bluuebunny/crossref_metadata_2025 huggingface dataset:
2072-LB: Effect of 5:2 Fasting Diet on Liver Fat Content in Patients with Type 2 Diabetic with Nonalcoholic Fatty Liver Disease
Authors: YAN XIN XIAO
Published: June 2024

Background: The prevalence of nonalcoholic fatty liver disease (NAFLD) is rapidly growing in China, especially in patients with type 2 diabetes mellitus (T2DM). Weight loss strategies have been shown to treat NAFLD effectively. We conducted a 24-week, prospective, randomized study in T2DM patients with NAFLD to evaluate the effects of 5:2 fasting diet on liver fat content.

Methods: In total, sixty-one T2DM patients with NAFLD were enrolled and randomly divided into a intervention group (5:2 diet group, n=31) and 1.8mg/day liraglutide intervention group (Lira group, n=30). Data of the body weight, waist circumference, plasma lipids and glucose profile, fasting plasma insulin, and liver function parameters were collected. Controlled attenuation parameter (CAP) was measured to assess the liver fat content. Superoxide dismutase (SOD) and malondialdehyde (MDA) were measured to evaluate oxidative stress status.

Results: At 24 weeks after intervention, compared to those at baseline, CAP was significantly decreased in both 5:2 diet group and Lira group, which was 7.4% and 5.5%, respectively. Body weight, plasma lipids and glucose profile, and liver function parameters improved significantly, while homeostasis model assessment-β (HOMA-β) was significantly increased in both groups (all P<0.05). Stepwise linear regression showed that increased HOMA-β and SOD, as well as reduced body mass index (BMI), were the independent predictors of CAP decrease in Lira group (P=0.000, 0.000, 0.015). In contrast, reduced BMI and MDA were the independent influencing factors of CAP decrease in 5:2 diet group (P=0.011, 0.043). The common side effects in 5:2 diet group were hunger (60%), weakness (10%) and constipation (0.3%).

Conclusions: A 5:2 fasting diet achieved comparable effects with liraglutide on liver fat content in patients with T2DM with NAFLD by reducing BMI and the oxidative stress. Both treatment strategies were safe and effective for glucose control.

Disclosure

X. Yan Xin: None.
2076-LB: Physician Views on Management of Patients with Both Obesity and Type 2 Diabetes (PwOT2D) in the U.S. and Germany
Authors: TAN MICHELLE S.F. , LOGENDRA RAMYA , CORTESE ROBERTO , SCHMUECKING RHODA
Published: June 2024

Obesity is a key risk factor for developing type 2 diabetes (T2D) and treating obesity is central to its management. In our study, we aimed to understand how anti-obesity medications (AOMs) impact US and German healthcare professionals’ (HCPs) views on managing patients with both obesity and Type 2 Diabetes (PwOT2D).

Data are from an online medical chart review study conducted among 141 primary care physicians (PCPs) and 128 endocrinologists treating PwOT2D in the US and Germany from Oct-Dec 2023. Physicians were screened for caseload.

A significantly higher percentage (p<0.01) of sampled US endocrinologists (66%, n=79) and PCPs (58%, n=71) reported higher agreement to ‘I proactively prescribe weight-loss strategies to prevent weight-related comorbidities’ compared to the German endocrinologists (29%, n=49) and PCPs (30%, n=70) [‘higher agreement’ based on top 2 box (6-7) of 7-point scale, where 7=completely agree]. A significantly higher percentage (p<0.01) of the US endocrinologists (62%) and PCPs (51%) also agreed (same scale) that ‘AOMs are top-of-mind when managing PwO with weight-related complications’ compared to the German endocrinologists (20%) and PCPs (24%). This aligns with our findings on HCP management of PwO, whereby 81% of sampled German HCPs would recommend lifestyle changes (versus 51% of US HCPs) and only 37% would prescribe AOMs (versus 56% of US HCPs). When specifically asked about treatment strategies for PwOT2D, 45% of the German endocrinologists would prioritize treating T2D over obesity; this is notably higher than the US sample (15%), where instead 80% of this cohort would choose to treat both conditions together.

In this study, there are significant differences in the cited approach to managing obesity and related comorbidities such as T2D between sampled German and US HCPs. US HCPs are more likely to prescribe AOMs for weight loss, but also consider their impact on other weight related comorbidities when doing so compared to German HCPs.

Disclosure

R. Logendra: None. R. Cortese: None. R. Schmuecking: None.
2084-LB: Real-World Effectiveness of Tirzepatide among People with Obesity or Overweight without Type 2 Diabetes (T2D)
Authors: HANKOSKY EMILY R. , DESAI KARISHMA , CHINTHAMMIT CHANADDA , GRABNER MICHAEL , STOCKBOWER GRACE , HE XUANYAO , MOJDAMI DONNA , WENZIGER CACHET , HUNTER GIBBLE THERESA
Published: June 2024

Introduction & Objective: Tirzepatide is a once weekly GIP and GLP-1 receptor agonist approved in the US for treatment of T2D (May 2022) and obesity (Nov 2023). We assessed real-world patient characteristics and effectiveness in people with obesity or overweight without T2D.

Methods: This retrospective study was conducted using the Healthcare Integrated Research Database (HIRD®). Date of first tirzepatide claim (index date; NDCs for Mounjaro®) was between May 13, 2022 - June 30, 2023. Because tirzepatide was only approved for the treatment of T2D during the index period, any use of tirzepatide by individuals without T2D during this time was off-label and solely at the discretion of their prescribing physician. Demographic and clinical characteristics were assessed among adults (≥18 years) without T2D diagnostic codes or treatment, but eligible for anti-obesity medication (AOM; BMI ≥30 kg/m2; or BMI ≥27 kg/m2 with ≥1 obesity-related comorbidity; ORC). Weight changes were assessed among individuals with ≥6 months tirzepatide persistence (<60-day gap) and weight data at baseline and 6-months post-index.

Results: Among the 699 AOM-eligible adults without TD2 diagnostic codes who filled a prescription for tirzepatide, most were female (77.1%), White (81.1%), mean age 47.2 years, mean BMI 38.3 kg/m2, mean weight 109.3 kg (241.0 lbs), and of those with a 6th prescription fill (n=405), 44.4% was for ≥10 mg. At least one ORC was reported in 86.4% of patients. Hypertension (44.5%), dyslipidemia (43.6%), and anxiety (35.8%) were the most common ORCs. Of the 68.8% (n=481) who were persistent for ≥6 months, weight data were available at baseline and 6-months post-index for n=199; 88.4% had ≥5%, 68.8% had ≥10%, and 36.7% had ≥15% weight reduction at 6-months post-index. The average weight reduction was 12.7% (14.1 kg [31.1 lbs]).

Conclusion: At 6-months, most users of tirzepatide without T2D diagnostic codes were persistent and lost ≥10% body weight with an average body weight loss of 12.7%.

Disclosure

E.R. Hankosky: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. K. Desai: Employee; Carelon Research. Stock/Shareholder; Anthem, Inc. C. Chinthammit: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. M. Grabner: Employee; Carelon Research. Stock/Shareholder; Anthem, Inc. G. Stockbower: None. X. He: Employee; Eli Lilly and Company. D. Mojdami: Employee; Eli Lilly and Company. C. wenziger: None. T. Gibble: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.
2089-LB: An Adult Clock Component Links Circadian Rhythms to Pancreatic ß-Cell Maturation
Authors: ALVAREZ JUAN R.
Published: June 2024

Pancreatic β cell clocks attune insulin secretion to daily energy cycles, and desynchrony from genetic or behavioral disruptions triggers metabolic dysfunction, fueling type 2 diabetes risk. How ubiquitous circadian clocks orchestrate β cell-specific outputs, however, is not well understood. In particular, major questions remain as to how core vs. ancillary clock components synchronize β cell genes to coordinate overall metabolism.

To dissect the control of metabolism by state specific clock components, we studied DEC1, as it partakes in the transcriptional regulatory circuit defining mature β-cell identity. We show that DEC1 is specifically induced in adult β cells, and coordinates their glucose responsiveness by synchronizing energy metabolism and secretory gene oscillations. Dec1-ablated mice develop lifelong hypo-insulinemic diabetes, despite normal islet formation and intact circadian Clock and Bmal1 activators. Dec1-/- mice show normal food intake and patterns of activity and energy expenditure, with delayed phase onset but sustained period length. Yet, Dec1-/- mice show low energy expenditure during the active phase, consistent with a hypometabolic state. DEC1, but not CLOCK/BMAL1, binds maturity-linked genes that mediate respiratory metabolism and insulin exocytosis, and Dec1 loss disrupts their transcription synchrony. Accordingly, β-cell Dec1 ablation causes hypo-insulinemia due to poor insulin responses to glucose, as with immature fetal/neonatal islets. Thus, DEC1 links circadian clockwork to the β-cell maturation process, aligning metabolism to diurnal energy cycles.

These findings show that synchrony of energy metabolism pathways by adult-specific clockwork is critical for physiological coordination of metabolism. As clocks are activated in metabolic tissues during onset of feeding-fasting rhythms, an intriguing possibility is that they unlock phenotypic maturity by optimizing specialized cellular tasks to daily cycles in energy availability.

Disclosure

J.R. Alvarez: None.
2091-LB: Viral Infection Drives Aberrant Pancreatic Beta-Cell Bioenergetics and Autophagy via a Candidate Type 1 Diabetes Gene PGM1
Authors: MILLER YI , QIU YUNPING , SUN YAN , JANKAUSKAS STANISLOVAS S. , KULKARNI RUCHA J. , SIDOLI SIMONE , KURLAND IRWIN J. , TOMER YARON
Published: June 2024

Introduction & Objective: Viral infection is one of the major environmental factors in Type 1 Diabetes (T1D). PGM1 is a T1D GWAS gene encoding phosphoglucomutase 1, which bidirectionally converts G6P to G1P. PGM1 resides at the junction between many arms of metabolic pathways. Our previous study suggests that PGM1 is potentially causal to T1D via epigenetic changes driven by genetic / environmental factors. We hypothesised that PGM1 is a crucial regulator of beta cell metabolism in response to viral infection.

Methods: Purified human islets, EndoC-BH1, and INS-1 cells were used. Poly (I:C), a double stranded viral RNA analogue was delivered into the cells via transfection or electroporation. PGM1 was knocked down by shRNA lentivirus. RNA and protein were analyzed using qPCR, western blot, and proteomics. For stable isotope labeling, EndoC-BH1 cells were cultured with 50% U-13C6 glucose. Metabolites and stable isotopes were analysed using LC-/GC-MS. Autophagy and mitophagy were assessed using western blot and live cell imaging. Unpaired t - test was used for statistical analyses.

Results: PGM1 expression was significantly lowered after the intracellular delivery of 10 μg/ml Poly(I:C) to human islets and EndoC-BH1 cells. Proteomics identified translational arrest in PGM1 shRNA treated human islets. ATF3 mRNA increased by approximately two-fold, suggesting integrated stress response. In EndoC-BH1 cells, PGM1 suppression increased flux to glycolysis, TCA cycle, pentose phosphate pathway, and hexosamine biosynthetic pathway. We found activation of autophagy but impaired autophagic and mitophagic flux in PGM1 deficient beta cells. Insulin secretion was unchanged, proinsulin content was lowered.

Conclusion: PGM1 is a novel driver of beta cell metabolic and energy stress following viral infection. The aberrant autophagic flux additionally suggests lysosomal defects. Activation of PGM1 potentially improves beta cell resistance to viral infection.

Disclosure

Y. Miller: None. Y. Qiu: None. Y. Sun: None. S.S. Jankauskas: None. R.J. Kulkarni: None. I.J. Kurland: None. Y. Tomer: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (1K01DK131329-01); Integrated Islet Distribution Program (BS526P)
21-OR: Use of Electronic Best Practice Advisories (BPA) to Increase Referral to Diabetes Self-Management Education and Support (DSMES) Services
Authors: YOUNG LAURA A. , HALLADAY JACQUIE , CHEN PING , MOTTUS KATHLEEN M. , GOEKE-AUSTIN KAREN K. , RICHMAN ERICA L. , REES JENNIFER , DONAHUE KATRINA
Published: June 2024

Introduction & Objective: DSMES is underutilized by people with Type 2 diabetes (T2D), in part due to low rates of referral by health care providers. We sought to determine if rates of referral to DSMES increase through the use of a BPA deployed during clinic visits to health care providers via the electronic health record.

Methods: In this randomized controlled trial in central North Carolina, we created a BPA within the Epic electronic health record that fired when a patient with T2D who qualified for DSMES attended a routine visit with their primary care provider. The BPA was deployed in four primary care practices within a large, university-based health care system. Two additional practices served as controls and did not receive the intervention. We conducted multilevel binary logistic regressions with patient data nested within the provider, using the indicator of the intervention (vs. control clinics) as the predictor to estimate the odds ratio of provider referring an eligible patient to DSMES services after a patient encounter. Clinic-level (percentages of patients with Medicare and Medicaid use) and patient-level (age, sex, and race) variables were controlled in the adjusted model.

Results: Between April and October 2023, 1,326 BPAs fired in the intervention clinics resulting in an 11% referral rate to DSMES. Control clinics had 938 patient visits that qualified for DSMES referral with a 4% referral rate of eligible patients to DSMES. The 7% increase in referral rate between the intervention and control practices is statistically significant (p<0.001). In the adjusted multivariate model, controlling for the covariates, patients who are in the intervention clinics with BPA firing have significantly higher odds of being referred for DSMES services than those who are in the control clinics without BPA firing (OR = 4.19 [95% CI 2.63-6.67], p < 0.001).

Conclusions: Electronic BPAs do significantly increase patient referrals to DSMES services.

Disclosure

L.A. Young: Research Support; Novo Nordisk, Eli Lilly and Company, vTv Therapeutics, Beta Bionics, Inc., Corcept Therapeutics, Rhythm Pharmaceuticals, Inc., Bayer Inc., Jaeb Center for Health Research. J. Halladay: None. P. Chen: None. K.M. Mottus: None. K.K. Goeke-Austin: None. E.L. Richman: None. J. Rees: None. K. Donahue: None.
211-OR: Massively Parallel Characterization of Thousands of Type 2 Diabetes–Associated Variants in Multiple Cell Types Nominates Candidate Causal Regulatory Alleles and Mechanisms
Authors: KOTHARI MADHAV , BHUIYAN REDWAN M. , ULIRSCH JACOB C. , DEWEY HANNAH , NERURKAR NIKETA , KURSAWE ROMY , KALES SUSAN , BERENZY DANIEL , TEWHEY RYAN , STITZEL MICHAEL L.
Published: June 2024

Genome-wide association studies have identified >500 loci associated with type 2 diabetes (T2D). Most of these variants are in non-coding regions and may play regulatory roles, but they have not been comprehensively tested for this role. Here, we assessed transcriptional regulatory activity of 6,109 fine-mapped variants in 204 T2D-associated loci from DIAGRAM, UKBB, and BBJ cohorts using massively parallel reporter assays (MPRA) in HepG2 hepatocytes, SGBS (pre)adipocytes, and EndoC-βH3 beta-cells, three cell types implicated in T2D pathophysiology, as well as K562, SK-N-SH, and A549 cells.

MPRA identified 946 expression-modulating variants (emVars) in a T2D-relevant cell type. 277 T2D-associated emVars in 81 loci overlapped an open chromatin region in T2D-relevant cell types; precision recall analysis revealed precision of 0.83 and recall of 0.3 for identifying high posterior inclusion probability (PIP > 0.9) variants using this integrated information. Importantly, MPRA nominated as high priority candidate causal variants a single functional variant at 45 loci, the majority of which were incompletely resolved using fine-mapping (PIP>0.9 (n=6), PIP 0.5-0.9 (n=3) and PIP< 0.5 (n=36)). These include well-characterized variants such as rs11257655 (CDC123/CAMK1D locus), whose risk allele increases MPRA activity via enhanced FOXA2 binding, and new variants like rs528350911 (PIP 0.99), whose T2D risk allele decreases MPRA activity through predicted disruption of a GATA binding site, and rs917195 (PIP 0.96), whose T2D risk allele in the CRHR2 locus is predicted to disrupt binding of RFXs. Together, this study provides new insights into the regulatory effects of non-coding T2D-associated variants across multiple cell types and nominates a set of high-confidence candidate causal variants for 39.7% of T2D-associated loci tested.

Disclosure

M. Kothari: None. R.M. Bhuiyan: None. J.C. Ulirsch: Employee; Illumina Inc. H. Dewey: Stock/Shareholder; Moderna, Inc. N. Nerurkar: None. R. Kursawe: None. S. Kales: None. D. Berenzy: None. R. Tewhey: None. M.L. Stitzel: None.

Funding

Opportunity Pool Funding (UM1DK105554); NIDDK (R01DK118011); The Jackson Laboratory Director's Innovation Fund NHGRI (UM1HG009435)
220-OR: Reduced Apolipoprotein C-I Truncation Is Associated with Worsening of Insulin Resistance and Risk of Diabetes in Persons with Impaired Glucose Tolerance
Authors: KOSKA JURAJ , NEDELKOV DOBRIN , BILLHEIMER DEAN , SCHWENKE DAWN , REAVEN PETER
Published: June 2024

Apolipoprotein C-I (apoC-I) is key regulator of triglyceride and HDL metabolism. It appears as native and truncated posttranslational proteoforms. Higher truncated-to-native apoC-I proteoforms ratio (C-I’/C-I) is associated with favorable cardiometabolic risk profile. Whether apoC-I proteoform composition is associated with declines in insulin sensitivity and secretion, and incident diabetes is unknown. Plasma apoC-I proteoforms (by mass spectrometry immunoassay) were measured at baseline in 524 participants of the ACT NOW, a placebo-controlled study of pioglitazone in impaired glucose tolerance. Baseline and follow-up indices of insulin sensitivity (ISI, by Matsuda’s equation) and secretion (∆I/∆G calculated as AUCinsulin/AUCglucose) were derived from glucose and insulin concentrations during an OGTT. At baseline, C-I’/C-I correlated with both ISI and ∆I/∆G (r=0.26; r=-0.17, both p<0.0001). Prospectively, higher baseline C-I’/C-I was associated with higher ISI (by 9.4% [95% CI: 4.1, 13.9] per 1 SD; follow-up adjusted for baseline, time of follow-up and treatment group), lower ∆I/∆G (-4.9% [-7.7, -1.0]) and reduced diabetes risk (n=59 events, HR 0.75 [95%CI: 0.57-0.98]). The C-I’/C-I associations with insulin sensitivity and diabetes were independent of diabetes risk factors (e.g., BMI) and plasma lipids (HR 0.72 [0.54-0.96]). The C-I’/C-I association with diabetes was attenuated after adjusting for change (follow-up adjusting for baseline) in ISI (HR 0.82 [0.61-1.11]) but not in ∆I/∆G (HR 0.67 [0.49-0.93]).

In conclusion, lower apoC-I truncation was associated, independently of typical diabetes risk factors, with decline in insulin sensitivity and increased risk of diabetes in individuals with impaired glucose tolerance. The association with incident diabetes appears to reflect favorable effects of apoC-I truncation on insulin sensitivity but not on insulin secretion.

Disclosure

J. Koska: None. D. Nedelkov: None. D. Billheimer: None. D. Schwenke: None. P. Reaven: Research Support; Dexcom, Inc.

Funding

National Institutes of Health (R24-DK090958); Takeda Pharmaceuticals
230-OR: Comparative Effectiveness of Semaglutide in Type 2 Diabetes—Year 2 Results of a Randomized Pragmatic Clinical Trial
Authors: BUSE JOHN B. , SOULE BENJAMIN P. , HARTY BRIAN J. , NORDAHL HELENE , CZIRAKY MARK J. , WILLEY VINCENT , SKIBSTED SIMON
Published: June 2024

The objective of this study was to generate real-world evidence to support clinical decision-making by evaluating the long-term effects of once-weekly SC semaglutide (sema) in routine clinical practice. SEPRA was a 2-year open-label, randomized, pragmatic study (NCT03596450) comparing the effectiveness of sema vs physician’s choice standard of care (SOC; any antidiabetes drug excluding sema) when added to ≤2 OADs for treatment intensification in adults with T2D. Endpoints at 2 years included percentage of patients achieving HbA1c <7%, %-point change in HbA1c from baseline, and change in body weight. Patients were randomized to receive sema (n=644) or SOC (n=634); 58% and 59% had recorded HbA1c levels at year 2, respectively. Baseline characteristics were comparable between groups (Table). Sema dosing at year 2 was 17.5% at 0.25 mg, 22.7% at 0.5 mg, and 27.5% at 1 mg (22.8% left the study, 8.9% were not on sema). Of patients receiving SOC at year 2, 37.4% were not receiving the treatment selected for intensification. At year 2, a significantly greater percentage of patients achieved HbA1c <7% and numerically greater weight loss with sema vs SOC. A lower percentage of patients required further treatment intensification with sema vs SOC. No new safety concerns were identified. SEPRA demonstrated that sema is more effective and durable than SOC for T2D treatment intensification in routine clinical practice.

Disclosure

J.B. Buse: Other Relationship; Novo Nordisk. Consultant; Corcept Therapeutics. Research Support; Corcept Therapeutics, Dexcom, Inc., Insulet Corporation. Consultant; Alkahest, Anji Pharmaceuticals, Aqua Medical, Altimmune Inc., AstraZeneca, Boehringer-Ingelheim, CeQur, Eli Lilly and Company, embecta, GentiBio, Glyscend Inc., Mellitus Health, Metsera, Pendulum Therapeutics, Praetego, LLC, Stability Health, Terns Pharmaceuticals, Insulet Corporation, Vertex Pharmaceuticals Incorporated, vTv Therapeutics. Other Relationship; Medtronic. Stock/Shareholder; Glyscend Inc., Mellitus Health, Pendulum Therapeutics, Praetego, LLC, Stability Health. B.P. Soule: Employee; Novo Nordisk. B.J. Harty: Research Support; Novo Nordisk. H. Nordahl: Employee; Novo Nordisk. M.J. Cziraky: Other Relationship; Carelon Research. V. Willey: Other Relationship; Carelon Research. S. Skibsted: Employee; Novo Nordisk A/S.

Funding

Novo Nordisk Inc.
249-OR: Cystatin C Predicts Cardiovascular Events in Patients with Coronary Artery Disease Both among Patients with and among Those without Type 2 Diabetes
Authors: PLATTNER THOMAS , LARCHER BARBARA , MADER ARTHUR , VONBANK ALEXANDER , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: June 2024

Cystatin C is an established biomarker for renal function, and, given the close association of chronic kidney disease and cardiovascular disease might indicate new-onset or deteriorating cardiovascular disease. However, evidence for cystatin C as a predictor of cardiovascular events is limited and controversial. We therefore aimed at investigating the role of cystatin C as a predictor of future cardiovascular events in a high risk-cohort of patients with established coronary artery disease (CAD). We prospectively recorded cardiovascular events in 1053 patients with angiographically verified CAD over a mean follow-up of 9.5±5.3 years. At baseline, 352 patients had type 2 diabetes mellitus (T2DM) and 701 did not have T2DM. During follow-up, 560 (53.2%) of our patients suffered cardiovascular events. Cystatin C proved to be a strong and independent predictor for cardiovascular events in the total study cohort (standardized adjusted HR 1.22 [1.12-1.33], p<0.001). When T2DM status was taken into account, cystatin C significantly predicted cardiovascular events both in patients with T2DM (HR 1.18 [1.04-1.35], p=0.011) and in nondiabetic patients (HR 1.23 [1.09-1.38], p<0.001). We conclude that cystatin C predicts cardiovascular events in CAD patients both among those with and among those without T2DM.

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.
250-OR: Ceramides Surpass LDL-Cholesterol in Predicting Cardiovascular Mortality in Diabetic and Nondiabetic Patients
Authors: LEIHERER ANDREAS , MUENDLEIN AXEL , SAELY CHRISTOPH H. , PLATTNER THOMAS , LARCHER BARBARA , MADER ARTHUR , VONBANK ALEXANDER , LAAKSONEN REIJO , FRAUNBERGER PETER , DREXEL HEINZ
Published: June 2024

The power of cardiovascular risk prediction is biased by comorbidities (including T2DM), medical treatment, and age, which impact cholesterol levels. Consequently, when applying LDL-C, the true cardiovascular risk of such confounded patients is often underestimated. However, it is not clear whether this constraint for risk prediction may likewise apply to other lipid risk markers in particular ceramides. In this observational cohort study, we recorded cardiovascular mortality for 16 years in 1195 patients. Their median age was 67 years, all of them had a high preexisting cardiovascular risk, 51% were taking statins, and 30% had T2DM. We found a U-shaped association between cardiovascular mortality and LDL-C. We thus stratified the population according to the vertex into high (≥150mg/dL) and lower LDL-C (<150mg/dL) and also according to the T2DM status. A Cox regression analysis revealed that LDL-C failed to predict cardiovascular mortality in any subgroup. In contrast, no U-shaped but a linear association was found for ceramide-based markers. They were able to significantly predict cardiovascular mortality after stratification and even after multivariate adjustment. We thus propose that ceramide-based predictors rather than LDL-C should be applied for a more accurate cardiovascular risk prediction in diabetic and other high-risk patients.

Disclosure

A. Leiherer: None. A. Muendlein: None. C.H. Saely: None. T. Plattner: None. B. Larcher: None. A. Mader: None. A. Vonbank: None. R. Laaksonen: None. P. Fraunberger: None. H. Drexel: None.
257-OR: ADA Presidents' Select Abstract: The Effect of a Reduced-Energy Diet upon Maternal Weight and Pregnancy Outcomes in Women with Gestational Diabetes—The DiGest Trial
Authors: KUSINSKI LAURA C. , JONES DANIELLE , ATTA NOORIA , TURNER ELIZABETH , OUDE GRIEP LINDA M. , RENNIE KIRSTEN L. , DE LUCIA ROLFE EMANUELLA , SHARP STEPHEN , MURPHY HELEN R. , TAYLOR ROY , MEEK CLAIRE L.
Published: June 2024

Background: Reduced-energy diets improve clinical outcomes in type 2 diabetes but are untested in gestational diabetes.

Methods: In a randomized, controlled, double-blind, whole-diet replacement trial (ISRCTN; 37866), women with gestational diabetes and BMI >25 kg/m2 were assigned (1:1) to receive a standard-energy (2000 kcal/day) (control) or a reduced-energy diet (1200 kcal/day) (intervention) until delivery, provided as weekly dietboxes containing 40% carbohydrate, 35% fat and 25% protein. Diagnosis used the National Institute of Health and Care Excellence (NICE) and interim UK Covid-19 criteria. Primary outcomes were maternal weight change (enrolment to 36wks) and offspring standardized birthweight. Secondary outcomes included maternal glycemia, treatment requirements and neonatal outcomes.

Results: 423 women were randomized at 29wks gestation; (n=211 control; n=212 intervention). Outcome data were available for 386 (91.3%) participants at 36wks and 358 (84.6%) at delivery. Intervention and control groups had similar maternal weight change to 36wks (mean 0.41(SD 4.25) vs 0.50(4.15) kg; baseline-adjusted difference intervention vs control -0.148 (95%CI -0.95 to 0.68); p=0.741). The intervention reduced requirements for short-acting (odds ratio 0.37 (0.14 to 0.97); p=0.044) and long-acting (0.38 (0.19 to 0.75); p=0.006) insulin therapy at 36wks. Offspring had similar standardized birthweight (0.44(1.03) vs 0.44(0.85) SDS; 0.004(-0.20 to 0.19) p=0.967) and comparable rates of large-for-gestational-age and neonatal intensive care admission. Serious adverse events and withdrawals were similar between groups. Weight loss in late pregnancy appeared safe.

Conclusions: The protocol did not result in differences in weight gain or primary outcomes between groups but the provision of a reduced energy diet was associated with a reduced requirement for insulin therapy.

Disclosure

L.C. Kusinski: None. D. Jones: None. N. Atta: None. E. Turner: None. L.M. Oude Griep: None. K.L. Rennie: None. E. De Lucia Rolfe: None. S. Sharp: Consultant; Shionogi & Co., Ltd. H.R. Murphy: Advisory Panel; Medtronic. Research Support; Abbott, Dexcom, Inc. Speaker's Bureau; Ypsomed AG, Eli Lilly and Company, Dexcom, Inc. R. Taylor: Advisory Panel; Fast800. C.L. Meek: Research Support; Dexcom, Inc.

Funding

Diabetes UK 17/0005712EFSD - NNF NNF19SA058974
282-OR: Nod1 Plays a Causal Role in Western-Diet–Induced Insulin Resistance and Glucose Intolerance in Microbiota-Deficient Conditions
Authors: M NIAZUR RAHMAN S , TSAKIRIDIS NICOLE , GARCIA MIGUEL A. , PARK JUNYOUNG , TAN YAO , GIACCA ADRIA
Published: June 2024

Introduction & Objective: Recent studies revealed that nucleotide-binding oligomerization domain 1 (Nod1), an innate immunity receptor, mediates high fat diet (HFD) effects to induce insulin resistance and glucose intolerance. Circulating free fatty acids, acting as damage-associated molecular patterns (DAMPs), activate Nod1, which also senses gut microbiota-derived pathogen-associated molecular patterns (PAMPs), which are thought to be absorbed into the circulation as HFD changes gut permeability. While Nod1-null mice showed protection from HFD-induced insulin resistance, it remains unclear if this is driven by PAMPs or DAMPs. To investigate whether the protective effect of Nod1 deficiency is abolished without PAMPs, we studied Nod1 knockout (KO) in germ-free (GF) conditions, minimizing PAMP influence to reveal DAMP-induced Nod1 activation's role in insulin resistance and T2D.

Methods: We subjected GF or conventionally maintained C57BL/6 Nod1 KO and wild type (WT) mice to an 8-week high-fat, high-sucrose diet (HFSD) starting at 5 weeks of age to mimic Western diet-induced glucose intolerance and early diabetes. At 13 weeks, mice underwent intraperitoneal insulin tolerance tests (IPITT) and glucose tolerance tests (IPGTT) three days apart to assess insulin sensitivity and glucose tolerance.

Results: HFSD-induced insulin resistance in WT mice was alleviated by Nod1 deficiency in both non-GF and GF KO groups, as demonstrated by IPITT. In IPGTT, calculated insulin sensitivity and disposition index revealed HFSD-induced insulin resistance and attenuated β-cell function in WT mice, which was improved in Nod1KO mice, regardless of GF conditions.

Conclusion: Our data suggest DAMP mediated Nod1 activation as displayed by protection from HFSD induced insulin resistance and glucose intolerance in the absence of microbial PAMPs. These findings indicate that Western diet exerts its diabetogenic effects via Nod1 independent of gut microbiota.

Disclosure

S. Rahman: None. N. Tsakiridis: None. M.A. Garcia: None. J. Park: None. Y. Tan: None. A. Giacca: None.

Funding

Canadian Institutes of Health Research (CIHR 507485)
284-OR: Androgen-Dependent Tissue Factor Pathway Inhibitor-Regulating Protein (ADTRP) Regulates Macrophage Polarization and Migration to Adipocytes
Authors: MIN ONG SZE , HENG CHEW-KIAT , SENG LEE YUNG , SHU QIN OOI DELICIA
Published: June 2024

Introduction: Macrophage infiltration into adipose tissue and their polarization from an anti-inflammatory M2 to pro-inflammatory M1 phenotype contributes to adipose tissue inflammation and the development of insulin resistance. Androgen-dependent tissue factor pathway inhibitor-regulating protein (ADTRP) is a recently discovered enzyme that breaks down a class of anti-inflammatory and anti-diabetic lipids in adipose tissues. Our study aims to investigate the effect of ADTRP on macrophage polarization and migration to adipocytes.

Methods: Mouse 3T3-L1 mature adipocytes were either transduced with AAV-ADTRP viral vectors or transfected with ADTRP siRNA to overexpress or knockdown ADTRP respectively. Conditioned media from the ADTRP-overexpressed and ADTRP-knockdown adipocytes were collected and treated to mouse RAW 264.7 macrophages. Lipopolysaccharide (LPS) was used to induce a pro-inflammatory state in the macrophages. Gene expression of macrophage M1 and M2 markers, including IL-1β, IL-6, TNF-α, iNOS, CD206 and IL-10 were measured using RT-qPCR. Macrophage migration assay was performed by co-culturing RAW 264.7 macrophages and 3T3-L1 adipocytes in a transwell system.

Results: Conditioned media from ADTRP-overexpressed adipocytes reduced the expression of anti-inflammatory M2 macrophage markers, CD206 and IL-10. On the contrary, conditioned media from ADTRP-knockdown adipocytes increased M2 markers in basal-state macrophages and decreased pro-inflammatory M1 markers, including IL-1β, TNF-α and iNOS, in LPS-stimulated macrophages. We also observed reduced macrophage migration towards ADTRP-knockdown adipocytes.

Conclusion: ADTRP regulates macrophage polarization and migration to adipocytes. Inhibition of ADTRP can be further studied as a possible strategy to reduce adipose tissue inflammation.

Disclosure

S. Ong: None. C. Heng: None. Y. Lee: None. D. Ooi: None.

Funding

Khoo Teck Puat - National University Children's Medical Institute research grant
288-OR: Inflammation-Induced Repression of Insulin Production by Targeting Its mRNA to Stress Granules via ADP-Ribosylation Machinery
Authors: SARKAR SOUMYADEEP , LI FANGJIA , ELLIOTT EMILY , RAMOS-RODRÍGUEZ MIREIA , YOU YOUNGKI , PASQUALI LORENZO , SUSSEL LORI , METZ THOMAS , MIRMIRA RAGHAVENDRA G. , NAKAYASU ERNESTO
Published: June 2024

ADP-ribosylation has been shown to contribute to the development of Type 1 diabetes (T1D); however, the mechanism through which each component of the ADP ribosylation machinery contributes to the disease is poorly understood. Here, we aimed to investigate the contribution of specific ADP-ribosyltransferases in the development of T1D. We conducted comprehensive bioinformatics analyses on our previously published RNA-Seq, ATAC-Seq, H3K27ac-Seq, and proteomic data, followed by qPCR to investigate the regulation of ADP-ribosyltransferases in islets and β cells. We found that PARP12 expression was induced by both cytokines and omega-3 fatty acids, which are inducers and reducers of insulitis, respectively. RNAi depletion of PARP12, followed by proteomics analysis, revealed that a variety of stress granule proteins are regulated by PARP12. We performed fluorescence in situ hybridization, ADP-targeted RNA pulldown and pulse-chase proteomics to demonstrate that PARP12 ADP-ribosylates Insulin2 mRNA, targeting it to stress granules and blocking its translation. Stress granules are a characteristic feature of the integrative stress response and unfolded protein response in T1D. Here, we showed that PARP12 directs insulin mRNA to stress granules, impeding translation in response to cytokines. This may have implications for insulitis and T1D, such that an abrupt inhibition of insulin translation may amplify the stress and immune responses. These insights also provide avenues for therapeutic strategies aiming to improve insulin production.

Disclosure

S. Sarkar: None. F. Li: None. E. Elliott: None. M. Ramos-Rodríguez: None. Y. You: None. L. Pasquali: None. L. Sussel: None. T. Metz: None. R.G. Mirmira: None. E. Nakayasu: None.

Funding

National Institutes of Diabetes and Digestion and Kidney Disease (U01 DK127505, U01 DK127786 and R01 DK105588); HIRN Catalyst Award.
303-OR: Notch Signaling Inhibitor ADPO-002 Promotes Browning in Human Adipose Tissue Explants
Authors: RAISUL ABEDIN MUHAMMAD , FREIJE WILSON , OSWALT MALLORY A. , ACTON ANTHONY J. , CRAWFORD CHRISTOPHER B. , INMAN MARGARET M. , CONSIDINE ROBERT V. , DENG MENG
Published: June 2024

Introduction: Transformation of white adipocytes into beige adipocytes, known as adipocyte browning, holds great promise for development of new therapeutics. Our previous studies have demonstrated nanoparticle-based delivery of dibenzazepine (ADPO-002), a γ-secretase inhibitor, induces browning of white adipose tissue in obese mice and in pigs. The current study aims to investigate the browning efficacy of ADPO-002 in human adipose tissue organ culture.

Methods: Abdominal subcutaneous and omental adipose tissue samples were collected from 24 subjects undergoing bariatric surgery (BMI 47.5±3.2 kg/m2, age 44.8±3.0 yr). The study was approved by the Ascension St. Vincent hospital IRB and all subjects provided informed consent. Tissues were cut into small pieces (~5-10 mg) using surgical scissors and cultured in medium M199 supplemented with 0.7 nM insulin and 10 nM dexamethasone. The treatment groups were DMSO (negative control), 50 µM forskolin (positive control), and 3, 10 and 30 µM ADPO-002. After 7-days treatment, total RNA was isolated, and RT-qPCR performed for the browning marker genes PRDM16 and PGC1A. Statistical significance was determined using Wilcoxon non-parametric paired t-test.

Results: In omental adipose tissue, 30 µM ADPO-002 significantly increased PRDM16 (429.1±149.3 vs 10.6±4.9 relative units, p=0.0020) and PGC1A (117.4±58.7 vs 58.5±30.2 relative units, p=0.0273) expression compared to the control group. In subcutaneous adipose tissue, 30 µM ADPO-002 significantly upregulated PRDM16 expression compared to control group (398.9±198.6 vs 22.06±6.28 relative units, p=0.0039).

Conclusion: These findings suggest that ADPO-002 treatment increases the expression of genes associated with increased mitochondrial expression. This finding supports the hypothesis that inhibition of γ-secretase can increase browning in human adipose tissue.

Disclosure

M. Abedin: Employee; Adipo Therapeutics LLC. W. Freije: None. M.A. Oswalt: None. A.J. Acton: None. C.B. Crawford: None. M.M. Inman: None. R.V. Considine: Research Support; Eli Lilly and Company, Adipo Therapeutics. M. Deng: Other Relationship; Adipo Therapeutics.

Funding

Indiana Innovation Voucher
315-OR: Task-Induced Alterations in the Salience Network amongst Patients with Type 1 Diabetes
Authors: SANCHEZ RANGEL ELIZABETH , BELFORT-DEAGUIAR RENATA , LACADIE CHERYL , CHUNG TAMMY J. , SCHEINOST DUSTIN , MASON GRAEME F. , HWANG JANICE J.
Published: June 2024

Introduction & Objective: Patients with Type 1 Diabetes (T1D) have altered brain functional connectivity (FC) at resting state, particularly in attention and decision-making brain regions. Recent studies have shown that assessing FC during a cognitive task may be more predictive of individual traits and function. In this study, we investigate how FC within the salience network (SAL), which integrates brain responses to external stimuli, is altered when patients with T1D perform cognitive tasks during euglycemia and mild hypoglycemia.

Method: Thirty-one subjects (20 T1D, 11M/9F, age 37 ± 13 yrs; BMI 27.4 ± 5.4 HbA1c 7.6 ± 0.9 %) and (11 HC, 4M/7F, age 30 ± 8 yrs; BMI 24.9 ± 2.9, HbA1c ± 5.3 ± 0.3%) completed a 2-step hyperinsulinemic-euglycemic (90 mg/dl)-hypoglycemic (60 mg/dl) clamp both at rest and during three tasks: 2-back  (working memory), card guess (reward), and gradual-onset continuous performance (gradCPT; sustained attention). After standard preprocessing, pairwise FC between the nodes of the Salience (SAL) network (Left and Right anterior insula, dorsal anterior cingulate cortex) was calculated. FC in the SAL network was defined as the average of these pairwise values.

Results: Patients with T1D had lower FC during hypoglycemia in the SAL network compared to HC during resting state (P<0.009) as well as 2-back (P<0.024), Card Guess (P<0.036), and gradCPT (P<0.036) tasks. There were no significant relationships between FC and counterregulatory hormones.

Conclusion: Compared to HC, patients with T1D have lower FC in the SAL network during mild hypoglycemia while performing memory, attention and reward stimulating cognitive tasks. These findings suggest an important role for the SAL network in integrating brain responses during hypoglycemia.

Disclosure

E. Sanchez Rangel: None. R. Belfort-DeAguiar: Research Support; Fractyl Health, Inc. C. Lacadie: None. T.J. Chung: None. D. Scheinost: None. G.F. Mason: Consultant; Merck & Co., Inc. J.J. Hwang: None.

Funding

National Institutes of Health (R01DK123227)
32-PUB: Glycemic Variability after Initiation of SGLT2 Inhibitors in CKD
Authors: TANG MENGYAO , DE BOER IAN , KALIM SAHIR
Published: June 2024

Background: SGLT2 inhibitors (SGLT2i) are widely used for cardiorenal protection in CKD patients, irrespective of diabetes. While their effect on A1C is smaller with lower eGFR, the impact of SGLT2i initiation on short-term glycemic variability is unclear.

Methods: In a pilot study, we enrolled 11 CKD patients with clinical indications for SGLT2i -7 with type 2 diabetes not on insulin, and 4 without diabetes. Participants wore DexCom G6 CGM for 10 days pre-SGLT2i and another 10 days post-SGLT2i initiation. Linear mixed-effects models with random intercepts were used to analyze glycemic variability, assessed by the hourly coefficient of variation (CV).

Results: The mean age of participants was 68 years, with 82% male, mean eGFR of 38 mL/min/1.73m², and median albuminuria of 347 mg/g. Mean A1C levels were 6.6% in participants with diabetes and 5.5% in those without. Nine participants received empagliflozin 10mg, two dapagliflozin 10mg. Following SGLT2i initiation, participants with diabetes showed no significant change in mean glucose (160±54 vs 155±50 mg/dL, p=0.52), GMI (7.1±1.3 vs 7.0±1.2, p=0.52), or TIR (67±37 vs 69±39%, p=0.66). There was no change in time above range or time below range. Only 1 participant on GLP-1 receptor agonist developed asymptomatic level 1 hypoglycemia. Similarly, patients without diabetes had no change in any of the previously mentioned CGM metrics. However, glycemic variability decreased post-SGLT2i initiation, as shown by hourly CV reductions (-0.40±0.13, p=0.002). The magnitude of hourly CV reduction was more pronounced in participants without diabetes compared to those with diabetes (p-interaction=0.002). Despite higher hourly CV during daytime than nighttime, the impact of SGLT2i initiation on CV was similar across time periods without significant interaction by time of day.

Conclusion: After SGLT2i initiation in CKD, while mean glycemia and TIR remained unchanged, glycemic variability diminished. This finding warrants further investigation in a larger study.

Disclosure

M. Tang: Research Support; Dexcom, Inc. I. de Boer: Consultant; Boehringer-Ingelheim, Lilly Diabetes, AstraZeneca, Novo Nordisk, Alnylam Pharmaceuticals, Inc., George Clinical. Research Support; Dexcom, Inc., Novo Nordisk. S. Kalim: Advisory Panel; Alnylam. Speaker's Bureau; Fresenius Kabi.

Funding

American Heart Association (23POST1010825); DexCom (IIS-2023-007)
323-OR: Genetic Basis of Diabetic Macular Edema and Proliferative Diabetic Retinopathy—Insights from Next Generation Sequencing in the DRGen Study
Authors: RANGASAMY SAMPATH , GENOMICS GROUP TGEN , MONICKARAJ FINNY , SUN JENNIFER K. , AIELLO LLOYD P. , DAS ARUP
Published: June 2024

Introduction & Objective: Our prior research has shown a clear distinction between two types of diabetic retinopathy (DR): predominantly exudative diabetic macular edema (DME) and predominantly proliferative diabetic retinopathy (PDR). These clinical presentations often occur separately, with a large percentage of patients (85% for PDR, 80% for DME) not showing signs of the other type. This suggests that DME and PDR may not be a single disease entity that progresses linearly but rather distinct diseases driven by different molecular mechanisms and genetic factors.

Methods: We analyzed two distinct patient groups: i) only PDR and no signs of DME (n=182), and the other with only center-involving DME and no PDR (n =77). The severity of PDR was graded using the ETDRS standard protocol on ultrawide field retinal images. Whole-exome and whole-genome sequencing were performed to identify genetic factors, and a novel algorithm was used to evaluate the impact of coding variants in the cohort.

Results: Comparative analysis of patients with exclusive manifestations of PDR compared to DME revealed a unique genetic framework differentiating the two cohorts. Notably, the prevalence of rare functional variants was significantly elevated in the PDR group (p<0.05). We discovered functional variants in genes, including CD36, MMRN2, EPHB2, PLAUR, and RAPGEF3, which are enriched in the angiogenesis pathway. Phenotype-centric gene variant analysis underscored the role of MMRN2, a key player in angiogenesis (p<0.001). MMRN2 (Multimerin-2) is a crucial regulator of endothelial cell movement, functioning as a negative modulator of angiogenesis by inhibiting KDR activation through its interaction with VEGFA.

Conclusions: Rare functional variants may act as phenotype modifiers, potentially modulating the trajectory of DR into DME or PDR. Functional validation of these factors could represent new biomarkers and therapeutic targets for DR.

Disclosure

S. Rangasamy: None. F. Monickaraj: None. J.K. Sun: Research Support; Optovue, Boehringer-Ingelheim, Novo Nordisk, Roche Pharmaceuticals. Other Relationship; Roche Pharmaceuticals. Research Support; Physical Sciences, Inc, Boston Micromachines. L.P. Aiello: Advisory Panel; Novo Nordisk. Stock/Shareholder; Kalvista. Other Relationship; Optos. Consultant; Ceramedix. A. Das: None.

Funding

5R01EY028606
367-P: Clinical Characteristics of Type 1 Diabetes and Severe Hypoglycemia in Adult Continuous Glucose Monitor Users
Authors: CALLAHAN PATRICK , BOATENG-KUFFOUR ADRIANA , CHANDARANA KEVAL , GUPTA TINA , CHEN LIANG , KELLY CAITLIN S. , NGUYEN HUYEN , CHAPMAN KATHERINE S.M. , CORNELIUS EMILEE M. , WOLF WENDY , POLONSKY WILLIAM H.
Published: June 2024

Introduction & Objective: Recurrent severe hypoglycemic events (SHE) are associated with impaired awareness of hypoglycemia (IAH). This study describes the demographic and clinical characteristics of adults with type 1 diabetes (T1D) and SHE/IAH.

Methods: Adult (≥18 years) continuous glucose monitor (CGM) users from the T1D Exchange Registry with self-reported T1D diagnosis ≥5 years completed an online survey with clinical and demographic characteristics. SHE cohorts were created based on SHE frequency in the past 12 months and the presence/absence of IAH (Modified Gold Score): problematic SHE (2+ SHE/IAH-; 1+ SHE/IAH+) and no SHE (0 SHE/IAH+; 0 SHE/IAH-). Participant characteristics were descriptively summarized (mean, standard deviation [SD]).

Results: A total of 1,847 T1D CGM users responded. The problematic SHE cohort (n=375) compared with the no SHE cohort (n=1,033) were older (age 49.0 vs. 45.6 years), more racially diverse (86.4% vs. 92.7% Caucasian), had lower levels of employment (58.4% vs. 71.2%), increased report of lower income <$50,000 (25.1% vs. 16.9%), and more often reported Medicaid as their primary health insurance (10.4% vs. 3.1%). The problematic SHE cohort reported longer duration of T1D (31.9 [SD 16.0] vs. no SHE 28.6 [SD 14.8]), lower insulin pump use (78.4% vs. 85.9%), slightly higher recent HbA1c (6.9 [SD 1.1] vs. 6.6 [SD 0.9]), with more participants with HbA1c ≥7% (42.4% vs. 31.3%). More T1D-related complications were reported in the problematic SHE vs. no SHE cohort (retinopathy 28.3% vs. 21.5%; neuropathy 24.5% vs. 10.5%; nephropathy 8.3% vs. 4.5%; gastroparesis 19.5% vs. 6.5%; and cardiovascular disease 12.5% vs. 5.5%). Based on BMI calculated from reported height and weight, >60% of participants were overweight or obese across all cohorts.

Conclusion: Findings suggest those who experience SHE have higher clinical burden and lower socioeconomic status, highlighting the need for innovative approaches to management for these individuals.

Disclosure

P. Callahan: Employee; Vertex Pharmaceuticals Incorporated. A. Boateng-Kuffour: Employee; Vertex Pharmaceuticals Incorporated. K. Chandarana: Employee; Vertex Pharmaceuticals Incorporated. Stock/Shareholder; Vertex Pharmaceuticals Incorporated, Novo Nordisk, Eli Lilly and Company. T. Gupta: Employee; Vertex Pharmaceuticals Incorporated. L. Chen: None. C.S. Kelly: None. H. Nguyen: None. K.S.M. Chapman: None. E.M. Cornelius: None. W. Wolf: None. W.H. Polonsky: Research Support; Abbott Diagnostics, Dexcom, Inc. Consultant; Eli Lilly and Company, Sanofi. Advisory Panel; embecta. Consultant; Vertex Pharmaceuticals Incorporated. Advisory Panel; 9am Health.

Funding

Vertex Pharmaceuticals Incorporated