bluuebunny/crossref_metadata_2025 huggingface dataset:
40-PUB: Impact of the Initiation of is-CGM Soon after Type 1 Diabetes Mellitus Diagnosis in Adults on Glycemic Indices and Fear of Hypoglycemia—Data from RCT
Authors: HOHENDORFF JERZY , WRÓBEL MARTA , GRZELKA-WOZNIAK AGATA , KANIA MICHAL , LAPINSKA LIDIA , ROKICKA DOMINIKA , KOWALSKA IRINA , STROJEK KRZYSZTOF , ZOZULINSKA-ZIOLKIEWICZ DOROTA , MALECKI MACIEJ
Published: June 2024

Use of CGMS has become the standard of glucose control in patients with T1DM. It was shown that use of CGM improves TIR and TBR, and QoL. We aimed to assess the impact of soon after diagnosis (within 1-6 months) initiation of is-CGM on glycemic indices and fear of hypoglycemia (FoH) in adults newly diagnosed with T1DM. After 14 days of wearing the blinded sensor, participants were randomly assigned (1:1) to is-CGM (intervention group) or to self-monitoring of blood glucose (SMBG) with glucometers and blinded CGM (control group). The primary outcomes were change in TB70 and FoH assessed in HFS and main secondary outcomes were change in mean glucose, TIR, TAR between baseline and 4 weeks after randomization. Finally, in this RCT, 23 patients aged 25.6±5.1 were analyzed (14 males, 9 females). All participants were on MDI. Main results of the study are shown in Table 1. The study was terminated early due to changes in reimbursement policy in Poland, as during the study groups of patients eligible for reimbursement were significantly expanded and next generation of is-CGMS was introduced on market. However, our study has shown that, in T1DM patients early after diabetes diagnosis, TIR is high and hypoglycemia risk low. In spite small study group, our data suggest that introducing is-CGM decreases mean glucose; additionally, trend to further increase TIR and decrease TAR was seen.

Disclosure

J. Hohendorff: Research Support; Abbott. Speaker's Bureau; Dexcom, Inc., Ascensia Diabetes Care. M. Wróbel: None. A. Grzelka-Wozniak: Consultant; Novo Nordisk. Other Relationship; Boehringer-Ingelheim, Novo Nordisk, AstraZeneca, Roche Diabetes Care, Sanofi. M. Kania: None. L. Lapinska: None. D. Rokicka: None. I. Kowalska: Advisory Panel; Abbott. Speaker's Bureau; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Novo Nordisk, Sanofi. Advisory Panel; Ascensia Diabetes Care. Speaker's Bureau; Berlin-Chemie AG. K. Strojek: None. D. Zozulinska-Ziolkiewicz: Advisory Panel; Abbott, BIOTON. Speaker's Bureau; Boehringer-Ingelheim, Eli Lilly and Company, Ascensia Diabetes Care, Novo Nordisk, Medtronic, Sanofi, Servier Laboratories. Advisory Panel; Eli Lilly and Company. M. Malecki: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Sanofi, Abbott, Dexcom, Inc., Boehringer-Ingelheim. Speaker's Bureau; AstraZeneca, Merck & Co., Inc. Advisory Panel; Krka. Speaker's Bureau; Servier Laboratories.

Funding

Diabetes Poland Grant 2021
403-P: Body-Weight Cycling and Risk of Diabetic Kidney Disease in People with Type 1 Diabetes
Authors: CAMOIN MARION , MOHAMMEDI KAMEL , SAULNIER PIERRE-JEAN , HADJADJ SAMY , GAUTIER JEAN-FRANÇOIS , RIVELINE JEAN-PIERRE , VENTECLEF NICOLAS , POTIER LOUIS , VELHO GILBERTO
Published: June 2024

Introduction & Objective: Chronic kidney disease (CKD) is a major issue in the management of people with type 1 diabetes (T1D). Intraindividual body weight variability (BWV) or cycling is associated with increased risk of cardiovascular events and all-cause death in T1D. We conducted a retrospective analysis of data from the DCCT/EDIC studies for the association between BWV and the risk of renal events.

Methods: Five BWV indices were calculated for 1,432 participants of the DCCT/EDIC studies taking into account body-weight measurements during the DCCT follow-up (average 6±2 years). Variability independent of the mean (VIM) was the main variable of interest. Six criteria of progression to CKD were studied during DCCT/EDIC follow-up (21 ± 4 years). Cox models were fitted to estimate associations of BWV indices with the outcomes. Hazard Ratios (HR) with 95% confidence interval (CI) were computed for 1 SD of the indices expressed as a Z-score.

Results: Progression to CKD stage 3 (eGFR<60ml/min/m2) during follow-up occurred in 128 participants (8.9%). A high VIM was significantly associated with occurrence of stage 3 CKD (adjusted HR 1.36 [95% CI, 1.12-1.63], p= 0.002), doubling of serum creatinine (1.36 [1.15-1.60], p=0.0005), decline in eGFR>3ml/min/m2 per year (1.47 [1.14-1.89], p=0.003), and “Certain drop in eGFR” KDIGO criterion (1.20 [1.02-1.41], p = 0.03), after adjustment for nephropathy risk factors at baseline and throughout follow-up, and use of nephroprotective drugs. VIM was also associated with the incidence of microalbuminuria (1.21 [1.08-1.36], p = 0.002) and macroalbuminuria (1.36 [1.14-1.61], p= 0.0009), adjusted for baseline covariates, but associations did not remain significant following adjustment for follow-up covariates. Similar results were observed for the other BWV indices.

Conclusion: BWV is significantly associated with an increased risk of renal events in people with T1D, regardless BMI and traditional risk factors.

Disclosure

M. Camoin: None. K. Mohammedi: None. P. Saulnier: Advisory Panel; Novo Nordisk. S. Hadjadj: Consultant; AstraZeneca. Research Support; Asten Santé, Air Liquide. Consultant; Bayer Inc., Boehringer-Ingelheim, Eli Lilly and Company. Research Support; LVL, Nestlé Health Science. Consultant; Novo Nordisk. Board Member; Valbiotis. Consultant; Sanofi. Research Support; Vitalaire. J. Gautier: Board Member; Sanofi. Other Relationship; Sanofi. Speaker's Bureau; AstraZeneca, Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; Pfizer Inc. J. Riveline: Board Member; Abbott, Novo Nordisk A/S, Sanofi, Eli Lilly and Company, Medtronic, Dexcom, Inc., Insulet Corporation, Air Liquide, AstraZeneca. N. Venteclef: None. L. Potier: Research Support; Abbott. Consultant; AstraZeneca, Bayer Inc., Eli Lilly and Company, Novo Nordisk, Sanofi, Boehringer-Ingelheim. G. Velho: None.
407-P: Kidney Transplant Infection Risks—CGM Parameters Insights and Glucagon-Like Peptide-1 Receptor Agonist (GLP1-RA) Strategies
Authors: CAMPANA MARIO S.
Published: June 2024

Introduction: Cytomegalovirus (CMV) and BK are common viral infections in kidney transplant (KT) recipients that tend to appear within the first year after KT. Uncontrolled post-transplant diabetes mellitus (PTDM) and Type 2 diabetes mellitus (T2DM) have been associated with an increased risk for these opportunistic infections. This study aims to examine the association of CMV and/or BKA infections with CGM parameters like time in range (TIR) and GLP1-RA status.

Methods: This is a prospective follow-up study conducted at the Transplant Institute of the University of Alabama at Birmingham. We analyzed the data of 50 adults with PTDM and T2DM who underwent KT between 10/2022 to 10/2023. Patients were followed for 12 months for CMV and/or BKA new infections defined by positive serology. The association of TIR and GLP1-RA was reported as a risk ratio using univariable and multivariable modified poison regression analyses with standard error models adjusted for age, sex, race, and insulin type.

Results: Overall, 25 (50%) participants had CMV/BK infections. Mean age was 56.6 years, 56% were female, 66% African American, 70% with pre-existing type 2 diabetes, and 56% using GLP1-RA. Of the 19 participants with a TIR >70%, 3 (15.8%) experienced infection as compared to 22/32 (71.0%) with a TIR ≤70%. Of the 28 participants with GLP1-RA, 12 (42.9%) experienced infection as compared to 13/22 (59.1%) without GLP1-RA. Adjusting for confounders, risk of infections was lower for the participants with TIR >70% than those with ≤70% (RRadj=0.22, 95% CI: 0.07 - 0.66; p= 0.007) and for the participants with GLP1-RA than those without (RRadj = 0.77, 0.42 - 1.39; p=0.384).

Conclusion: KT patients with diabetes mellitus who were started on CGM for the first time, with a TIR >70% and GLP1-RA usage had a lower risk of transplant-related infections: BK and CMV. Early use of CGM with monitoring of TIR as a potential marker of diabetes control will improve transplant outcomes and rates of rejection.

Disclosure

M.S. Campana: None.
41-PUB: Pharmacy Intervention in the Management of Poorly Controlled Type 2 Diabetes
Authors: STERRETT YAMINI R. , REDDY VARSHA , BEHNKE ANDREW , LUCAS KARA
Published: June 2024

The prevalence of type 2 diabetes continues to increase worldwide leading to increased health and economic burden on healthcare system. Pharmacists are an essential part of healthcare delivery, play a significant role in patient outreach and can assist with medication titration. Our study was a retrospective review of clinical pharmacists in the management of patients with poorly controlled type 2 diabetes, defined as a A1c level of >9.0%, and the efficacy of reduction in A1c using this intervention. This study involved six clinical pharmacists who provided diabetes management using ADA Standards of Care guidelines for outpatient family medicine and internal medicine clinics with 115 patients who completed the study. Patients referred included those with an A1c >9% and were contacted on a one to four week basis up to the discretion of pharmacist with patients followed for at least three months with a goal of a reduction in A1c to <9%. Results were significant for a decrease in A1c levels in 90% of patients. Average starting A1c was found at 10.5% ± 2.3 to 8.0 ± 1.6 with a decline in A1c over an average period of 6.7 months of 2.5% ± 2.4 (p value <0.001).

In conclusion, the use of clinical pharmacists in the management of type 2 diabetes showed a statistically significant reduction in A1c prior to referral to an endocrinologist. This model poses a possible solution to help lighten the burden that diabetes produces on the health care system.

Disclosure

Y.R. Sterrett: None. V. Reddy: None. A. Behnke: Research Support; Abbott. K. Lucas: None.
42-PUB: Income-Related Inequalities in Self-Reported Vision Problems among U.S. Adults, 1999–2018
Authors: CHEN YU , KIM MINCHUL , LUNDEEN ELIZABETH A. , ROLKA DEBORAH B. , EHRLICH JOSHUA R. , ANNE NEWMAN-CASEY PAULA , ELAM ANGELA , REIN DAVID B. , HOLLIDAY CHRISTOPHER S. , SAADDINE JINAN B.
Published: June 2024

Introduction & Objective: Research has shown that the prevalence of vision problems is higher among U.S. adults with low income. Recent changes in income-related inequalities (IRI) in the prevalence of vision problems are unknown. We aim to examine trends in IRI in vision problems and to identify the relative contribution of determining factors.

Methods: We estimated annual IRI in vision problems in 1999−2018 among US adults aged ≥18 years using data from the National Health Interview Survey. Vision problems are defined as an affirmative response to the question: “Do you have trouble seeing, even when wearing glasses or contact lenses?”. We used the concentration index (CI) to measure IRI and quantified the extent to which the prevalence of vision problems concentrates in lower income versus higher income groups. We used the Wagstaff decomposition method to decompose CI into contributors. We examined trends from 1999−2018 in vision problems inequality and contributors to those trends over time.

Results: Between 1999−2018, the CIs were below 0, signifying that vision problems were more concentrated among individuals with lower incomes. The degree of IRI in vision problems increased from 1999−2018 (annual percent change=0.6, p=0.03). IRI in vision problems was greater among adults aged 45-64 years than other age groups. Decomposition analysis revealed that poverty-to-income ratio and public health insurance coverage were the largest contributors to IRI in vision problems, with smaller contributions made by smoking, physical inactivity, and female sex. Among all variables, non-White race/ethnicity, lower physical activity, and poverty-to-income ratio were the main factors explaining trends in vision problems inequality over time.

Conclusion: Self-reported vision problems were more prevalent in low-income populations, and IRI widened over time. The sustained growth in income inequality may lead to a larger population burden of vision problems.

Disclosure

Y. Chen: None. M. Kim: None. E.A. Lundeen: None. D.B. Rolka: None. J.R. Ehrlich: None. P. Newman-Casey: None. A. Elam: None. D.B. Rein: None. C.S. Holliday: None. J.B. Saaddine: None.
426-P: Association of Succinate and Adenosine Nucleotide Metabolic Pathways with the Progression of Diabetic Kidney Disease in Patients with Type 2 Diabetes Mellitus
Authors: JUNG INHA , NAM SEUNGYOON , PARK SOYOUNG , YOUNG LEE DA , HEE YU JI , A SEO JI , HO LEE DAE , HEE KIM NAN
Published: June 2024

Introduction & Objective: The prevalence of diabetic kidney disease (DKD) is increasing, and biomarkers that can enhance prognosis beyond renal function and albuminuria are rare. This study aimed to evaluate the potential of adenosine, succinate, and their related pathways, including hyaluronic acid (HA), as predictors of DKD progression.

Methods: We examined 230 participants categorized as healthy controls, DKD non-progressors, and rapid progressors. Eligible patients with diabetes had at least five prior urine creatinine measurements during a median of 5.8 years of follow-up. Using previously collected eGFR data, rapid progressors were identified based on a decline in eGFR (ΔeGFR/year ≤−3 mL/min/1.73 m2/year or annual rate of eGFR decline ≥ 3.3%) before enrollment. At the end of the cohort, we measured the concentrations of urinary adenosine, succinate, HA, and serum cluster of differentiation 39 (CD39) and CD73, which are involved in adenosine generation. Associations between eGFR, ΔeGFR, and albuminuria were analyzed after adjusting for DKD progression risk factors.

Results: Urinary succinate and serum CD39 levels were more elevated in rapid progressors compared to controls and non-progressors. This trend persisted when using the percentage criterion (≥40% decline in eGFR) for renal disease progression. Correlation analysis consistently linked urinary succinate and serum CD39 concentrations with eGFR at enrollment, ΔeGFR and albuminuria. However, among the various metabolites studied, multivariate regression analysis identified urinary succinate as an independent metabolite of rapid DKD progression and albuminuria.

Conclusion: Among several potential metabolites, only urinary succinate exhibited associations with rapid DKD progression.

Disclosure

I. Jung: None. S. Nam: Consultant; HieraBio Inc., Korea, Republic of. S. Park: None. D. Lee: None. J. Yu: None. J. Seo: None. D. Lee: None. N. Kim: None.

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2023R1A2C2003479) and the Bio & Medical Technology Development Program of the NRF funded by MSIT (NRF-2019M3E5D3073102). This study was also supported by a National IT Industry Promotion Agency (NIPA) grant funded by the MSIT (No. S0252-21-1001, Development of AI Precision Medical Solution (Doctor Answer 2.0)) and a Korea Health Industry Development Institute (KHIDI) grant funded by the Ministry of Health & Welfare of Korea (No. HI16C1997 and No. HI23C0679).
431-P: Identification of the Serum Uric Acid Threshold for Predicting Diabetic Nephropathy Risk in Patients with Type 1 Diabetes
Authors: ZHANG MEI , HUANG MEI , WEI QIANYING , CHEN XIN , WANG SUYU , QIN YAO , DAI LIUYAN , YANG TAO
Published: June 2024

Introduction & Objective: To clarify the correlation between SUA levels and the risk of DN in Chinese patients with T1DM, and determine the SUA threshold associated with an increased risk of DN.

Methods: Both cross-sectional study and longitudinal study were conducted. The cross-sectional study was conducted with 681 subjects with T1DM. Adjusted multivariable logistic regression analysis was used to investigate the association between SUA levels and the risk of developing DN in patients with T1DM. Restricted cubic spline (RCS) was applied to determine the optimal threshold for SUA. Longitudinal data were collected from 94 patients with at least 3 visits to evaluate the variability of SUA levels with estimated glomerular filtration rate (eGFR) and urinary albumin creatinine ratio (UACR).

Results: The 681 patients were divided into four groups based on the quartile SUA levels. The median SUA level was 4.18mg/dL. Among 681 participants in this analysis, median age was 42 (IQR 28-55) years and 52.4% were male, the incidence of DN was 12.6%. After adjusting for confounding factors, the SUA level was inversely significantly correlated with the risk of DN (OR 1.57 [95% confidence interval (CI) 1.26; 1.95], P<0.001). The RCS plot revealed a U-shaped relationship between SUA levels and DN, with the identified threshold of SUA being 3.85mg/dL in female and 4.64mg/dL in male (Figure 1). Correlation analysis showed the SUA variability was significantly correlate with eGFR variability (r=0.206, p=0.046) and UACR variability(r=0.405, p<0.01) (Figure 2).

Conclusion: Our study identified SUA as a significant risk factor for DN in Chinese T1DM patients and established the optimal threshold with 3.85mg/dL in female and 4.64mg/dL in male for predicting DN risk. Our findings provide important evidence for improving risk discrimination and reclassification of high-risk DN subjects in clinical practice.

Disclosure

M. Zhang: None. M. Huang: None. Q. Wei: None. X. Chen: None. S. Wang: None. Y. Qin: None. L. Dai: None. T. Yang: None.
439-P: Beat-to-Beat Blood Pressure Variability, Linkage with Sudden, High Blood Pressure Elevations, Implications to Treat Labile Arterial Hypertension in Diabetes
Authors: GMITROV JURAJ
Published: June 2024

The goal was to estimate the link between blood pressure (BP) variability (BPV) and catecholamine BP surges. Mean femoral arterial BP (MAP), heart rate (HR) and ear lobe skin microcirculatory blood flow, by microphotoelectric plethysmography (MPPG), were recorded in conscious rabbits after 40 min carotid baroreceptor (CB) exposure to 350 mT static magnetic field (SMF), induced by Nd2-Fe14-B (n = 14) or sham magnets (n = 14), Fig. 1. Arterial baroreflex sensitivity (BRS) was estimated by HR and MAP responses to i.v. bolus inj. of phenylephrine (Ph) and nitroprusside (Ni), beat-to-beat BPV by MAP standard deviation (SD). SMF CB exposure significantly increased BRSNi (74.5 ± 17.8%, P < 0.001) and microcirculation (23.8% ± 11.0%, P = 0.039); decreased MAP (−5.7 ± 1.7%, P < 0.014), and Ph-induced MAP surge (−19.1%, P = 0.043), which is positively correlated with resting MAP (r = 0.342, P = 0.0383) and MAP SD (r = 0.383, P = 0.0194), and inversely with BRSPh (r = −0.47, P = 0.0156). CB magnetic stimulation increased Ni vasodilator effect, which acts as a nitric oxide (NO) donor, suggesting baroreflex to improve vessels sensitivity to NO-mediated dilation (impaired in diabetes), being a new physiology with BP buffering result. Enhanced BPV suggested to be a diagnostic tool for diabetics' susceptibility to morning surges of BP linked with major macrovascular events.

Disclosure

J. Gmitrov: None.
445-P: Waist–to–Body-Mass-Index Ratio Predicts Cardiovascular Events in Patients with Cardiovascular Disease Independently of Type 2 Diabetes
Authors: PLATTNER THOMAS , LARCHER BARBARA , MADER ARTHUR , VONBANK ALEXANDER , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: June 2024

Waist circumference reflects central fat accumulation and is an important additive information to BMI. The Waist Circumference-to-Body-Mass-Ratio (W/BMI-Ratio) has been suggested to provide additional information on cardiovascular event risk. Its power to predict cardiovascular events in patients with established cardiovascular disease is unclear and is addressed in the present study. We prospectively recorded cardiovascular events in 1200 patients with angiographically verified coronary artery disease (n=938) or sonographically proven peripheral artery disease. The mean follow-up time was 10.4±5.0 years. At baseline, there was no significant difference in the W/BMI-Ratio between patients with (n=422) and those without T2DM (3.6±0.4 vs. 3.6±0.3; p=0.442). Prospectively, the W/BMI-Ratio significantly predicted the incidence of cardiovascular events (n=642) both univariately (standardized HR 1.14 [1.07-1.22], p<0.001) and after adjustment for age, gender, smoking, LDL cholesterol, HDL cholesterol, hypertension and T2DM (standardized adjusted HR=1.15 [1.07-1.23], p<0.001); HRs were 1.12 [1.02±1.22], p=0.014 in patients without diabetes and 1.23 [1.09-1.38], p<0.001 in those with T2DM, with a non-significant interaction W/BMI-Ratio x diabetes status (p=0.159). We conclude that the W/BMI-Ratio independently from diabetes status is a predictor for cardiovascular events in patients with established cardiovascular disease.

Disclosure

T. Plattner: None. B. Larcher: None. A. Mader: None. A. Vonbank: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None. C.H. Saely: None.
470-P: Severe Liver Fibrosis (F4) Assessed via Liver Fibroscan Is Associated with Elevated NT-ProBNP in Asymptomatic Type 2 Diabetes Mellitus Patients Receiving SGLT2i Therapy
Authors: GUPTA VISHAL
Published: June 2024

Aim: Identify relationship between different stages of liver fibrosis (LF) & N-terminal pro-B type natriuretic peptide (NT-ProBNP).

Methods: Between Oct’ 22 & Mar’ 23, 66 T2DM patients receiving dapagliflozin & waist cmf > 80 cms (F) & > 90 cms (M) irrespective of their A1c & who underwent Liver Fibroscan (Lfib) were retrospectively analysed & studied. Metavir stg classified patients: F0 (N); F1 (N - mild); F2 (Mild - mod); F3 (mod - severe); F4 (cirrhosis). LF was assessed by Lfib performed using ARFI. Exclusion: pregnancy, <3 mnth illness, hospitalisation, H/O heart disease, alcoholism & hep B, C & autoimmune hepatitis (if raised LFT). Weight-kg (W), systolic/diastolic BP (mmHg), Lipid profile mg/dl (TC, LDL, TG, HDL), LFT, Hs-CRP mg/L, NT-ProBNP pg/ml, eGFR (Cr & Cyst-C) & UACR were recorded every 2-3 mnths & data presented over 1 yr.

Statistics: ANOVA - compared means between 3 data points & stgs of LF. One-Way ANOVA followed by post-hoc Tukey test compared NT-ProBNP to LF stages & P value <0.05 was considered statistically significant (S). Baseline (B) characters: Males 86.4%, avg (age 56.88+8.82, W 83.72+11.96, SBP 134.79+17.46, DBP 86.61+11.94, A1c 7.77+1.54, TC 153.72+ 46.18, LDL 86.76+40.29, HDL 38.86+8.08, TG 164.16+90.82, hs-CRP 2.57+2.83, GGT 49+51.96, SGPT 40.44+25.89, NT-ProBNP 46.65+45.71, UACR 33.43+99.55 & eGFRCys-C 84.98+20.55). (B) - 1 yr: S reduction seen in Wt, DBP, A1c, TC, LDL, TG, hs-CRP & SGPT. S relation was seen with stage F4 LF & NT-ProBNP (123.36+124.01, p-0.049) but not with other stages of LF (F0 49.67+42.57, F1 54.40+34.64, F2 17.66+10.38, F3 27.35+10.96) at the end of the study. There was no S association seen between liver enzymes & NT-ProBNP at any LF stg.

Conclusion: Severe liver fibrosis (F4) is associated with elevated NT-ProBNP in Indian patients with T2DM compared to other stages of LF despite receiving SGLT2i therapy. Further cardiac evaluation may be warranted in this population.

Disclosure

V. Gupta: None.
479-P: Imeglimin Improves Hyperglycemia-Induced Mitochondrial Dysfunction and Increases SIRT1 and NAD+ Biosynthesis in Schwann Cells
Authors: KATO AYAKO , NIHEI WATARU , YAKO HIDEJI , SANGO KAZUNORI , NAKAMURA NOBUHISA , NARUSE KEIKO , HIMENO TATSUHITO , KATO YOSHIRO , NAKAMURA JIRO , KAMIYA HIDEKI , KATO KOICHI
Published: June 2024

Hyperglycemia-induced oxidative stress is a major cause of the pathogenesis of diabetic neuropathy, and hyperglycemia-induced mitochondrial ROS production is considered as a significant mechanism of increased oxidative stress. On the other hand, imeglimin is the first in a new glimin class of anti-diabetic drugs targeting mitochondrial bioenergetics. In addition, imeglimin has been reported to enhance insulin secretion by increasing nicotinamide adenine dinucleotide (NAD+) levels in rat islets via the salvage pathway involving nicotinamide phosphoribosyltransferase (NAMPT). Moreover, NAD+ has been shown to modulate sirtuin and PGC1α, which in turn ameliorate mitochondrial dysfunction. We investigated the effects of imeglimin on high glucose-induced cell death and mitochondrial dysfunction in Schwann cells. In addition, the effects of imeglimin on NAD+ levels, NAMPT activity, the rate-limiting enzyme in the salvage pathway for NAD+ synthesis, and SIRT1 expression, a longevity gene, were evaluated. Immortalized adult mouse Schwann (IMS32) cells were cultured in 5.5 mM normal glucose (NG) and 25 mM high glucose (HG) medium. Compared to NG, HG decreased cell viability and increased mitochondrial oxidative stress. HG decreased mitochondrial membrane potential, increased mitochondrial oxygen consumption rate (OCR), increased activity of complex I and decreased ATP levels. Imeglimin ameliorated the reduction in cell viability and improved these mitochondrial dysfunctions. In addition, imeglimin increased NAMPT activity and NAD+ levels in IMS32 cells under HG conditions. Furthermore, imeglimin also ameliorated the reduction in SIRT1 expression by HG. These results suggest that imeglimin may prevent diabetic neuropathy by attenuating hyperglycemia-induced mitochondrial dysfunction and cell death in Schwann cells, at least in part, through the enhancement of SIRT1 and NAD+ biosynthesis.

Disclosure

A. Kato: None. W. Nihei: None. H. Yako: None. K. Sango: None. N. Nakamura: None. K. Naruse: None. T. Himeno: None. Y. Kato: None. J. Nakamura: None. H. Kamiya: Speaker's Bureau; Novo Nordisk, Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Boehringer-Ingelheim, Daiichi Sankyo, AstraZeneca, Ono Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Kowa Company, Ltd., Novartis Pharmaceuticals Corporation, Merck & Co., Inc., Sanwa Kagaku, Otsuka Pharmaceuticals Corporation. Research Support; Kissei Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Eli Lilly and Company, Taiho Pharmaceutical Co. Ltd., Sumitomo Dainippon Pharma Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Japan Tobacco Inc, Novo Nordisk. Speaker's Bureau; Taiho Pharmaceutical Co. Ltd., Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Teijin Pharma Limited, Bayer Inc. K. Kato: None.
483-P: Understanding the Macrostructural Foundations of Nerve Dysfunction in Diabetic Neuropathy
Authors: FLEMING THOMAS H. , KENDER ZOLTAN , SZENDROEDI JULIA
Published: June 2024

Background & Objectives: Focal fascicular lesions have been identified in the sciatic nerves of individuals with diabetic neuropathy (DN). The presence of these lesions, which occurs in proximal-to-distal gradient, closely correlates with the severity of clinical symptoms. The objective of this study was to understand the structural nature of the fascicular lesions and gain insights into their pathophysiology.

Methods: A combinational approach of ex vivo magnetic resonance neurography (MRN) and in vitro imaging was used to identify, isolate, and analyze the structural nature of fascicular lesions from the sciatic nerves of individuals with and without type-2 diabetes (T2D). Comparative spatial proteomic analysis was then used to decipher the molecular composition of the lesions.

Results: Three fascicle types were identified: normal appearing fascicles (NAF-Ctrl), T2D-fascicles (NAF-T2D), and T2D-fascicles with lesions (T2D lesions). The T2D lesions, identified as hypertensive based on MRN signals, showed distinct differences from other fascicles—increased area, perineurium loss, accumulation of acid mucin, and reduced myelinated axons, suggesting endoneurial edema. 346 proteins were common across all types, with significant variations between NAF-Ctrl and T2D lesions. Notably, T2D lesions exhibited reduced neuroprotective pathways, such as such as protein kinase A, the pentose-phosphate pathway, and aldo-keto reductase/aldehyde dehydrogenase metabolism and activation of pathways linked to liver-derived autoantibody complement activation.

Conclusion: The combination of MRN imaging with histological analysis, had led to a deeper understanding of structural nature of fascicular lesions. The incorporation of spatial proteomics has furthered insights into lesion pathophysiology, unveiling potential therapeutic treatment strategies for this complex condition.

Disclosure

T.H. Fleming: None. Z. Kender: None. J. Szendroedi: None.

Funding

Deutsche Forschungsgemeinschaft (DFG; SFB1118 and SFB1158); the German Center for Diabetes Research (DZD)
490-P: Ongoing Treatments with High Concentration Capsaicin Topical System Results in Progressive Pain Reduction for Painful Diabetic Neuropathy—A Retrospective Real-World Analysis
Authors: GRAF GARY , ALLEN SAMUEL , CARNEVALE AUDREY
Published: June 2024

The capsaicin 8% topical system is FDA-approved for the treatment of pain associated with diabetic neuropathy (PDPN) of the feet and post-herpetic neuralgia. The hypothesis that patients experience a progressive response with ongoing treatments was the purpose of this analysis. Eighteen patients who received at least 3 treatments were selected, some patients were not analyzed due to missing data. Efficacy was measured using a pain rating scale from 0-10. Initial pain level was taken before administering capsaicin 8%, with follow-up scores measured during an evaluation between treatments. Most patients had a 50% or greater reduction in pain, with fifteen responding on the first treatment, one on the second treatment, and two non-responders. Patients experienced an acute reduction in average pain intensity following each application, with an additive reduction in pre-treatment pain scores prior to the second and third applications (Figure 1). Capsaicin 8% induces analgesia by lysing aberrant nociceptive fibers. The regeneration of these nociceptors is associated with pain recurrence due to the continual consequence of diabetes. These data are consistent with previous studies and may signify a more normal nerve fiber regrowth in PDPN patients, suggesting the need for ongoing treatments to maintain this progressive response.

Disclosure

G. Graf: Consultant; Averitas Pharma, Inc. Speaker's Bureau; Averitas Pharma, Inc. S. Allen: Employee; Averitas Pharma, Inc., Lundbeck. A. Carnevale: Employee; Averitas Pharma, Inc.
495-P: Diabetic Retinopathy Is a Ceramidopathy Reversible by Systemic Anticeramide Therapy
Authors: BUSIK JULIA V. , DORWEILER TIM F. , SINGH ARJUN , GRANT MARIA B. , KOLESNICK RICHARD
Published: June 2024

Introduction: Diabetic retinopathy (DR) is characterized by retinal endothelial cell (REC) death and inadequate vascular repair by dysfunctional circulating angiogenic cells (CACs). We have previously demonstrated an increase in ASM-mediated C16 ceramide and ceramide-rich platform (CRP) formation as a major pathogenic mechanism in the development of REC damage and CAC dysfunction in DR. Using anti-ceramide Abs, we aimed to prevent REC damage and restore CAC-mediated repair by dispersing CRPs, thus restoring retinal microvascular health and preventing DR.

Methods: Anti-ceramide Abs were administered in vitro or ex vivo at 10 (short chain fragment antibody; scFv) /100 (monoclonal antibody; mAb) μg/mL and in vivo (subcutaneously) at 60μg/g (mAb) bodyweight in STZ induced diabetic mouse model. Migration of CACs was assessed using trans-well assays ex vivo. In vivo vascular degeneration was captured using FITC-albumin technique. In vivo migration of GFP+ CACs (JAX:006567) was examined via confocal imaging.

Results: In vitro studies in BRECs show generation of vast ceramide rich platforms followed by apoptosis upon acute stimulation with 20ng/mL TNFa or 10ng/mL IL-1β. This phenotype was fully ameliorated when treated with anti-ceramide scFv. STZ mice showed a significant increase (42% CRP pos. cells) in CRP formation on day 3, with gradual increases on day 7, 14, 42, and 180 (70% pos.) post-hyperglycemia (n=9-12, p<0.0001. Anti-ceramide treatment reduced CRP formation on CACs and protected from retinal vascular permeability 6-weeks post hyperglycemia in vivo (n=10-12; p<0.01. In vivo migration and vascular repair of CACs was impaired in 6-month diabetic STZ mice compared to their age matched controls and rescued following anti-ceramide Abs intervention (scFv and mAb) in vivo (n=4-7; p<0.08).

Conclusion: Anti-ceramide Abs restore microvascular health via normalization of both REC and CACs homeostasis to halt or reverse DR.

Disclosure

J.V. Busik: Consultant; Ceramedix, Inc. T.F. Dorweiler: None. A. Singh: None. M.B. Grant: None. R. Kolesnick: Stock/Shareholder; Ceramedix Holding LLC.

Funding

R01EY030766R01EY025383R01EY016077
497-P: Combination Epigenetic Therapy Normalizes Epithelial Wound Healing and Stem Cell Marker Expression in Human Organ-Cultured Diabetic Corneas
Authors: LJUBIMOV ALEXANDER V.
Published: June 2024

Diabetes mellitus (DM) is a major cause of vision loss worldwide. Diabetic corneas have epithelial alterations such as impaired wound healing, possibly due to dysfunctional limbal epithelial stem cells (LESC). We previously used gene therapy and DNA demethylation to modulate DM-altered proteins cathepsin F (increased in DM), c-Met (decreased in DM), and Wnt-5a (decreased in DM) to stimulate wound healing and LESC marker expression. Here, we used combined therapy with a DNA methylation inhibitor and a nanobioconjugate (NBC) targeting cathepsin F and c-Met. Human donor diabetic organ-cultured corneas (6 pairs) were treated with 20 µM of biodegradable NBC based on polymalic acid scaffold containing antisense oligonucleotides (AON) to cathepsin F and miR-409 (c-Met inhibitor) or control scrambled AON twice for 2 days, with 20 µM of DNA demethylator zebularine or DMSO control for 2 days. One cornea received combined treatment, and the fellow one, combined controls. Healing of 5-mm epithelial wounds made with 1-heptanol was monitored, and marker expression was examined by immunostaining or western blot. Organ-cultured DM corneas treated with combined zebularine and NBC suppressed DNA methyltransferase 1 and cathepsin F, and increased Wnt-5a and c-Met. This resulted in significant decrease (by 38.4%, p<0.02) of corneal epithelial wound healing time vs. DMSO and control NBC. Zebularine alone stimulated healing by 29.4%, and NBC alone, by 20.4%. Combination treatment increased the expression of putative LESC markers, keratins 15 and 17. DM markers integrin α3β1 and nidogen-1, and wound healing mediators p-Akt and p-p38 also had increased staining. There was no change in activated caspase-3 staining, indicating lack of treatment toxicity.Combination therapy with DNA methylation inhibitor and NBC targeting diabetes-altered protein markers may thus have a potential for the treatment of impaired diabetic corneal epithelial wound healing.

Disclosure

A.V. Ljubimov: None.

Funding

National Institutes of Health (EY013431; EY031377; EYEY025377)
499-P: Association between Diabetic Retinopathy and Number of Urinary Exfoliated Proximal Tubule Kidney Cells
Authors: HL WU HENRY , THE NGUYEN LONG , BHAGAVATH VENKATESHA , GOLDYS EWA , POLLOCK CAROL , SAAD SONIA
Published: June 2024

Introduction & Objective: Emerging evidence suggests cell exfoliation could be operating under the control of cell metabolism. Recent studies indicate kidney cell exfoliation into urine may reflect metabolic status. Proximal tubule cell (PTC) exfoliation can be particularly sensitive to hyperglycemia in diabetes mellitus (DM) as glucose entry into PTCs is insulin independent. While it appears that number of urinary exfoliated PTCs increases with DM, it is unclear if there are associations between number of exfoliated PTCs with diabetic severity and co-morbidities. Our study aims to explore this.

Methods: Adults age ≥ 18 yrs with type 1 or 2 DM were included. Collected urine samples were stored at -80°C. On assessment, exfoliated PTCs were extracted from thawed urine using a validated specific immunomagnetic separation method based on anti CD13 and anti SGLT2 antibodies. Number of PTCs present was visualized using brightfield microscopy. A Poisson regression model adjusting for HbA1c%, eGFR (ml/min/1.73m2), presence of diabetic retinopathy (DR), cardiovascular events (CVE) history, age (yrs), sex, ethnicity, BMI, urine volume (ml) collected, estimated urinary creatinine clearance rate, serum creatinine, uACR and blood pressure (mmHg) as variables was constructed to determine association with mean exfoliated PTCs. Incidence rate ratios (IRR) determined significance of association.

Results: Eighty four patients with DM were included. Mean age is 63.8 yrs (std dev 11.6) and 81% are male. Each 1% increase in HbA1c% was associated with an increase of 1.03 times in mean exfoliated PTCs (IRR 1.03, 95%CI 1.01-1.04, p=0.007). Presence of DR was associated with an increase of 1.68 times in mean exfoliated PTCs (IRR 1.68, 95%CI 1.07-2.62, p=0.024). There were no significant associations between eGFR or CVE history with mean exfoliated PTCs.

Conclusion: Our results indicate increased shedding of PTCs into the urinary tract in patients with DM with poorer glycemic control and presence of DR.

Disclosure

H. Wu: None. L. Nguyen: None. V. Bhagavath: None. E. Goldys: None. C. Pollock: Advisory Panel; AstraZeneca, Vifor Pharma Management Ltd. Speaker's Bureau; Eli Lilly and Company, Boehringer-Ingelheim, Novartis AG, Janssen Scientific Affairs, LLC, Otsuka America Pharmaceutical, Inc., AstraZeneca, Vifor Pharma Management Ltd., Merck Sharp & Dohme Corp. S. Saad: None.
501-P: Neutrophil Extracellular Traps Contribute to Retinal Fibrosis Development in Diabetic Retinopathy
Authors: MONICKARAJ FINNY , DAS ARUP , SMOAKE JANE
Published: June 2024

Purpose: Retinal fibrosis, characterized by fibroblasts, myofibroblasts, and extracellular matrix formation, occurs on the surface of the retinas following retinal neovascularization and vitreous hemorrhage. We have previously shown the contribution of neutrophils in the blood-retinal barrier alteration in an animal model of diabetic retinopathy (DR). We evaluated the hypothesis that the neutrophil signaling pathway contributes to the development of retinal fibrosis in DR.

Methods: Neutrophil extracellular traps (NETs) were prepared by treating human neutrophils with 25 mM glucose and 250ug advanced glycation endproducts. Transendothelial resistance of NETs and disulfiram (NET inhibitor) in human retinal endothelial cells was measured by electric cell-substrate Impedance Sensing (ECIS). The mRNA and protein expression of NETs, fibrosis, and endothelial mesenchymal transition (EndoMT) markers were analyzed on Streptozotocin-induced diabetic mice (3 months). NETs marker (Citrullinated Histone H3) was measured on serum samples of diabetic and nondiabetic subjects (n=10 in each group).

Results: Endothelial monolayer permeability was increased by NETs and significantly reduced by 10μM disulfiram. mRNA expression of EndoMT markers (TGFb1, MMP2, MMP9, ICAM1, VCAM1, & VE-Cad) and protein expression of NETs markers (PAD4 & Cit H3) were significantly increased in the retinas of diabetic animals compared with nondiabetic. Serum levels of Cit H3 were significantly increased in diabetic compared with nondiabetic subjects.

Conclusions: Overall, we have shown evidence that neutrophil extracellular traps triggered by neutrophil infiltration in diabetes play an essential role in EndoMT process and fibrosis. Targeting the NETs may be a potential therapeutic approach to preventing retinal fibrosis formation and traction retinal detachment.

Disclosure

F. Monickaraj: None. A. Das: None. J. Smoake: None.

Funding

NIH 5R01EY0286061I01BX005348-01A1
505-P: The Prevalence, Risk Factors and Predictors of Diabetic Retinopathy in Patients with Type 1 and Type 2 Diabetes in Riyadh, Saudi Arabia
Authors: ALMAZROU LULWA R. , SHBEAR ABDULRHMAN A. , ALZAHRANI SAAD H. , BREMA IMAD
Published: June 2024

Introduction & Objectives: Diabetic retinopathy(DR) is associated with significant visual impairment and quality of life in people living with diabetes, however, studies on the prevalence and risk factors from Saudi Arabia have been inconsistent, hence the aim of this was to define the prevalence, risk factors and predictors of DR in a large sample of subjects with type 1 diabetes (T1DM) and T2DM.

Methods: This was a cross-sectional study that included subjects with both T2DM and T1DM (if duration > 5 years) who attended the diabetes clinics at King Fahad Medical City in Riyadh between January 2022 and December 2022. Data are presented as Mean ± SD.

Results: The study sample included 1399 subjects of whom 566(40.5%) had T1DM and 833 (59.5 %) subjects had T2DM. Mean Hba1c for T1DM subjects was 8.8 ± 3.0 %, mean diabetes duration 10.2 ±5.6 years, and mean Time in Range (TIR) was 42.7 ± 18 % (N=354 subjects). Mean HbA1c for T2DM subjects was 7.8 ± 1.5 %, mean diabetes duration was 14.1 ± 8.8 years and mean TIR was 52.7 ± 25 (N=139). The prevalence of DR in the overall study population was 20.0 % (280/1399) with the majority ( 86.5 %) in the Mild and Moderate Non-Proliferative DR stages. The prevalence of DR in T1DM & T2DM subjects was 12.7 % and 24.8 %, respectively. Subjects with T1DM & DR were significantly older and had longer diabetes duration while subjects with T2DM & DR were older, had longer diabetes duration, higher Systolic BP, higher urinary albumin/Creatinine ratio( UACR) and lower estimated GFR. Logistic regression showed that in T1DM subjects, longer diabetes duration, lower TIR and higher glucose variability were independently associated while, longer diabetes duration and higher UACR were independently associated with DR in T2DM subjects.

Conclusion: In a large sample of Saudi subjects with diabetes, the prevalence of DR was 20 %. Efficient screening and targeting modifiable risk factors are important measures in the prevention as well as avoidance of progression of DR.

Disclosure

L.R. AlMazrou: None. A.A. Shbear: None. S.H. Alzahrani: None. I. Brema: None.

Funding

KFMC Research Centre
506-P: Branched-Chain Amino Acids Promote Occurrence and Development of Cardiovascular Disease Dependent on Triglyceride Metabolism via Activation of the mTOR/SREBP-1/Betatrophin Pathway
Authors: ZHANG JIE , HU WEN
Published: June 2024

Background: Branched-chain amino acids (BCAAs) has been associated with the development of cardiovascular disease (CVD). However, the underlying mechanism remains uncertain.

Methods: The clinical study included 1302 subjects guided by diet and exercise intervention for 4 years and subsequent follow-up. We established a hyperbranched-chain aminoacidemia rat model induced by high fructose diet (HFTD). Additionally, we investigated the relationship between BCAAs and TG level and its regulatory mechanism in vitro.

Results: As baseline BCAA percentile increased, subjects were more likely to have a higher prevalence and incidence of diabetes, non-alcoholic fatty liver disease, and CVD risk. Both individual BCAAs and total BCAAs were independently associated with subsequent CVD risk. HFTD led to insulin resistance (IR) and higher levels of BCAAs in the rat model. Further investigation indicated that HFTD led to IR via the IRS-1/Akt/GSK-3β pathway and betatrophin expression was increased. Metformin significantly reversed the above effects. In vitro, we found BCAAs increased TG levels by regulating the mTOR/SREBP-1/betatrophin signaling pathway.

Conclusions: BCAAs promote occurrence and development of cardiovascular disease dependent on TG metabolism via activation of the mTOR/SREBP-1/betatrophin pathway.

Disclosure

J. Zhang: None. W. Hu: None.

Funding

the National Natural Sciences Foundation of China (81700776)
513-P: Sustained Reduction of Atherogenic Lipoproteins Two Years after Modest Weight Loss in the POUNDS Lost Trial
Authors: THOMAS MELBIN , FURTADO JEREMY , SACKS FRANK , TONG JENNY
Published: June 2024

Apolipoprotein C-III (ApoC3) delays clearance of VLDL and LDL. Lipoprotein subspecies that contain ApoC3 are most predictive of CHD in type 2 diabetes. Our study's objective was to determine if diet-induced weight loss would reduce the concentration of atherogenic lipoproteins including ApoC3.

Methods: The POUNDS LOST trial was a two-year interventional study where 811 participants were randomized into four diet groups with varying macronutrient compositions. Standard lipid panels were performed at 0, 6, and 24 months. Lipoprotein subspecies by ApoC3 content and density (VLDL, LDL & HDL) were analyzed for ApoC3, ApoB, ApoE, triglyceride and cholesterol concentrations at baseline and 24 months on ~100 samples in each diet group (age 53 ± 9 y, BMI 32 ± 4 kg/m2, 60% female). Samples. Data were analyzed utilizing STATA software to perform non-parametric tests and multivariate regression models on lipoprotein subspecies.

Results: On average, participants lost 7% of the baseline weight at 6 months and 5% at 24 months. There were significant reductions in total cholesterol (-10.4±26 mg/dL, p<0.001), LDL-C (-5.7± 23 mg/dL, p=0.004), non-HDL-C (-11.4 ± 24 mg/dL, p<0.001), and triglyceride (TG) (-31.6 ± 59 mg/dL, p<0.001) as well as an increase in HDL-C (1.2± 7 mg/dL, p=0.02) at 6 months. The reduction in non-HDL-C and TG remained significant at 24 months, but changes in LDL-C, HDL-C or total cholesterol did not. At 24 months, despite an average 1.6% weight regain, plasma concentration of ApoC3 in LDL (p=0.02), HDL (p=0.03), and VLDL (p < 0.001) remained lower than baseline. Weight change (0-24 months) was positively associated with changes in ApoC3 level independent of age, sex, race, BMI, and dietary assignment (r=0.03, p=0.002).

Conclusion: Even modest weight loss reduces the concentration of atherogenic lipoproteins and increases the protective lipoprotein concentrations in individuals who were overweight or obese. These effects appear sustainable despite weight regain.

Disclosure

M. Thomas: None. J. Furtado: Employee; Biogen. Stock/Shareholder; Biogen. F. Sacks: None. J. Tong: None.
515-P: Do Circulating Sphingolipid Species Correlate with Age? A Study in a Normoglycemic Population
Authors: ALIYE FETO NASER , ASUZU PEACE , STENTZ FRANKIE B. , WAN JIM Y. , DAGOGO-JACK SAMUEL , MANDAL NAWAJES
Published: June 2024

Objective: Sphingolipids (SPL) in circulation have been associated with pathological outcomes of metabolic and cardiovascular diseases that are known to be influenced by aging. We sought to determine the age association of plasma SPL species in people with no diabetes.

Methods: We determined plasma levels (pmole/mL) of 58 SPL species, including ceramides (Cer), monohexosylceramides (MHC), sphingomyelins (SM), sphingosine (So), and sphingosine 1-phosphate (S1P) in 239 normoglycemic participants using LC-MS/MS after dividing them into five age groups, 19-29y (n=46), 30-39y (n=47), 40-49y (n=64), 50-59y (n=67), and ≥60y (n=15). Correlation analysis identified SPL species that differ significantly among the age groups and that significantly correlate with aging.

Results: We identified the ratio of C18:0/C18:1 in Cer, MHC, and SM differed significantly in different age groups along with some very-long-chain (VLC) species of MHC and SM, SM C14:0, total SM, and SM% of SPL, which remained significant after adjusting for gender, race, BMI, waist circumference, FPG, and 2hPG. Interestingly, Cer C18:1 (r=0.20, p<0.01) positively correlated with aging, and the ratio of Cer C18:0/C18:1 (r= -0.27, p<0.0001) and MHC (r= -0.23, p<0.001) correlated negatively. While levels of So (r= -0.29, p<0.0001) and MHC C26:0 (r= -0.20, p<0.01), MHC C28:0 (r= -0.25, p<0.0001), MHC C34:0 (r= -0.23, p<0.001) and MHC ratio of C26:0/C26:1 (r= -0.27, p<0.0001) and MHC% of SPL (r= -0.20, p<0.01) correlated negatively, SM% of SPL (r=0.21, p<0.001) correlated positively.

Conclusions: Our results show that the plasma concentration of certain SPL species and ratios differ with age and correlate differentially with age. Thus, alterations in SPL metabolism may be linked to aging and age-related disorders.

Disclosure

N. Feto: None. P. Asuzu: None. F.B. Stentz: None. J.Y. Wan: None. S. Dagogo-Jack: Consultant; Merck Sharp & Dohme Corp., Medtronic, Bayer Inc. Stock/Shareholder; Aerami. N. Mandal: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK128129, R01 DK067269, and DK 48411)