bluuebunny/crossref_metadata_2025 huggingface dataset:
328-OR: Effect of Unblinded vs. Blinded Dexcom G6 CGM Wear in Outpatients with Type 2 Diabetes—Real-World Data
Authors: HICKS CHRISTIAN , ZHOU TERESA , MENON SIDDHARTH , CRAWFORD MARGARET A. , CHERÑAVVSKY DANIEL R. , RATERMAN DANIEL , SMITH NICOLE , TRESSLER MICHELLE , WELSH JOHN , SINGH HARSIMRAN
Published: June 2023

Recent studies have demonstrated the value of CGM in optimizing Type 2 diabetes (T2D) management. There is an interesting debate in the literature examining the value of unblinded vs blinded wear of CGM, which is especially relevant in T2D management. We sought to understand the glycemic effects of transitioning from unblinded to blinded CGM wear in a small cohort of T2D outpatients from a community hospital. Participants (n=46) wore unblinded Dexcom G6 sensors for 90 days. After a 90-day washout period, they wore blinded G6 sensors for 10 days. They then completed surveys regarding device acceptability and behavioral changes attributable to CGM wear. Paired t-tests were used to compare unblinded vs. blinded intervals. Median (IQR) age was 59 (54-63) years and 72% were CGM naïve. Median (IQR) baseline A1C was 7.4% (6.7-8.5). Twenty-one participants completed the program in full. The post-washout mean TIR was 15 percentage points lower than during rt-CGM use (Table), attributable to more time in hyperglycemia. Most participants reported that CGM was helpful in making dietary decisions. In adults with T2D, discontinuation of CGM is associated with worsening of glycemic control. Ongoing access to CGM data is likely necessary to maintain good control in T2D. Further research with large and diverse T2D samples is needed to understand how CGM impacts patient behavior and how to sustain long-term improvements.

Disclosure

C.Hicks: Employee; Dexcom, Inc. H.Singh: Employee; Tandem Diabetes Care, Inc., Dexcom, Inc. T.Zhou: Employee; Pfizer Inc. S.Menon: Employee; Dexcom, Inc. M.A.Crawford: Employee; Dexcom, Inc. D.R.Cherñavvsky: None. D.Raterman: None. N.Smith: None. M.Tressler: Employee; Dexcom, Inc. J.Welsh: Employee; Dexcom, Inc.

Funding

Dexcom, Inc.
336-OR: Insulin Delivery Modality Does Not Impact Glycemic Change during Physical Activity in Youth with Type 1 Diabetes (T1D)—Results from the Real-World T1DEXI Pediatric Study
Authors: RIDDELL MICHAEL , BERGFORD SIMON , GAL ROBIN L. , PATTON SUSANA R. , CLEMENTS MARK A. , CALHOUN PETER , SHERR JENNIFER ,   T1DEXIP STUDY GROUP
Published: June 2023

Despite its well-established benefits, exercise can cause blood glucose levels to drop precipitously. Factors such as pre-exercise glucose, exercise type and insulin on board (IOB) all appear to influence the magnitude of drop in glucose during exercise, but it is currently unclear if insulin delivery modality (i.e., MDI vs. standard pump vs. closed loop pump) has a clinically significant effect. Data from the Type 1 Diabetes Exercise Initiative Pediatric (T1DEXIP) study allowed us to examine if insulin delivery modality influences the change in glucose during exercise in youth with T1D. Youth (N=248) with T1D ([mean ± SD] age= 14±2 years; T1D duration= 5.4±3.9 years; HbA1c= 7.1±1.3%; BMI percentile= 62±27%; 58% male) wore a continuous glucose monitor (Dexcom G6) and a Garmin, Vivosmart 4 activity monitor while logging meals and activity with the bant smartphone app over a 10-day period. Drop in glucose level during exercise was associated with pre-exercise glucose and IOB (mean change in glucose of 5.7 mg/dL, -15.7 mg/dL, and -26.5 mg/dL for IOB of 0 U/kg, >0 to <0.1 U/kg, and ≥0.1 U/kg, respectively; p<0.001), but did not differ significantly by insulin delivery modality (Figure). Pre-exercise glucose and IOB, but not insulin delivery method, are associated with changes in glucose during exercise in youth with T1D.

Disclosure

M.Riddell: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Indigo Diabetes, Consultant; Lilly Diabetes, Eli Lilly and Company, Jaeb Center for Health Research, Speaker's Bureau; Dexcom, Inc., Novo Nordisk, Sanofi, Stock/Shareholder; Supersapiens, Zucara Therapeutics. S.Bergford: None. R.L.Gal: None. S.R.Patton: None. M.A.Clements: Consultant; Glooko, Inc., Research Support; Dexcom, Inc., Abbott Diabetes. P.Calhoun: None. J.Sherr: Advisory Panel; Bigfoot Biomedical, Inc., Insulet Corporation, Medtronic, Vertex Pharmaceuticals Incorporated, Cecelia Health, StartUp Health T1D Moonshot, Consultant; Bigfoot Biomedical, Inc., Insulet Corporation, Medtronic, Lilly, Research Support; Insulet Corporation, Medtronic, NIH - National Institutes of Health, Juvenile Diabetes Research Foundation (JDRF), Speaker's Bureau; Insulet Corporation, Zealand Pharma A/S, Lilly, Medtronic. T1dexip study group: n/a.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust; Dexcom, Inc.
34-OR: Postprandial Glucagon Action in the Human Brain
Authors: WAGNER ROBERT , KULLMANN STEPHANIE , HUMMEL JULIA , VEIT RALF , PRYSTUPA KATSIARYNA , HOSENFELD ELENA , BIRKENFELD ANDREAS L. , HÄRING HANS-ULRICH , PREISSL HUBERT , FRITSCHE ANDREAS , PETER ANDREAS , HENI MARTIN
Published: June 2023

While elevated fasting glucagon is linked to hyperglycemia, the impact of postprandial changes in glucagon is less clear. Recent findings suggest potential metabolic benefits of rising glucagon after oral glucose intake. In addition to the prominent hepatic action of the hormone, animal data indicate that glucagon signaling in the brain contributes to its effects on whole-body metabolism. To elucidate the translational relevance of these findings, we studied postprandial effects of glucagon on the human brain. We performed oral glucose tolerance tests combined with fMRI to quantify brain activity and connectivity at fasting, 30- and 60-minutes post glucose load in 29 volunteers. In 14 out of 22 volunteers with physiologically suppressed glucagon during OGTT, a second OGTT with low-dose glucagon infusion was performed (0.5 pmol/kg/min). All participants had their first OGTT with intravenous saline infusion. This was compared to 7 participants with endogenous rising glucagon during OGTT. Low-dose glucagon infusion did not elevate plasma glucose levels during OGTT. Also, no changes in insulin sensitivity and insulin secretion were observed. However, experimentally elevating glucagon during the OGTT significantly increased postprandial brain responsivity in the hippocampal gyrus and in brain regions important for the regulation of food intake and systemic metabolism (i.e. hypothalamus, nucleus accumbens, midbrain). Postprandial brain responsivity during glucagon infusion was directionally consistent with the findings in persons with endogenously rising glucagon. Moreover, the postprandial brain response correlated with the rise in glucagon, regardless of exogenous or endogenous source of glucagon. Our findings demonstrate postprandial effects of glucagon in metabolically relevant human brain areas. This may underly the promising effects on body weight achieved with upcoming pharmacological multi-agonists that activate the glucagon receptor.

Disclosure

R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. A.Fritsche: Advisory Panel; Novo Nordisk, Lilly, Sanofi, Boehringer-Ingelheim, Speaker's Bureau; AstraZeneca, SYNLAB Holding Deutschland GmbH. A.Peter: None. M.Heni: Advisory Panel; Boehringer-Ingelheim, Sanofi, Research Support; Boehringer Ingelheim Inc., Speaker's Bureau; Lilly, Bayer Inc., Sanofi, Boehringer-Ingelheim, Novo Nordisk, Amryt Pharma Plc. S.Kullmann: None. J.Hummel: None. R.Veit: None. K.Prystupa: Other Relationship; Berlin-Chemie AG. E.Hosenfeld: None. A.L.Birkenfeld: None. H.Häring: None. H.Preissl: None.
350-OR: Transcriptomics Identification of a-Cell Subpopulations in Human Islets Using Integrated scRNA-seq and snRNA-seq
Authors: KANG RANDY , LEE JUNGEUN , GARCIA-OCANA ADOLFO , LU GEMING
Published: June 2023

Loss of β cells leads to diabetes. α cells are refractory to spontaneous conversion to β cells, but a small percentage are reprogrammed to β cells with acute β cell loss. β cell heterogeneity and identification of β cell subpopulations and their transcriptomic profiles have been reported. However, α cell subpopulations in the human islet have not been clearly defined yet. Moreover, whether specific human α cell subpopulations can potentially evolve into β cells is unknown. Here, we integrated scRNA- and snRNA-seq data of human islets from 3 adult healthy donors to determine α cell subpopulations and their transcriptomic profiles. We extracted the α cell cluster (7,535 cells) and using Louvain resolution 0.8, we identified 5 subclusters: 1) α cells (GCGhigh/TTRhigh/PTPRT high); 2) αβ-Transition-1 (αβ-Tr1) cells; 3) αβ-Tr2 cells; 4) αβ1 cells (GCGhigh/INSlow/IAPPlow); and 5) αβ2 cells (GCGlow/INShigh/IAPPhigh). To investigate the transcriptomics connectivity among clusters, we performed RNA velocity and Partition-based Graph Abstraction (PAGA) analyses. PAGA showed that αβ-Tr1 cells (15.3% of cells) are the root subcluster from where α cells and αβ-Tr2 cells are formed, suggesting a precursor nature. αβ-Tr2 cells are the origin of αβ1 and αβ2 cells. We next projected this finding into the pseudotime algorithm and analyzed gene expression gradients in the trajectories. Interestingly, the αβ-Tr1/αβ-Tr2/αβ2 cells trajectory showed a gradual increase in the expression of β cell genes (INS, ZNF385D, CASR, MAFA) while decreasing expression of ribosomal genes, GCG and MALAT1. Single cell pathway analysis with escape package showed that αβ-Tr1 cells are enriched in ribosome and translation gene pathways and that αβ-Tr2 cells are enriched in transdifferentiation genes INSM1, PDX1 and SMAD3. In summary, these studies identified 5 α cell subpopulations with different transcriptomic profiles and highlight the potential plasticity of αβ-Tr cells to generate αβ cells.

Disclosure

R.Kang: None. J.Lee: None. A.Garcia-ocana: Consultant; Sun Pharmaceutical Industries Ltd. G.Lu: None.
411-P: Extended Validation of KidneyIntelXTM in Diabetic Kidney Disease
Authors: NADKARNI GIRISH N. , FLEMING FERGUS , DONOVAN MICHAEL J. , COCA STEVEN
Published: June 2023

We have previously shown that plasma TNFR1, TNFR2, and KIM-1 combined with clinical variables provides effective risk stratification for kidney outcomes in individuals with diabetic kidney disease (DKD) stages 1-3. With the recommended use of a race-free eGFR and a refinement of our progression endpoint, we sought to develop and independently validate a version 2.0 of KidneyIntelX assay in a previously untested, independent, contemporary cohort of subjects from BioMe Biobank (Mount Sinai Health System, NYC, NY). The primary outcome was a composite of ≥40% sustained decline in eGFR or kidney failure (sustained eGFR<15 ml/min/1.73 m2) within 5 years from enrollment. In a training cohort of 573 patients with DKD from the Penn Medicine Biobank (PMBB), 15.4% experienced the progressive decline in kidney function over a median of 3.1 years. The following features were selected in a training model utilizing optimized random forests to predict the kidney outcome: TNFR1, TNFR2, KIM-1, baseline UACR, HbA1c, and blood urea nitrogen. The external validation cohort (BioMe, n=657) had an 11.7% event rate over a median of 3.8 years. Based on risk categorization cutoffs derived from training, 57%, 35% and 8.3% of participants were classified as low, intermediate and high-risk, respectively. The cumulative event incidence probability in the low, intermediate, and high-risk groups were 5.9% (95% CI: 3.6-9.4%), 21.2% (95% CI: 15.6-28.3%) and 66.9% (95% CI:, 49.3-83.5%). The unadjusted HRs for high vs. low and intermediate vs. low were 18.4 (95% CI: 9.4 -34.6) and 4.2 (95% CI: 2.4-7.4), respectively. After adjustment for age, sex, race, baseline eGFR, uACR, SBP, and HbA1c, the adjusted HRs were 7.7 (95% CI: 3.0-19.6) and 3.7 (95% CI: 2.0-6.8), respectively. In summary, we developed and independently validated a version 2.0 KidneyIntelX with previously established biomarkers combined with selected clinical variables and demonstrated robust prediction of progressive decline in kidney function, independent of common risk factors.

Disclosure

G.N.Nadkarni: Advisory Panel; Renalytix, Consultant; Renalytix, Other Relationship; Renalytix, Speaker's Bureau; Daiichi Sankyo, GlaxoSmithKline plc., Menarini Group, Stock/Shareholder; Renalytix. F.Fleming: Employee; Renalytix. M.J.Donovan: Employee; Renalytix. S.Coca: Advisory Panel; Renalytix, Bayer Inc., Boehringer Ingelheim International GmbH, Consultant; Renalytix, Nuwellis, 3ive Labs, Reprieve Cardiovascular, Vifor Pharma Management Ltd., Stock/Shareholder; Renalytix.

Funding

Renalytix
438-P: Very-Low-Dose Metformin Can Safely Improve Glycemic Control in Type 2 Diabetic Patients Receiving Maintenance Hemodialysis (HD)
Authors: FUNAKOSHI SATOSHI
Published: June 2023

Objective: Use of metformin in patients with impaired renal function is controversial as it may increase the risk of lactic acidosis. To evaluate metformin with appropriate dose reduction can safely improve glycemic control in patients with type 2 diabetes (T2D) on HD.

Methods: In six relatively poor-controlled HD patients with T2D (av. BMI=29.7±5.9, glycoalbumin: GA>27%) treated with insulin degludec (8-35 units/day) + dulaglutide (0.75mg/week), low-dose metformin (250-500mg/day) was added on. From starting of metformin administration serum lactate level and pH were monitored biweekly in all patients. Glycemic control was assessed by CGM and the mean amplitude of glycemic excursions (MAGE) was calculated before and 4 weeks after.

Results As shown in figure (each color represents the average glycemic profile of one patient), glycemic control was improved by low-dose metformin as average MAGE was significantly decreased from 128.4+69.1 mg/dL to 83.4+43.3 mg/dL (p<0.05) without episode of hypoglycemia. Average GA was significantly reduced from 32.0% to 22.62% (p<0.01), whereas serum pH and lactate stayed stable up to 3 months.

Conclusion More than 90% of metformin or lactate is cleared, and acid-base balance is adjusted by a single hemodialysis session. Unlike pre-HD patients with impaired renal function, in patients on maintenance HD metformin is potentially safe and useful in controlling plasma glucose level when the dose is appropriately reduced.

Disclosure

S.Funakoshi: None.
452-P: Risk of Cardiovascular Disease according to Baseline LDL Cholesterol Level in Different Age Groups among 2 Million Diabetes Patients
Authors: LEE WON-YOUNG , RHEE EUN-JUNG , HAN KYUNGDO
Published: June 2023

Background: In the population with diabetes mellitus (DM), the impact of age on the association between low density lipoprotein-cholesterol (LDL-C) level and cardiovascular disease (CVD) risk is unclear. Therefore, we conducted a cohort study to elucidate the relationship.

Methods: We assessed the 2009-2012 Korean National Health Screening and the National Health Insurance Service record, with follow up to primary outcome (myocardial infarction [MI] or stroke) or December 2018. Participants with a history of MI and stroke were excluded. Finally, 2,227,394 participants with DM were included. Participants were categorized based on baseline LDL-C level and age. Cox proportional hazard modeling was conducted with confounding factor adjustment. CVD risk of age <40, LDL-C <70mg/dL were set as a reference. In each age group, LDL-C <70mg/dL was set as a reference and subgroup analysis was done.

Results: The cut-off LDL-C value for increased MI risk were different in each age group (<40 year old, LDL-C ≥160mg/dL, HR 2.03, 95% CI 1.644-2.506; 40-49 year old, LDL-C <115 mg/dL, HR 1.245, 1.04-1.489; 50-59 year old, LDL-C <115 mg/dL, HR 1.21, 1.014-1.445; 60-69 year old, LDL-C <145mg/dL, HR 1.229, 1.022-1.479; ≥70year old group, LDL-C <100mg/dL, HR 1.238, 1.018-1.504). The cut-off LDL-C value for increased stroke risk were different in each age subgroup (<40 year old, LDL-C ≥160mg/dL, HR 1.395, 1.094-1.779; 40-49 year old, LDL-C <145 mg/dL, HR 1.13, 1.019-1.253; 50-59 year old, HR 1.079, 1.008-1.154, 60-69 year old, LDL-C <130mg/dL, HR 1.07, 1.022-1.119; ≥70year old; LDL-C <115mg/dL, HR 1.064, 1.019-1.112)

Conclusions: The impact of LDL-C on the risk of CVD varies according to the age of DM population.

Disclosure

W.Lee: None. E.Rhee: None. K.Han: None.
455-P: Waist–to–Body-Mass-Index Ratio Independently from Type 2 Diabetes Predicts MACE in Patients with Cardiovascular Disease
Authors: MADER ARTHUR , SPRENGER LUKAS , VONBANK ALEXANDER , LARCHER BARBARA , MAECHLER MAXIMILIAN , PLATTNER THOMAS , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: June 2023

Waist circumference reflect 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 not known and is addressed in the present study. We prospectively recorded cardiovascular events in 1833 patients with angiographically verified coronary artery disease or sonographically proven peripheral artery disease. The mean follow-up time was 9.4±5.1 years. At baseline, there was no significant difference in the W/BMI-Ratio between patients with and those without T2DM (3.6±0.3 vs. 3.6±0.3; p=0.465). Prospectively, the W/BMI-Ratio significantly predicted the incidence of MACE (n=716) both univariately (standardized HR 1.46 [1.18-1.80], p<0.001) and after adjustment for age, gender, smoking, LDL cholesterol, HDL cholesterol, hypertension and T2DM (standardized adjusted HR=1.29 [1.02±1.63], p=0.032); HRs were 1.29 [1.02±1.85], p=0.013 in patients without diabetes and 1.08 [0.98-1.21], p=0.138 in those with diabetes, with a non-significant p for interaction W/BMI-Ratio x diabetes status. We conclude that the W/BMI-Ratio independently from diabetes status is a predictor for MACE in patients with established cardiovascular disease.

Disclosure

A.Mader: None. C.H.Saely: None. L.Sprenger: None. A.Vonbank: None. B.Larcher: None. M.Maechler: None. T.Plattner: None. A.Leiherer: None. A.Muendlein: None. H.Drexel: None.
456-P: Ceramide- and Phosphatidylcholine-Based Coronary Event Risk Tests 1 and 2 (CERT1, CERT2) Predict Both Type 2 Diabetes and Chronic Kidney Disease
Authors: PLATTNER THOMAS , SAELY CHRISTOPH H. , MUENDLEIN AXEL , VONBANK ALEXANDER , MADER ARTHUR , SPRENGER LUKAS , MAECHLER MAXIMILIAN , LARCHER BARBARA , DREXEL HEINZ , LEIHERER ANDREAS
Published: June 2023

The ceramide- and phosphatidylcholine-based scores CERT1 and CERT2 are predictors for cardiovascular events. The presence of chronic kidney disease (CKD) indicates a high risk of cardiovascular events, particularly in patients who also have type 2 diabetes (T2DM). However, little is known about the associations between T2DM, CKD and CERT1 or CERT2. Therefore, we determined CKD status (eGFR <60 ml/min. 1,73 m2 or albuminuria with an albumin/creatinine ratio >30 mg/g) and analyzed CERT1/2 in 945 high-risk patients, of whom 259 had T2DM. T2DM was diagnosed using ADA criteria. Both CERT1 and CERT2 were significantly higher in patients with T2DM than in nondiabetic subjects (4.5±3.4 vs. 3.5±2.9;p<0.001 and 5.9±2.6 vs. 5.2±2.3; p<0.001, respectively). Further, CERT1 and CERT2 predicted T2DM after adjusting for age, sex, smoking, BMI, LDL-C, HDL-C, with ORs of 1.10 [1.05-1.15]; p<0.001 and 1.10 [1.03-1.17]; p=0.004, respectively. CKD was present in 52.5% of our patients with T2DM and in 30.3% of nondiabetic subjects (p<0.001). CERT1 predicted the risk of CKD in patients with T2DM as well as in patients who did not have T2DM (with ORs of 1.11 [1.03-1.20]; p=0.005 and 1.10 [1.04-1.17]; p=0.001; respectively), as did CERT2 (ORs 1.16 [1.05-1.29]; p=0.005 and 1.14 [1.06-1.24]; p<0.001; respectively). We conclude that CERT1 and CERT2 are strong and significant predictors of T2DM as well as of CKD.

Disclosure

T. Plattner: None. C.H. Saely: None. A. Muendlein: None. A. Vonbank: None. A. Mader: None. L. Sprenger: None. M. Maechler: None. B. Larcher: None. H. Drexel: None. A. Leiherer: None.
475-P: Intermittent Hypoxia Increased the Expression of Intercellular Adhesion Molecule-1 and Endothelial Cell–Specific Molecule-1 in Vascular Endothelial Cells via the Downregulation of MicroRNA-181a1
Authors: TAKASAWA SHIN , MAKINO MAI , YAMAUCHI AKIYO , SAKURAMOTO-TSUCHIDA SUMIYO , TAKEDA YOSHINORI , UCHIYAMA TOMOKO , SHOBATAKE RYOGO
Published: June 2023

Sleep apnea syndrome (SAS), which is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]), is a risk factor for vascular dysfunction, as well as hypertension, and insulin resistance/Type 2 diabetes. We have reported correlations between IH and insulin resistance/Type 2 diabetes, and hypertension. However, the question of why vascular dysfunction is induced by IH has remained unanswered. Here, we investigated the effects of IH on the expression of endothelial inflammatory transcripts such as intercellular adhesion molecule-1 (ICAM-1), interleukin (IL)-8, C-C motif chemokine ligand 5 (CCL5), endothelial nitric oxide synthase (NOS3), vascular cell adhesion molecule-1 (VCAM-1), endothelial cell specific molecule 1 (ESM1), and endothelin-1 (EDN-1) using an in vitro IH system. Human and mouse vascular endothelial cells (HUEhT-1 and UV2) were exposed to IH or normoxia for 24 hours. Real-time RT-PCR revealed that IH significantly increased the mRNA levels of ICAM-1 and ESM1 in both HUEhT-1 (P=0.0436 and P=0.0145, respectively) and UV2 cells (P<0.0001 and P=0.0422, respectively). ELISA showed that ICAM-1 and ESM1 were significantly increased (P=0.0105 and P<0.0001, respectively) in the UV2 cell medium by IH. Reporter assays revealed that the promoter activities of ICAM-1 and ESM1 were not increased by IH. The microRNA (miR)-181a1 level of IH-treated cells was significantly decreased relative to that of normoxia-treated cells (P=0.0374). The IH-induced upregulation of ICAM-1 and ESM1 was abolished by the introduction of miR-181a1 mimic, indicating that IH stress increased levels of ICAM-1 and ESM1 via the inhibition of miR-181a1-mediated mRNA degradation, leading SAS patients to develop atherosclerosis.

Disclosure

S.Takasawa: None. M.Makino: None. A.Yamauchi: None. S.Sakuramoto-tsuchida: None. Y.Takeda: None. T.Uchiyama: None. R.Shobatake: None.
485-P: Proteomic Analysis Reveals Different Therapeutic Mechanisms for Diabetic Neuropathy between DPP-4 Inhibitor and SGLT2 Inhibitor
Authors: TAKEUCHI YUKI , OSONOI SHO , SASAKI TAKANORI , MIZUKAMI HIROKI
Published: June 2023

Aim: Diabetic neuropathy (DN) is the most prevalent complication with microangiopathy in diabetes. Although, DN would decrease quality of life, currently there is no radical treatment for DN. DPP-4 inhibitor (DP4i) and SGLT-2 inhibitor (SG2i) have been experimentally shown to possibly ameliorate DN. However, the difference in the mechanism between two agents has not been clarified so far. In this study, we performed proteomic analysis of the sciatic nerve (SN) and dorsal root ganglion (DRG) of Goto-Kakizaki rats (GK), a model of lean type 2 diabetes, treated with DP4i and/or SG2i.

Methods: Male GK and control Wister rats (W) were used. Since 5 weeks of age, GK rats were treated with 10mg/day DP4i (Te), 10mg/ day SG2i (Ca), and DP4i + SG2i (CaTe) until 29 weeks of age. Thermal perception was evaluated by tail flick test. At the end of experiment, SN, DRG, and skin tissue were dissected. Proteomic analysis was performed with SN and DRG tissues by mass spectrometry. In the skin, fluorescent immunostaining with anti-PGP 9.5 antibody was performed for the assessment of intraepidermal nerve density (IENFD).

Results: Tail flick test and IENFD were significantly decreased in GK compared to W (p<0.05), and significantly improved in Te, Ca, and CaTe (p<0.05, p<0.05 and p<0.01 vs GK, respectively). Proteomic analysis for SN showed only two pathways changed in Te, whereas seven and six pathways changed in the Ca and CaTe, respectively. Conversely, in the DRG, only two pathways changed in Ca, whereas the five and seven pathways changed in Te and CaTe, respectively.

Conclusion: Our results suggest that the DP4i and SG2i act on the different sites of peripheral nervous system with different mechanism. Combining these two agents possibly have complementary effects on DPN treatment.

Disclosure

Y.Takeuchi: None. S.Osonoi: None. T.Sasaki: None. H.Mizukami: None.

Funding

Mitsubishi Tanabe Pharma Corporation
489-P: Abnormal Combined Point-of-Care-Device DPN-Check and SUDOSCAN Results Predict All-Cause Mortality in People with Diabetes
Authors: SHAAN GOONOO MOHUMMAD , SELVARAJAH DINESH , SLOAN GORDON P. , TESFAYE SOLOMON
Published: June 2023

Aims: Diabetic peripheral neuropathy (DPN) has been associated with increased mortality; however, data is not available for objectively diagnosed DPN using point-of-care-devices (POCDs). We therefore examined the predictive validity of POCD-diagnosed DPN for increased mortality in a prospective study.

Methods: A total of 245 consecutive people with diabetes (17 type 1 diabetes, age 62.3+14.3) attending retinal-screening had all annual review health checks in a One-stop Screening Service. DPN assessments included Toronto Clinical Neuropathy Score (TCNS) evaluation, 10g-monofilament test(10g-MFT) and two validated, objective POCDs, DPN-Check (handheld device measuring sural nerve conduction velocity/amplitude), and SUDOSCAN (measuring sudomotor function). Mortality data was collected at 7-year follow-up. Kaplan-Meier survival curves and Cox-proportional hazards models were generated to assess associations of DPN measures with all-cause mortality.

Results: At follow-up, 52 [21.2% (SE 6.8%)] had died. Those who died were older at screening [72.4 (10.9) vs 59.6 (13.9) years; (p<0.001)]. The prevalence of screen-detected DPN was 12.6% (SE 4.4%) for 10g-MFT, 27.7% (SE 8.2%) for TCNS and 33.4% (SE 9.1%) for combined POCDs. In crude Kaplan-Meier analyses all-cause mortality risk was greater in patients with abnormal TCNS (p<0.001) and POCDs (p<0.001) but was equivalent in patients with normal or abnormal 10g-MFT (p=0.21). After adjusting for age, HbA1c and Total Cholesterol, only abnormal POCDs was significantly associated with all-cause mortality [HR 1.18 (p=0.04, 95%CI 1.00:1.39) vs TCNS [HR 1.33 (p=0.06, 95%CI 0.99:1.78)].

Conclusions: This is the first prospective study showing abnormal combined DPN-Check and SUDOSCAN results predict all-cause mortality after adjusting for other risk factors. However, 10g-MFT and TCNS that diagnose DPN late did not predict all-cause mortality.

Disclosure

M.Goonoo: None. D.Selvarajah: None. G.P.Sloan: None. S.Tesfaye: Advisory Panel; Bayer Inc., Wörwag Pharma GmbH & Co. KG, Angelini, Speaker's Bureau; Viatris Inc., Nevro Corp., Procter & Gamble, Novo Nordisk, Berlin-Chemie AG.
5-OR: Adipocyte ANGPTL8 Regulates Insulin Sensitivity and Thermogenic Programing
Authors: GHOSH ANINDYA , PRENTKI MARC , LEUNG YAT H. , YU JEFFREY C.Y. , SLADEK ROBERT M. , CHENIER ISABELLE , OPPONG ABEL , PEYOT MARIE-LINE , MADIRAJU MURTHY , AL-KHAIRI IRINA , ABUBAKER JEHAD , AL-MULLA FAHD , ABU-FARHA MOHAMED
Published: June 2023

ANGPTL8 (A8), expressed mainly in the liver and adipocytes, regulates lipoprotein lipase (LPL) and lipid metabolism. Hepatic A8 and ANGPTL3 form a complex that inhibits LPL. However, the precise intracellular role of A8 in adipocytes is yet to be explored. We observed that RNAi-knockdown of A8 in mouse primary subcutaneous (SC) pre-adipocytes reduces adipocyte differentiation, glycerol, and fatty acid release at day 7 post-differentiation. RNAseq analysis of A8 siRNA or control siRNA transfected SC pre-adipocytes on days 0, 2, 4 and 7 of differentiation showed that A8 silencing impeded adipogenic and oxidative phosphorylation pathways and reduced expression of insulin signaling pathway genes IRS1, IRS2, PPARG, mTOR, early during differentiation, suggesting a role for A8 in the regulation of insulin sensitivity. Next, we investigated the functional role of adipose A8 by generating conditional adipocyte-specific A8 Knockout (AT-A8-KO) mice. AT-A8-KO mice on 45% high fat diet (HFD) with 30% fructose for 20 weeks showed a decrease in body weight gain, glycemia, brown fat mass, plasma TG and smaller cell size of SC adipocytes, while increased rectal temperature compared to controls. Interestingly, OGTT revealed AT-A8-KO mice in control diet or in HFD have significantly lower insulinemia. ITT results confirmed significant improvement of insulin sensitivity of AT-A8-KO mice on HFD. In addition, upon exposure to 6°C for 24h, AT-A8-KO mice exhibited elevated body temperature and energy expenditure compared to control mice, indicating that adipose tissue A8 negatively modulates cold-induced thermogenesis. Our results reveal that A8 regulates in vitro adipocyte differentiation, probably by modulating insulin signaling and mitochondrial respiration, and that deletion of adipocyte A8 in mice enhances insulin sensitivity, cold induced body temperature and energy expenditure. Therefore, targeting adipose specific A8 may be beneficial in promoting insulin sensitivity and preventing obesity.

Disclosure

A.Ghosh: None. I.Al-khairi: None. J.Abubaker: None. F.Al-mulla: None. M.Abu-farha: None. M.Prentki: None. Y.H.Leung: None. J.C.Y.Yu: None. R.M.Sladek: None. I.Chenier: None. A.Oppong: None. M.Peyot: None. M.Madiraju: None.

Funding

Dasman Diabetes Institute (731)
50-LB: Impact of an Avocado Voucher Program on Cardiometabolic Health in Hispanic/Latino Adults With or At-Risk of Type 2 Diabetes—A Pilot Study
Authors: BEVIER WENDY C. , MELERO LILIANA , SATO IMURO SANDRA E. , PAI AMRUTA , GORDON MAREA , GONZALEZ KARLA , GLANTZ NAMINO , SABHARWAL ASHUTOSH , KERR DAVID
Published: June 2023

Hispanic/Latino (HL) adults bear a greater burden of type 2 diabetes (T2D), and dietary factors have been linked to almost half of cardio-metabolic disease deaths. Avocados are rich in beneficial fats, vitamins, minerals, & fiber. To test the hypothesis that avocado consumption will improve glucose control and cardio-metabolic health in HL adults with or at-risk of T2D, we recruited 59 HL adults (45 women) who were randomized to an Active (A) group - receiving free avocado vouchers for 12 weeks, or a Control (C) group - no avocado vouchers. Subjects (53 T2D, 4 at risk, 2 unknown) had clinical measurements, blood draws, and continuous glucose monitors (CGMs) at Baseline (BL) and Conclusion (CL). Daily avocado consumption logs were kept. At BL, A and C groups did not differ in avocado consumption/day (0.8±0.6 vs 0.5±0.3, respectively). At CL, A group consumption was significantly greater (1.4±0.4 vs 0.4±0.3), p<0.001. Results are shown below. No significant differences between groups were found for time in range (TIR) 70-140 or 70-180 mg/dL or time above (TAR) 180 mg/dL. Providing vouchers to HL adults with or at-risk of T2D significantly increased avocado consumption and did not affect HbA1c, fasting glucose, weight, or CGM metrics but may have influenced waist circumference (WC) and triglycerides.

Disclosure

W. C. Bevier: None. L. Melero: None. S. E. Sato imuro: None. A. Pai: None. M. Gordon: None. K. Gonzalez: None. N. Glantz: None. A. Sabharwal: None. D. Kerr: Consultant; Sanofi-Aventis U. S.

Funding

Hass Avocado Board (C2021-0068)
507-P: Trajectories of Inflammatory Proteins over Diabetic Wound Healing Course
Authors: PICKETT SARA , MOON SALINA , THEOCHARIDIS GEORGIOS , MD DOM ZAIPUL , NIEWCZAS MONIKA , VEVES ARISTIDIS
Published: June 2023

Background: Inflammatory processes are dynamic over the Diabetic Foot Ulceration (DFU) course. We aimed to evaluate longitudinal trajectories of circulating biomarkers in subjects with DFU.

Methods: The study cohort comprised 39 subjects with DFU from the Joslin-Beth Israel Deaconess Foot Center. During the 12 weeks of follow-up (6 bi-weekly visits), 15 subjects (38%) had their DFU healed (healers). Twenty-eight proteins were measured at each visit on the Luminex platform.

Results: Circulating IL-10 levels at baseline were significantly higher in DFU healers in comparison with non-healers (OR: 2.4, p=0.047). Moreover, IL-10 levels remained stable over time within each group (IL10 Δ in DFU healers: p=0.2 and in non-healers: p=0.8). Levels of 6 other proteins revealed dynamic trajectories over time in one or both groups: MMP-2, EGF, IFNγ, TNF, IL-8, and MIP1b. MMP-2 levels in healers increased from baseline to V6 (β=0.07, p=0.0003), but remained stable in non-healers.

Conclusion: We identified an anti-inflammatory cytokine, IL-10, as a prognostic biomarker of the diabetic wound healing course. Six inflammatory proteins (MMP-2, EGF, IFNγ, TNF, IL-8, and MIP1b) revealed dynamic temporal changes in levels within or across groups.

Disclosure

S.Pickett: None. S.Moon: None. G.Theocharidis: None. Z.Md dom: None. M.Niewczas: None. A.Veves: None.

Funding

National Institutes of Health (R61DK131915, R01DK091949); Joslin Diabetes Center; National Rongxiang Xu Foundation
508-P: Association between Initial Outpatient Diabetic Foot Ulcers Infection Management Strategy and Hospitalization
Authors: SCHMIDT BRIAN M. , ARMSTRONG DAVID G. , BUSUI RODICA
Published: June 2023

The objective was to evaluate the impact of the initial management strategies for DFU infections diagnosed at an outpatient multidisciplinary center. In 2019, people with newly diagnosed DFU infection were followed for duration of therapy to determine hospitalization rates within 30 days of diagnosis. Consecutive patients were stratified according to Infectious Disease Society of America infection severity. Demographic, socioeconomic, and antibiotic data was recorded. Among 147 persons treated for DFU infection, 59% infections were mild, while 30% and 4% were moderate and severe, respectively. Empiric antibiotics, consisting of either a cephalosporin or penicillin (76%) were prescribed for initial treatment in 116 individuals, and 66% (n=77) of these had tissue cultures preceding the treatment. Despite initial management of outpatient infection, 42% of the entire cohort required hospitalization within 30 days of diagnosis; 50%, 38%, and 12% hospitalizations were mild, moderate, and severe infections, respectively. The percentage of hospitalizations which occurred in mild infection treated with only empiric antibiotic (58%) was 1.5x greater than culture-directed antibiotic therapy (34%) despite similar empiric antibiosis. High rates of hospitalizations occurred in moderate (49%) and severe (100%) DFU infection. Overall, there was a negative association (r = -0.50, p<0.05) between implementation of culture-directed antibiotic strategy and hospitalization, and increased hospitalizations with applying empiric therapy for mild DFU infection. These data strongly support the practice to obtain tissue culture regardless of DFU infection severity to guide further treatment, as it is negatively associated with hospitalization rates. It is therefore essential to ensure foot infection treatment involves culture-directed antibiotic therapy and is applied uniformly across infection severity.

Disclosure

B.M.Schmidt: None. D.G.Armstrong: Research Support; Medaxis LLC. R.Busui: Board Member; American Diabetes Association, Consultant; Averitas Pharma, Inc., Lexicon Pharmaceuticals, Inc., Nevro Corp., Novo Nordisk, Roche Diagnostics, Procter & Gamble, Research Support; Novo Nordisk, Medtronic, National Institutes of Health.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (1K23DK131261-01A1)
509-P: There Is No Blood for Improvement—Anemia Cuts Down Healing Chances in Diabetic Foot Patients
Authors: GIANGRECO FRANCESCO , IACOPI ELISABETTA , MALQUORI VITTORIO , PIERUZZI LETIZIA , GORETTI CHIARA , PIAGGESI ALBERTO
Published: June 2023

Aim: Anemia is considered a marker of severity of diabetes and diabetic foot syndrome (DFS) but is still controversial if it can be taken as a predictor of negative outcomes in these patients. Our study aimed to evaluate if anemia could be associated with a reduction of healing chances in patients admitted for DFS.

Methods: We retrospectively analysed all patients admitted in our Department in 2021 for DFS, dividing them in two groups according to presence (Group A) or absence (Group B) of anemia, diagnosed on levels of total Hemoglobin (HB) and red blood cells (RBC) below normal values (HB 13 g/dl for men and 12 g/dl for women and RBC 4.5×106/mm3 for men and 4.2×106/mm3 for women). We compared the groups for clinical and demographic characteristics, blood chemistry, procedures and clinical outcomes: healing rate (HR) and recurrences rate (RR). Among anemic patients we compared clinical outcomes according to the reduction of HB or RBC alone or both.

Results: We derived data from 196 patients: 114 patients in Group A [58.1%; age 70.9±10.6 yrs; male/female 75.4/24.6%; DM1/DM2 7.0/93.0%; Hba1c 57.5±18.6 mmol/mol; diabetes duration (DD) 20.1±11.9 yrs] and 82 in Group B (41.8%; age 68.4±10.9 yrs; male/female 61.0/39.0%; DM1/DM2 9.8/90.2%; Hba1c 60.6±16.2 mmol/mol; DD 16.8±11.9 yrs). Group A presented higher (p<0.05) male prevalence and shorter disease duration but no differences in comorbidities, and surgical or vascular procedures. Group A showed a lower HR (55.2% vs 76.8%, p=0.0028) and a higher RR (23.6% vs 17.1%, p<0.002). No difference in terms of HR, HT or R according to the different diagnostic criteria for anemia. In Cox’s logistic regression analysis only anemia negatively affected healing (HR 2.8, CI 95% 1.4-5.4, p=0.0037).

Conclusions: Anemia is associated to a reduction in healing chances in DFS patients and represents an independent predictor of healing failure.

Disclosure

F.Giangreco: None. E.Iacopi: None. V.Malquori: None. L.Pieruzzi: None. C.Goretti: None. A.Piaggesi: None.
543-P: A Peer-Led Diabetes Self-Management Education (DSME) and Support (DSMS) Intervention for Black Men with Type 2 Diabetes—Results of a Three-Month Pilot Randomized Clinical Control Trial
Authors: EWEN ALANA , KLOSS KATHERINE A. , NWANKWO ROBIN , FUNNELL MARTHA M. , PIATT GRETCHEN , HAWKINS JACLYNN M.
Published: June 2023

Black men are disproportionately impacted by Type 2 diabetes (T2D) and are more likely to die from diabetes complications than non-Hispanic White men. To address the unique challenges this group faces in diabetes self-management, we implemented a 3-month peer-led and empowerment-based DSME/S intervention in metro-Detroit. Twenty-five Black men ≥55 years of age with self-reported T2D were recruited and randomized to either the intervention group (n=12) − 10 hours of DSME and 9 hours of DSMS, or to an enhanced usual care (EUC) group (n=13) − 10 hours of DSME. Peer leaders (n=3), trained by certified diabetes care and education specialists (CDCES) who used training materials related to Black men with diabetes, led the sessions (mean age: 59.7 years; 100% Black, male, and with at least some college education). Changes in A1C levels, diabetes self-care activities, and diabetes distress levels were assessed at baseline and post-intervention. In the intervention group, the mean A1C at baseline was 7.73%, SD 2.16, and at follow-up, 7.06%, SD 1.39. The EUC group experienced a 0.13% decrease in A1C levels (p = 0.68). Within the intervention group, differences in average diet and blood-glucose testing scores, both measured using the Summary of Diabetes Self-Care Activities (SDSCA) measure, from baseline were statistically significant [(p = 0.03, mean change: 1.32, SD 1.71) and (p < 0.05, mean change: 0.50, SD 0.74), respectively]; EUC group general diet scores were: p = 0.08, mean change: 1.77. Diabetes distress scores among those who attended 1-6 sessions, ≤ 50%, (n=4): p = 0.92, mean change: −0.75, SD 14.06. Of those who attended 7-12 sessions, > 50%, (n=7), the decrease in score was statistically significant: p = 0.003, mean change: −5.71, SD 3.20. Implementing a peer-led DSMS program for Black men was feasible, adopted, and led to positive changes in outcomes. Scaling up the program is warranted to measure sustainability.

Disclosure

A.Ewen: None. K.A.Kloss: None. R.Nwankwo: None. M.M.Funnell: None. G.Piatt: None. J.M.Hawkins: None.

Funding

National Institute on Aging (2P30AG024824–16); Blue Cross Blue Shield Foundation of Michigan (003063.MG)
55-OR: HSK7653, a Novel Ultralong-Acting DPP-4 Inhibitor, as Monotherapy in Patients With Type 2 Diabetes—A Randomized, Double-Blind, Placebo-Controlled Phase III Trial
Authors: JI LINONG , BIAN FANG , PAN TIANRONG , JIANG HONGWEI , JIANG CHENGXIA , REN QIAN
Published: June 2023

Background: HSK7653 is a novel ultralong-acting DPP-4 inhibitor that maintains the average plasma DPP-4 inhibition over 80% for 14 days after 10mg or 25mg dosing. This randomized, double-blind, placebo-controlled phase III trial was conducted to evaluate the efficacy and safety of HSK7653 biweekly as monotherapy for 52 weeks in drug naive type 2 diabetes patients with inadequate glycemic control on diet and exercise.

Methods: A total of 475 patients with a mean HbA1c level of 8.1% were randomized to HSK7653 10mg, 25mg or placebo biweekly at a ratio of 1:1:1 for 24 weeks of double-blind treatment, followed by 28 weeks of open-label extension treatment with HSK7653 25mg for all patients. The primary endpoint was the change in HbA1c from baseline at 24 weeks.

Results: At week 24, the least-squares mean change in HbA1c from baseline was -0.96% in HSK7653 10mg, -0.92% in HSK7653 25mg and -0.33% in placebo. HSK7653 10mg and 25mg treatment resulted in significant placebo-subtracted changes in HbA1c of -0.63% (95% CI: -0.81%, -0.46%, p<0.0001) and -0.59% (95% CI: -0.77%, -0.42%, p<0.0001), respectively. The percentage of patients achieving HbA1c<7.0% was 44.2% in HSK7653 10mg group and 44.4% in HSK7653 25mg group versus 20.6% in placebo group (p<0.0001 for HSK7653 groups vs. placebo). No meaningful body weight changes were observed in all treatment groups. In the open-label extension treatment (from week 24 to week 52), the sustaining reduction of HbA1c from baseline were observed in HSK7653 10mg switched to 25mg group and HSK7653 25mg maintenance group. There were no excess hypoglycemia events in HSK7653 vs. placebo, and the incidence of adverse events was similar in all groups during the treatment.

Conclusions: In people with type 2 diabetes who had inadequate glycemic control on diet and exercise, HSK7653 monotherapy significantly improved glycemic control with well tolerability and safety. Clinical trial information: NCT04556851.

Disclosure

L.Ji: Other Relationship; Eli Lilly and Company, Novo Nordisk, Merck & Co., Inc., Bayer Inc., Sanofi-Aventis U.S., Roche Pharmaceuticals, MSD Life Science Foundation, AstraZeneca, Boehringer Ingelheim Inc., Abbott, Metronics. F.Bian: None. T.Pan: None. H.Jiang: None. C.Jiang: None. Q.Ren: None.
550-P: Food Insecurity and the Efficacy of a Gestational Diabetes (GDM) Risk Reduction Intervention—Healthy Eating Outcomes among American Indian and Alaska Native (AI/AN) Female Adolescents and Young Adults (FAYAs)
Authors: SEREIKA SUSAN M. , STOTZ SARAH A. , HEBERT LUCIANA E. , SCARTON LISA , MOORE KELLY R. , CHARRON-PROCHOWNIK DENISE
Published: June 2023

AI/ANs are unduly impacted by GDM and food insecurity. Employing a clinical trials design, this secondary analysis used Stopping GDM trial data to describe and explore food insecurity as a moderator of the efficacy of a GDM risk reduction intervention on healthy eating behaviors and self-efficacy at 3 months among AI/AN FAYAs. Participants were AI/AN FAYAs and their mothers. Assessments included mother’s food insecurity using USDA Household Food Security Survey Module and FAYA’s healthy eating self-efficacy using Self-Efficacy for Healthy Eating and healthy eating behaviors from CDC Youth Risk Behavior Surveillance System. The sample (N=149 dyads) was FAYAs (mean age 16.7±3.0 years) and their mothers, with 64% (n=95) living together. More than one-third (38.1%) reported food insecurity. At baseline food insecurity was associated with higher levels of eating vegetables and fruit for the full sample (p=.045) and cohabitating dyads (p=.002). By 3 months healthy eating self-efficacy (p=.048) and limiting snacking between meals (p=.031) improved more in the control group than the intervention group but only for cohabitating dyads. For the full sample the intervention group had increases in times eating vegetables (p=.022) and fruit (p=.015), while the control group had declines. In the full sample food insecurity did not moderate the group by time interaction for self-efficacy for healthy eating (p≥.05) but did moderate the group by time interaction for times drinking soda (p=.004) and days eating breakfast (p=.013). For cohabitating dyads food insecurity did moderate self-efficacy for eating 3 meals a day (p=.024) and days eating breakfast (p=.012). These results suggest food insecurity is an important factor regarding the efficacy of interventions designed to reduce GDM risk and offer unique insight on ‘upstream causes’ of GDM health disparities among AI/AN communities.

Disclosure

S.M.Sereika: None. S.A.Stotz: None. L.E.Hebert: None. L.Scarton: None. K.R.Moore: Consultant; Novo Nordisk. D.Charron-prochownik: None. The stopping gdm study group: n/a.

Funding

National Institutes of Health (R01NR014831)
56-LB: “They did not anticipate anybody living a full life with type 1”—Perspectives on Aging with Type 1 Diabetes
Authors: HUGHES ALLYSON , KRUPAR MEGHAN , STUCKEY HEATHER L. , VANDYKE ERIKA
Published: June 2023

People with type 1 diabetes are living longer and in 2030, 1/5 of the U.S. population will be older adults - 65 years of age and older. This study addressed the scarcity of research on the experiences of aging people with type 1 diabetes. All participants were recruited from T1D Exchange, an online community for individuals with type 1 diabetes. Nineteen older adults with diabetes (average age = 65.63, SD = 6.27 years, average type 1 diabetes duration = 36.97, SD = 18.94 years) were interviewed. The interviews were recorded, transcribed, and thematically analyzed by two independent coders. Participants described their disease management challenges, and gaps in available resources. Themes included positive and negative changes over their lifespan due to advancements in technology and knowledge, diabetes micro-management strategies, hypoglycemia unawareness, diabetes psychological health, and lack of diabetes resources about aging. Also, a lack of support may promote poor health outcomes and diabetes distress. Additional research should be conducted to better understand the needs of this population and what federal and state policies can be created or tailored to support them.

Disclosure

A. Hughes: None. M. Krupar: None. H. L. Stuckey: Consultant; Eli Lilly and Company. E. Vandyke: None.