bluuebunny/crossref_metadata_2025_split huggingface dataset:
293-OR: Mitochondrial Hexokinase Dissociation Correlates with Obesity-Induced Inflammation and Regulates the Fate of Glucose
Authors: NEJAD FARNAZ KEYHANI , DEJESUS ADAM , GEIER JUSTIN A. , ARDEHALI HOSSEIN 
Published: June 2020

It has been shown that high fat diet (HFD) induced obesity triggers local immune cell infiltration leading to pro-inflammatory cytokine production and subsequently to a state of chronic low-grade inflammation in adipose and spleen tissues. However, the underlying mechanisms driving this chronic inflammation remains poorly defined. The product of hexokinase (HK) enzymes, glucose-6-phosphate, can be metabolized through glycolysis to produce ATP and pyruvate or alternative pathways, such as the pentose-phosphate-pathway (PPP) to generate anabolic intermediates. HK1 contains an N-terminal domain that permits mitochondrial binding, but its physiologic significance is unclear. We found that adipose and spleen tissues from HFD mice had increased cytosolic HK1, which correlated with an increase in inflammatory cytokine mRNA levels. To elucidate whether HK1 subcellular localization to the mitochondria affects the inflammatory response we generated mice lacking the HK1 mitochondrial binding domain, termed ΔE1HK1. These mice appear normal and show no change in body weight, Mendelian ratios, glucose tolerance or hexokinase activity across different tissues as compared to littermate controls. However, lipopolysaccharide challenge in these mice produced a hyper-inflammatory phenotype in vitro and in vivo. We performed steady-state and flux metabolomics in ΔE1HK1 mouse tissues and found increased glucose derived metabolites above the level of GAPDH, including PPP metabolites. Additionally, we found that GAPDH activity was attenuated in the ΔE1HK1 mice and may explain the elevated PPP flux upstream of GAPDH. Since PPP is vital for proper inflammatory cell activation, we treated cells from these mice with PPP inhibitors and found a reversal of the hyper-inflammatory phenotype observed in ΔE1HK1 mice. Our data suggests that mitochondrial dissociation of HK1 alters glucose utilization, which subsequently increases the pro-inflammatory response.

Disclosure
F. Keyhani Nejad: None. A. DeJesus: None. J.A. Geier: None. H. Ardehali: None.
294-OR: Discovery of a Novel Secretory Protein from the Gut Microbiome That Promotes Immune Tolerance and Ameliorates Autoimmunity via Dendritic Cell Induction of IL-10
Authors: KOSTIC ALEKSANDAR 
Published: June 2020

The human gut microbiota has been associated with diverse autoimmune diseases; however, the underlying mechanisms are largely unknown. To identify gut microbes and derived bioactive molecules that can promote immune tolerance, we systematically investigated the immunoregulatory potential of each member in the Altered Schaedler Flora (ASF) that has demonstrated diverse immune functions in mice. We observed that the eight ASF members presented a division of labor in promoting distinct immunophenotypes of bone marrow-derived dendritic cells, such as the production of IL-10, TNF-a, and TGF-b, and the induction of regulatory T cells. Interestingly, Parabacteroides goldsteinii ASF519 induced strong immune tolerance via novel mechanisms as evidenced by non-pan T cells-mediated promotion of Foxp3+ Treg proliferation and reduction of cytotoxic CD8 T cells, as well as TNF-a signaling-independent IL-10 production. Via bioactivity-guided fractionation, ASF519-derived molecules responsible for inducing immune tolerance were identified to be heat-labile secretory proteins with yet-uncharacterized functions. Genome-wide screening additionally identified a complex regulatory network that controls the immunoregulatory potency of ASF519. ASF519 colonization in germ-free mice significantly reduced IL-4 and IL-5 in sera and increased the transcript abundance of ll-10 and ll-17A in colon, suggesting potential roles of ASF519 in modulating both intestinal and systemic immune functions. In mouse immune disease models, oral administration of ASF519 demonstrated a protective role in the development of dextran sodium sulfate-induced colitis and collagen-induced arthritis. Relevant mechanisms are now under investigation. This study has the potential to provide novel therapeutic avenues for the prevention and treatment of autoimmune diseases.

Disclosure
A. Kostic: None.

Funding
American Diabetes Association/Pathway to Stop Diabetes (1-17-INI-13)
30-LB: Does CKD Adversely Affect the Outcome of Diabetic Patients Who Were Admitted with Diabetic Ketoacidosis? An Analysis of the Nationwide Inpatient Sample
Authors: SHAKA HAFEEZ , EDIGIN EHIZOGIE , GOMEZ TRISHA MARIE A. , XU JING , YAP SARA ELIZABETH T. , PADILLA SORTO MARIA ELENA 
Published: June 2020

Background: Diabetic ketoacidosis (DKA) is managed with insulin and fluids, which can be challenging in patients with CKD. Diabetes is a common cause of CKD.
Objective: To ascertain if patients admitted with DKA with CKD had worse outcomes compared to patients without CKD.
Method: Data were extracted from the Nationwide Inpatient Sample (NIS) Database for 2016 and 2017. The numbers in the database are weighted to optimize national estimates. Hospitalizations involving adults with a principal diagnosis of DKA were included. This group was further categorized based on the presence of CKD as a secondary diagnosis. The primary outcome was inpatient mortality and secondary outcomes were Length of stay (LOS) and Total hospital Charge (THC). Multivariate regression analysis was used to adjust for possible confounders.
Results: There were 245,170 adults who had a principal discharge diagnosis of DKA, of which 22700 had a secondary diagnosis of stage 1-5 CKD or ESRD. Those with CKD were significantly older on average (45.1 vs. 34.7 years) but without sex variation, compared to those without CKD.
A total of 650 inpatient mortality (0.27%) occurred in patients with DKA, 135 occurring in patients with CKD (0.60%). After accounting for age, sex, disease severity and type of diabetes, the adjusted odds ratio (aOR) for mortality in patients with CKD compared to those without CKD was 0.89 (95% CI: 0.511 1.551, p= 0.682). CKD patients had an adjusted increase in total hospital charge of $5970 (95% CI: 2823 - 9116, p&lt;0.001) and adjusted increase in length of hospitalization of 0.6 days ((95% CI: 0.3 - 0.8, p&lt;0.001).
Conclusions: In patients hospitalized with a principal diagnosis of DKA, there was no significant difference in mortality among patients with co-existing CKD. A modest increase in LOS and THC was however noted in those with CKD which was statistically significant. More research needs to be done to elucidate the effect of CKD stages on these outcomes.

Disclosure
H. Shaka: None. E. Edigin: None. T.A. Gomez: None. J. Xu: None. S.T. Yap: None. M. Padilla Sorto: None.
305-OR: Glycemic Variability and Progression of CKD: PERL Substudy
Authors: MCGILL JANET B. , HIRSCH IRL B. , CALHOUN PETER , GALECKI ANDRZEJ , RUEDY KATRINA , WU CHUN-YI , DORIA ALESSANDRO 
Published: June 2020

To test the hypothesis that glucose variability may impact the progression of kidney disease in type 1 diabetes (T1D), we studied a subgroup of the Preventing Early Renal Loss (PERL) study population with T1D and mild to moderate diabetic kidney disease, using blinded continuous glucose monitoring (CGM) for up to 14 days for each wear period. We studied 175 participants wearing 366 blinded FreeStyle Libre CGMs on one to five occasions between weeks 96 and 164 of the follow-up in the parent study. The mean age of the population was 52.2 ± 10.9 (mean ± SD) years, mean duration of T1D was 36.1 ± 12.2 years. Baseline BMI, A1C, and iothalamate GFR (iGFR) were 29.9 ± 6.3 kg/m2, 8.2 ± 1.2%, and 67.5 ± 17.2 ml/min/1.73m2 respectively. During the study, mean glucose (MG) and coefficient of variation glucose (CV) were 174.5 ± 41.4 mg/dL and 44.5± 8.8% respectively. Mean amplitude of glycemic excursions (MAGE) was 146.0 ± 43.9 mg/dL while time-in-range (TIR) was 50.5 ± 16.1%. A 10% increase in the mean CV was associated with a 1.4 ml/min/1.73m2 decrease in iGFR at the end of the study [95%CI (-3.33, 0.44); p=0.13] while a 10 mg/dL increase in MAGE was associated with a 0.01 ml/min/1.73m2 decrease [95%CI (-0.41, 0.38); p=0.95]. For those with CV &gt;36, iGFR was 2.56 ml/min/1.73m2 lower compared with those with CV &lt;36 [95%CI (-7.44, 2.31); p=0.30]. Low blood glucose index, high blood glucose index, MG, and TIR were not significantly associated with iGFR. Given the non-significant associations between CGM metrics and iGFR, we conclude in this study of a population with T1D and mild to moderate kidney disease that there is no evidence that glycemic variability or glucose control impacts the rate of loss of iGFR. Limitations of the study include the observational study design, the relatively small sample size, the variability of how frequently CGM data were collected, and the short duration of observation. A larger prospective study using real-time CGM to improve glycemic parameters and reduce glycemic variability is required to answer this question definitively.

Disclosure
J.B. McGill: Advisory Panel; Self; Aegerion Pharmaceuticals, Bayer AG, Lilly Diabetes, Novo Nordisk A/S. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Inc. Research Support; Self; Medtronic, Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; Aegerion Pharmaceuticals, Dexcom, Inc., Janssen Pharmaceuticals, Inc. I.B. Hirsch: Consultant; Self; Abbott, Bigfoot Biomedical, Roche Diabetes Care. Research Support; Self; Medtronic, Omnipod. P. Calhoun: Stock/Shareholder; Self; Dexcom, Inc. A. Galecki: None. K. Ruedy: None. C. Wu: None. A. Doria: Research Support; Self; Sanofi.

Funding
The Leona M. and Harry B. Helmsley Charitable Trust (2018PG-TD1014); National Institute of Diabetes and Digestive and Kidney Diseases (R03DK094484, R34DK097808, UC4DK101108); JDRF (17-2012-377)
310-OR: Role of Glucose Flux to Elevate Hepatic Lipogenesis in Biopsy-Proven NASH
Authors: MUCINSKI JUSTINE M. , SHARMA NEAL , MOORE MARY P. , IBDAH JAMAL A. , RECTOR R. SCOTT , PARKS ELIZABETH J. 
Published: June 2020

Hepatic de novo lipogenesis (DNL) contributes to the development of nonalcoholic fatty liver disease (NAFLD) and the more advanced form, nonalcoholic steatohepatitis (NASH). The purpose of the present study was to test the effects of glucose control on hepatic DNL in subjects with biopsy-proven NASH. Ten subjects [mean±SD, age 38.6±8.4y, BMI 42.2±5.9kg/m2, NAFLD activity score (NAS 1-8) of 5.7±1.3] completed metabolic studies to quantitate glucose oxidation (GluOx) measured by indirect calorimetry, liver fat by MRI/MRS, hepatic DNL using d2O administration, and VLDL-TG sources by GC/MS. Fed state GluOx was associated with NAS (Figure 1A) and fractional DNL (Figure 1B). Fasting GluOx was related to fibrosis (data not shown, r=0.690, P=0.027), ALT (r=0.631, P=0.051), AST (r=0.663, P=0.037), and absolute DNL (r=0.684, P=0.042). Subjects are participating in a 9-month diet/exercise intervention; six of whom have completed the trial increased VO2max (Figure 1C, P=0.015), reduced body mass 9.3±6.3% (P=0.008), DNL (P=0.045, n=5), liver fat (P=0.018), and ALT (P=0.001); NAS score fell from 6.3±1.0 to 3.8±2.2 (P=0.029). These data highlight how elevations in fasting and fed glycolysis can upregulate hepatic DNL to cause NASH. Lifestyle modifications that reduce DNL are likely to contribute to improvements in NAFLD/NASH.

Disclosure
J.M. Mucinski: None. N. Sharma: None. M.P. Moore: None. J.A. Ibdah: None. R. Rector: None. E.J. Parks: None.

Funding
National Institutes of Health (R01DK113701)
311-OR: Reduced Hepatic Mitochondrial Metabolism and Markers of Mitochondrial Turnover in Humans Are Linked to NAFLD Progression
Authors: MOORE MARY P. , CUNNINGHAM RORY , MEERS GRACE M. , JOHNSON SARAH A. , WHEELER ANDREW A. , GANGA RAMA RAO , PITT JAMES , SPENCER NICOLE , DIAZ-ARIAS ALBERTO A. , SWI AHMED , IBDAH JAMAL A. , PARKS ELIZABETH J. , RECTOR R S. 
Published: June 2020

Considerable ambiguity exists in the literature regarding the role of hepatic mitochondrial dysfunction in the pathological progression of nonalcoholic fatty liver disease (NAFLD) to steatohepatitis (NASH) and fibrosis. To investigate this relationship, liver biopsies were obtained from patients with morbid obesity undergoing bariatric surgery [n=110, age 44.7±11.7 y, weight 136.3±25.5 kg, BMI 48.7±7.4 kg/m2, AST 35.6±32.1 U/L, ALT 41.0±35.6 U/L, NAFLD activity score 3±2 (NAS; liver injury score: steatosis, ballooning, and inflammation; range: 0-8), fibrosis score 0.5±1.0 (range: 0-4), glucose 104±33 mg/dL] and assessments of mitochondrial function and turnover performed. Data were clustered into four groups based on NAS (No Disease, NAS=0, n=13; Mild NAS=1-2, n=28; Moderate NAS=3-4, n=41; and Severe NAS≥5, n=28). Complete hepatic mitochondrial oxidation of palmitate to CO2 was reduced by ∼50% with Moderate and Severe NAS vs. no disease (p&lt;0.05). This was accompanied by a 50% decrease in hepatic β-HAD activity in all groups with NAFLD (p&lt;0.01), without any differences in citrate synthase activity (p&gt;0.05). In addition to reduced hepatic mitochondrial function, elevated NAS was associated with reduced hepatic mitochondrial biogenesis (PGC1α, SIRT1, PPARα, and AMPKα1 mRNA; p&lt;0.05) and mitochondrial turnover (BNIP3, PARKIN mRNA; p&lt;0.05) markers. Furthermore, hepatic mitochondrial H2O2 emission was elevated in Severe NAS (p&lt;0.01) and positively related to lobular inflammation (r=0.336, p&lt;0.01) and hepatocellular ballooning (r=0.379, p&lt;0.001). Here, we provide novel insight into the relationship between NAFLD severity and hepatic mitochondrial dysfunction. Our findings suggest that compromised hepatic mitochondrial fatty acid metabolism and reduced hepatic mitochondrial biogenesis/turnover may be linked to NAFLD progression in patients with morbid obesity.

Disclosure
M.P. Moore: None. R. Cunningham: None. G.M. Meers: None. S.A. Johnson: None. A.A. Wheeler: None. R. Ganga: None. J. Pitt: None. N. Spencer: None. A.A. Diaz-Arias: None. A. Swi: None. J.A. Ibdah: None. E.J. Parks: None. R.S. Rector: None.

Funding
National Institutes of Health (R01DK113701); U.S. Department of Veterans Affairs (I01BX003271)
315-OR: Hyperglycemia Increases Central Aortic Stiffness in Response to Insulin in Healthy Humans
Authors: HORTON WILLIAM B. , JAHN LINDA , HARTLINE LEE , PATRIE JAMES T. , BARRETT EUGENE 
Published: June 2020

Introduction: Insulin exerts several opposing hemodynamic vascular actions, including stimulation of both nitric oxide-mediated vasodilation and endothelin-1-mediated vasoconstriction. Notably, hyperglycemia switches the vascular response to insulin from dilation to constriction in pre-clinical studies. To our knowledge, hyperglycemia’s effect on insulin’s action on vascular stiffness in humans is unknown. The American Heart Association recently recommended that vascular stiffness be determined noninvasively by carotid-femoral pulse wave velocity (cfPWV) and/or using wave separation analyses (WSA) instead of aortic augmentation index (AIx).
Methods: Thirteen lean, healthy subjects twice received a 1 mU/kg/min 2-hour insulin clamp. In one study, subjects were euglycemic and in the second, hyperglycemic (∼200 mg/dL) for 2 hours before and throughout the clamp. In each study, octreotide was infused to block endogenous insulin secretion. We assessed vascular stiffness with cfPWV, AIx, and WSA at baseline and after the 2-hour insulin clamp. Linear mixed model was used for statistical analysis, with Bonferroni correction for between-study comparisons. Spearman correlation was used to evaluate the relationship between PWV and WSA components.
Results: Compared to baseline, insulin increased cfPWV (p=0.03) during hyperglycemia without affecting AIx or components of WSA. No changes were observed during euglycemia, and insulin levels did not differ between groups. Neither AIx nor WSA components (i.e., backward and forward wave amplitude and reflection magnitude) correlated with cfPWV.
Discussion: We provide the first evidence that 4 hours of moderate hyperglycemia unmasks an action of physiologic hyperinsulinemia to increase central aortic stiffness (as measured by cfPWV) in healthy humans. Second, our results suggest that neither AIx nor WSA components correlate with cfPWV as measures of vascular stiffness.

Disclosure
W.B. Horton: None. L. Jahn: None. L. Hartline: None. J.T. Patrie: None. E. Barrett: None.
316-OR: Oral vs. Intravenous Glucose Administration Produce Opposing Microvascular Actions in Skeletal Muscle of Healthy People
Authors: ROBERTS-THOMSON KATHERINE , PARKER LEWAN , BETIK ANDREW C. , KESKE MICHELLE 
Published: June 2020

Skeletal muscle microvascular blood flow (MBF) increases in response to an insulin infusion (hyperinsulinemic-euglycemic clamp) or the consumption of a mixed meal to augment glucose disposal. This microvascular action is impaired during insulin resistance. We recently demonstrated that an oral glucose challenge (50g glucose) acutely impairs skeletal muscle MBF in healthy people, compared to a mixed meal challenge, despite similar levels of hyperinsulinemia. We aimed to determine whether post-prandial hyperglycemia or gut-derived factors are the primary mediators of impaired MBF observed in response to orally ingested glucose. Seven healthy overnight-fasted subjects (sex 2M/5F, age 29±9 yrs, BMI 23.5±3.2 kg/m2, blood glucose 4.5±0.3 mM, HbA1c 5.2±0.3%, total cholesterol 3.9±1.0 mM, triglycerides 0.8±0.3 mM) underwent an oral glucose tolerance test (OGTT, 75g glucose) and an intravenous glucose tolerance test (IVGTT- bypassing the gut) matched for similar blood glucose levels, on successive visits (&lt;4 weeks apart: cross-over design). MBF was assessed in the vastus lateralis by contrast-enhanced ultrasound at baseline, 60 and 120 minutes post-OGTT and -IVGTT. Despite similar area under the glucose time curve (OGTT: 846.8±124.8, IVGTT: 845.9±121.1 mMx2hr, P=0.98), MBF was only stimulated with the IVGTT, at 60 min (Δ MBF: OGTT -0.3± 0.5; IVGTT 0.3± 0.3 Acoustic intensity/sec, P=0.02) and 120 min post- infusion (Δ MBF: OGTT -0.4± 0.3; IVGTT 0.2± 0.3 Acoustic intensity/sec, P&lt;0.01). Therefore, the extent of post-prandial hyperglycemia per se does not acutely impact microvascular responses in skeletal muscle in healthy humans. These data support the role of gut-derived factor(s) in the impairment of MBF following orally ingested glucose. These findings have important physiological implications for the consumption of high glycemic index meals.

Disclosure
K. Roberts-Thomson: None. L. Parker: None. A.C. Betik: None. M. Keske: None.
319-OR: First Responder Beta-Cell Subpopulation Affects Islet Response to Glucose
Authors: KRAVETS VIRA , DWULET JAEANN M. , SCHLEICHER WOLFGANG , BENNINGER RICHARD K. 
Published: June 2020

Glucose-stimulated insulin secretion from the pancreatic β-cells is driven by calcium (Ca2+) uptake. In mice Ca2+ is disproportionally controlled by functional subpopulations of β-cells, identified in affecting 2nd phase oscillatory Ca2+ response. Yet, the “1st-responder” cells that lead the 1st Ca2+phase disrupted in early diabetes were overlooked. It is unknown whether 1st responders are a distinct subpopulation, and if so, which factors underlie this distinction, and what is their role. We hypothesized that 1st responder metabolic and electrical parameters are distinct from the known β-cell subpopulations, and they play an important role in the 1st Ca2+phase of the islet response. We simultaneously measured Ca2+ dynamics and electrical coupling in intact islets using β-cells specific expression of the Ca2+ sensor GCaMP6s. We performed repeated glucose and Kapt channel blocker stimulation of the islet. We used femtosecond laser ablation of specific cells. This was complimented by multicellular islet electrophysiology model where we could remove specific cells from the islet and evaluate glucokinase rate, Katp and coupling conductance of the cells. We found no overlap of 1st responder with either “wave-initiator”, leading Ca2+ wave, or highly connected “hub” cell subpopulations, based on the oscillatory 2nd phase Ca2+ wave coordination. Interestingly 1st responders were less electrically coupled (p=0.0157), supported by simulations. 1st responders were consistent under repeatable glucose stimulation and remained 1st responders under the Katp channel blocker, supported by computational results of lower than average Katp channel conductance (p&lt;0.0001). Removing 1st responder from the islet resulted in delayed 1st phase islet response compared to the random cell removal, both in experiment and simulation (p=.0428).
In conclusion, 1st responders are distinct β-cell sub-population, which influences the islet 1st phase Ca2+response.

Disclosure
V. Kravets: None. J.M. Dwulet: None. W. Schleicher: None. R.K. Benninger: None.

Funding
JDRF (63012150); National Institutes of Health (R0163012150)
328-OR: Retinopathy Screening in Adolescents with Type 1 Diabetes
Authors: JANUSZEWSKI ANDRZEJ S. , VELAYUTHAM VALLIMAYIL , BENITEZ-AGUIRRE PAUL Z. , CRAIG MARIA E. , LIEW GERALD , CHO YOON HI , JENKINS ALICIA , DONAGHUE KIM C. 
Published: June 2020

Introduction: Current ISPAD guidelines recommend biennial diabetic retinopathy (DR) screening starting at age 11 yrs with type 1 diabetes (T1D) duration 2-5 yrs. Growing evidence suggesting less frequent screening.
Methods: DR was ETDRS graded and progress assed by Markov chain model analysis. Retinal photos were from 2,169 patients (baseline (mean±SD): age 13.1±2.1 yrs, HbA1c 8.5±1.4%, 5.4±2.9 yrs T1D, follow-up 5.3±3.6 yrs) who attended the T1D clinic at least twice in 1990-2018.
Results: In 11/2,169 patients DR progressed to severe non-proliferative (SNP) DR or above. See tables 1 and 2 below for detailed results.
Conclusions: Our data support less frequent DR screening in T1D youth without any DR. Although DR progression is generally slow, poor glycaemic control greatly accelerates it.

Disclosure
A.S. Januszewski: None. V. Velayutham: None. P.Z. Benitez-Aguirre: None. M.E. Craig: None. G. Liew: None. Y. Cho: None. A. Jenkins: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Sanofi-Aventis. K.C. Donaghue: None.
342-OR: Optimal Ages for Screening for T1D Risk in Children
Authors: GHALWASH MOHAMED , ANAND VIBHA , HAGOPIAN WILLIAM , LUNDGREN MARKUS , REWERS MARIAN , VEIJOLA RIITTA , ZIEGLER ANETTE-GABRIELE , DUNNE JESSICA L. ,   T1DI STUDY
Published: June 2020

Screening for pre-symptomatic T1D can significantly reduce the risk of DKA at diagnosis. Screening can also identify children who may benefit from interventions to delay/prevent progression from islet autoimmunity (IA) to diabetes. To help design a rational screening schedule, we analyzed data to determine the optimal ages to screen children for IA. Longitudinal data sets from birth cohort studies (DIPP, BABYDIAB, DiPiS, and DAISY) were harmonized for analyses. We analyzed the age of screening for multiple autoantibodies to insulin, GAD and IA-2 to maximize the sensitivity and positive predictive value (PPV) to predict development of T1D by age 15. Inverse probability censoring weighting was used to account for right censored outcomes. Cumulative sensitivity, dynamic specificity, positive and negative predictive values were used to describe the models. In the combined cohorts (n=6061), a one-time screening for multiple autoantibodies achieved a maximum sensitivity of 35% and a PPV of 70-80% when applied at age 3-5 yr. To increase the sensitivity above 50% and retain PPV &gt;70%, two screenings should occur: at 2-3 yr and at 5-6 yr (Fig). Public health screening efforts to identify children progressing to T1D must make compromises based on feasibility, cost, optimal metrics. Our data represent a starting point for these considerations that should be customized based on the population’s underlying disease characteristics and public health infrastructure.

Disclosure
M. Ghalwash: None. V. Anand: None. W. Hagopian: Consultant; Self; Novo Nordisk Inc. M. Lundgren: None. M. Rewers: None. R. Veijola: None. A. Ziegler: None. J.L. Dunne: None.