bluuebunny/crossref_metadata_2025 huggingface dataset:
258-OR: Type 2 Diabetes and Chronic Kidney Disease as Predictors of Cardiovascular Mortality in Patients with Established Cardiovascular Disease
Authors: SPRENGER LUKAS , MAECHLER MAXIMILIAN , VONBANK ALEXANDER , LARCHER BARBARA , MADER ARTHUR , PLATTNER THOMAS , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: June 2023

This study aims to investigate the single and joint effects of T2DM and CKD on cardiovascular mortality in patients with established cardiovascular disease. We prospectively investigated 1755 patients with established cardiovascular disease, angiographically proven coronary artery disease (CAD) or sonographically proven peripheral artery disease (PAD), over 10.8±5.0 years. Cardiovascular death occurred more frequently in T2DM patients (n=568) than in nondiabetic subjects (30.4% vs 18.1%, p<0.001) and in patients with CKD (eGFR<60ml/min/1.73m2; n=300) than in those without CKD (35.7% vs 19.3%, p=0.001). When both T2DM and CKD were considered, 1015 subjects had neither T2DM nor CKD, 440 had T2DM but not CKD, 172 did not have diabetes but had CKD, and 128 had T2DM and CKD. Compared to the incidence of cardiovascular death among patients with neither T2DM nor CKD (15.8%), cardiovascular death occurred more frequently in patients with T2DM who did not have CKD (27.4%; p<0.001) as well as in nondiabetic patients with CKD (31.6%; p<0.001); the incidence of cardiovascular death was highest in patients with T2DM and CKD (41.3%; p<0.001), in whom it was higher than in those with T2DM but not CKD (p<0.001) or those without T2DM but with CKD (p=0.039); the incidence of cardiovascular death did not differ significantly between nondiabetic CKD patients and T2DM patients who did not have CKD (p=0.075). In Cox regression analysis, T2DM (HR 1.78 [1.43-2.21]; p<0.001) and CKD (HR 1.74 [1.36-2.23]; p<0.001) proved to be mutually independent predictors of cardiovascular mortality after multivariate adjustment for age, sex, BMI, history of smoking, hypertension, LDL-C and HDL-C. We conclude that T2DM and CKD in patients with established cardiovascular disease are mutually independent predictors of cardiovascular mortality. Cardiovascular disease patients with both CKD and T2DM are at an extremely high risk for cardiovascular death.

Disclosure

L. Sprenger: None. M. Maechler: None. A. Vonbank: None. B. Larcher: None. A. Mader: None. T. Plattner: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None. C.H. Saely: None.
259-OR: Arterial Stiffness and Diabetes-Associated Complications in the SEARCH for Diabetes in Youth Study
Authors: BRADY RYAN , URBINA ELAINE M. , GAO ZHIQIAN , DOLAN LAWRENCE M. , DABELEA DANA , LUSTIGOVA EVA , MOTTL AMY K. , PIHOKER CATHERINE , REYNOLDS KRISTI , SANCRAINTE LEANNE , SHAH AMY S.
Published: June 2023

Arterial stiffness and vascular complications contribute to the burden of disease in diabetes, and it is unclear how they relate to each other. The relationship between arterial stiffness, an early marker of cardiovascular disease, and microvascular complications has not been comprehensively assessed in youth-onset diabetes. This study included 1226 individuals (mean age 22.8 years, 58% female, 53% Non-Hispanic White, 22% Non-Hispanic Black, 20% Hispanic) with type 1 (n=999) and type 2 (n=227) diabetes. Arterial stiffness measures included pulse wave velocity for carotid-femoral (PWVcf), carotid-radial (PWVcr), and femoral-foot (PWVff) and augmentation index (AIx). Microvascular complications included diabetic kidney disease, peripheral neuropathy, and retinopathy. Logistic regression was used to analyze associations between arterial stiffness and microvascular complications. PWVcf and AIx were associated with higher odds of having any microvascular complication, p<0.05 (Table). PWVcf, PWVff, and AIx were each associated with diabetic kidney disease. PWVcf was associated with peripheral neuropathy and PWVcr and AIx were associated with retinopathy. Arterial stiffness is related to diabetes microvascular complications in youth-onset diabetes. Future work will determine whether arterial stiffness is a marker for early onset and progression of microvascular complications.

Disclosure

R.Brady: None. L.Sancrainte: None. A.S.Shah: None. E.M.Urbina: Advisory Panel; Astellas Pharma Inc., Other Relationship; Targus Medical, Inc. Z.Gao: None. L.M.Dolan: None. D.Dabelea: None. E.Lustigova: None. A.K.Mottl: Advisory Panel; Bayer Inc., Chinook Therapeutics Inc., Consultant; Bayer Inc., Research Support; Bayer Inc., Alexion Pharmaceuticals, Inc., Pfizer Inc., Boehringer Ingelheim Inc., Calliditas. C.Pihoker: None. K.Reynolds: Research Support; Novartis Pharmaceuticals Corporation.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK127208-01); Centers for Disease Control and Prevention (00097, DP-05-069, DP-10-001)
262-LB: Fasting Intact Insulin by Liquid Chromatography–Tandem Mass Spectrometry (LC-MS/MS) as a Predictor of Nonalcoholic Fatty Liver Disease in Pediatric Patients
Authors: HUNEAULT HELAINA , AYINDE DAMILOLA , HE ZHULIN , RAMIREZ ANA M. , COHEN CATHERINE C. , MCPHAUL MICHAEL J. , VOS MIRIAM B.
Published: June 2023

Background: Recent research in adults has shown fasting intact insulin levels measured by mass spectrometry can predict nonalcoholic fatty liver disease (NAFLD) in patients without diabetes; however, there is limited research in children. This study aimed to evaluate fasting intact insulin by LC-MS/MS as a predictive biomarker of NAFLD in adolescents.

Methods: This retrospective, cross-sectional study was based on data from four previously conducted studies. Existing clinical laboratory values included fasting intact insulin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), C-peptide, and the insulin resistance (IR) score. Hepatic fat was assessed by magnetic resonance imaging proton density fat fraction (MRI-PDFF) or MR spectroscopy (MRS). NAFLD was defined as intrahepatic fat of ≥5%.

Results: A total of 73 children were included in the analysis (64% male; 13.9 ± 2.8 years of age; body mass index (BMI) 29.1 ± 8.5 kg/m2; 56% with NAFLD). Intact fasting insulin, C-peptide, AST, ALT, and IR scores were higher in children with NAFLD compared to non-NAFLD children (P<0.05). Fasting intact insulin measurements predicted NAFLD (area under the receiver operating characteristic curve [AUROC] of 0.83 [95%CI, 0.73-0.93]). When combined with ALT (intact insulin (μU/mL) × ALT (× U/L)), the combined biomarker slightly improved the prediction of NAFLD (AUROC 0.89 [0.81-0.96]), with positive and negative predictive values of 79% and 100%, respectively. Based on maximizing Youden's index, the optimal cutoff points to predict NAFLD were 13.0 μU/mL for intact insulin and 380 μU/mL × U/L for intact insulin × ALT.

Conclusion: Our findings support that fasting intact insulin alone, or combined with ALT (intact insulin × ALT), show promise as predictive biomarkers for pediatric NAFLD with high positive and negative predictive values. Additional studies are needed to validate these findings in other pediatric populations.

Disclosure

H. Huneault: None. D. Ayinde: None. Z. He: None. C. C. Cohen: None. M. J. McPhaul: Employee; Quest Diagnostics. M. B. Vos: Consultant; Boehringer Ingelheim International GmbH, BMS, Intercept Pharmaceuticals, Inc., Novo Nordisk, ProSciento, Eli Lilly and Company. Research Support; Quest Diagnostics, TARGET PharmaSolutions, Inc.

Funding

National Institutes of Health (R01DK125701); Georgia Clinical Translational Science Alliance (UL1TR002378)
263-LB: Food Intake Impacts on Insulin Secretion, Resistance, and Glucose Variability in Free-Living Individuals with Type 2 Diabetes Mellitus
Authors: PAULA COMARELLA ANA , BELFORT-DEAGUIAR RENATA
Published: June 2023

Changes in eating habits and physical activity are the cornerstone of treatment of type 2 diabetes mellitus (T2D). Dietary composition has important effects on the postprandial glucose and insulin response, but little is known about its impact in a real-life context. We analyzed the self-reported daily food composition of 13 individuals with obesity and T2D not on insulin (7F/6M, age 48±9, BMI 33±2, A1C 7±1) with ASA24 (NIH), while wearing continuous glucose monitor (Dexcom G4) for 3±1 days. They also underwent an oral glucose tolerance test to explore correlations with standard indices of insulin secretion and sensitivity. The mean consumption per meal of total calorie was: 534±110Kcal, carbohydrate: 51±19g, total grains: 1.78±0.66g (refined 1.61±0.59g, whole 0.17±0.18g), total fat: 25±6g (10±3.17g monounsaturated fat), and protein: 24±7g. We observed a positive correlation between average intake of total and monounsaturated fat with the insulin secretion index (ρ= 0.630, p=0.02,) and Disposition Index (DI) (p=0.001, ρ=0.821). An inverse relationship between the consumption of total and refined grains was noted with the insulin sensitivity indexes (p=0.01, ρ= -0.663); as well as with whole grains and DI (p=0.03, ρ= -0.601). We documented glycemic variability (GV) related to meal nutrient intake through macro program: CGM peak and nadir analysis, Microsoft Excel. Total and monounsaturated fats correlated with lower GV (p=0.02), while total and refined grains were associated with greater GV (p<0.03). Glucose nadir after a meal and glucose at the time of the meal inversely correlated with insulin secretion indexes and with DI (p<0.05). These data suggest, in a real-life context, the impact of food composition on modulation of GV, with fats being associated with greater insulin secretion and refined grains with decreased insulin sensitivity, reinforcing the importance of the effect of diet on management of diabetes.

Disclosure

A. Comarella: None. R. Belfort-DeAguiar: Research Support; Fractyl Health, Inc., Silver Palate Kitchens.

Funding

National Institutes of Health (DK098286-02)
265-LB: Human Skeletal Muscle Mitochondrial Dynamics across the Insulin-Sensitivity Spectrum
Authors: AXELROD CHRISTOPHER L. , DANTAS WAGNER S. , ZUNICA ELIZABETH R.M. , BELMONT KATHRYN , HEINTZ ELIZABETH C. , DAVULURI GANGARAO , MEY JACOB T. , ERICKSON MELISSA , FUJIOKA HISASHI , FEALY CIARAN , HOPPEL CHARLES L. , KIRWAN JOHN P.
Published: June 2023

Introduction: There is immense dispute as to whether perturbations in skeletal muscle mitochondrial function contribute to the onset and progression of type 2 diabetes (T2D). The purpose of this study was to examine differences in mitochondrial dynamics, structure, and energetic function in humans across the spectrum of insulin sensitivity.

Methods: 58 sedentary adults (37±12 years) were enrolled into one of three groups based upon the following criteria: (1) healthy weight without T2D (HW; BMI: 22.6±1.8 kg/m2 and HbA1c: 5.0±1.1 %); (2) overweight/obesity without T2D (Ov/Ob; BMI: 32.6±3.3 kg/m2 and HbA1c: 5.6±0.4 %); or (3) overweight/obesity with T2D (T2D; BMI: 36.1±6.5 kg/m2 and HbA1c: 6.9±0.9 %). Participants underwent a 3-day inpatient stay consisting of body composition (DXA), aerobic capacity (VO2MAX), and insulin sensitivity (hyperinsulinemic euglycemic clamp). Prior to insulin sensitivity testing, a skeletal muscle biopsy was obtained for determination of mitochondrial dynamics (Western blot), DNA content (qPCR), ultrastructure (electron microscopy), and respiratory capacity (respirometry). Comparisons were made using a one-way ANOVA with contrasts.

Results: Insulin sensitivity and aerobic capacity were lower in Ov/Ob and T2D compared to HW. Markers of mitochondrial fission were higher in T2D (Drp1Ser616, MiD49), and fusion lower in T2D and Ov/Ob (Mfn2). The mitophagy marker Parkin was higher in T2D only while Pink1 was lower in T2D relative to Ov/Ob but not HW. The autophagy marker LC3II was higher in Ov/Ob. Mitochondrial content was lower in Ov/Ob and T2D relative to HW. Mitochondrial respiratory capacity was similar between groups.

Conclusions: T2D is associated with heightened expression of proteins required for mitochondrial quality control and reduced mitochondrial volume despite intact respiratory function. These data support the notion that mitochondria adapt to progressive insulin resistance by increasing fragmentation to maintain bioenergetic capacity.

Disclosure

C. L. Axelrod: None. C. Fealy: Employee; Mission Therapeutics. C. L. Hoppel: None. J. P. Kirwan: None. W. S. Dantas: None. E. R. M. Zunica: None. K. Belmont: None. E. C. Heintz: None. G. Davuluri: None. J. T. Mey: None. M. Erickson: None. H. Fujioka: None.

Funding

National Institutes of Health (DK108089, GM104940)
265-OR: Effectiveness of a Virtual Diabetes Clinic in a Racially Diverse Population
Authors: WARING AVANTIKA C. , SCHANDL BERNHARD , HEINEMANN LUTZ , HOFNER MICHAEL , GEEVARGHESE PAUL
Published: June 2023

Objective: To evaluate the outcome of a novel virtual diabetes clinic on glycemic control in a diverse group of patients with type 2 diabetes.

Methods: 86 patients completed a medical questionnaire, which generates recommendations based on clinical algorithms. All participants had at least one physician consult and unlimited access to a virtual care team (RDs, RN, and PharmD). Participants self-identify race, insurance status, prior conditions and medications. HbA1c levels were documented when joining the program (patient-reported from prior lab or an initial result obtained as part of the program). Subsequent HbA1c results were measured through the lab program (dried blood spot or in-home phlebotomy) or were confirmed results from a non-integrated lab. We compared the first and last HbA1c levels using a paired t-test. In addition, we evaluated the percentage of participants whose HbA1c levels were lowered to target (from >7% to ≤7%).

Results: Participants were highly diverse, with 45.4% self-identifying as non-white. During the study period, 21 of 86 participants received at least one new generic medication or dose adjustment. Among the 24 patients (27.9%) with an initial HbA1c >8%, there was a significant improvement in HbA1c (mean decline 1.7, from 9.5% to 7.8%, p<0.01). Upon joining the program, 39 (45%) participants had an HbA1c >7%; at the end of the study period (ave. 148 days), only 24 (27.9%) had an HbA1c >7% (p=0.018, X2-test).

Conclusions: Participation in a virtual diabetes clinic improved HbA1c significantly over a 3-6 month period in a racially and ethnically diverse population. Prospective studies are needed to confirm the initial effectiveness of a virtual clinic for diabetes over longer periods. Approximately 50% of program members are uninsured and pay an affordable monthly fee. This initial effectiveness suggests that affordable cash-pay virtual clinic solutions may be an efficient and convenient option for patients with diabetes who experience barriers to accessing traditional care.

Disclosure

A.C.Waring: Employee; 9amHealth. B.Schandl: Employee; mySugr, Roche Diabetes Care, Stock/Shareholder; Boydsens, 9amHealth Inc. L.Heinemann: Consultant; 9am.health. M.Hofner: Consultant; 9amHealth Inc. P.Geevarghese: Employee; 9amHealth, Roche Diabetes Care.
266-OR: Development of an EMR Dashboard to Enable Remote Patient Monitoring and Proactive Diabetes Care
Authors: LYONS SARAH , SONABEND RONA Y. , SCHWARTZ DAVID D. , TIMMONS KELLY D. , DESALVO DANIEL
Published: June 2023

We developed a pediatric T1D remote patient monitoring (RPM) program, ROCKET T1D (Remote Outreach & Care for Kids’ Empowerment and Technology use in T1D), with the aims of supporting youth at risk for chronic hyperglycemia and DKA and their families to leverage emerging technology, improve self-management habits, and achieve self-care goals to thrive with T1D. The ROCKET T1D program, supported by diabetes educators and social workers, includes a proactive “Launch Phase” with frequent virtual touchpoints for education, psychosocial support, and therapy adjustments, followed by an “Orbit Phase” with a less frequent remote data review and therapy adjustments. Prior to ROCKET T1D go-live, we developed an electronic medical record (EMR)-based diabetes registry with dashboards to enable remote monitoring, visualization of a validated DKA risk score and clinical data (e.g., pump/CGM use, A1C, etc.) to quickly assess clinical progress and facilitate targeted outreach. Patients are added to the ROCKET T1D Registry via the EMR’s “FYI Flag” feature, which allows visualization of progress through the Launch and Orbit Phases in the dashboard (Figure 1). We are actively working on automated integration of CGM data into ROCKET T1D dashboards to enable proactive outreach to patients at highest glycemic risk, with intent to optimize time in range and prevent DKA.

Disclosure

S.Lyons: None. R.Y.Sonabend: None. D.D.Schwartz: None. K.D.Timmons: None. D.Desalvo: Consultant; Dexcom, Inc., Research Support; Insulet Corporation.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust (2206-05307)
27-OR: Residual Beta-Cell Function Associates with Lower Glycaemic Variability and More Time in Range in Individuals with Type 1 Diabetes
Authors: FUHRI SNETHAGE COCO , MCDONALD TIMOTHY J. , RAMPANELLI ELENA , DE GROEN PLEUN , SCHIMMEL ALINDA W.M. , VAN RAALTE DANIËL , BROUWER CATHERINE B. , ORAM RICHARD A. , ROEP BART O. , NIEUWDORP MAX , HANSSEN NORDIN
Published: June 2023

Introduction: A significant proportion of individuals with type 1 diabetes (T1D) have long-term preservation of beta-cell function. Residual beta-cell function (RBCF) is associated with fewer long-term complications and hypoglycemic events. Yet, little is known about the influence of RBCF on daily glycemic control. Therefore, we investigated the associations between RBCF and daily markers of glycemic control in individuals with T1D.

Methods: In this cross-sectional study 500 individuals with T1D were included (41.0 ±14years), 64% female, HbA1c 55.6 ±12mmol/mol, median T1D duration 14 years [IQR: 6-29years]. As a validated marker of RBCF, postprandial urinary C-peptide/creatinine ratios (UCPCR) were measured. Time in euglycemic range (TIR) (3.9-10mmol/L) and hypoglycemic range (TUR) (<3.9-10mmol/L) were monitored 14 days prior to the study visit, with a continuous glucose monitoring device. Spearman correlations were calculated in Rstudio.

Results: The median UCPCR was 0.03 (IQR: 0.00-0.88) nmol/mmol and strongly correlated with duration of T1D (r = -0.651, p < 0.001). Higher UCPCR correlated with longer TIR (r = 0.330, p < 0.001), lower mean glucose levels (r =-0.318, p=0.005) and shorter TUR (r= -0.237, p <0.001) and lower glucose variation (-0.356, p <0.001). In line, higher UCPCR associated with lower HbA1c levels (r= -0.183, p<0.001) and less 24-hour insulin use (r = -0.183, p = <0.001). The associations remained significant in linear regression models when adjusted for sex, age, plasma glucose and duration of diabetes.

Conclusion: UCPCR correlates with more time in range, shorter time under range, and lower HbA1c levels in individuals with T1D. Beneficial effects of beta-cell preservation in T1D may therefore be attributable to less intermittent glucotoxicity and hypoglycaemic episodes.

Disclosure

C.Fuhri snethage: None. M.Nieuwdorp: Advisory Panel; caelus health. N.Hanssen: Consultant; Novo Nordisk, Research Support; Novo Nordisk. T.J.Mcdonald: None. E.Rampanelli: None. P.De groen: None. A.W.M.Schimmel: None. D.Van raalte: Consultant; Boehringer Ingelheim and Eli Lilly Alliance, AstraZeneca, Merck & Co., Inc., Research Support; Boehringer Ingelheim and Eli Lilly Alliance, AstraZeneca, Merck & Co., Inc. C.B.Brouwer: None. R.A.Oram: Consultant; Janssen Research & Development, LLC, Research Support; Randox R & D. B.O.Roep: None.

Funding

DNF DON Grant 2020 (2020.10.002)
276-LB: STR-Mediated Glucose Sensing and GLUT2-Regulated Glucose Absorption Are Repaired by DJB Surgery in Diabetic Rats
Authors: WANG ANPING , KOU RONGGUAN , ZHAO XIANGYU , SUN SIPENG , WANG YI , GAO ZHIQIN
Published: June 2023

Abstract: Our previous study demonstrated that duodenal-jejunal bypass (DJB) ameliorated glycemic control in a diabetic rat model but the underlying mechanisms are still unclear. This study aimed to identify the regulatory function of sweet taste receptors and glucose transporters within the DJB-remodeled small intestine and gut peptide secretion. DJB or sham surgeries were performed in streptozotocin (STZ)-induced diabetic rats. The blood GLP-1 and GLP-2 levels were evaluated under feeding and fasting conditions. The effects of sweet taste receptors (STR) inhibition on glucose control were measured in vivo with lactisole (STR inhibitor). The results showed that the glucose tolerance was improved in DJB-operated rats compared with Sham group, similar to that of normal control rats without significant differences in food intake and body weight. The plasma levels of insulin were increased after DJB in both feeding and fasting conditions. The plasma GLP-1 levels of DJB rats were increased under diet-fed condition, and GLP-2 levels of DJB rats were increased after fasting. The villus height and crypt depth were significantly increased in the intestinal alimentary limb (A limb) of DJB-operated rats, while decreased in the biliopancreatic limb (BP limb). The expression levels of T1R2, T1R3, sweet taste signaling effector Gα-gustducin and glucose transporters SGLT1, GLUT2 was downregulated in the BP and common limbs, but was elevated in the A limb after DJB. However, the beneficial effects of DJB on glood control was abolished in the presence of lactisole. Furthermore, the immunofluorescence results displayed that GLUT2 localization was normalized after DJB.

In conclusion, these findings indicate that DJB ameliorates glycemic control probably via repairing sweet taste receptor-mediated glucose sensing and absorption with the responses of GLP-1 and GLP-2 to dietary carbohydrate.

Keywords: Sweet taste receptor; Lactisole; GLUT2; SGLT1; GLP-1; GLP-2; DJB;

Disclosure

A. Wang: None. R. Kou: None. X. Zhao: None. S. Sun: None. Y. Wang: None. Z. Gao: None.

Funding

National Natural Science Foundation of China (82070856, 82100842); Natural Science Foundation of Shandong Province (ZR201807090175, ZR2020QH084)
276-OR: Postprandial Hyper- and Hypoglycemia Are Related to Injection Time—An Insulclock Connected Insulin Cap–Based Real-World Study
Authors: GOMEZ-PERALTA FERNANDO , VALLEDOR XOÁN , LOPEZ-PICADO AMANDA , ABREU CRISTINA , FERNÁNDEZ-RUBIO ELSA , PUJANTE ALARCÓN PEDRO , GARCÍA ELENA , AZRIEL SHARONA , CORCOY ROSA , CERQUEIRA CRISTINA , PÉREZ JESUS , RUIZ-VALDEPEÑAS LUIS
Published: June 2023

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

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

Results: Meal glycemic excursions (n=2784) were analyzed in 82 people. In 63% insulin was injected after the meal started. The best balance between PHE control and LPH risk is obtained by injecting -15 to 0 minutes before meals. Higher PHE (glucose peak-baseline; mg/dL) was observed in delayed injections (mean±SD): Early (-45-15 min) (n=348) 101.8 ± 34.0; Optimal (-15-0 min)(n=612) 98.3± 29.8; Delayed (0-+45 min) (n=1528) 114.8±40,2 (n=348), (p <0.001). LPH risk also increased with delayed injections, n (%): Early 31 (8.9); Optimal 47 (7.7); Delayed 171 (11.2), (p 0.038).

Conclusion: The correct timing of insulin injection is crucial to reduce postprandial hyper- and hypoglycemia.

Disclosure

F.Gomez-peralta: Advisory Panel; Abbott Diabetes, Insulcloud S.L., Speaker's Bureau; A. Menarini Diagnostics, Boehringer Ingelheim and Eli Lilly Alliance, Lilly Diabetes, Novartis, Novo Nordisk. C.Cerqueira: Employee; Insulcloud S.L. J.Pérez: Employee; Insulcloud S.L. L.Ruiz-valdepeñas: Employee; Insulcloud S.L., Stock/Shareholder; Insulcloud S.L. X.Valledor: Employee; Insulcloud S.L. A.Lopez-picado: Employee; Insulcloud S.L.. C.Abreu: Speaker's Bureau; Lilly, Novo Nordisk. E.Fernández-rubio: Speaker's Bureau; Lilly Diabetes, Novo Nordisk, AstraZeneca. P.Pujante alarcón: None. E.García: Advisory Panel; Airliquide, Speaker's Bureau; Abbott Diabetes, Dexcom, Inc., Boehringer Ingelheim and Eli Lilly Alliance, Novo Nordisk, Sanofi, Airliquide. S.Azriel: Advisory Panel; Boehringer-Ingelheim, Novo Nordisk, Medtronic, Speaker's Bureau; Dexcom, Inc., Lilly Diabetes, AstraZeneca, Sanofi. R.Corcoy: Advisory Panel; Novo Nordisk, Other Relationship; Novo Nordisk, Lilly, Sanofi, Abbott, Speaker's Bureau; Sanofi, Roche Diabetes Care.
277-LB: Weight Cycling Is Associated with ICU Admission and Mechanical Ventilation in Adults with Diabetes Hospitalized with COVID-19
Authors: MI KANG YU , SIMONSON DONALD C. , CHAUGULE AKSHATA S. , GARG RAJESH K. , GOPALAKRISHNAN GEETHA , HOWARD KYRA , LEBASTCHI JASMIN , MITRI JOANNA , PALERMO NADINE E. , WEINSTOCK RUTH S. , MCDONNELL MARIE E.
Published: June 2023

Weight variability in diabetes is an emerging risk factor for macrovascular complications and mortality, potentially via increased inflammation. We examined the impact of pre-admission weight cycling (WC) on COVID-19-related outcomes, including in-hospital mortality, ICU admission, and mechanical ventilation (MV), using a large multicenter cohort. This study included 277 adults with diabetes hospitalized with COVID-19 (March 2020-February 2021) at 5 university hospitals in the eastern US (COVIDEastDM Consortium) with body weight measurements at 0, 6, and 12 months before admission. Weight change was considered significant if it exceeded 5% in each 6-month interval. The cohort was grouped into four weight categories: unchanged (n=57; reference group), weight loss (WL; n=88), weight gain (WG; n=50) and WC (n=32), and was 54.6% male, 58.6% White, 24.2% Black, 18.5% Hispanic, with mean (SD) age 65.1 (12.6) years and HbA1c 7.7 (2.0)%. During hospitalization, 41.9% subjects were admitted to the ICU, 25.1% received MV, and 15.0% died. Age was the strongest risk factor for mortality (OR = 1.08 [95% CI: 1.03-1.13), and the presence of pre-existing comorbidity for both ICU admission (OR = 2.58 [1.13-5.90]) and MV (OR = 3.89 [1.30-11.64]). In an adjusted model, WC, but not WL or WG, was associated with ICU admission (OR = 3.09 [1.11-8.59]) and MV ((OR = 4.59 [1.48-14.19]), but not with mortality (OR = 3.19 [0.76-13.32]). The glycemic gap, shown previously to be associated with increased MV and mortality, did not change the relationship between WC and outcomes. The WC group trended toward higher peak ESR (94.3±23.1 ml/h vs. 62.2±33.5 ml/h, P=0.044) and hsCRP levels (150.0±133.9 mg/L vs. 104.1±105.3 mg/L, P=0.142).

Conclusion: Weight cycling is associated with ICU admission and mechanical ventilation in adults with diabetes and COVID-19. Our findings identify a unique vulnerability of individuals with diabetes and recent weight cycling.

Disclosure

Y. Kang: None. R. S. Weinstock: Consultant; Jaeb Center for Health Research, Other Relationship; Wolters Kluwer Health, Research Support; Insulet Corporation, Medtronic, Eli Lilly and Company, Novo Nordisk, Boehringer Ingelheim Inc., Hemsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases, Tandem Diabetes Care, Inc., Kowa Pharmaceuticals America, Inc. M. E. Mcdonnell: None. D. C. Simonson: Stock/Shareholder; Phase V Technologies, Inc., GI Windows. A. S. Chaugule: None. R. K. Garg: None. G. Gopalakrishnan: Research Support; Spruce Biosciences, Sparrow Pharmaceuticals Inc, Medtronic. K. Howard: None. J. Lebastchi: None. J. Mitri: Other Relationship; Novo Nordisk, Research Support; Kowa Company, Ltd. N. E. Palermo: Research Support; Dexcom, Inc.
28-LB: Role of Glycine N-methyltransferase in Electronegative Lipoproteins-Induced Vascular Dysfunction in a Diabetic Rodent Model
Authors: LEE AN-SHENG , CHEN YUN-FANG , CHEN WEI-YU
Published: June 2023

Several studies showed low-density lipoprotein (LDL) is associated with high risk of atherosclerosis in patients with diabetes. However, aggressively decreasing total LDL does not prevent all vascular complications. A novel culprit electronegative LDL (L5) was significantly increased in diabetic patients and could induce vascular damage according to our previous studies. However, the mechanism of L5 formation and how to reduce plasma L5 level are still unclear. In the present study, we found both aqueous and ethylacetate extracts of a traditional Chinese remedy Artemisia capillaris (AC) could decrease plasma L5 level in western diet-fed hamster (22.45 and 28.64 vs. 56.83%, respectively), while clinical remedies Simvastatin and Niacin could not. AC could also reverse western diet-induced vascular senescence (b-gal staining) and relaxation dysfunction in aortic rings (63.66±2.14 vs 40.13±1.48% of maximum contraction when compared to western diet hamsters; P<0.01). To further determine the underlying mechanism, we have found that AC reversed western diet-reduced Glycine N-methyltransferase (GNMT) protein abundance and altered several microRNA expression by analyzing the microarray heatmap in liver tissue.

In conclusion, AC could significantly reverse western diet-induced vascular injury by lowering plasma L5 level through restore the liver enzyme GNMT activity.

Disclosure

A. Lee: None. Y. Chen: None. W. Chen: None.
28-OR: Characterising a Novel Peptide That Inhibits and Reverses Type 1 Diabetes
Authors: KING THOMAS W. , TAY SZUN S. , COLAKOGLU FEYZA , DEVALARAJA MATT , REMALEY ALAN , BIRO MATÉ , COCHRAN BLAKE , ANNE RYE KERRY
Published: June 2023

Aims: Interventions that regenerate functional pancreatic β-cells are a potential treatment option for type 1 diabetes. D6PV is a small peptide that lowers plasma triglyceride levels. We have found that it also enhances expression of the β-cell survival gene Pdx1 and stimulates insulin production in INS-1E insulinoma cells. This study asks whether D6PV delays diabetes onset and preserves β-cell mass in mice with autoimmune β-cell loss.

Methods: Female 8-week-old NOD/ShiLtJ (NOD) mice (n=10-20/group) were treated twice/week for 16 weeks with D6PV (40 mg/kg i.p) or PBS. Diabetes onset was evaluated by measuring blood glucose levels. A separate cohort of female NOD mice were treated with D6PV or PBS twice/week for 4 weeks after they developed diabetes. Glycaemic control was evaluated by glucose tolerance test (1 g/kg i.p). Islet insulin content was quantified by immunostaining of paraffin-embedded, formalin-fixed pancreatic tissue. Expansion of CD8+ T-cells was analysed ex vivo from OTI-TCR transgenic mouse splenocytes and healthy human donors following stimulation via IL-7/15 and incubation ± D6PV.

Results: D6PV treatment for 16 weeks decreased fed and fasted blood glucose levels (p<0.05 for both) and delayed diabetes onset in NOD mice (p<0.01). This was accompanied by increased insulin +ve islet area in the D6PV treated, but not the PBS treated animals (p<0.05). D6PV treatment also reduced lymphocyte infiltration into islets but increased lymphocytic migration to the basement membrane (0.2 ± 0.1% vs 1.8 ± 1.7%, p<0.05). When NOD mice with diabetes were treated with D6PV, glucose tolerance improved (AUC 1167±341 vs 543±328, p<0.01). Treatment of both mouse and human cytokine-activated isolated CD8+ T-cells with D6PV suppressed T-cell expansion (p<0.001).

Conclusions: D6PV treatment delays diabetes onset, improves glycaemic control in mice with established disease, increases pancreatic insulin expression and inhibits T-cell expansion in NOD mice. D6PV is a potential treatment option for type 1 diabetes.

Disclosure

T.W.King: None. S.S.Tay: None. F.Colakoglu: None. M.Devalaraja: None. A.Remaley: None. M.Biro: None. B.Cochran: None. K.Rye: None.

Funding

National Health and Medical Research Council of Australia (RG201951)
282-OR: Closed-Loop Insulin Delivery Postpartum in Type 1 Diabetes
Authors: DONOVAN LOIS E. , FEIG DENICE , LEMIEUX PATRICIA , MURPHY HELEN R. , BELL RHONDA C. , SIGAL RONALD J. , HO JOSEPHINE , YAMAMOTO JENNIFER M.
Published: June 2023

Background: Postpartum demands of caring for a newborn, breastfeeding, and sleep deprivation result in little time for self care of type 1 diabetes (T1D). Data are limited on the efficacy, safety and feasibility of closed loop insulin delivery postpartum.

Methods: We performed an open label, controlled pilot trial randomizing women to hybrid closed loop insulin delivery Medtronic MiniMed™ 670G/770G in auto mode or sensor augmented insulin pump (SAP) therapy in the first 12 twelve postpartum weeks. The primary outcome was the percent time in target glucose range of 70-180 mg/dL (3.9-10.0 mmol/L). Mixed models analysis assessed between group differences in glucose measures from median start time of closed loop (8 days) to 12wks postpartum.

Results: Twenty women were recruited. Two withdrew prior to randomization. The remaining 18 women completed 12 weeks of postpartum follow up in their assigned randomization group. Overall baseline mean age, duration of T1D and first pregnancy A1c was 32 years, 22 years and 6.9% respectively. Analyses adjusted for first pregnancy A1c and was intention to treat. Time in range did not differ between groups (79 ± 8.0% versus 80 ± 6.4% p =.079). Time below 70mg/dL (3.9 mmol/L) and 54mg/dL (3.0 mmol/L) was less for women randomized to closed loop versus SAP (1.6 ± .72 % vs 5.3 ± 3.3 % p <0.001 and .23 ± .16 % vs .95 ± .82 % p = 0.002 respectively). Time above 180 mg/dL (10 mmol/L) was not different between groups 19.5 ±8.7% vs 15.9 ±7.8% p = .823. Mean glucose was 146 ± 13 and 133 ± 14 mg/dL p <.001 for closed loop and SAP groups respectively. No episodes of diabetic ketoacidosis or severe hypoglycemia occurred in either group.

Conclusions: Closed loop insulin delivery postpartum was associated with less hypoglycemia than SAP and slightly higher mean glucose. There were no safety concerns. Time in target glucose range was high, minimizing the potential for further improvement with closed loop. These findings are reassuring for the use of closed loop insulin delivery postpartum because of its’ potential to reduce hypoglycemia.

Disclosure

L.E.Donovan: Research Support; Dexcom, Inc., Medtronic, Tandem Diabetes Care, Inc., Inner Analytics. D.Feig: Advisory Panel; Novo Nordisk Canada Inc., Speaker's Bureau; Sanofi, Novo Nordisk Canada Inc. P.Lemieux: Other Relationship; Dexcom, Inc. H.R.Murphy: Advisory Panel; Medtronic, Research Support; Dexcom, Inc. R.C.Bell: None. R.J.Sigal: Research Support; Novo Nordisk. J.Ho: None. J.M.Yamamoto: None.

Funding

Calgary Health Trust
283-OR: ADA Presidents' Select Abstract: An Isogenic hPSC-Based Platform for Functional Interrogation of the Role of Multiple T2D-Associated Genes in Pancreatic Beta-Cell Failure
Authors: XUE DONGXIANG , NARISU NARISU , YAN TINGFEN , ZHANG MEILI , GRENKO CALEB , TANG XUMING , ZHU JIAJUN , BONNYCASTLE LORI L. , ERDOS MICHAEL , VANDANA J JEYA , CHONG ANGIE , COLLINS FRANCIS S. , CHEN SHUIBING
Published: June 2023

Type 2 diabetes (T2D) mellitus is a complex polygenic disease. Multiple genome-wide association studies (GWAS) have identified hundreds of T2D-related genetic variants, the vast majority of which are non-coding. Pinpointing the actual causal variants and their target gene transcripts has been challenging. Building on recent advances in CRISPR technology and protocols that allow differentiation into functional pancreatic beta cells, we created isogenic hPSCs encompassing knockout (KO) mutations in 20 GWAS-identified T2D risk genes, and systematically examined their roles in beta cell differentiation, insulin production, glucose response, and apoptosis. As a result, loss of TCF7L2, HNF4A, TLE4, TGFB1, GIPR and COBLL1 severely impaired the differentiation capacities of hPSCs into functional beta cells and over half of the 20 T2D genes shared implications in beta cell dysfunctions including decreased insulin content, impaired insulin secretion and high susceptibility to lipotoxicity. Next, we sorted beta cells from each KO and performed RNA-seq and ATAC-seq assays. An integrative analysis revealed KO of HNF4A, HNF1A, ABCC8, KCNJ11, TLE4 and WDR13 resulted in extensive transcriptomic and epigenetic changes in the beta cells. We identify that KO of HNF4A results in dramatic expressional changes of dozens of known T2D effector genes and additional ones critical to beta cell functions and biology. An analysis of T2D GWAS credible set of SNPs using ATAC-seq and RNA-seq coupled with functional assays, helped us to nominate a single likely T2D causal SNP (rs7132908) at FAIM2 locus. Finally, a correlation analysis of gene expression levels and insulin content across KO lines identified 1,867 differential genes including PCSK1N that likely serves as a hub gene by mediating insulin production in beta cells. This study thus offers a powerful strategy to interrogate shared molecular pathways among multiple risk genes for diabetes.

Disclosure

D.Xue: None. J.Vandana: None. A.Chong: None. F.S.Collins: None. S.Chen: Consultant; Vesalius Therapeutics, Stock/Shareholder; Oncobeat Theraputics. N.Narisu: None. T.Yan: None. M.Zhang: None. C.Grenko: None. X.Tang: None. J.Zhu: None. L.L.Bonnycastle: None. M.Erdos: None.

Funding

American Diabetes Association (9-22-PDFPM-06 to D.X.)
286-OR: Using iPSC-Derived Islets to Model the Effect of an ABCC8 Arg1420His Mutation in Fetal and Adult Islets
Authors: NAIR ANUP K. , BARKHO KATIYA , TRAURIG MICHAEL , NELSON ROBERT G. , BOGARDUS CLIFTON , BAIER LESLIE
Published: June 2023

We previously reported an Arg1420His mutation in ABCC8 in an Indigenous community that resulted in hyperinsulinemic hypoglycemia in infancy in a homozygous carrier and a doubling in type 2 diabetes (T2D) risk in heterozygous carriers (3% of the population). Previous studies of ABCC8 mutations have suggested a loss of pancreatic beta cells as a probable cause of future T2D. To understand the pathomechanism behind the increased risk of T2D due to the Arg1420His mutation, we generated two sets of isogenic iPSCs from two different Indigenous community members. These iPSCs were used to generate pancreatic islets and assess insulin secretion using a dynamic glucose stimulated insulin secretion (D-GSIS) assay when the islets were immature (resembling fetal islets) and during multiple days after maturation (resembling adult islets). In immature islets, the D-GSIS assay confirmed the clinical phenotype of significantly higher insulin secretion in islets with the His-allele under basal conditions (2mM glucose) and a lower response to diazoxide in islets homozygous for the His-allele. Both Arg1420 and His1420 mature islets had lower insulin secretion under basal conditions, however, insulin secretory response to high glucose (20mM) and Tolbutamide (sulphonylurea) was significantly lower in islets heterozygous for the His-allele whereas no response was seen in islets homozygous for the His-allele despite having similar proportion of beta cells as assessed by flow cytometry (~50% cells positive for INS and NKX6-1). This suggests a mechanism other than beta cell loss as the cause of lower insulin secretory response in these impaired islets. Single cell RNA sequencing showed higher expression of G6PC2, which inhibits insulin secretion by opposing the action of GCK, in islets with the His-allele. Our ongoing work includes knockout of G6PC2 in the isogenic iPSCs and using a GCK activator (Dorzagliatin) to correct the insulin secretory response to high glucose in the His-allele carrying islets.

Disclosure

A.K.Nair: None. K.Barkho: None. M.Traurig: None. R.G.Nelson: None. C.Bogardus: None. L.Baier: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases
287-OR: An ABCC8 R1420H Loss-of-Function Variant Affects Insulin Secretory Function and Microvascular Disease in American Indians
Authors: VAZQUEZ ARREOLA ELSA , KNOWLER WILLIAM C. , BAIER LESLIE , HANSON ROBERT L.
Published: June 2023

The ABCC8 gene regulates insulin secretion and plays a critical role in glucose homeostasis. An R1420H loss-of-function variant in ABCC8 was previously detected in ~3% of people in an American Indian Community with a high prevalence of type 2 diabetes (T2D); heterozygous carriers had a doubling in T2D risk and developed this disease at younger ages and lower BMIs. To further examine the phenotype of this variant, we analyzed the relationship between insulin secretion (2-h post-load corrected insulin response) and insulin sensitivity index [104/(fasting insulin*glucose)] in 5701 members of this population without diabetes aged ≥5 years using standard major axis regression, which adjusts insulin secretion for sensitivity. We used hierarchical logistic regression models in up to 7672 individuals to study cross-sectional associations with diabetes complications including increased albuminuria [albumin to creatinine ratio (ACR) ≥30 mg/g], severe albuminuria (ACR ≥ 300 mg/g), reduced eGFR (eGFR<60 mL/min/1.73m2), and retinopathy assessed by fundoscopic examination. Variant carriers had worse beta-cell function than non-carriers both in children and adults (p=0.0003) with no difference in insulin sensitivity (p=0.50). This variant did not associate significantly with increased albuminuria, severe albuminuria or reduced eGFR after adjustment for age, sex, and presence and duration of diabetes. By contrast, carriers had significantly higher odds of retinopathy (OR=1.74, 95% CI: 1.19, 2.53). Increased odds of retinopathy were also observed among individuals with and without diabetes, and when adjusted for fasting plasma glucose (FPG) [carriers had higher FPG (b=6.1 mg/dl, 95% CI: 3.0, 9.2) adjusted for age, sex, and presence and duration of diabetes]. In sum, carriers of the R1420H ABCC8 variant have a higher risk of retinopathy but not of abnormal ACR or eGFR; this may be partially explained by higher glycemia levels and worse beta-cell function.

Disclosure

E.Vazquez arreola: None. W.C.Knowler: None. L.Baier: None. R.L.Hanson: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases
289-LB: Intestinal Stem Cells as a Source of Insulin-Positive Beta-Like Cells for Treating Diabetes
Authors: XIAO YU , XIAO YAO , JIANG YINAN
Published: June 2023

Shortage of functional pancreatic beta-cells is the basic cause of type 1 and some late-stage type 2 diabetes, making generation of new beta-cells from stem cells a promising strategy for treating diabetes. Intestinal stem cells (ISCs) are adult stem cells found in the base of the crypts of the adult intestine, which is responsible for the continuous life-long renewal of intestinal epithelia cells and thus could also be used a potential source for autologous transplantation. Unlike the most extensively studied bone marrow derived stem cells, ISCs share the advantage of having a common endodermic origin with beta-cells, making their differentiation into beta-cells easier. However, purifying ISCs has been a challenge. Here, we reported a novel method that successfully purifies ISCs from wildtype mice by exploiting their specific binding to a lectin. The only other cell type in the intestine that also binds to this lectin was found to be Paneth cells, which could be excluded through a negative selection for CD24. The purified Lectin+CD24-ISCs, confirmed by gene profiling, were labeled with a fluorescent tag and shown to differentiate into insulin-producing beta-like cells when injected into day 11.5 mouse embryonic pancreatic explants and grown for a week. Further analysis of gene profile alterations and signaling pathways allowed us to develop a time-sensitive protocol with recombinant growth factors to optimize the differentiation of ISCs into beta-like cells in vitro, without the need for an embryonic environment. Our results not only demonstrate a new method for purifying ISCs, but also their potential to differentiate into insulin-producing beta-like cells. This study provides a promising strategy for beta-cell replacement therapy in diabetes.

Disclosure

Y. Xiao: None. Y. Xiao: None. Y. Jiang: None.

Funding

University of Pittsburgh; Children?s Hospital of Pittsburgh; Cochrane-Weber Endowed Fund in Diabetes Research
290-LB: Single-Cell Analysis of Endocrine Development Identifies Novel Roles for GLIS3 in Pancreatic ß-Cell Fate
Authors: SCOVILLE DAVID W. , GRIMM SARA , JETTEN ANTON M.
Published: June 2023

The Krüppel-like zinc finger transcription factor GLIS3 has been identified as a critical regulator of pancreatic beta cell development and function. Mice lacking a functional Glis3 gene fail to produce enough insulin and suffer from severe hyperglycemia soon after birth. This phenotype matches what has been observed in humans with genetic mutations in GLIS3 and who have been diagnosed with permanent neonatal diabetes within the first month of life. Additional and ongoing work has begun to identify some of the transcriptional mechanisms utilized by GLIS3, yet many questions remain unanswered.

One such question is whether GLIS3 has roles in endocrine development prior to the formation of functional β-cells. To address this question, I have utilized single cell RNA-sequencing of mouse embryonic pancreas, at embryonic days (e)15.5 and e18.5, of both wild type (WT) and Glis3 knockout (KO) embryos. Analysis of this data has identified the expected developmental populations, from bipotent progenitor cells to pro-endocrine cells and ultimately hormone positive β-, α-, δ-, and ε-cells. Interestingly, there is little difference in gene expression between the WT and Glis3 KO pancreas in most of the populations observed (pro-endocrine, FEV+, α-/δ-/ε-cells). However, there are significant differences in gene expression between WT β-cells and KO β-cells. Surprisingly, most of the differences are in genes upregulated in the KO cells, with only a small number of genes downregulated. These upregulated genes are normally downregulated over the course of development from FEV+ to β-cells. These data indicate that GLIS3 plays a unique role in developing β-cells in that it primarily represses genes during the course of development but is also critical for the transcriptional activation of specific targets, particularly Ins2. Understanding how GLIS3 regulates β-cell generation, and how GLIS3 itself is regulated, could potentially provide new therapeutic avenues for the treatment of diabetes.

Disclosure

D. W. Scoville: None. S. Grimm: None. A. M. Jetten: None.

Funding

National Institutes of Health (Z01-ES-101585)