bluuebunny/crossref_metadata_2025_split huggingface dataset:
212-LB: Reporting History of Diabetes Symptoms and Random Blood Glucose Testing to Detect Presymptomatic Type 1 Diabetes (T1D) in the General Pediatric Population
Authors: WAUGH KATHLEEN , FROHNERT BRIGITTE I. , REWERS MARIAN , BAXTER JUDITH , GENO RASMUSSEN CRISTY R. 
Published: June 2019

Objective: Detection of pre-symptomatic T1D by islet autoantibody (IA) screening prevents hospitalization and diabetic ketoacidosis at clinical onset. It is unknown if presence of diabetic symptoms and random blood glucose predict islet autoantibodies. We report the efficacy of random blood glucose (RBG) measurement, among those who reported multiple symptoms for T1D, for detecting T1D autoimmunity.
Methods: In 2017-18, the Autoimmunity Screening for Kids (ASK) study screened 14,418 Denver children 1-17 y old for autoantibodies to insulin, GAD, IA-2, and ZnT8. At the time of screening, the parent and/or child were asked whether or not the child had increased urination, thirst, weight loss or vomiting in the last 3 months. If two or more symptoms were reported, RBG was tested using a glucometer and IA testing was fast-tracked with results available in &lt;7 days.
Results: Of the children screened, 0.9% were positive for multiple IA or a single high-affinity IA conferring, respectively, a 44% and 29% 5-year risk of clinical T1D. A fast-track protocol with RBG testing was applied to 501/12,726 children screened between 6/2017-12/2018, flagged for priority testing. Ten (2%) of the 501 fast-track participants had multiple or single high-affinity IA, compared to 91/12,050 (0.8%) IA in those with one or no symptoms (p=0.002). At screening, children found later to have multiple or high-affinity IA more often reported ≥2 symptoms: 9.6% (10/104) compared with low-affinity IA, 4.3% (11/254, p=0.05), or negative, 4.9% (602/12,368, p=0.03). Among those with increased thirst and polyuria, 16/358 (4.5%) had IA. For IA positive, none reported all symptoms (12 IA neg reported all symptoms). RBG&gt;140 mg/dl was detected in 1/14 (7.1%) children with multiple symptoms and IA vs. 15/440 (3.4%) children with symptoms and no IA (p=0.5). None had RBG&gt;200.
Conclusions: Symptoms history is helpful but RBG is not, in finding children with pre-symptomatic T1D.

Disclosure
K. Waugh: None. B.I. Frohnert: None. M. Rewers: None. J. Baxter: None. C.R. Geno Rasmussen: None.

Funding
JDRF
2122-P: System x(c)- Is a Key Molecule in Oxidative Stress-Induced ß-Cell Damage
Authors: YOO SOYEON , BAE JUYOUNG , CHIN HYOUNJUNG , KOH GWANPYO 
Published: June 2019

Pancreatic β-cells are vulnerable to oxidative stress, which is related to β-cell failure in type 2 diabetes. System x(c)- is a sodium-independent cystine/glutamate antiporter that mediates the exchange of extracelluar L-cystine and intracellular L-glutamate. The import of L-cystine through this transporter is the limiting state of intracellular glutathione (GSH) synthesis that has a major role in defends against oxidative stress. Our previous study reported that 2-deoxy-D-ribose (dRib) induces oxidative damage through GSH depletion in pancreatic β-cells. The aim of the present study was to elucidate the mechanism underlying oxidative stress-induced β-cell damage. We measured intracellular L-[14C] cysteine uptake, GSH content and reactive oxygen species (ROS) levels, cytotoxicity and apoptosis in rat insulinoma cell line (RINm5F cells). Stimulation with dRib dose- and time-dependently decreased intracellular L-[14C] cystine uptake and GSH content and increased intracellular ROS levels, cytotoxicity and apoptosis. The addition of 2-mercaptoethanol (2-ME), a cystine uptake enhancer, sodium-independently recovered the dRib-induced decreases in L-[14C] cystine uptake, GSH content and cell viability. To determine clearly whether system x(c)- deficiency mediate the oxidative stress-induced β-cell damage, we overexpressed xCT, the substrate-specific subunit of the system x(c)-, by using a lentiviral vector in RINm5F cells. Overexpression of xCT fully recovered the dRib-induced decreases in L-[14C] cystine uptake and GSH content and prevented the dRib-induced ROS rises, cytotoxicity and apoptosis.
In summary, overexpression of xCT showed protective effects against oxidative damage in RINm5F cells. It suggests that system x(c)- deficiency play a critical role in oxidative stress-induced β-cell damage.

Disclosure
S. Yoo: None. J. Bae: None. H. Chin: None. G. Koh: None.
2125-P: Increased StAR (Steroidogenic Acute Regulatory Protein) Is Detrimental to ß Cells and Promotes Mitochondrial Dysfunction
Authors: HOGAN MEGHAN F. , ESSER NATHALIE , TEMPLIN ANDREW T. , ZRAIKA SAKENEH , HULL REBECCA L. , EL-OSTA SAM , KAHN STEVEN E. 
Published: June 2019

StAR is a cholesterol transport protein that transports cholesterol from the cytoplasm into the mitochondrial matrix for further metabolism by CYP enzymes. Depending on the CYP expressed, this results in production of corticosteroids, gonadal steroids, neurosteroids or oxysterols. These products generally exert positive effects on cellular health and function but can also be harmful. We previously showed that StAR is produced in β cells and is increased under conditions of amyloid formation in human islet amyloid polypeptide (hIAPP) transgenic mouse islets, a model of human islet amyloidosis in type 2 diabetes (T2D). Further, CYP11A1, CYP11B1, CYP7A1 and CYP17A1 are not expressed in mouse islets, and CYP27A1 is expressed but decreases with amyloid deposition. Therefore, we hypothesized that increased StAR in islets is deleterious to β-cell health as the downstream CYP enzymes are not present to metabolize mitochondrial cholesterol.
We first demonstrated (by immunoblot) that StAR is expressed in human islets, a requirement if it is to play a role in T2D. Also in human islets, only CYP27A1 is detectable, while CYP11A1 and CYP7A1 are not (n=4). We next used a lentivirus to increase StAR expression (or a control lentivirus) in INS-1 cells, which resulted in reduced mitochondrial membrane potential (100±2.0% vs. 78.1±1.2%, n=2, p&lt;0.05) and cell viability (100±4.1% vs. 89.7±7.7%, n=3, p&lt;0.05). Finally, we determined whether reducing StAR expression with an siRNA oligonucleotide in hIAPP transgenic islets had beneficial effects. A 40% knockdown in StAR expression did not alter amyloid deposition, but tended to increase islet viability (100±3.1% vs. 134.7±12.2%, n=2, p=0.1).
In summary, StAR is expressed in human islets and increasing its expression is deleterious due to changes in mitochondrial function and β-cell survival. Thus, reducing StAR expression and/or increasing expression of downstream CYP enzymes may be a novel strategy to protect β cells in T2D.

Disclosure
M.F. Hogan: None. N. Esser: None. A.T. Templin: None. S. Zraika: Research Support; Self; Novartis Pharmaceuticals Corporation. R.L. Hull: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. S. El-Osta: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S.

Funding
American Diabetes Association (1-18-PDF-174 to M.F.H.); National Institutes of Health (T32HL007028, F32DK109584); U.S. Department of Veterans Affairs (BX001060); University of Washington
2127-P: Reduced Islet Parasympathetic Nerve Density Correlates with Decrease in Beta-Cell Volume of Islet in Lean Type 2 Diabetic Goto-Kakizaki Rat
Authors: MIZUKAMI HIROKI , GUO DANYANG , TAKAHASHI KAZUHISA , OSONOI SHO , KUDO KAZUHIRO , YAGIHASHI SOROKU 
Published: June 2019

Pancreatic branch of vagus nerve (pvn) signaling plays a pivotal role in the maintenance of islet β cell volume density (Vβ). In type 2 diabetes (T2D), small fibers in the epidermis is decreased by diabetic insult. It is not still uncovered yet, however, that the reduction of terminal pvn fibers is associated with Vβ in T2DM. Herein, we explored the association between islet pvn fiber density and Vβ. We recruited non-obese spontaneous T2D Goto-Kakizaki (GK) rats and control Wistar rats (W) at 5 weeks of age. GK was divided into DPP-4 inhibitor (DPi)-treated group (GTe) (10mg/kg teneligliptine), SGLT2 inhibitor (SGi)-treated group (GCa) (10mg/kg canagliflozin) and both treated group (GTeCa). During experimental period, 2g/kg oral glucose tolerance test (OGTT) and glucose-stimulated insulin secretion test (GSIS) was performed. At end, pancreata were underwent for the pathological evaluation. OGTT in GK was attenuated (p&lt;0.01 vs. W). Although DPi and SGi in each significantly improved OGTT compared to GK, the effect was the most robust in GTeCa. Low GSIS in GK (p&lt;0.01 vs. W) was significantly improved in GTe and GCaTe (p&lt;0.05 and p&lt;0.01 vs. GK, respectively), although it was comparable between GK and GCa. Pathological evaluation disclosed a significant decrease in Vβ in GK (p&lt;0.01 vs. W). Vβ was the most well-preserved in GCaTe (p&lt;0.05 vs. GTe), followed by GTe (p&lt;0.05 vs. GK), while it was comparable between GK and GCa. The density of pvn fibers labeled by the antibody for vesicular acetylcholine transporter (VachT) were significantly decreased in the islet of GK (p&lt;0.01 vs. W). It was significantly improved in GCa, GTe and GCaTe compared to GK (p&lt;0.05 vs. GCa and GTe; p&lt;0.01 GCaTe, respectively). pvn fiber density in the islets significantly correlated with Vβ (r=0.53, p&lt;0.01). Our results shed light on the association between terminal fiber density of pvn in the islet and Vβ, and the maintenance of the fibers may be beneficial for the prevention from Vβ loss in T2D.

Disclosure
H. Mizukami: None. D. Guo: None. K. Takahashi: None. S. Osonoi: None. K. Kudo: None. S. Yagihashi: None.
213-LB: Developing a Prognostic Model to Assess Dysglycemia Risk in Canadians Aged 18-39
Authors: SRUGO SEBASTIAN A. , JIANG YING , MORRISON HOWARD I. , DEGROH MARGARET M. 
Published: June 2019

In Canada, the prevalence of diabetes has seen the greatest relative increase in young adulthood, where the disorder is severely pathological compared to later-onset. Still, few prognostic models have been developed to screen young adults for dysglycemia risk and boost early identification and intervention. We sought to establish predictors of dysglycemia risk among young Canadian adults (aged 18-39) and evaluate their utility in identifying high-risk individuals. The Canadian Diabetes Risk Questionnaire (CANRISK) study collected questionnaire, anthropometric, and oral glucose tolerance test (OGTT) data from a large, multiethnic convenience sample of Canadians over two phases. Young adults with diagnosed diabetes, missing OGTT data, or pregnant were excluded. Potential factors that modestly predicted (p&lt;0.20) dysglycemia status (FPG≥6.1mmol/L or 2h-PG≥7.8mmol/L) were entered into a lenient stepwise function, producing a young adult-specific model; risk scores were developed from adjusted odds ratios. Discriminatory ability was assessed by optimism-corrected area under the curve (AUC) via bootstrapping and goodness-of-fit by Hosmer-Lemeshow (H-L) test and calibration plot. More than half of the 3334 participants were female (62.4%), non-white (79.2%), less than 25kg/m2 (50.7%), and reported a family history of diabetes (55.4%); based on OGTT results, 7.3% were dysglycemic. The young adult-specific model displayed an adjusted AUC of 72.9%, and reasonable goodness-of-fit (H-L p=0.49). Model performance was similar when run sex-specifically (males: unadjusted AUC of 72.1%, H-L p=0.67; females: 73.6%, p=0.67). Employing a cut-point of 22, the tool displayed high sensitivity (78.8%) but low specificity (54.0%). Only 3% of those identified as low risk by the tool were misclassified.
This young adult-specific risk score shows promise to identify high-risk individuals in a multiethnic Canadian sample. Additional studies are needed to assess its generalizability to new datasets.

Disclosure
S.A. Srugo: None. Y. Jiang: None. H.I. Morrison: None. M.M. deGroh: None.
2132-P: Islet Amyloid Deposition Is Cytotoxic to Islet Endothelial Cells
Authors: CASTILLO JOSEPH J. , HOGAN MEGHAN F. , APLIN ALFRED , HACKNEY DARYL J. , HULL REBECCA L. 
Published: June 2019

Islet endothelial cells [ECs] produce numerous factors that support normal β-cell function and survival. Under diabetic conditions, islet ECs develop an activated (pro-inflammatory, pro-adhesive) phenotype which contributes to β-cell failure. In human type 2 diabetes [T2D], aggregation of the β-cell product, islet amyloid polypeptide [IAPP], results in amyloid deposition in the islet perivascular space. The toxic effects of IAPP aggregation on the β-cell are well established, however, whether islet ECs are also susceptible to IAPP toxicity remains unknown. We hypothesized that aggregation of amyloidogenic human IAPP (hIAPP) contributes to islet EC activation in T2D. To test this hypothesis, we performed 24h treatments of primary rat islet ECs with hIAPP [0-20 µM] for 24h, along with non-amyloidogenic rat IAPP [rIAPP; 20 µM] as a control, and, subsequently, the MS1 islet EC line with hIAPP [0-20 µM] ± the amyloid inhibitor Congo Red [CR; 100 µM]. In primary islet ECs, hIAPP, but not rIAPP, reduced cell viability and increased activation markers (interleukin-6, endothelin-1, vascular cell adhesion molecule; Table). A similar effect was seen in MS1 cells, and this was abrogated with CR (Table). Our data suggest that islet ECs are susceptible to hIAPP-induced toxicity. The resulting EC activation may interrupt the cross talk between the EC and β-cell, and thereby contribute to the β-cell toxicity of IAPP in T2D.

Disclosure
J.J. Castillo: None. M.F. Hogan: None. A. Aplin: None. D.J. Hackney: None. R.L. Hull: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK088082); National Heart, Lung, and Blood Institute (T32HL007028); U.S. Department of Veterans Affairs (BX004063)
2136-P: Effects of Cytokine Exposure on the Proteome of Human Islets as Evaluated by Shotgun and 2DE Analysis
Authors: GRANO FRANCESCA , CIREGIA FEDERICA , RONCI MAURIZIO , MAZZONI MARIA ROSA , OVERBERGH LUTGART , LUCA CARMELA DE , SULEIMAN MARA , MARSELLI LORELLA , SIMONE PAOLO DE , BOGGI UGO , MATHIEU CHANTAL , EIZIRIK DECIO L. , LUCACCHINI ANTONIO , GIUSTI LAURA , MARCHETTI PIERO , BUGLIANI MARCO 
Published: June 2019

Pro-inflammatory cytokines (CYT) lead to several changes in human islet (HI) protein expression, but few data are available on CYT-induced alterations at the whole proteome level, including post-translational modifications (PTM). We used label-free shotgun analysis (SG) and bi-dimensional gel electrophoresis (2DE) to explore how CYT modify the proteome of isolated HI. For this purpose, HI were isolated from the pancreas of 5 nondiabetic organ donors (age: 74±6 years; gender: 3M/2F; BMI: 27.9±3.6 kg/m2) and then cultured for 48h in the presence of 50 U/ml interleukin (IL)-1β + 1000 U/ml interferon (IFN)-γ. Then, 40 or 250 μg protein extracts were used respectively for SG or 2DE (to assess lysine-acetylation) analysis, with the SG mass spectrometry data acquired by nano-liquid chromatography tandem mass spectrometry. SG identified around 3000 proteins, of which 286 were differentially expressed after CYT exposure. Of these, 176 were upregulated and 110 downregulated. Among the former, we found mediators of inflammation, proteins of the ER and the immunoproteasome system and oxidative stress modulators (e.g., CXCL2, CXCL10, PSMB8, PSMB9, PSMB10, SOD2). Among the downregulated proteins, there were cathepsins, antioxidant molecules and enzymes of glycolysis and Krebs’ cycle (e.g., CTSH (a candidate gene for T1D), PRDX2, MDH). Ingenuity Pathway Analysis indicated that several upstream regulators were predicted to be differentially affected. Of them, 118 were presumably activated, including STAT1 and STAT2, NF-κB, JAK1, IRF1, HMGB1 and 36 inhibited, such as ACKR2, TRIM24, MAPK1, SUMO3. Bi-dimensional gel electrophoresis showed 151 spots that were lysine-acetylated, of which 2 were upregulated (PRDX3 and SOD1) and 4 downregulated (GDH, CTSD, ACAD9 and EIF4A1) by CYT. The present study shows novel proteomic changes, including specific PTM, induced in human islets by cytokine treatment that could play a role in beta cell dysfunction and demise and be the target for specific treatments.

Disclosure
F. Grano: None. F. Ciregia: None. M. Ronci: None. M. Mazzoni: None. L. Overbergh: None. C. De Luca: None. M. Suleiman: None. L. Marselli: None. P. De Simone: None. U. Boggi: None. C. Mathieu: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Roche Diabetes Care, Sanofi. Speaker's Bureau; Self; AstraZeneca, Novartis AG, Novo Nordisk A/S, Sanofi. D.L. Eizirik: None. A. Lucacchini: None. L. Giusti: None. P. Marchetti: None. M. Bugliani: None.

Funding
INNODIA
2141-P: Nrf2 Mediates Glucose-Stimulated Beta-Cell Proliferation
Authors: BAUMEL-ALTERZON SHARON , KATZ LIORA S. , BRILL GABRIEL , GARCIA-OCAÑA ADOLFO , SCOTT DONALD 
Published: June 2019

Glucose catabolism drives adaptive beta cell mass expansion by promoting proliferation under conditions of increased insulin demand. Previously, we showed that induction of the antioxidant regulator, Nrf2, is required for glucose-stimulated β-cell proliferation, and that overexpression of Nrf2 stimulates human beta cell proliferation. Here we manipulate the Nrf2 pathway using pharmacological and genetic approaches to explore the link between glucose metabolism, Nrf2 activation and beta cell proliferation. Treatment of isolated mouse islets with either a Nrf2 inhibitor (brusatol) or Cre-recombinase deleted Nrf2, resulted in complete inhibition of glucose-stimulated proliferation (both n=3, p &lt; 0.01). Conversely, stimulation of Nrf2 by CDDO-me or genetic gain of function (Cre-mediated depletion of Nrf2 inhibitor, Keap1) increased beta cell proliferation of beta cells from isolated mouse islets cultured in 5 mM glucose (4.9 ± 0.2 fold and 6.9 ± 1.4 fold, respectively; n=3, p &lt; 0.05). Inhibition or depletion of Nrf2 was associated with a remarkable decrease in insulin content, suggesting that beta cell identity requires basal levels of Nrf2 expression. Importantly, isolated human beta cells displayed similar responses to Nrf2 loss and gain of function. Activation and nuclear translocation of Nrf2 requires dissociation from its inhibitor, Keap1, and phosphorylation of Ser-40 on Nrf2. Five minutes of 20 mM glucose treatment profoundly increased Ser-40 phosphorylation and translocation of Nrf2, while the same effect by CDDO-Me treatment took 50 minutes in INS1 cells. The glucose-mediated activation and translocation of Nrf2 was blocked by the antioxidant N-acetylcysteine (NAC), which also attenuated glucose-stimulated proliferation of isolated mouse beta cells. In addition, the activation and phosphorylation of Nrf2 was prevented by the pan-PKC inhibitor, calphostin C. We conclude that manipulation of the Nrf2 pathway is an exciting novel target for regulation of beta cell proliferation.

Disclosure
S. Baumel-Alterzon: None. L.S. Katz: None. G. Brill: None. A. Garcia-Ocaña: None. D. Scott: None.

Funding
American Diabetes Association (1-17-IBS-116 to D.S.); National Institutes of Health
2148-P: Islet Endocrine Cells Shows a Unique Pattern on Development and Growth of Each Cell Type in Human Subjects
Authors: OSONOI SHO , MIZUKAMI HIROKI , TAKAHASHI KAZUHISA , KUDO KAZUHIRO , YAGIHASHI SOROKU 
Published: June 2019

Development and growth of islet endocrine cell volume are assumed to mainly depend on cell proliferation. In addition, the partial contribution of islet neogenesis and chromogranin A positive hormone negative cell (CPHN cell) is recently clarified. Detailed evaluation for the islet cell development and growth, however, is not well explored linking to the change of cell replication, neognesis and CPHN cell for each type of endocrine cells in human specimens. For this purpose, we recruited human autopsied pancreata, aged from 24 weeks old to 19 years old (n=32). Formalin-fixed paraffin embedded sections from pancreatic body were used for immunohistochemistry (IHC) and immunofluorescence (IF) analysis. The subjects were divided into 4 groups, Fetus (F: 24-31 weeks), Infant (I : 0-1 years), Child (C : 2-12 years) and Adolescence (A : 13-19 years). Quintuple-IHC with antibodies for glucagon, insulin, somatostatin, pp and Ki-67 was performed for the measurement of islet cell volume density (V) and replication status. Vαand Vβwere increased with age. Vβin A was more abundant than in F (p&lt;0.01). On the other hand, Vδnegatively correlated with age (r=-0.701, p&lt;0.01) and was more in F than in C and A (p&lt;0.01). Ki-67 positive index for αand δ cells showed the highest in F (p&lt;0.01), whereas that of β cells was the highest in I (p&lt;0.01). Neogenic islet density, evaluated in IHC with an antibody for chromogranin A, showed negative correlation with age (r=-0.608, p&lt;0.01). Double-IF with a cocktail of four kinds of antibodies for islet hormones and for chromogranin A was performed to evaluate VCPHN. CPHN cell was identified in both islets and neogenic islets. VCPHNwas more abundant in neogenic islets of F and I than those of C and A. Our results suggest that each kind of islet cell owns a unique pattern of the cell development and growth. In particular, neogenic islet and CPHN cell may play a role as the source of βcells in the later life.

Disclosure
S. Osonoi: None. H. Mizukami: None. K. Takahashi: None. K. Kudo: None. S. Yagihashi: None.
216-OR: Cardiovascular (CV) Impact of BMI in Youth with Type 1 Diabetes (T1D)
Authors: TOMMERDAHL KALIE L. , BAUMGARTNER KARL V. , BJORNSTAD PETTER , BAUMGARTNER AMY , PYLE LAURA , REGENSTEINER JUDITH G. , REUSCH JANE E.B. , NADEAU KRISTEN J. 
Published: June 2019

Insulin resistance (IR) and obesity are independently associated with T1D and are known risk factors for CV disease, the leading cause of mortality in T1D. We evaluated the impact of BMI on CV outcomes in T1D youth and compared obese T1D (OT1D) youth to youth with type 2 diabetes (T2D). Pubertal youth aged 12-21 years with T1D and T2D were recruited from the RESistance to InSulin in type 1 and type 2 diabetes (RESISTANT) and Effects of MEtformin on CardiovasculaR Function in AdoLescents with type 1 Diabetes (EMERALD) cohorts. Participants were stratified as lean (LT1D), overweight, or obese T1D or T2D (Table). CV outcomes included resting heart rate (HR), systolic and diastolic blood pressure (SBP, DBP), leptin, hsCRP, and adiponectin. T1D participants performed bicycle ergometry for peak oxygen consumption (VO2peak), brachial artery (BA) distensibility by Dynapulse, and aortic MRI. HR, SBP, DBP, mean arterial pressure, and prevalence of hypertension were higher and BA distensibility, descending aorta oscillatory shear index, VO2peak, leptin, and hsCRP were worsened in OT1D vs. LT1D. Beyond hypertension prevalence in OT1D vs. T2D, which was worse in OT1D, T2D did not differ significantly from OT1D. Higher BMI, which is increasingly prevalent in T1D, is associated with a worsened CV profile in T1D youth, nearly approximating the CV phenotype of T2D youth. Closer attention to lifestyle management in T1D youth is needed to help reduce CV risk.

Disclosure
K.L. Tommerdahl: None. K.V. Baumgartner: None. P. Bjornstad: Advisory Panel; Self; Horizon, XORTX. Consultant; Self; Bayer US, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company. A. Baumgartner: None. L. Pyle: None. J.G. Regensteiner: None. J.E.B. Reusch: Board Member; Self; American Diabetes Association. Other Relationship; Self; Merck & Co., Inc. K.J. Nadeau: None.

Funding
American Diabetes Association (7-11-CD-08 to K.J.N.); JDRF (11-2010-343); National Institutes of Health (1R56DK088971-01)