bluuebunny/crossref_metadata_2025_split huggingface dataset:
329-OR: REDD1 Suppresses the Retinal Antioxidant Response to Diabetes by Destabilizing Nrf2
Authors: MILLER WILLIAM P. , TORO ALLYSON , GIORDANO JOSEPH , DENNIS MICHAEL D. 
Published: June 2020

Oxidative stress is a major contributor to the pathophysiology of diabetes. To combat oxidative stress, the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2) promotes the expression of an array of antioxidant gene products. However, in both the retina of diabetic patients and in preclinical diabetes models, there is a failure to properly upregulate Nrf2 activity. We previously demonstrated that retinal REDD1 protein expression is enhanced by diabetes-induced hyperglycemia and necessary for both the rise in retinal reactive oxygen species and the development of visual dysfunction in diabetic mice. In the present study, we investigated the hypothesis that signaling events downstream of REDD1 act to limit the retinal Nrf2 antioxidant response to the diabetic metabolic environment. We found that REDD1 ablation not only enhanced retinal Nrf2 activity, but also prevented the suppressive effect of streptozotocin-induced diabetes as compared to wild type mice. Nuclear Nrf2 protein expression and activity were enhanced in REDD1 knockout human MIO-M1 retinal Müller cells in culture, independent of a change in Nrf2 mRNA abundance. REDD1 deletion prevented oxidative stress in response to hyperglycemic conditions, and this protective effect was absent upon Nrf2 knockdown. REDD1 suppressed Nrf2 stability independent of Keap1 by promoting GSK3-mediated nuclear exclusion and proteasomal degradation via the ubiquitin ligase adapter β transducin repeat containing protein (β-TrCP). In the retina of diabetic REDD1-deficient mice, enhanced GSK3 phosphorylation was associated with a decrease in oxidative stress as compared to diabetic wild type mice. Pharmacological inhibition was used to suppress GSK3 activity in both cells in culture and in the retina of diabetic mice. Remarkably, GSK3 inhibition prevented the suppressive effect on Nrf2. Overall these findings support therapeutic approaches targeting REDD1 to prevent diabetes-induced visual dysfunction.

Disclosure
W.P. Miller: None. A. Toro: None. J. Giordano: None. M.D. Dennis: None.

Funding
American Diabetes Association/Pathway to Stop Diabetes (1-14-INI-04 to M.D.D.); National Eye Institute (1F31EY031199-01)
33-OR: A Novel Data Mining Approach to Detect Adverse Events of New Diabetes Drugs in Routine Care
Authors: FRALICK MIKE , KULLDORFF MARTIN , WANG SHIRLEY , SCHNEEWEISS SEBASTIAN , REDELMEIER DONALD , PATORNO ELISABETTA 
Published: June 2020

Clinical trials are underpowered to detect serious but rare adverse events (AEs). We applied a novel data mining approach to detect potential AEs for canagliflozin (CANA), the first marketed SGLT2 inhibitor, prior to public awareness of its potential safety concerns. In a U.S. commercial claims dataset (3/2013-9/2015), two pair-wise cohorts of patients with T2DM initiating CANA or a comparator, i.e., a DPP-4i or a GLP-1RA, were identified and propensity score matched. We used variable ratio matching with up to 4 comparators for each CANA initiator (44,733 CANA vs. 99,458 DPP-4i; and 55,974 CANA vs. 74,727 GLP-1RA). Using a tree-based scan statistic data mining method, we assessed thousands of incident outcomes in CANA vs. comparator initiators, scanning for statistical AE alerts after adjusting for multiple testing. Incident outcomes were defined by hierarchical groupings of clinically related ICD-9 codes. For inpatient and emergency room diagnoses, diabetic ketoacidosis was the only severe AE associated with CANA (p&lt;0.05 in both cohorts) (Table). When outpatient diagnoses were also considered, alerts for female and male genital infections emerged in both cohorts (p&lt;0.05). The identification of known but no other AEs provides reassurance for the safety of CANA in adults and suggests that the tree-based scan statistic is a useful post-market safety monitoring tool for new diabetes drugs.

Disclosure
M. Fralick: None. M. Kulldorff: None. S. Wang: Research Support; Self; Boehringer Ingelheim International GmbH, Johnson & Johnson, Novartis Pharmaceuticals Corporation. S. Schneeweiss: None. D. Redelmeier: None. E. Patorno: Other Relationship; Self; Boehringer Ingelheim International GmbH.

Funding
National Institute on Aging (K08AG055670)
34-LB: Reliability of the UENS for Primary Care Neuropathy Screening
Authors: FOSTER-PALMER STORMY C. , SINGLETON J. ROBINSON , REVERE CATHY , MARCUS ROBIN L. , SHAKERI MEHRNOOSH , CASTILLO ALMA , SHAFI SONIA 
Published: June 2020

Background: Metabolic syndrome polyneuropathy (MSP), sensory peripheral neuropathy associated with diabetes or prediabetic metabolic syndrome affects more than 10% of Americans over 40 years old. Screening exam measures commonly used in primary care (PC), such as 10 gram monofilament testing measure loss of protective sensation and predict development of foot ulcers and infection, but are not sensitive enough to detect early sensory loss. The Utah Early Neuropathy Scale (UENS) is a 2-minute exam scale focused on sensory loss to pin sensation in the foot that has been validated for early neuropathy screening.
Objectives: To examine reliability of the UENS when performed by medical assistants in a PC setting.
Methods: PC medical assistants were trained to perform the UENS, then screened consenting primary care patients selected by best practice alert (BPA) for age &gt;40 and BMI &gt; 30 with 3 neuropathy-focused questions and the UENS. A blinded neurologist (JRS), performed UENS and a brief exam at the same visit to examine reliability.
Results: 135 patients meeting BPA criteria were screened with UENS. Of these, 18% had a UENS score &gt;4, suggesting neuropathy. Intraclass correlation coefficient for 20 comparison UENS exams was 86%. Sub-scores for pin sensation, strength and joint position sense were highly coherent, while vibration sense proved less reliable. Pin (37.9%), vibration (34.8%) and deep tendon reflex (23.4%) sub scores contributed the most to total UENS score overall, with pin sub score most likely to contribute to UENS scores 4-8 (44%).
Discussion: UENS can be performed reliably by medical assistants in a primary care setting, and is a sensitive screening modality for MSP. Pin and vibration contribute the bulk of UENS score points in patients with mild neuropathy, suggesting that a simplified UENS could be used in PC screening.

Disclosure
S.C. Foster-Palmer: None. J. Singleton: None. C. Revere: None. R.L. Marcus: None. M. Shakeri: None. A. Castillo: None. S. Shafi: None.

Funding
University of Utah Health
340-OR: Outcomes of a Digital Diabetes Self-Management Support Program Stratified by A1C
Authors: PATTERSON JONATHAN , ALLISON MATT , BRASSIL KELLY J. , BURTON STEPHEN B. , NORBU THUPTEN T. , RASULNIA MAZI , PATEL DHIREN 
Published: June 2020

Background: Diabetes Self-Management Support (DSMS) programs are designed to assist people with diabetes as they implement and sustain the behaviors needed to manage their disease. In-person DSMS programs have many attendance barriers that can be mitigated through digital delivery. This study looks at results from the only ADA recognized online digital DSMS program (as of Jan 2020). The program collects diverse Patient Reported Outcomes (PROs) to track patient progress and program impact. This analysis presents digital DSMS program outcomes, focusing on individuals with an A1c &gt;9%, for whom health risk is markedly increased.
Methods: A retrospective analysis of individuals enrolled in a 12-week digital DSMS program evaluated changes from baseline to program completion. Changes in anxiety, depression, financial toxicity, overall physical and mental health, medication adherence, stress, diabetes distress, body mass index, and A1c were evaluated for cohorts delineated by baseline A1c values. Descriptive statistics define frequency and data collected from validated PROs were analyzed to evaluate the outcomes of the digital DSMS program.
Results: To date, 1,349 people with diabetes have participated in the digital DSMS program. Of these, 843 completed and provided both baseline and 3-month outcome measures. Across all A1c categories, there were significant improvements in physical health, medication adherence, stress, and BMI (p &lt; 0.05). Elevated A1c categories (A1c ≥ 7%) all showed decreased A1c values at month 3 compared to enrollment (p &lt; 0.01), people with higher baseline A1c values saw the greatest decrease, A1c ≥ 10% decreased 4.17% (pre:11.32 - post: 7.15%), A1c 9-9.9% decreased 1.34% (pre: 9.29 - post: 7.95%). Conclusions: Outcomes suggest that a digital DSMS program can improve glycemic control, as previously reported, but also PROs, and that a digital delivery of a DSMS program is an effective intervention, particularly for individuals with elevated A1c for whom health risks are elevated.

Disclosure
J. Patterson: None. M. Allison: Employee; Self; Pack Health. K.J. Brassil: None. S.B. Burton: None. T.T. Norbu: None. M. Rasulnia: None. D. Patel: None.
349-OR: Pancreas Volume Is Smaller in Individuals with Stage 1 Type 1 Diabetes (T1D) and Correlates with Disease Progression
Authors: VIROSTKO JOHN , WILLIAMS JONATHAN M. , HILMES MELISSA A. , WRIGHT JORDAN J. , HAMMEL BRENNA D. , DU LIPING , KANG HAKMOOK , RUSSELL WILLIAM E. , POWERS ALVIN C. , MOORE DANIEL J. 
Published: June 2020

Pancreas size is smaller at the onset of T1D and in individuals at risk for T1D, as measured by MRI. To determine whether pancreas volume predicts T1D progression, we measured pancreas size and dynamics in Type 1 Diabetes TrialNet Pathway to Prevention study participants with Stage 1 T1D, as defined by the presence of two or more autoantibodies and normal glucose tolerance. Individuals with Stage 1 T1D (n = 25, median age = 13.9 y.o.) exhibited a smaller pancreas volume than controls without T1D (n = 34, median age = 15.2 y.o, p &lt; 0.001), but larger than individuals with Stage 3 T1D (n = 67, median age = 13.4 y.o, p &lt; 0.05). This intermediate pancreas size in individuals with Stage 1 T1D persisted when pancreas volume was normalized by either body weight (pancreas volume index) or BMI. There was no correlation between the number or specificity of autoantibodies expressed and the pancreas volume index. Using longitudinal pancreas MRI in 25 autoantibody-positive individuals (total of 80 MRIs), we found that pancreas volume was stable over time, with no increase or decrease up to three years after the initial MRI (95% CI of slope: -0.094 to 0.5788 ml/month). Two of the 25 autoantibody-positive participants who developed Stage 3 T1D during follow up had the smallest pancreas volume index at study entry (0.43 +/- 0.04 ml/kg, p &lt; 0.005 compared with those who did not progress to Stage 3). An additional 11 of the 25 participants developed impaired glucose tolerance during follow up. Initial pancreas volume index in the 13 total participants who developed Stage 2 or Stage 3 T1D (0.75 +/- 0.06 ml/kg) was significantly smaller (p &lt; 0.05) than the 12 participants who retained normal glucose tolerance over the course of the study (0.95 +/- 0.05 ml/kg). These data suggest that small pancreas size may be predictive of progression of T1D.

Disclosure
J. Virostko: None. J.M. Williams: None. M.A. Hilmes: None. J.J. Wright: None. B.D. Hammel: None. L. Du: None. H. Kang: None. W.E. Russell: None. A.C. Powers: None. D.J. Moore: None.

Funding
JDRF (3-SRA-2019-759-M-B, 3-SRA-2015-102-M-B)
353-OR: Oral Small Molecule GLP-1R Agonist PF-06882961 Robustly Reduces Plasma Glucose and Body Weight after 28 Days in Adults with T2DM
Authors: SAXENA ADITI , GORMAN DONAL , CHIDSEY KRISTIN , BUCKERIDGE CLARE , KIM ALBERT M. , BERGMAN ARTHUR 
Published: June 2020

Background: PF-06882961 is an oral small molecule glucagon-like peptide-1 receptor (GLP-1R) agonist with efficacy in nonclinical models comparable to injectable peptidic GLP-1R agonists. This randomized, double-blind, placebo-controlled, multiple ascending dose, Phase 1 study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics (PD) of PF–06882961 administered for 28 days in patients with type 2 diabetes mellitus (T2DM).
Methods: A total of 98 patients with T2DM taking metformin were randomized, in 8 cohorts (5 planned, 3 optional), to PF–06882961 (up to 120 mg twice daily [BID]) or placebo in a 3:1 ratio for 28 days, and 92 completed the inpatient study. Fasting plasma glucose (FPG), 24-hour mean daily glucose (MDG) and body weight were assessed at baseline and at Day 28.
Results: Multiple, oral doses of PF-06882961 were safe and well tolerated in adult participants with T2DM, and resulted in robust reductions in FPG, MDG and body weight at Day 28. The majority of adverse events (AEs) were mild, with AEs of nausea, dyspepsia, diarrhea, headache, constipation, and vomiting most commonly reported. There were no deaths and no serious AEs related to dosing of PF–06882961. No clinically significant adverse trends in labs, electrocardiogram or vital sign abnormalities were apparent.

Disclosure
A. Saxena: Employee; Self; Pfizer Inc. Stock/Shareholder; Self; Pfizer Inc. D. Gorman: Employee; Self; Pfizer Inc. K. Chidsey: None. C. Buckeridge: Employee; Self; Pfizer Inc. A.M. Kim: Employee; Self; Pfizer Inc. A. Bergman: Employee; Self; Pfizer Inc.
356-OR: Effect of Dulaglutide on Kidney Function–Related Outcomes in Type 2 Diabetes: Post Hoc Analysis from the REWIND Trial
Authors: SHAW JONATHAN E. , BOTROS FADY T. , MALIK RALEIGH , ATISSO CHARLES , COLHOUN HELEN M. , GERSTEIN HERTZEL C. 
Published: June 2020

In participants with type 2 diabetes (T2D) in the REWIND trial, dulaglutide (DU) use for median follow-up of 5.4 years was associated with reduced composite renal outcomes, defined as the first occurrence of new macroalbuminuria, sustained decline in estimated glomerular filtration rate (eGFR) of ≥30%, or chronic renal replacement therapy. The objective of this post-hoc analysis was to evaluate the effect of dulaglutide on renal outcomes related to kidney function that are typically used in renal outcomes studies, defined as the composite endpoint of sustained eGFR decline ≥40%, end-stage renal disease (ESRD), or all-cause death. Participants with T2D at cardiovascular (CV) risk were randomized (1:1) to DU 1.5 mg once-weekly or placebo. This post-hoc analysis used Cox proportional hazards modeling for time to first event to determine the risk of renal outcomes. Sensitivity analyses were conducted by replacing the all-cause death component with CV or renal death, or renal death. At baseline, treatment groups had similar eGFR (mean±SD: DU=77.2±22.7; placebo=76.6±22.8). The incidence rate of the composite endpoint was significantly lower for the DU group compared with placebo (Table). Treatment with DU 1.5 mg was associated with a 17% risk reduction in kidney function-related outcomes, suggesting potential delay in progression of diabetic kidney disease in patients with T2D at CV risk.

Disclosure
J.E. Shaw: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mylan, Sanofi. Research Support; Self; AstraZeneca. Speaker’s Bureau; Self; Eli Lilly and Company, Mylan. F.T. Botros: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. R. Malik: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. C. Atisso: Employee; Self; Eli Lilly and Company. H.M. Colhoun: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Novo Nordisk Inc., Pfizer Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Speaker’s Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. Other Relationship; Self; Eli Lilly and Company, Sanofi. H.C. Gerstein: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Kowa Pharmaceuticals America, Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Sanofi.

Funding
Eli Lilly and Company
357-OR: Efficacy and Safety of Dulaglutide 3mg and 4.5mg vs. Dulaglutide 1.5mg: 52-Week Results from AWARD-11
Authors: FRIAS JUAN P. , BONORA ENZO , NEVAREZ RUIZ LUIS A. , LI GRACE , YU ZHUOXIN , MILICEVIC ZVONKO , MALIK RALEIGH , BETHEL ANGELYN , COX DAVID 
Published: June 2020

Dulaglutide (DU) is approved at 2 doses (0.75 and 1.5 mg) for treatment of T2D. In this phase 3 study, once weekly DU 3 mg and 4.5 mg were compared to DU 1.5 mg for efficacy and safety through 52 weeks (wks) (primary endpoint at 36 wks) in patients with inadequately controlled T2D on metformin therapy. Patients were randomized (1:1:1) to once weekly DU 1.5 mg (n=612), DU 3 mg (n=616), and DU 4.5 mg (n=614). All patients were initiated on once weekly DU 0.75 mg for 4 wks, followed by step-wise dose escalation every 4 wks to the randomized dose of 1.5 mg, 3 mg, or 4.5 mg. Efficacy measures were analyzed based on data on-treatment without initiation of rescue medication. Mean age was 57.1 yrs, mean baseline (BL) A1C was 8.6%, and mean BL body weight (BW) was 95.7 kg. DU 1.5 mg, 3 mg and 4.5 mg showed significance (p&lt;0.001) compared to BL for A1C, BW and fasting serum glucose (Table). DU 3 mg and 4.5 mg were both superior to DU 1.5 mg at the 36 wk primary endpoint, and remained significantly greater at 52 wks, for improvements in measures of glycemic control and body weight (Table). As expected for the GLP-1 receptor agonist class, commonly reported adverse events were nausea, diarrhea, and vomiting (Table). There were no new safety findings with the higher DU doses.
In conclusion, escalation from DU 1.5 mg to DU 3 mg or 4.5 mg provided clinically relevant, dose-related improvements in glycemic control and body weight with an acceptable safety profile.

Disclosure
J.P. Frias: Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., LifeScan, Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; Allergan plc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi. Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. E. Bonora: Advisory Panel; Self; Lilly Diabetes, Novartis AG, Sanofi. Speaker’s Bureau; Self; Abbott, Lilly Diabetes, Novo Nordisk A/S, Sanofi. L.A. Nevarez Ruiz: None. G. Li: Employee; Self; Eli Lilly and Company. Z. Yu: None. Z. Milicevic: Employee; Self; Eli Lilly and Company. R. Malik: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. A. Bethel: Employee; Self; Eli Lilly and Company. D. Cox: Employee; Self; Eli Lilly and Company.
366-OR: Characterization of Gene Expression Networks That Are Oppositely Regulated by Human and Mouse Metabolic Disease Using a Humanized Mouse Model
Authors: CAO HAIMING 
Published: June 2020

Mouse is the most widely used preclinical animal model yet the translational rate from mouse studies to therapies of human disease is dismal. To identify differentially expressed gene networks that underlie the distinct pathophysiological responses in human and mouse, we compared the patterns of gene regulation by nonalcoholic fatty liver disease (NAFLD) in human and mouse. As expected, we identified approximately 1,600 genes whose expressions are similarly regulated by NAFLD in human and mouse. Intriguingly, however, we also identified a similar number of genes that exhibit completely opposite regulation. Pathway analysis revealed that similarly regulated genes performed similar function in human and mouse whereas oppositely regulated genes perform very different function, despite the same set of genes were analyzed in either mouse or human. To determine if these oppositely regulated genes truly reflect differences in human and mouse liver biology, we analyzed gene expression in chimera mice in which human and mouse hepatocytes co-exist in the humanized liver and are exposed to identical in vivo metabolic milieu. Strikingly, we were able to recapitulate a sizable fraction of oppositely regulated genes in a fast/refeeding cycle. We further analyzed the promoter activities and RNA stability of regulated genes and found that promoter occupancy by RNA pol II and a HuR-dependent post-transcriptional mechanism both contribute to the divergent regulations. Our findings suggest that there are a core set of genes, despite their conserved molecular function, might be differentially regulated and contribute to distinct physiological outcomes in human and mouse. Thus our work provide a timely resource to understand the molecular basis for divergent metabolic responses in human and mouse liver and also highlight the areas of human liver biology where mouse is not a suitable model, and a human or humanized system is needed for translational studies.

Disclosure
H. Cao: None.

Funding
National Institutes of Health
367-OR: High-Fat and Fructose Feeding Severely Impairs Hepatic Glucose Effectiveness
Authors: EDGERTON DALE S. , KRAFT GUILLAUME , FARMER BEN , SCOTT MELANIE , SMITH MARTA S. , CHERRINGTON ALAN D. 
Published: June 2020

Diets high in fat and fructose (HFFD) disrupt glucose metabolism. The aim of this study was to determine if HFFD impairs hepatic glucose effectiveness (i.e., the ability of glucose per se to stimulate net hepatic glucose uptake [NHGU] and/or to suppress glucose production [Ra]). In overnight fasted dogs fed either a chow diet or HFFD for 1 month, somatostatin, 3-3H-glucose, and basal hepatic portal vein infusions of insulin and glucagon were given. After a basal sampling period, these infusions continued for 4h while glucose was infused to create a 3-fold rise in plasma glucose. Since hepatic glucose uptake is also stimulated by a negative arterial to portal vein glucose gradient, such as occurs with glucose ingestion, glucose was either all infused into a peripheral vein (Chow-PeG, n=6; HFFD-PeG, n=6), or a portion was also given into the portal vein (4 mg/kg/min; Chow-PoG, n=5; HFFD-PoG, n=5). There were no differences in plasma insulin, glucagon, arterial glucose, or hepatic glucose load between groups. In response to hyperglycemia, the liver switched from making (basal period) to storing (last h) glucose in the chow fed groups (1.1±0.1 to -2.0±0.5* mg/kg/min in Chow-PeG, and 1.3±0.1 to -3.0±0.9* in Chow-PoG; a negative rate indicates uptake). Conversely, HFFD markedly reduced liver glucose effectiveness. In fact, with HFFD the liver did not take up glucose in response to hyperglycemia whether the portal signal was absent (1.4±0.1 to 1.0±0.3 in HFFD-PeG) or present (1.6±0.3 to 0.0±0.3* in HFFD-PoG). Thus, in the Chow vs. HFFD groups, the impact of hyperglycemia on overall net hepatic glucose balance was 3.1±0.5 vs. 0.4±0.4* (13% of normal) in the absence of portal glucose delivery and 4.3±0.9 vs. 1.6±0.5* (37% of normal) in its presence. Hyperglycemia suppressed Ra by 75±12 vs. 22±6%* (last h) in Chow vs. HFFD-PeG, respectively, and by 81±14 vs. 34±7%* in Chow vs. HFFD-PoG.
In summary, HFFD induced a severe impairment in hepatic glucose effectiveness but did not affect the liver’s response to the portal glucose signal. (*P&lt;0.05).

Disclosure
D.S. Edgerton: None. G. Kraft: None. B. Farmer: None. M. Scott: None. M.S. Smith: None. A.D. Cherrington: Advisory Panel; Self; Biocon, Fractyl Laboratories, Inc., Metavention, Sekkei Bio, Sensulin, LLC., vTv Therapeutics, Zafgen, Inc. Consultant; Self; Thetis Pharmaceuticals LLC. Research Support; Self; Diasome Pharmaceuticals, Inc. Other Relationship; Self; Abvance Therapeutics, Novo Nordisk Inc.

Funding
National Institutes of Health (R01DK18243)