bluuebunny/crossref_metadata_2025_split huggingface dataset:
260-LB: Elucidating the Role of NTPDase3 and Purinergic Signaling in Islet Hormone Secretion
Authors: RICHARDSON TIFFANY M. , DAI CHUNHUA , ARAMANDLA RADHIKA , DURAI HEATHER H. , REIHSMANN CONRAD , DAVIS COREY , MEI SHAOJUN , GIBSON DANNIELLE , SHRESTHA SHRISTI , SAUNDERS DIANE C. , COATE KATIE C. , ROBSON SIMON C. , POWERS ALVIN C. , BRISSOVA MARCELA 
Published: May 2022

ATP release from β cell secretory vesicles during insulin exocytosis is postulated to modulate islet hormone secretion via purinergic signaling in an autocrine or paracrine manner. Ecto-enzymes, including a family of ectonucleotidases (NTPDase) , control the concentration of extracellular nucleotides. One member of this family, ectonucleotidase triphosphate diphosphohydrolase 3 (NTPDase3) , is specifically expressed in human β cells during postnatal maturation, and its enzymatic activity is present in isolated adult human islets. The role of NTPDase3 in islet hormone secretion is not understood. We hypothesized that NTPDase3 regulates islet hormone secretion by modulating local extracellular nucleotide levels that signal through purinergic receptors expressed by islet cells. To define the cellular distribution of purinergic ecto-enzymes and nucleotide receptors in human islets, we used single-cell RNA sequencing (scRNA-seq) data. In addition to β cell NTPDase3 expression, ecto-enzymes ENPP1, and ENPP2 were abundant in α and ε cells while ecto-5'-NT and ADA were expressed in endothelial and stellate cells. These ecto-enzymes can further hydrolyze β cell-derived ATP to ADP, AMP, and adenosine which all bind purinergic receptors. We found that the ATP receptor, P2RY1, was enriched in β cells, and an adenosine receptor, ADORA2A, was expressed in α cells by both bulk and scRNA-seq. To study the function of this purinergic niche, we further assessed extracellular ATP levels which increased concomitantly (4.2E-12 vs. 4.3E-13 moles/100 IEQ/hour; n=9; p=0.03) with insulin secretion (21 vs. 60 ng/100 IEQ/hour; n=9; p=0.02) upon stimulation with 16.7 mM glucose + IBMX. To directly test NTPDase3 loss of function, we genetically manipulated human pseudoislets using an shRNA knockdown approach, resulting in a 1.7-fold increase of insulin secretion (AUC=3 vs. 5 ng/100 IEQs; n=3) . Overall, these studies provide an insight into how extracellular nucleotides and purinergic signaling mechanisms fine-tune human islet hormone secretion.

Disclosure
T. M. Richardson: None. D. C. Saunders: None. K. C. Coate: None. S. C. Robson: Advisory Panel; eGenesis, Consultant; Puretech, Synlogic, Research Support; Tizona Inc, Stock/Shareholder; EPurines, Purinomia. A. C. Powers: None. M. Brissova: None. C. Dai: None. R. Aramandla: None. H. H. Durai: None. C. Reihsmann: None. C. Davis: None. S. Mei: None. D. Gibson: None. S. Shrestha: None.
285-OR: Economic Impact of Novel Interventions in Children’s Health Care (NICH) in Youth with T1D
Authors: WAGNER DAVID V. , MIJANOVICH TOD , BARRY-MENKHAUS SAMANTHA A. , HARRIS MICHAEL A. 
Published: May 2022

Objective: Youth with T1D and high social risk experience health disparities, including acute complications. Novel Interventions in Children’s Healthcare (NICH) , designed to target social risk, is associated with improved health, fewer complications, and lower medical costs. This is the first study to compare NICH outcomes in youth with T1D to a control group using claims data.
Methods: Using a state-based claims database, a difference-in-differences study with a matched comparison group was conducted, comparing youth with T1D served by NICH (n=25) to youth referred to NICH but denied access by insurance or with similar claims history and demographic characteristics (n=47) . Data across a 36-month follow up period were examined.
Results: Mahalanobis matching and entropy balance weighting created well-balanced groups on matched covariates. NICH reduced hospitalizations by 1.6 (p&lt;.01) , ED visits by 4.1 (p&lt;.01) , and cost by &gt;$18k per youth (p&lt;.05) , with maximum impact in the 2nd follow up year (&gt;$9k, p&lt;.01) .
Conclusion: Youth served by NICH had fewer acute medical events and lower costs following NICH initiation than control youth. Youth with complication history did not “regress to the mean,” and continued to experience acute health emergencies - highlighting the potential value of interventions that target youth with T1D and high social risk in need of alternatives to standard medical and behavioral health care.

Disclosure
D.V.Wagner: None. T.Mijanovich: None. S.A.Barry-menkhaus: None. M.A.Harris: None.

Funding
The Leona M. and Harry B. Helmsley Charitable Trust
294-OR: The Type 1 Diabetes Protective Variant of Tyrosine Kinase 2 (TYK2) Protects ß-Cells from Autoimmunity
Authors: TAMAYO AYMEE RODRIGUEZ , HUBER MOLLIE , BUTFILOSKI EDWARD J. , MATHEWS CLAYTON E. 
Published: May 2022

Type 1 diabetes (T1D) is a complex autoimmune disease where genes and environmental factors impact pathogenesis. Analysis of the &gt;150 loci identified by GWAS reveals the compelling theme that candidate genes cluster into pathways. A pathway connecting environment to T1D genetics is the anti-viral/Type 1 interferon (IFN1) pathway that is regulated by at least 7 T1D linked loci, including Tyrosine Kinase 2 (TYK2) which regulates IFN1 receptor signaling. We test the hypothesis that the T1D protective variant of TYK2 restrains signaling though the IFN1 receptor functions in β-cells reduce interactions with and killing by autoreactive, cytolytic CD8+ T lymphocytes (CTL) . These studies employed β-cells edited in the endogenous TYK2 locus with CRISPR/Cas9 to express the T1D protective TYK2110A or common allotype, TYK2110P. These cells were treated with Poly I:C (50ng/mL) , to see IFN1 response to an imitated viral infection. Outcomes were IFN1 production, gene expression, antigen presentation, and responses to CTL. When allotypic β-cells were treated with Poly I:C, both produced equivalent levels of IFN1. While β-cells with TYK2110P showed increased mechanisms of antigen presentation, this pathway was attenuated in TYK2110A β-cells (p&lt;0.05) . These results were replicated by treating TYK2110P and TYK2110A IFN1 (100U/mL) , where we observed increased antigen presentation in TYK2110P β-cells but not TYK2110A β-cells (p&lt;0.05) . Interestingly, prior to treatment cell surface human leukocyte antigen class I levels were reduced in TYK2110A β-cells (p&lt;0.01) . Studies to test the interactions of autoreactive CTL with β-cells supported our hypothesis. TYK2110P β-cells were efficiently lysed by CTL and lysis was increased by pre-treatment of β-cells with IFN1 or PolyI:C. In stark contrast, TYK2110A β-cells exhibited low levels of CTL-lysis and pre-treatment with IFN1 or PolyI:C did not modify lysis.
In conclusion, TYK2110A protects β-cells from autoimmune-mediated death.

Disclosure
A.Rodriguez tamayo: None. M.Huber: None. E.J.Butfiloski: None. C.E.Mathews: None.

Funding
National Institutes of Health PAI42288National Institutes of Health RR01DK127497
295-OR: Identification of Type 1 Diabetes Genes and Regulatory Processes Mediating Pancreatic Beta-Cell Survival in Response to Proinflammatory Cytokines
Authors: BENAGLIO PAOLA , ZHU HAN , OKINO MEI-LIN , YAN JIAN , ELGAMAL RUTH , NARIAI NAOKI , BEEBE ELISHA , KORGAONKAR KATHA , QIU YUNJIANG , DONOVAN MARGARET , CHIOU JOSHUA , NEWSOME ASHMUS JACKLYN M. , KAUR JASPREET , CORBAN SIERRA , REN BING , FRAZER KELLY , SANDER MAIKE , GAULTON KYLE J. 
Published: May 2022

The response of beta cells to inflammatory cytokines contributes to type 1 diabetes (T1D) risk, but the specific genes that underlie this response and mediate beta cell survival remain largely unknown. In this study we used a suite of functional genomics assays combined with human genetics, to map cis-regulatory programs in beta cells and to identify T1D genes that affect beta cell survival upon exposure to the pro-inflammatory cytokines IL1β, IFNγ and TNFα. We mapped 38,931 cytokine-responsive candidate cis­­ -regulatory elements (cCREs) active in beta cells using ATAC-seq and single nuclear ATAC-seq (snATAC-seq) , and linked cytokine-responsive beta cell cCREs to putative target genes using single cell co-accessibility and HiChIP. We performed a genome-wide pooled CRISPR loss-of-function screen in EndoC-βH1 cells, which identified 867 genes affecting cytokine-induced beta cell loss. Genes that promoted beta cell survival and had up-regulated expression in cytokine exposure were specifically enriched at T1D loci, and these genes were preferentially involved in inhibiting inflammatory response, ubiquitin-mediated proteolysis, mitophagy and autophagy. We identified 2,229 variants in cytokine-responsive beta cell cCREs altering transcription factor (TF) binding using high-throughput SNP-SELEX, and variants altering binding of TF families regulating stress, inflammation and apoptosis were broadly enriched for T1D association. Finally, through integration with genetic fine mapping, we identified T1D risk variants regulating beta cell survival in cytokine exposure. At the 16p13 locus, a T1D variant affected TF binding in a cytokine-induced beta cell cCRE that physically interacted with the SOCS1 promoter, and increased SOCS1 activity promoted beta cell survival in cytokine exposure. Together our findings reveal processes and genes acting in beta cells during cytokine exposure that intrinsically modulate risk of T1D.

Disclosure
P.Benaglio: None. M.Donovan: None. J.Chiou: Employee; Pfizer Inc. J.M.Newsome ashmus: None. J.Kaur: None. S.Corban: None. B.Ren: Stock/Shareholder; Arima Genomics, Epigenome Technologies. K.Frazer: n/a. M.Sander: None. K.J.Gaulton: Consultant; Genentech, Inc., Stock/Shareholder; Neurocrine Biosciences, Inc., Vertex Pharmaceuticals Incorporated. H.Zhu: None. M.Okino: None. J.Yan: None. R.Elgamal: None. N.Nariai: None. E.Beebe: None. K.Korgaonkar: None. Y.Qiu: None.

Funding
NIH DK122607
303-OR: Localized CTLA-4-Ig and Antioxidant Islet Encapsulation Delays Allograft Rejection
Authors: BARRA JESSIE , BURNETTE KALIA S. , KOZLOVSKAYA VERONIKA , KHARLAMPIEVA EUGENIA , TSE HUBERT M. 
Published: May 2022

Type 1 diabetes is characterized by beta-cell-specific autoimmune destruction, leading to life-long exogenous insulin-dependence. Islet transplantation can restore proper glycemic control, but graft longevity remains low due to immune-mediated rejection. The use of nanothin encapsulation materials consisting of poly (N-vinylpyrrolidone) (PVPON) and tannic acid (TA) , an antioxidant, can delay islet allograft rejection and decrease inflammatory immune responses. However, when (PVPON/TA) -encapsulated C57BL/6 islets were transplanted into streptozocin-treated diabetic NOD mice in the absence of systemic immunosuppression, only 50% of recipients maintained long-term allograft function. Therefore, modification of (PVPON/TA) coatings to include immune inhibitors are needed to prolong islet allograft survival. The adaptability of our (PVPON/TA) layers allow for its conjugation to CTLA-4-Ig, a fusion protein that can block CD28-mediated co-stimulation of T cells. We hypothesize that the addition of CTLA-4-Ig to (PVPON/TA) outer layers, denoted as (PVPON/TA/CTLA-4-Ig) , will extend islet allograft survival by inhibiting proinflammatory effector T cell responses. Transplantation of (PVPON/TA/CTLA-4-Ig) -encapsulated NOD.Rag islets significantly delayed islet allograft rejection in diabetic C57BL/6 mice compared to non- (p&lt;0.0001) and control IgG-containing (PVPON/TA/IgG) -encapsulated islets (p&lt;0.01) . Additionally, (PVPON/TA/CTLA-4-Ig) -encapsulation significantly increased FOXP3+ regulatory and CD73+ FR4+ anergic CD4+ T cell count when compared to both non- and (PVPON/TA/IgG) -encapsulation. Since CTLA-4-Ig can affect the tryptophan catabolism pathway, future studies will investigate the effect of (PVPON/TA/CTLA-4-Ig) -encapsulation on indolamine-2,3-dioxygenase expression in antigen-presenting cells. The success of (PVPON/TA/CTLA-4-Ig) coatings to delay allograft rejection warrant their use in future human translational studies.

Disclosure
J.Barra: None. K.S.Burnette: None. V.Kozlovskaya: None. E.Kharlampieva: None. H.M.Tse: None.

Funding
NIH/NIDDK Raward (DK099550) NIH/NIDDK Raward (DK127497) JDRF award (SRA-2016-270-S-B) JDRF award (2-SRA-2019-692-S-B) NIH/NIDDK R56 award (DK126456) NIH/NIDDK Raward (DK126456) NIH/NIGMS (T32GM109780) NIH/NIGMS (T32GM008111)
31-LB: Improvements in Glycemic Control following Use of an Established mHealth Program among Individuals with Diabetes
Authors: ZIMMERMANN GRETCHEN , VENKATESAN AARATHI , RAWLINGS KELLY , FRANK RICHARD S. , EDWARDS CAITLYN 
Published: May 2022

Background: The prevalence of diabetes continues to rise worldwide. mHealth programs with 24/7 app access and frequent interaction with remote providers ease the learning, practice, application, and daily integration of self-care skills and health improvement behaviors for people diagnosed with diabetes, especially those at high risk for cardiometabolic and mental health complications. This study aimed to evaluate the effectiveness of an established mHealth program on measures of glycemic control in a population at high risk for the development of diabetes-related complications (hemoglobin A1c (HbA1c) ≥ 8.0%) .
Methods: This study protocol employed a single-arm, retrospective design. Participants were offered the app-based Vida Health Diabetes Management program as part of their medical insurance benefit. This intervention utilized one-to-one remote sessions with Registered Dietitians and Certified Diabetes Care and Education Specialists as well as structured lessons and tools related to diabetes management. Participants were included if they had a valid laboratory HbA1c completed between 365 to 21-days of enrollment and a follow-up laboratory HbA1c value within 90 to 365-days following enrollment. Two-tailed paired t-tests were used to evaluate changes in HbA1c between baseline and follow-up.
Results: Participants with HbA1c ≥ 8.0% at baseline (n=1023) demonstrated a decrease in HbA1c of -1.37 points between baseline (mean: 9.84, SD: 1.64) and follow-up (mean: 8.47, SD: 1.77, p&lt;0.001) . Additionally, we observed a decrease in HbA1c of -1.94 points between baseline (mean: 10.77, SD: 1.48) and follow-up (mean: 8.83, SD: 1.94, p&lt;0.001) among participants with HbA1c ≥ 9.0% (n = 618) .
Conclusion: This study demonstrated clinically meaningful improvements in glycemic control among participants enrolled in the Vida Health Digital Diabetes Management Program. Future work should aim to identify mechanisms of this, and other mHealth interventions, most associated with glycemic control.

Disclosure
G. Zimmermann: Employee; Vida Health. A. Venkatesan: Employee; Vida Health. K. Rawlings: Employee; Vida Health. R. S. Frank: Employee; Vida Health. C. Edwards: Employee; Vida Health.

Funding
Vida Health
312-OR: Glucose Oxidation in Brown Fat
Authors: JIANG LEI , WANG QIONG (ANNABEL) , WANG ZHICHAO 
Published: May 2022

In the United States, more than 70% of adults are overweight or obese, caused primarily by excess energy intake in modern society. Brown adipose tissue (BAT) can function as an “energy sink” in mammals, since BAT is specialized with uncoupling respiration, which burns energy to maintain body temperature. Unfortunately, thermogenesis in brown adipocytes dramatically declines in obese individuals, contributing to the development of obesity-related metabolic disorders. Although both lipids and glucose have been viewed as major energy substrates for thermogenesis, most of the early studies have been focusing on fatty acid oxidation. Recently, we found that BAT had the most active glucose oxidation among metabolic active tissues, and chronic cold exposure significantly enhanced glucose oxidation in mice BAT. Furthermore, in vivo administration of a mitochondrial pyruvate carrier (MPC) inhibitor impaired glucose oxidation and thermogenesis in BAT, which was consistent with the impaired thermogenesis of a recently published mouse model of constitutive BAT-selective deletion of MPC1 (Ucp1-MPC1-KO) . In order to directly study the role of MPC in mature brown adipocytes, we generated a Tet-on inducible Ucp1‑specific MPC2 knockout (Ucp1‑MPC2‑iKO) mouse model. As expected, Ucp1-MPC2-iKO mice couldn’t maintain body temperature upon acute cold exposure, after prolonged loss of MPC in mature brown adipocytes. Interesting, adult Ucp1-MPC2-iKO mice were cold-resistant, after the acute loss of MPC in the mature brown adipocytes, which were different from the constitutive Ucp1-MPC1-KO mice. Together, our study suggests that although glucose oxidation is essential to optimal BAT thermogenesis, MPC-independent metabolism exists to maintain glucose oxidation and thermogenesis in BAT.

Disclosure
L. Jiang: None. Q. Wang: None.
314-OR: Synaptotagmin-9 Regulates Early Phase Insulin Secretion by Regulating Tomosyn-1
Authors: RAHMAN MD MOSTAFIZUR , ALSHARIF HAIFA , BHATNAGAR SUSHANT 
Published: May 2022

Insulin secretion from pancreatic β-cells occurs in a biphasic manner. The loss of insulin secretion, entailing the inability of insulin granules to fuse with the plasma membrane (PM) via the formation of the SNARE complex, is a key determinant in impaired glucose tolerance and development of type 2 diabetes (T2D) . Synaptotagmins (Syt) are calcium sensors that regulate insulin-containing granule fusion to the PM for insulin secretion. Syt9 is highly expressed in β-cells; however, its role in insulin secretion is not well-characterized. Our goal is to determine how Syt9 affects insulin secretion from pancreatic β-cells. Mice lacking Syt9 (Syt9-/-) have improved glucose clearance with no change in insulin action than wild-type control mice. Interestingly, Syt9-/- mice showed increased plasma insulin levels at 5 min and 15 min post-glucose challenge. Similarly, islets isolated from Syt9-/- mice demonstrate increased stimulation of insulin secretion in response to the early phase insulin secretagogues (KCl and tolbutamide) compared to WT control islets. Similarly, siRNA-mediated knockdown of Syt9 in INS1 cells increased KCL-stimulated insulin secretion at 5 min and min. Altogether, these data suggest that Syt9 regulates the early phase of insulin secretion from β-cells. Strikingly, Syt9-/- mouse islets have reduced Tomosyn-1 levels (∼50%) without altering the levels of other key SNARE proteins (Stx1A, Stx4A, SNAP25) . Tomosyn-1, an inhibitor of insulin secretion whose increased protein abundance is associated with reduced insulin secretion, binds, cofractionates, and colocalizes with Syt9 and Stx1A. The knockdown of Tomosyn-1 in INS1 β-cells treated with KCL prevents the localization of Syt9 with Stx1A. Further, the knockdown of Syt9 or Tomosyn-1 increases the SNARE complex formation. In sum, these data demonstrate the identification of a novel Stx1A-Tomosyn-1-Syt9 molecular complex that regulates the fusion of insulin granules in the early phase.

Disclosure
M.Rahman: None. H.Alsharif: n/a. S.Bhatnagar: None.

Funding
R01DK120684-01
321-OR: Empagliflozin Improves Beta-Cell Function Independently of Glucose Toxicity in Patients with Type 2 Diabetes
Authors: THIRUMATHYAM ROOPAMEERA , RICHTER ERIK A. , GOETZE JENS PETER , MADSEN PER L. , HOLST JENS J. , MADSBAD STEN , JØRGENSEN NILS B. 
Published: May 2022

Introduction: SGLT2-inhibitors improve beta-cell glucose sensitivity (BGS) and insulin sensitivity in patients with type 2 diabetes (T2D) . This effect has been attributed to relief of glucotoxicity, but very few studies have controlled for differences in glycemia. Here, we explore the effects of empagliflozin on BGS and secondarily, peripheral insulin sensitivity (IS) , compared to similar glycemic control with insulin treatment.
Materials and Methods: 17 subjects with T2D (13 males, 58±3 years (mean±sem) , BMI 32.9±0.9 kg/m2, HbA1c 52.4±2.4 mmol/L, T2D duration 8.9±1.3 years) were treated with empagliflozin (E) and NPH-insulin (I) for 5 weeks in a randomized cross-over study design with 3 weeks of washout. Insulin was titrated to obtain similar glycemic control as with empagliflozin. An OGTT with stable iv and oral glucose tracers was performed prior to and at the end of each treatment.
Results: Glycemia was similarly reduced on both treatments (Δfasting glucose: E: -1.3±0.2, p&lt;0.01; I: -0.8±0.2, p&lt;0.01; E vs. I: p=NS) . Fasting insulin concentrations were lower with empagliflozin and higher with insulin (E: 92±12 vs. 180±27 pmol/L, p&lt;0.001) . Fasting hepatic glucose production (HGP) was increased with empagliflozin compared to insulin (19.5±0.8 vs. 16.6±0.6 µmol/kg/min, p&lt;0.001) , but postprandial HGP did not differ between treatments. BGS was greater with empagliflozin compared to insulin (0.82±0.1 vs. 0.59±0.pmol/ (kg·min·mM) , p=0.001) . IS (AUC Glucose Rd, tissue /AUC Insulin) was unchanged with empagliflozin, but decreased with insulin compared to washout (0.09±0.vs. 0.11±0.02 µmol/ (kg FFM·pM·min) , p=0.025) . Fatty tissue insulin resistance (Adipo-IR: fasting FFA x fasting insulin) was lower with empagliflozin compared to insulin (77±vs. 110±17 mmol/L x pmol/L, p=0.012) .
Conclusion: Improved beta-cell function during empagliflozin treatment is not a result of reduced glucotoxicity. Peripheral hyperinsulinemia may induce insulin resistance.

Disclosure
R.Thirumathyam: None. E.A.Richter: None. J.Goetze: Consultant; Novo Nordisk A/S. P.L.Madsen: None. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. S.Madsbad: None. N.B.Jørgensen: Advisory Panel; Novo Nordisk A/S, Research Support; Boehringer Ingelheim International GmbH, Speaker's Bureau; Novo Nordisk A/S, Stock/Shareholder; Eli Lilly and Company, Novo Nordisk A/S.

Funding
Boehringer Ingelheim Gmbh Investigator initiated study grant
329-OR: Videoconferencing for Diabetes Self-Management Support—A Viable Option for Meeting the Needs of High-Risk Patients in Rural Areas?
Authors: HAMMOUDEH RAWAN , KRALL JODI S. , JOHNSON PATRICIA A. , REYNOLDS SHARI L. , RUPPERT KRISTINE , NG JASON , SIMINERIO LINDA M. 
Published: May 2022

Ongoing support is critical for effective diabetes (DM) self-management, but difficult to deliver, particularly in areas with limited resources. The purpose of the study was to assess the impact of a virtual support model on DM outcomes for high-risk patients in rural underserved communities.
Methods: Patients with HbA1c&gt;9% receiving care in federally qualified centers were referred to the Telemedicine for Reach, Education, Access, Treatment and Ongoing Support (TREAT-ON) program, where a Diabetes Care and Education Specialist (DCES) provided in person diabetes self-management education and ongoing support through videoconferencing. Participant demographics, BMI and HbA1c were collected from patient records. Participants completed the DM Summary of Self-Care Activities, Distress and Empowerment Scales and Morisky Medication Adherence Measure at baseline and 6 months, and the Telehealth Usability Questionnaire at study completion. Pre/post values were compared for HbA1c, self-care, psychosocial and process outcomes.
Results: Participants (n=37) were 84% white, mean age 46.1 years with mean BMI 37.5. Glycemia improved with a mean reduction in HbA1c from 11.2% at baseline to 9.1% at follow-up (p&lt;.001) . There was significant improvement in self-care behaviors of general diet (p=.001) and foot care (p=.041) . DM distress was reduced significantly (p&lt;.001) , attributed to less emotional and regimen distress. Participants also reported a high level of satisfaction with TREAT-ON and interest in future use (4.6/5 points) .
Conclusions: Findings offer evidence of significant benefits and acceptability of a video-conferencing delivery model for DM self-management support. Future research should explore additional ways to empower individuals to continue and sustain improvements.

Disclosure
R.Hammoudeh: None. J.S.Krall: Research Support; Becton, Dickinson and Company, Sanofi. P.A.Johnson: None. S.L.Reynolds: None. K.Ruppert: None. J.Ng: Research Support; Sanofi. L.M.Siminerio: Advisory Panel; Abbott, Bayer AG, Research Support; Becton, Dickinson and Company, Sanofi.

Funding
National Institute of Diabetes Digestive and Kidney Diseases of the National Institutes of Health (R34DK123370) .