells: None. T.Mcgill: Employee; Sana Biotechnology Inc. M.Rukstalis: Employee; Sana Biotechnology Inc. C.Gattis: None. R.Basco: None. J.R.Millman: Consultant; Sana Biotechnology Inc., Other Relationship; Sana Biotechnology Inc., Vertex Pharmaceuticals Incorporated, Research Support; Sana Biotechnology Inc., Stock/Shareholder; Salentra Biosciences. S.Schrepfer: Other Relationship; Sana Biotechnology Inc. K.White: None. A.G.Olroyd: None. R.Dejesus: None. A.Dominguez: Employee; Sana Biotechnology Inc. W.E.Dowdle: Employee; Sana Biotechnology Inc., Stock/Shareholder; Sana Biotechnology Inc. E.Y.L.Chu: None. A.Friera: None. C.Young: Employee; Sana Biotechnology Inc.