bluuebunny/crossref_metadata_2025_split huggingface dataset:
327-LB: Transgenic Overexpression of MicroRNA-30d Impairs Glucose Homeostasis by Regulating Beta-Cell Proliferation and Dedifferentiation
Authors: TANG XIAOQING 
Published: June 2019

MicroRNAs (miRNAs) are small non-coding RNAs that bind to target mRNAs and inhibit the translation in mammals. Abnormal miRNA functions are closely associated with pancreatic beta-cell loss and dysfunction in type 2 diabetes. Downregulation of miR-30d has been observed in the islets of diabetic mice. To investigate the in vivo function of miR-30d in pancreatic beta cells, we generated the transgenic mice that overexpressed miR-30d specifically in the pancreatic beta cells. Compared to wild type mice, the transgenic mice that overexpressed miR-30d resulted in hyperglycemia and glucose intolerance with reduced beta-cell mass and insulin production following high fat diet treatment. Strikingly, loss of beta-cell mass was partially due to beta-cell dedifferentiation to glucagon-producing alpha-cells, resulted in increased plasma glucagon level. The transcriptomic analysis combined with bioinformatic analysis of islets isolated from transgenic verses control mice identified connective tissue growth factor (CTGF) and Cyclin E2 as miR-30d potential targets. Moreover, several β-cell disallowed genes (e.g., MCT4/SLC16A3, LDHA) were observed upregulated in transgenic mice, which have been reported as positive markers of dedifferentiated human β-cells from type 2 diabetic patients. Taken together, miR-30d plays an essential role in maintaining mature beta-cell identity.

Disclosure
X. Tang: None.

Funding
National Institutes of Health
330-OR: A 30% Increased Insulin Dose Is Necessary to Control Postprandial Hyperglycemia for High Protein Meals in Individuals with Type 1 Diabetes Using Insulin Pump Therapy
Authors: PATERSON MEGAN A. , SMART CARMEL E. , RAFFERTY JORDAN , FENTON BRETT , PRICE DARRELL , FOSKETT DEBORAH C. , MAHER ANDREW , HOWLEY PETER , KING BRUCE R. 
Published: June 2019

Dietary protein increases the postprandial glycemic response and insulin requirements in people with type 1 diabetes (T1D). The aim of this study was to determine the appropriate amount of additional insulin required for the protein content of a meal to prevent postprandial hyperglycemia. Twenty-nine subjects (12 male) with T1D using CSII (HbA1c&lt;8.1%/65mmol/mol) aged 10-40 years consumed 5 test meals containing 50g protein, 0g fat and 30g CHO. Insulin doses were calculated based on the individual insulin:CHO ratio with 0 (standard), 15, 30, 45 and 60% additional insulin added to the dose and delivered over 3 hours using a dual/combination bolus. Postprandial glycemia was assessed by 4 hours of CGM. Standard insulin dosing resulted in delayed and sustained postprandial hyperglycemia. From 150 minutes, additional insulin doses of 30% resulted in significantly lower postprandial glycemic excursions, returning to baseline by 4 hours; compared with 0-15% additional insulin (p&lt;0.05). Additional insulin doses of 45 and 60% resulted in increased episodes of hypoglycemia in 50% (n=15) and 80% (n=23) of participants respectively. This study demonstrates that adding 30% more insulin to a standard meal-time dose for a high protein meal, delivered using a dual/combination bolus, improves postprandial glycemia in individuals with T1D using CSII.

Disclosure
M.A. Paterson: None. C.E. Smart: None. J. Rafferty: None. B. Fenton: None. D. Price: None. D.C. Foskett: None. A. Maher: None. P. Howley: None. B.R. King: None.

Funding
John Hunter Children's Hospital; Dexcom External Research Program
331-LB: A Switch in Nutrient Sensing Controls Functional Maturation of Pancreatic Beta Cells
Authors: HELMAN AHARON , MELTON DOUGLAS 
Published: June 2019

A drastic transition at birth, from constant maternal nutrient supply in-utero to intermittent postnatal feeding, requires functional changes in the metabolic system. Considering their central role in controlling metabolic homeostasis, little is known about how beta-cells adjust to the new nutritional challenge. Our experiments show that after birth beta-cells undergo a functional shift from amino acids- to glucose-stimulated insulin secretion. Moreover, a change in mTORC1 activity, from dependence on amino acids in the amino acid-rich environment in-utero to a postnatal dependence on glucose, corresponds with the initiation of glucose-responsive insulin secretion. Disrupting nutrient sensitivity of mTORC1 in mature beta-cells, via deletion of leucine-responsive inhibitors Sestrin1 and Sestrin2, reverts beta-cells to an immature state. Finally, manipulating mTORC1 nutrient sensitivity in stem-cell-derived beta-cells in-vitro shifts them from constitutive to glucose-dependent insulin secretion. These results reveal a post-transcriptional mechanism where nutritional environment and mTORC1 signaling regulate glucose responsiveness, thereby promoting beta-cell maturation.

Disclosure
A. Helman: None.
334-OR: Supplementation with Histidine-Containing Dipeptides Improves Cardiometabolic Risk Factors: A Meta-analysis of Randomized Controlled Trials
Authors: MENON KIRTHI ARAVIND , MOUSA AYA , MARQUINA CLARA , DE COURTEN BARBORA 
Published: June 2019

Background: The burden of obesity and type 2 diabetes is rapidly increasing. Carnosine (β alanyl L-histidine), a dipeptide with anti-inflammatory, anti-glycating, and anti-oxidative properties, may be a potential strategy to mitigate cardiometabolic risk factors. However, studies examining the effects of carnosine and related histidine-containing dipeptides (HCDs; e.g., beta-alanine) on cardiometabolic risk have been inconsistent.
Objective: We conducted a systematic review and meta-analysis examining the effects of all HCDs on cardiometabolic risk factors in all population groups.
Methods: MEDLINE, CINAHL, EMBASE, and EBM were searched for randomized controlled trials investigating the effects of carnosine and/or HCDs on cardiometabolic risk factors, compared with placebo, usual care, or other interventions. Meta-analyses using random-effects models were used to calculate the mean difference (MD) and 95% confidence interval (CI) for each outcome.
Results: Forty- nine RCTs totaling 1709 participants were included. Carnosine and/or HCD supplementation lowered waist circumference (n= 162, MD [95% CI]= -3.53 cm [-5.65,1.41], p=0.001); post-prandial glucose (PPG) (n=230, MD [95% CI]= -0.79 mmol/L [-1.23,-0.35], p=0.0004), HbA1c (n=283, MD [95% CI]= -0.37% [-0.64,-0.10], p=0.006) and C-reactive protein (CRP) (n=272, MD [95% CI]= -0.43 mg/L [-0.64,-0.22], p&lt; 0.0001) compared with control. In sensitivity analyses of RCTs using carnosine only, PPG, HbA1c, and CRP remained significantly lower with carnosine supplementation (all p&lt;0.05), and fasting glucose and triglycerides became significantly lower with carnosine versus control (n=309 for both, MD [95% CI]= -0.58 mmol/L [-1.12,-0.05], p=0.03; and -0.2 mmol/L [-0.27,-0.13], p&lt;0.0001, respectively).
Conclusion: Our findings provide level 1 evidence that carnosine and HCDs have potential benefits for prevention and treatment of diabetes.

Disclosure
K. Aravind Menon: None. A. Mousa: None. C. Marquina: None. B. de Courten: None.
34-LB: Clinically Meaningful Improvements of Gastroparesis Overall Symptoms Using Tradipitant
Authors: CARLIN JESSE L. , LIEBERMAN VERNA R. , DAHAL ARYA , KEEFE MADISON S. , XIAO CHANGFU , BIRZNIEKS GUNTHER , POLYMEROPOULOS MIHAEL H. 
Published: June 2019

Background: Patients with diabetic and idiopathic gastroparesis with delayed gastric emptying and moderate to severe nausea were enrolled into a phase II multicenter, randomized, double-blind, placebo-controlled trial. Subjects were randomized to receive oral 85mg tradipitant bid or placebo (1:1) for 4 weeks. Of the 152 patients, 60% of patients had idiopathic and 40% had diabetic gastroparesis.
Methods: The primary outcome was change in average nausea from baseline, measured using the 5-point Gastroparesis Core Symptom Daily Diary (GCSDD). Overall gastroparesis symptoms were evaluated using the Gastroparesis Cardinal Symptom Index (GCSI), and Patient Assessment of Gastrointestinal Disorders Symptom Severity Index (PAGI-SYM).
Results: A statistically significant and clinically meaningful improvement in nausea and overall gastroparesis symptoms was observed in patients on tradipitant. Subjects receiving tradipitant had a significant decrease in their average nausea score compared to placebo with LS mean difference (95% CI) of -0.53 (-0.92, -0.13, p=0.0099) as well as a significant increase in nausea free days (28.8% increase on tradipitant compared to 15.0% increase on placebo, p=0.0160). A clinically meaningful response of 1-point or more improvement on the GCSI total score was observed in 46.0% of patients on tradipitant compared to 24.2% of patients on placebo (p=0.0086).
Conclusions: Tradipitant treatment resulted in statistically and clinically meaningful improvements in nausea and overall gastroparesis symptoms. Tradipitant was well tolerated with comparable rates of adverse events between tradipitant and placebo groups. These robust efficacy results suggest tradipitant has the potential to become a first line treatment for idiopathic and diabetic gastroparesis.

Disclosure
J.L. Carlin: Employee; Self; Vanda Pharmaceuticals, Inc. V.R. Lieberman: Employee; Self; Vanda Pharmaceuticals, Inc. Stock/Shareholder; Self; Vanda Pharmaceuticals, Inc. A. Dahal: Employee; Self; Vanda Pharmaceuticals, Inc. Stock/Shareholder; Self; Vanda Pharmaceuticals, Inc. M.S. Keefe: Employee; Self; Vanda Pharmaceuticals. Stock/Shareholder; Self; Vanda Pharmaceuticals. C. Xiao: Employee; Self; Vanda pharmaceutical inc. G. Birznieks: Employee; Self; Vanda Pharmaceuticals. M.H. Polymeropoulos: Employee; Self; Vanda Pharmaceuticals Inc.
342-LB: Iron Regulatory Protein 2 Regulates Proinsulin Production in Pancreatic Beta Cells through Iron-Dependent Cdkal1-Catalyzed tRNA Modification
Authors: FERREIRA DOS SANTOS MARIA C. , RAJAN MALINI , LEIBOLD ELIZABETH 
Published: June 2019

Iron regulatory protein 2 (Irp2) is a key regulator of cellular iron metabolism in vertebrates. Irp2 controls the post-transcriptional expression of the iron-uptake protein transferrin receptor 1 (TfR1) and the iron-storage protein ferritin. Here we show that Irp2-/-mice develop diabetes characterized by glucose intolerance and impaired glucose-stimulated insulin secretion from pancreatic β-cells. Impaired glucose-stimulated insulin secretion in Irp2-/-β-cells is not due to insulin resistance but rather to a reduction in insulin stores caused by impaired proinsulin processing. Loss of Irp2 reduces TfR1 expression and iron content, and increases ferritin expression and iron sequestration causing cellular iron deficiency that impairs mitochondrial Fe-S cluster biosynthesis. This in turn reduces the function of Cdk5-regulated subunit-associated protein 1 like (Cdkal1), a 4Fe-4S cluster enzyme that catalyzes the 2-methythio (ms) modification of t6A37 of tRNALys(UUU)to ms2t6A37, which is critical for efficient translation of lysine codons in proinsulin. Irp2-deficient β cells show reduced ms2t6A37 levels and lysine incorporation into proinsulin. Increasing cellular iron content in Irp2-deficient β cells normalizes mitochondrial function, ms2t6A37 levels, proinsulin and insulin content, and insulin secretion. These study reveals a previously unidentified link between insulin processing and cellular iron homeostasis, and show that Irp2 is required for normal β cell function and whole body glucose homeostasis.

Disclosure
M.C. Ferreira dos Santos: None. M. Rajan: None. E. Leibold: None.

Funding
American Diabetes Association (1-18-PMF-020 to M.C.F.D.S.); National Institute of Diabetes and Digestive and Kidney Diseases
345-LB: Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF): A New Therapeutic Target for Wolfram Syndrome
Authors: MORIKAWA SHUNTARO , MAHADEVAN JANA , YAGI TAKUYA , ABREU DAMIEN , KANEKURA KOHSUKE , BROWN CRIS M. , URANO FUMIHIKO 
Published: June 2019

Endoplasmic reticulum (ER) stress is an emerging target for human chronic disorders, including β cell death in type 1 and type 2 diabetes, as well as neurodegenerative diseases. However, there is currently no treatment for preventing ER stress-mediated cell death due to its complex nature. Our strategy for overcoming this challenge is to focus on a rare monogenic disease, Wolfram syndrome. Wolfram syndrome is a rare genetic disease characterized by juvenile-onset diabetes mellitus, optic nerve atrophy, diabetes insipidus, impaired hearing and neurodegeneration. As this syndrome is caused by the loss-of-function of the WFS1 gene which is involved in ER calcium homeostasis and ER stress-mediated cell death, it is ideal for testing potential new treatments targeting the ER. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a trophic factor whose expression and secretion is enhanced by ER stress and ER calcium depletion. It has been demonstrated that MANF plays a critical role in the survival of ER stressed β cells and neurons, raising the possibility that MANF can be beneficial for patients suffering from ER stress-related disorders. In this study, we show that treatment with recombinant MANF peptide in cell models of Wolfram syndrome suppresses the caspase 3/7 activation and terminal ER stress markers, including C/EBP homologous protein (Chop) and Tribbles 3 (Trb3), and activates the mTOR/S6K signaling pathway. Furthermore, the proliferation of β cells in a WS mouse model is activated by recombinant MANF peptide treatment and adeno-associated virus induced MANF overexpression. Our results indicate that molecular pathways regulated by MANF are promising drug targets for ER stress-related disorders, including β cell death in diabetes and Wolfram syndrome.

Disclosure
S. Morikawa: None. J. Mahadevan: None. T. Yagi: None. D. Abreu: None. K. Kanekura: None. C.M. Brown: None. F. Urano: Board Member; Self; Healthbeat. Research Support; Self; Aetas, Amylyx, JDRF, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Stock/Shareholder; Self; CytRx. Other Relationship; Self; Novus Biologicals.

Funding
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (DK112921, DK020579); National Institutes of Health/National Center for Advancing Translational Science (TR002065); Unravel Wolfram Syndrome Fund; Lois and Samuel Silberman Fund; Stowe Education Fund; Ellie White Foundation for Rare Genetic Disorders; Eye Hope Foundation; Snow Foundation (to F.U.); National Institutes of Health (F30DK111070 to D.A.)
359-OR: 12/15-Lipoxygenase in Islets and Macrophages Independently Promotes Autoimmune Diabetes in NOD Mice
Authors: PINEROS ALVAREZ ANNIE ROCIO , KULKARNI ABHISHEK , ORR KARA , GLENN LINDSEY , REISSAUS CHRISTOPHER A. , HERNANDEZ-PEREZ MARIMAR , GANNON MAUREEN , MCDUFFIE MARCIA J. , NADLER JERRY , MIRMIRA RAGHAVENDRA , MORRIS MARGARET A. , TERSEY SARAH A. 
Published: June 2019

The pathogenesis of type 1 diabetes (T1D) involves the interaction of the immune system with β cells. 12/15-lipoxygenase (12/15-LOX), an enzyme involved in arachidonic acid metabolism, is expressed in both β cells and macrophages. Global deletion of the gene encoding 12/15-LOX (Alox15) prevents diabetes in the NOD mouse model of T1D via reduction in production of proinflammatory mediators in islets and macrophages. However, the importance of 12/15-LOX in islets vs. macrophages remains unclear. To address this issue, we generated both inducible islet-cell-specific (NOD-Alox15∆islet) and myeloid-lineage-specific (Alox15∆myel) Alox15 knockout mice on the NOD background. Control female mice (Alox15loxp/loxp, Pdx1PB-CreERTM+, and LysM-Cre+) exhibited diabetes incidence greater than 75%, whereas both Alox15∆islet and Alox15∆myel showed a dramatic decrease in the incidence of diabetes (&lt;10%, P&lt;0.05). During the pre-diabetic phase (8 weeks of age), both control and Alox15∆islet mice exhibited similar β-cell mass (0.70±0.08 g vs. 0.72±0.06 g, P=NS) and insulitis severity (score 1.89±0.17 vs. 1.74±0.19, P=NS), whereas Alox15∆myel mice had increased β-cell mass (1.56±0.02c g, P&lt;0.05) and insulitis (score 1.18±0.08, P&lt;0.05). We next examined the nature of immune cells present in the spleen and pancreatic lymph node (pLN). Alox15∆islet mice showed increased Tregs (CD4+FoxP3; P&lt;0.05) with no changes in Th1 (CD4+IFNγ+) and Th17 (CD4+IL17+) cells in both the spleen and pLN compared to control mice (P=NS). Additionally, Alox15∆islet female mice exhibited decreased IL-1β production by dendritic cells. By contrast, Alox15∆myel mice showed only decreased pLN proinflammatory macrophages (F480+IL1β+) and dendritic cells (CD11c+IL1β+) compared to controls (P&lt;0.05). Together, these data suggest that 12/15-LOX functions independently in both the islet and macrophage through different mechanisms, promoting the destruction of β cells during the pathogenesis of autoimmune T1D.

Disclosure
A. Pineros Alvarez: None. A. Kulkarni: None. K. Orr: None. L. Glenn: None. C.A. Reissaus: None. M. Hernandez-Perez: None. M. Gannon: None. M.J. McDuffie: Stock/Shareholder; Self; Adenosine Therapeutics, LLC. J. Nadler: None. R. Mirmira: None. M.A. Morris: Stock/Shareholder; Spouse/Partner; Sanofi US. S.A. Tersey: None.

Funding
National Institutes of Health (R01DK105588 to R.M., J.N.)
368-P: Effects of Mild Hypoglycaemia on Cognitive Function in Type 2 Diabetes
Authors: NILSSON MALIN , JENSEN NICOLE J. , GEJL MICHAEL , BRANDSLUND IVAN , STORGAARD HEIDI , ZANDER METTE , MISKOWIAK KAMILLA , RUNGBY JØRGEN 
Published: June 2019

Background: Previous studies have demonstrated cognitive impairment during severe hypoglycaemia. This study provides quantitative results on cognitive function during an acute mild hypoglycaemic episode in patients with type 2 diabetes.
Methods: In this double-blinded randomized cross-over study, 25 patients with type 2 diabetes attended two experimental visits with hyperinsulinaemic glucose clamping; one hypoglycaemic clamp (PG 3.0 ± 0.2 mmol/l) and one euglycaemic clamp (PG 6.0 ± 0.2 mmol/l). Cognitive function was assessed during each condition with a neurocognitive test battery measuring verbal memory, executive function, sustained attention and psychomotor speed.
Results: The participant’s cognitive performances were impaired during hypoglycaemia with mean score in the primary outcome test, SDMT, of 48.7 (hypoglycaemia) and 56.6 (euglycaemia); the estimated treatment difference was -7.9 (95% CI -10.9, -4.9; p=&lt;0.0001). The composite score of overall speed of complex cognitive processing showed a highly significant deterioration during the hypoglycaemic condition of -0.7 (95% CI -0.9, -0.6; p=&lt;0.0001) (Figure). Age, sex, fasting C-peptide and hypoglycaemic symptom severity did not influence the effect of hypoglycaemia on cognitive function.
Conclusion: Acute mild hypoglycaemia (3 mmol/l [54 mg/dl]) negatively affects cognitive function in patients with type 2 diabetes.

Disclosure
M. Nilsson: None. N.J. Jensen: None. M. Gejl: Other Relationship; Self; Novo Nordisk A/S. I. Brandslund: None. H. Storgaard: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc. M. Zander: None. K. Miskowiak: None. J. Rungby: None.

Funding
Investigator Initiated Studies Program of Merck Sharp & Dohme Corp.
369-P: Effects of Nocturnal Hypoglycemia on Quality of Life and Mood During Daily Life in Type 1 Diabetes—A CGM-Based Analysis
Authors: HENRIKSEN MARIE M. , ANDERSEN HENRIK U. , THORSTEINSSON BIRGER , PEDERSEN-BJERGAARD ULRIK 
Published: June 2019

Objective: To assess the effect of spontaneous nocturnal hypoglycemia on quality of life and mood the subsequent days in type 1 diabetes.
Research Design and Methods: A total of 153 persons with type 1 diabetes participated in 6 days of blinded continuous glucose monitoring (CGM) while daily documenting hypoglycemic symptoms, quality of life and mood. Hypoglycemia was defined by interstitial glucose ≤ 70 mg/dl (IG70) and ≤ 54 mg/dl (IG54) for &gt; 15 minutes and was classified as asymptomatic if no hypoglycemic symptoms were reported in the diary.
Results: Self-estimated quality of life assessed by the EQ-5D VAS (but not by the WHO Well-Being Index) was higher the day after an asymptomatic (but not after a symptomatic) hypoglycemic night as compared with non-hypoglycemic nights (IG70: p = 0.021 and IG54: p = 0.048). The effect increased with longer duration and lower glucose nadir of nocturnal hypoglycemia (IG70: p = 0.04). The finding was confined to participants with reduced hypoglycemia awareness. There was no effect on mood of nocturnal hypoglycemia.
Conclusions: Individuals with type 1 diabetes and impaired awareness report higher quality of life following nights with asymptomatic - but not symptomatic - hypoglycemia. The effect was amplified by lower glucose nadir and longer duration of the episodes and may contribute to explain resistance to implementation of interventions against hypoglycemia in many people with impaired hypoglycemia awareness.

Disclosure
M.M. Henriksen: None. H.U. Andersen: Advisory Panel; Self; Abbott Laboratories, AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; Nordic Infucare. Stock/Shareholder; Self; Novo Nordisk Inc. B. Thorsteinsson: None. U. Pedersen-Bjergaard: Advisory Panel; Self; AstraZeneca, Sanofi-Aventis, Zealand Pharma A/S. Speaker's Bureau; Self; Novo Nordisk A/S.

Funding
Nordsjællands Hospital; Jascha Foundation; Danish Medical Research Grant; The Toyota Foundation, Denmark
37-LB: Diabetic Retinopathy (DR) Screening Performance of an Artificial Intelligence (AI) System: Analysis from a Pivotal Multicenter Prospective Clinical Trial
Authors: BODE BRUCE W. , IPP ELI , SHAH VIRAL N. , SADDA SRINIVAS R. 
Published: June 2019

A prospective study (NCT03112005) evaluated DR screening using the EyeArt AI eye screening system against the ETDRS clinical reference standard (CRS). A total of 893 subjects with diabetes were enrolled at 15 U.S. clinical centers and completed 2-field fundus photography for analysis by the EyeArt system and dilated 4-wide field stereo fundus photography for adjudicated expert grading to establish CRS.
The EyeArt system provided eye-level results for referable DR (rDR) [moderate non-proliferative DR (NPDR) or higher on the International Clinical DR (ICDR) severity scale or clinically significant diabetic macular edema (CSDME)] and for vision-threatening DR (vtDR) [severe NPDR or higher on the ICDR scale or CSDME]. Out of 1718 eyes with gradable CRS for rDR, 1392 eyes were negative and 326 were positive. Out of 1702 eyes with gradable CRS for vtDR, 1588 were negative and 114 were positive.
The EyeArt system was evaluated against CRS for identifying rDR and vtDR under an undilated protocol and a dilate-if-needed protocol (where dilated images were used for subjects with ungradable EyeArt results on undilated images). Results (Table) indicate that the EyeArt AI system compares favorably with the clinical reference standard and meets the predetermined study endpoints for the detection of referable and vision-threatening DR in people with diabetes.

Disclosure
B.W. Bode: Consultant; Self; ADOCIA, Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; Becton, Dickinson and Company, Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Eyenuk Inc., Insulet Corporation, National Institutes of Health, Novo Nordisk Inc., Sanofi Research & Development, Senseonics, Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi US, Senseonics. Stock/Shareholder; Self; AgaMatrix, Glytec, LLC. E. Ipp: Research Support; Self; Eyenuk Inc., Novartis Pharmaceuticals Corporation. V.N. Shah: Advisory Panel; Self; Sanofi US. Consultant; Self; Dexcom, Inc. S.R. Sadda: Consultant; Self; Carl Zeiss Meditec, Centervue, Heidelberg Engineering, Optos. Other Relationship; Self; Nidek. Other Relationship; Spouse/Partner; Topcon.

Funding
National Institutes of Health (EY027241, EY026864)