bluuebunny/crossref_metadata_2025 huggingface dataset:
2457-PUB: Microcirculatory Alterations Are Associated with Increased Risk of Total Death in Patients with Type 2 Diabetes
Authors: OKADA HIROSHI , OKADA YUKI , FUKUI MICHIAKI
Published: June 2019

Rationale and Objective: It has been well known that patients with diabetes had shorter life expectancy, compared to patients without diabetes. Although several studies have been reported the significance of microciculatory dysfunction particularly in the early phase of critical illness, it has been not reported the association between microcirculatory dysfunction and long-term prognosis. Therefore, we evaluated the relationship between microcirculatory dysfunction and the risk of total death in patients with type 2 diabetes.

Methods: A total of 1017 patients with diabetes (657 men and 360 women), who were admitted to the department of internal medicine from September 2015 to December 2017, were included in this study. We measured perfusion index (PI), which could reflect microcirculation, using a pulse oximeter (Masimo Radical 7; Masimo Corp., Irvine, CA, U.S.) on the day of admission. Cox proportional hazards models was used in multivariate analysis.

Results: The median duration of follow-up was 670.0 days and a total of 117 patients died during follow-up duration. The average age, HbA1c and PI value was 71.0 ± 11.6 years, 7.7 ± 1.9% and 3.2 ± 2.4%. PI value was negatively correlated with age (β = -0.18, P < 0.0001), pulse rate (β = -0.06, P = 0.04) and serum creatinine (β = -0.16, P < 0.0001). PI value was positively correlated with body mass index (β = 0.11, P = 0.0007) and hemoglobin level (β = 0.19, P < 0.0001). Adjusted Cox regression analyses demonstrated that PI value was associated with an increased hazard of total death; hazard ratios were 1.11 (95% confidence interval, 1.01 - 1.23).

Conclusion: The present study indicates the importance of microciculatory dysfunction and monitoring as a potential independent prognostic factor of mortality in patients with type 2 diabetes.

Disclosure

H. Okada: None. Y. Okada: None. M. Fukui: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Johnson & Johnson, Kyowa Hakko Kirin Co., Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.
246-OR: Contribution of Plasma Glucose and Hormones to the Acute Compensatory Rise in Endogenous Glucose Production (EGP) during Glucosuria in T2D Patients
Authors: ALATRACH MARIAM , AGYIN CHRISTINA , LAICHUTHAI NITCHAKARN , ADAMS JOHN M. , ABDUL-GHANI MUHAMMAD , TRIPLITT CURTIS L. , DEFRONZO RALPH A. , CERSOSIMO EUGENIO
Published: June 2019

Aim: To examine the role of plasma glucose (GLU), insulin (INS) and glucagon (GG) changes in EGP stimulation during glucosuria (UGE) following SGLT2i administration.

Methods: Using tracer (3-3H-glucose), 30 T2D patients (Age=55±1y, BMI=32.2±0.7kg/m2, FPG=140±6mg/dl, A1c=7.3±0.1%) received three 300-min procedures at 2-weeks intervals: (I) control clamp (CON) with no glucose/hormone infusions; (II) pancreatic clamp (PAN) with somatostatin (0.75mg/h), basal replacement of insulin (0.1mU/kg.min) and glucagon (0.3ng/kg.min); (III) isoglycemic clamp (ISO) with variable dextrose infusion to maintain GLU equal to baseline. Prior to start of each clamp subjects received placebo (PCB, n=10) or dapagliflozin 10mg (DAPA, n=20).

Results: After DAPA (CON), INS decreased (-7±1µU/ml) while GG increased (+10±1pg/ml) (both p<0.05 vs. PCB). Despite UGE of 0.48mg/kg.min, GLU decline was modest (-31±1) due to a “paradoxical” rise in EGP after DAPA. During PAN with DAPA and PCB, INS and GG were unchanged from baseline, and EGP stimulation in DAPA compared to PCB still increased, yet GLU decline was modest (-28.4±3.0). During ISO, EGP decreased markedly with DAPA as well as PCB despite similar plasma GG and INS concentrations.

Conclusion: DAPA-induced glucosuria stimulation of EGP cannot be entirely explained by the rise in plasma glucagon or decline in plasma insulin.

Disclosure

M. Alatrach: None. C. Agyin: None. N. Laichuthai: None. J.M. Adams: None. M. Abdul-Ghani: None. C.L. Triplitt: Consultant; Self; Abbott. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. E. Cersosimo: None.
2463-PUB: Prevalence of Metabolic Syndrome in Patients with Type 1 Diabetes: Impact on Microvascular Complications and Subclinical Inflammation
Authors: LECUMBERRI EDURNE , LUQUE-RAMÍREZ MANUEL , QUIÑONES SILVA JHONATAN , FERNÁNDEZ ELENA , DIAZ SARA ALONSO , ESCOBAR-MORREALE HÉCTOR FRANCISCO , NATTERO-CHÁVEZ LÍA
Published: June 2019

Introduction: The MS might also be present in patients with DM1 worsening vascular prognosis.

Objective: We aimed to determine the prevalence of MS and its association with microvascular disease and to describe the differences between patients with or without MS in markers of subclinical inflammation and adiposity.

Methods: A cross-sectional study including 289 consecutive patients with DM1. MS was defined according to the criteria of the IDF but for the presence of fasting hyperglycemia or diabetes. Microvascular complications were assessed according to ADA. Serum inflammation markers such as high hsCRP, ESR, homocystein and fibrinogen were measured.

Results: The mean age was 36 ± 12 years-old. 40% were female. Duration of DM1 was 20 ± 11 years. The mean HbA1c was 7.6±1.3% and the GFR was 94±18 ml/min/1.73m2. The prevalence of MS, as defined, was 12.5% (95% CI: 9.1 - 16.8). The odds of having microvascular complications was 2.4 higher among MS+ group [OR: 2.4 (1.0-5.7); P = 0.042] compared with MS- group, after adjusting for age and DM1 duration. Adiposity and markers of subclinical inflammation were significantly higher in MS+ group compared to their MS- counterparts (Table 1).

Conclusions: The prevalence of MS was considerable in patients with DM1. MS was an independent risk factor for the presence of microvascular complications regardless of age and DM1 duration. The presence of MS in patients with DM1 is associated with adiposity and subclinical inflammation.

Disclosure

E. Lecumberri: None. M. Luque-Ramírez: None. J. Quiñones Silva: None. E. Fernández: None. S. Alonso Diaz: None. H. Escobar-Morreale: None. L. Nattero-Chávez: None.

Funding

Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness (PI1400649, PI151686, PIE1600050)
248-OR: Empagliflozin and Cardiorenal Outcomes in Patients with Nonproteinuric Kidney Disease in the EMPA-REG OUTCOME Trial
Authors: INZUCCHI SILVIO E. , ZINMAN BERNARD , GEORGE JYOTHIS , MATTHEUS MICHAELA , EYNATTEN MAXIMILIAN VON , WANNER CHRISTOPH , HAUSKE SIBYLLE
Published: June 2019

Proteinuria in chronic kidney disease (CKD) is a strong risk predictor for adverse cardiorenal outcomes. However, non-proteinuric CKD in type 2 diabetes (T2D) is rarely studied in clinical trials despite epidemiological evidence indicating a recent shift towards this phenotype. We explored the effect of empagliflozin (EMPA) on cardiorenal outcomes in a subgroup of patients from EMPA-REG OUTCOME with non-proteinuric CKD at baseline. 7020 patients with T2D and prior CV disease were treated with EMPA 25mg, 10mg or placebo (PBO) (median follow-up of 3.1 years). Post hoc, Cox regression assessed effects of EMPA vs. PBO on the composite outcome of CV death/HHF, CV death, HHF, a composite kidney outcome of incident/worsening nephropathy and all-cause mortality. Non-proteinuric CKD was defined as low eGFR and absence of overt albuminuria (eGFR <60 ml/min/1.73m2 and UACR <300 mg/g). Overall, 1290 (18.4%) met this criterion. In this exploratory analysis, beneficial effects of EMPA vs. PBO on cardiorenal outcomes were consistent in patients with T2D and non-proteinuric CKD as compared to all other patients. This result suggests that absence of overt proteinuria may not alter the cardiorenal treatment response to EMPA. The ongoing EMPA-KIDNEY study investigates effects of EMPA on cardiorenal outcomes in a broad CKD population with and w/o diabetes including patients with lower proteinuria levels.

Disclosure

S.E. Inzucchi: Consultant; Self; vTv Therapeutics, Zafgen, Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. B. Zinman: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc. Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc. J. George: Employee; Self; Boehringer Ingelheim International GmbH. M. Mattheus: Employee; Self; Boehringer Ingelheim Pharma GmbH&Co.KG. M. von Eynatten: Employee; Self; Boehringer Ingelheim International GmbH. C. Wanner: Advisory Panel; Self; Bayer AG, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp. Board Member; Self; Boehringer Ingelheim International GmbH. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Mitsubishi Tanabe Pharma Corporation. S. Hauske: Employee; Self; Boehringer Ingelheim International GmbH.

Funding

Boehringer Ingelheim; Eli Lilly and Company
2487-PUB: Purinergic Regulation of Adiponectin Exocytosis and the Role of Sympathetic Innervation for Adiponectin Secretion
Authors: MUSOVIC SALIHA , KOMAI ALI M. , MICALLEF PETER , WU YANLING , ASTERHOLM INGRID WERNSTEDT , OLOFSSON CHARLOTTA S.
Published: June 2019

The white adipocyte hormone adiponectin improves insulin sensitivity and has a protective role in the development of type 2 diabetes. The rapid incidence of obesity-associated disorders emphasizes the importance of understanding the regulation of adiponectin secretion. Hormones are typically secreted via regulated exocytosis but the mechanisms controlling adiponectin release remains inadequately investigated. We have previously demonstrated that catecholamines/cAMP trigger adiponectin exocytosis via activation of adrenergic beta-3-receptors (β3ARs) and Epac1, while elevations of intracellular Ca2+ potentiate the exocytotic process. White adipose tissue is highly innervated by sympathetic nerves, co-releasing norepinephrine (NE) and ATP, thus suggesting a role of the sympathetic nervous system in regulation of adiponectin secretion. Here we have studied the role of sympathetic innervation and purinergic signaling in adiponectin release. Extracellular NE triggered adipocyte exocytosis, whereas extracellular ATP potentiated NE-triggered adipocyte exocytosis. Short-term adiponectin secretion was stimulated by NE while ATP augmented the catecholamine-stimulated release. The effect of ATP was abolished in adipocytes pre-treated with a P2Y2-receptor antagonist. In adipocytes isolated from obese/diabetic mice, ATP-induced adiponectin release was abrogated together with a reduced gene expression of the P2Y2-receptor. Moreover, white adipose tissue content of NE and tyrosine hydroxylase was reduced in obese/diabetic mice. We propose that the physiological stimulatory pathway for adiponectin exocytosis is via sympathetic innervation, co-releasing NE and ATP which activates β3ARs (elevates cAMP) and P2Y2Rs (increases Ca2+). We also suggest that decreased NE and ATP release within the adipose tissue together with disrupted adipocyte purinergic signaling results in disturbed adiponectin release in diabetic/obese conditions.

Disclosure

S. Musovic: None. A.M. Komai: None. P. Micallef: None. Y. Wu: None. I. Wernstedt Asterholm: None. C.S. Olofsson: None.
249-OR: Empagliflozin Selected Cardiovascular and Safety Outcomes in Routine Care: First Results from the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) Study
Authors: PATORNO ELISABETTA , PAWAR AJINKYA , FRANKLIN JESSICA , NAJAFZADEH MEHDI , DERUAZ-LUYET ANOUK , BRODOVICZ KIMBERLY , SAMBEVSKI STEVEN , BESSETTE LILY G. , KULLDORFF MARTIN , SCHNEEWEISS SEBASTIAN
Published: June 2019

EMPRISE studies the effectiveness, safety and healthcare utilization of empagliflozin (EMPA), a SGLT2 inhibitor, using data from Medicare and 2 U.S. commercial claims datasets (2014-2019). In an analysis on data from 2014-2016, we identified 17,551 pairs of 1:1 propensity score-matched patients ≥18 years with type 2 diabetes initiating EMPA or a DPP-4 inhibitor (DPP-4i). We assessed a composite CV outcome (MI, stroke, or all-cause mortality) and an extended CV outcome (plus heart failure hospitalization or coronary revascularization). Safety outcomes of interest were lower-limb amputations, bone fractures, diabetic ketoacidosis (DKA), and acute kidney injury. We estimated pooled HR and 95% CI adjusting for >140 baseline covariates. Compared to DPP-4i, EMPA was associated with a trend to lower risk of the CV outcome [HR (95% CI) = 0.82 (0.62-1.10)], and a lower risk of the extended CV outcome [0.73 (0.60-0.88)], heart failure hospitalization [0.56 (0.43-0.73)]. Risk of safety outcomes were in line with current evidence despite small numbers, Table 1. We observed a numerical increase in DKA risk [1.74 (0.84-3.58)]. Early findings from EMPRISE showed that compared with DPP-4i, EMPA was associated with a lower risk of CV outcomes with varying levels of precision, and a safety profile consistent with currently documented information.

Disclosure

E. Patorno: Research Support; Self; National Institute on Aging. Other Relationship; Self; Boehringer Ingelheim International GmbH. A. Pawar: None. J. Franklin: Research Support; Self; U.S. Food and Drug Administration. M. Najafzadeh: Consultant; Self; Epigenomics. A. Deruaz-Luyet: Employee; Self; Boehringer Ingelheim International GmbH. Employee; Spouse/Partner; Medtronic, Sanofi. K. Brodovicz: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. S. Sambevski: Employee; Self; Boehringer Ingelheim International GmbH. L.G. Bessette: None. M. Kulldorff: None. S. Schneeweiss: Consultant; Self; Aetion, WHISCON, LLC.

Funding

Boehringer Ingelheim
2490-PUB: The Relationship between Circulatory Levels of Fractalkine, Omentin, and the Mass of Adipose Tissue and Their Role in the Pathogenesis of Diabetes Mellitus Type 2
Authors: LAVRYNENKO OLGA , KRAVCHUN NONNA , MISURA KATHERINE , ZEMLIANITSYNA OLHA , DUNAEVA INNA , KRAVCHUN PAVLO , DEFRONZO RALPH A. , CERSOSIMO EUGENIO , KARACHENTSEV IURIY
Published: June 2019

Objective: To examine the extent to which circulating levels of omentin and fractalkine are dependent on the degree of adipose tissue accumulation, waist circumference, plasma insulin and НО??-IR in representatives of Ukrainian population.

Materials and Methods: 250 individuals mean age of 65.48±11.86 years were examined; waist circumference was measured; adipose tissue mass was assessed by bio-impedance with relative body weight. Content of insulin, blood fractalkine and omentin were determined by immune enzyme method and НО??-IR index was calculated.

Results: There was an inverse correlation between blood fractalkine and omentin levels(r = -0.863, p<0.001). Blood fractalkine level correlates positively with adipose mass of the body(r=0.5341, p<0.001)); waist circumference- (r =0.4542, p<0.001); insulinemia (r =0.7798, p<0.001) and НО??-IR levels (r= 0.745, p<0.001). Omentin level correlates negatively with adipose body mass(r = -0.609, p<0.001); waist circumference- (r = -0.397, p<0.001); insulinemia (r = -0.799, p<0.001) and НО??-IR levels (r = -0.7706, p<0.001). The data also showed that accumulation of adipose mass greater than 25% of total body mass determines an increase in blood fractalkine levels up to750 ng/mL and higher, and НО??-IR> 2.77 is associated with decreased omentin levels down to500 ng/mL and less.

Conclusion: These data indicate strong associations, which suggest that there may be an important role for fractalkine and omentin in markers of diabetes mellitus and obesity.

Disclosure

O. Lavrynenko: None. N. Kravchun: None. K. Misura: None. O. Zemlianitsyna: None. I. Dunaeva: None. P. Kravchun: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. E. Cersosimo: None. I. Karachentsev: None.
2492-PUB: KCNK16 Deficiency Protects Mice against High-Fat Diet-Induced Weight Gain
Authors: BRACHS SEBASTIAN , SCHWAHN UWE , STEINMEYER KLAUS , SCHÄFER MATTHIAS , GASSENHUBER JOHANN , SPRANGER JOACHIM
Published: June 2019

Potassium Channel, Two Pore Domain Subfamily K, Member 16 (TALK-1/KCNK16) is a K+ channel protein expressed in human and murine pancreas. Recent research by Vierra et al suggested a regulatory function of KCNK16 in mice for glucose-dependent β-cell second-phase insulin and δ-cell somatostatin secretion and a protective effect on fasting glycemia during 3 weeks high-fat diet (HFD). We tested the hypothesis, that deletion of KCNK16 affects body weight and glucose metabolism in vivo during prolonged HFD feeding. Therefore, we analyzed KCNK16-deficient knockout mice (KCNK16-/-) during HFD up to 21 weeks investigating body weight and composition, insulin sensitivity as well as insulin secretion. In HFD-fed KCNK16-/-, we observed a reduced body weight gain. Both, fat and lean mass were reduced and notably body-length was also significantly shorter. KCNK16-/- mice showed reduced food intake, an elevated oxygen consumption and energy expenditure. KCNK16-/- islets showed enhanced insulin secretion under glucose and GIP-1 simulation, but we did not reveal significant changes in fasting or fed plasma glucose or insulin. We found a moderate decrease in blood glucose during an ipITT. However, we did not observe an enhanced insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps nor a beneficial effect of KCNK16 deficiency on the modulation of in vivo insulin secretion during hyperglycemic clamps in HFD-fed mice.

In conclusion, we observed a reduced body weight gain, but also shorter body-length in the KCNK16-deficient mouse model during prolonged HFD feeding. Notably, food intake was reduced while energy expenditure was increased.

Disclosure

S. Brachs: Employee; Spouse/Partner; Treamid Therapeutics GmbH. Research Support; Self; Sanofi-Aventis Deutschland GmbH. U. Schwahn: Employee; Self; Sanofi-Aventis Deutschland GmbH. K. Steinmeyer: Employee; Self; Sanofi-Aventis Deutschland GmbH. M. Schäfer: Employee; Self; Sanofi-Aventis Deutschland GmbH. J. Gassenhuber: Employee; Self; Sanofi-Aventis Deutschland GmbH. Employee; Spouse/Partner; Sanofi-Aventis Deutschland GmbH. J. Spranger: None.

Funding

Sanofi Aventis Deutschland GmbH
2498-PUB: Autoimmune Chronic Thyroiditis—Risk Factor for Increasing the Prevalence of Obesity in Patients with Impaired Glucose Tolerance
Authors: GHERBON ADRIANA , TIMAR ROMULUS
Published: June 2019

Objective: To study the prevalence of obesity in patients with impaired glucose tolerance (IGT) and autoimmune chronic thyroiditis (ACT).

Material and Methods: The study group consists in 104 patients with IGT and ACT and 124 patients with IGT but without ACT. Were evaluated:

Lipid profile (total cholesterol, triglycerides, HDLc, LDLc).

Systolic and diastolic blood pressure.

Fasting glucose, oral glucose tolerance test.

Waist circumference and body mass index.

The thyroid gland:TSH, FT4, FT3, antithyroid antibodies, thyroid ultrasound.

Results: In group with IGT and ACT prevailed android obesity (65.38% vs. 47.58%, p=0.007, X2 =7.26). Also 30.62% were overweight (30.62% vs. 38.70%, p=0.11, X2=2.44). Regarding the class of android obesity, 50% had class I (50% vs. 57.63%, p=0.39, X2=0.73), 20.59% class II (20.59% vs. 25.42%, p=0.51, X2 =0.41 and 29.41% class III (29.41% vs. 16.95%, p=0.09, X2=2.71). Also, 32.65% had hypertension, and 73.47% dyslipidemia. Significance difference we obtain between group with ACT and hypothyroidism and without hypothyroidism (60.29% vs. 39.7%, p=0.016, X2=5.76).

Conclusions: In patients with IGT and ACT prevailed android obesity which increased risk of cardiovascular morbidity-mortality, particularly for atherosclerotic cardiovascular disease. The association of thyroid disease, which over time can evolve with hypothyroidism, is an additional risk factor for atherosclerotic cardiovascular disease.

Disclosure

A. Gherbon: None. R. Timar: None.
25-OR: Investigating a Candidate Causal Allele in Type 2 Diabetes Susceptibility Gene PAM as a Cause of Neonatal Diabetes Mellitus
Authors: SENGUPTA SHAHANA , BONNYCASTLE LORI L. , HASTOY BENOIT , GROTZ ANTJE , UMAPATHYSIVAM MAHESH M. , RAIMONDO ANNE , SWIFT AMY , CHINES PETER S. , CLARK ANNE , HUOPIO HANNA , COLLINS FRANCIS S. , LAAKSO MARKKU , GLOYN ANNA L.
Published: June 2019

Peptidylglycine α-amidating monooxygenase (PAM) catalyses the amidation of glycine-extended peptides, thereby maximising their biological potency. We recently showed that coding alleles in PAM mediate type 2 diabetes (T2D) risk through alterations to PAM protein activity and expression in the β cell. Identifying alleles along a continuum of functional severity informs on the relationship between protein perturbation and clinical effect. We hypothesised that rare, loss of function PAM alleles could cause severe β cell dysfunction presenting as neonatal diabetes.

Sequencing of 15 probands presenting with diabetes at ≤ 6 months of age and their unaffected immediate family, identified a novel de novo nonsynonymous coding variant (p.R36S) in PAM in a single proband. We investigated the impact of the variant allele on amidating activity, protein stability and localisation as a measure of PAM function and the consequences on β cell viability.

Recombinant R36S-PAM exhibited normal amidating activity in vitro which was consistent with PAM activity measured in patient serum (WT: 391pmol/μl/hr vs. R36S: 305pmol/μl/hr). In human β cells (EndoC-βh1) the secreted luminal R36S-PAM isoform displayed reduced protein expression (-78%, p=0.004) compared to WT-PAM, which could be rescued by inhibiting the proteosomal pathway (+120% of WT); whilst the non-secreted membrane-integral isoform was retained in the endoplasmic reticulum (ER). We observed that overexpression of R36S-PAM elevated levels of ER stress (p-IRE1: +196%, p=0.02; CHOP: +114%, p=0.051) and pro-apoptotic markers (ASK1: +145%, caspase-3: +154%) compared with WT-PAM.

We have identified a novel, de novo coding variant, in a gene with a proven role in T2D risk, in a single patient with neonatal diabetes. Functional studies provide evidence for protein mislocalisation and instability and support a role for this allele in ER stress and β cell dysfunction consistent with neonatal diabetes pathogenesis.

Disclosure

S. Sengupta: None. L.L. Bonnycastle: None. B. Hastoy: None. A. Grotz: None. M.M. Umapathysivam: None. A. Raimondo: None. A. Swift: None. P.S. Chines: None. A. Clark: None. H. Huopio: None. F.S. Collins: None. M. Laakso: None. A.L. Gloyn: Consultant; Spouse/Partner; Eli Lilly and Company, Merck & Co., Inc. Consultant; Self; Merck & Co., Inc. Consultant; Spouse/Partner; Novo Nordisk A/S, Pfizer Inc. Research Support; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Diabetes UK, European Foundation for the Study of Diabetes.

Funding

UK Wellcome Trust
252-LB: Oxidative Stress Induces Toll-Like Receptor -2 and -4 in Human Peripheral Blood Mononuclear Cells: Implications for Metabolic Inflammation
Authors: SINDHU SARDAR T. , MADHOUN ASHRAF AL , AKHTER NADEEM , AL-MULLA FAHD , AHMAD RASHEED
Published: June 2019

Background: Toll-like receptors (TLRs) are emerging as immunometabolic receptors and nutrient sensors. In obese and T2D patients, oxidative stress acts as a critical early-trigger of altered pathophysiology. In immune cells, it remains unclear whether the oxidative stress can modulate expression of the receptors. We assessed the expression of TLR2 and TLR4 in the peripheral blood mononuclear cells (PBMCs) following H2O2 treatment.

Methods: Human PBMCs were isolated from healthy donors and were subjected to oxidative stress by H2O2 with or without antioxidants or ROS inhibitors. Using qRT-PCR and flow cytometry, the gene expression of TLR2 and TLR4 was determined, Moreover, expression of the phosphorylated c-Jun, ERK1/2, p38, and NF-?B signaling proteins was determined.

Results: TLR2 and TLR4 gene and protein expression was elevated in PBMCs following induction of oxidative stress compared to controls (P<0.001); and this induction was abrogated by cell pre-treatment with apocynin or N-acetyl cysteine (P<0.05). Treatments with palmitate or LPS, in the presence of oxidative stress, further promoted the TLR2 and TLR4 expression. Oxidative stress also upregulated the expression of MyD88, IRF3, IRF5, and FOXO1 in PBMC. Both the MAPK and NF-?B signaling pathways were involved in H2O2-mediated TLR2 and TLR4 upregulation. Oxidative stress also increased the gene expression of proinflammatory IL-1β, IL-6, TNF-α, IFN-γ and MCP-1 (P<0.001).

Conclusion: Taken together, oxidative stress upregulates the TLR2 and TLR4 expression in PBMC through the MAPK/NF-?B dependent mechanism in parallel with increased expression of proinflammatory cytokines/chemokine. We speculate that TLR2/TLR4 suppression by ROS-inhibition or antioxidant strategies may alleviate metabolic inflammation.

Disclosure

S.T. Sindhu: None. A. Al Madhoun: None. N. Akhter: None. F. Al-Mulla: None. R. Ahmad: None.

Funding

Kuwait Foundation for the Advancement of Sciences; Dasman Diabetes Institute
258-LB: Vitamin D Directly Regulates TRPV1 Channel Activity and May Play an Important Role in the Autoimmune Disease of Type 1 Diabetes
Authors: LONG WENTONG , FATEHI MOHAMMAD , SONI SHUBHAM , PANIGRAHI RASHMI , KELLY REES G. , PHILIPPAERT KOENRAAD , BARR AMY J. , HELD MORGANNE , YU YI , CAMPBELL SCOTT A. , ONDRUSOVA KATARINA , BALDWIN TROY , LEMIEUX JOANNE , LIGHT PETER E.
Published: June 2019

The autoimmune disease of type 1 diabetes (T1D) results in the immune destruction of β-cells. Recent studies suggest supplementation of vitamin D along can significantly improve patients’ β-cell function and glycemic control possibly by dampening naïve T-cell activation. However, the underlying cellular mechanism for this effect has not been elucidated completely, especially as naïve T-cells possess absent or very low VDR expression. Therefore, the effects of Vitamin D on naïve T-cells may involve a VDR-independent pathway. Interestingly, TRPV1 channel activation is necessary for naïve T-cell activation. Our initial calcium imaging and electrophysiological data show that Vitamin D (25OHD) can partially activate TRPV1. 25OHD can inhibit capsaicin induced TRPV1 activity. We propose that vitamin D is a partial agonist of TRPV1, through direct binding to TRPV1 and modulating naïve T-cell activation. Furthermore, our flow cytometry studies confirm both 25OHD and 1,25OHD significantly reduce TNFα/INFγ and IL2/IL4 production of mouse CD4+ naïve T-cells after 24 hours activation. Our results support the concept that naïve T-cell activation can be dampened by vitamin D in a VDR-independent manner, via an as yet undescribed mechanism involving the modulation of TRPV1 activity. Moreover, in silico and point-muatgenic experiments indicate 25-OHD binds to the same region as known TRPV1 agonist and antagonists. These novel findings provide evidence of an additional pathway for the action of Vitamin D action and advance our knowledge of the underlying cellular mechanism by which vitamin D may beneficially regulate naive T-cell activation in autoimmune disease such as T1D.

Disclosure

W. Long: Research Support; Self; JDRF. M. Fatehi: None. S. Soni: None. R. Panigrahi: None. R.G. Kelly: None. K. Philippaert: None. A.J. Barr: None. M. Held: None. Y. Yu: None. S.A. Campbell: None. K. Ondrusova: None. T. Baldwin: None. J. Lemieux: None. P.E. Light: None.

Funding

JDRF
259-LB: Stable Graft Function and Glycemic Control after Clinical Islet Transplantation on the Omentum
Authors: BAIDAL DAVID , BERMAN DORA M. , RICORDI CAMILLO , ALVAREZ GIL ANA M. , PADILLA NATHALIA , CIANCIO GAETANO , LINETSKY ELINA , ALEJANDRO RODOLFO
Published: June 2019

We have shown safety and efficacy of islet transplantation (ITx) in the omentum using a biological scaffold in 3 subjects with type 1 diabetes (T1D). Two subjects (#1 and #3) achieved primary outcome at 1 year (A1c ≤6.5%; No severe hypoglycemia). Subject 1 developed progressive decline in C-peptide after 15 months likely attributed to change in immunosuppression. Subject 3 has had stable graft function for over 2 years. We report on 18 month follow-up data for subject 3. A 46 y/o woman with T1D of 26 years duration underwent single ITx on the omentum (12,648 IEQ/Kg) using a biologic scaffold under ATG induction and combination mycophenolate sodium and tacrolimus maintenance. Pre-ITx insulin dose was 0.45 units/Kg/day and A1c 6.3%. At 18 months, 90 min C-peptide was 1.49 ng/mL, A1c 5.7%, and insulin dose 0.18 units/Kg/day; 14-day continuous glucose monitoring (Guardian Sensor 3, Medtronic) showed glucose 109±28mg/dL (mean±SD), 92% time in glucose range 70-180 mg/dL, 6% time in <70mg/dL, and 0% time in <54 mg/dL. Mixed meal tolerance test data is shown in Table 1. Decline in BETA-2 score was observed by 1 year followed by stabilization. ITx resulted in stable graft function, excellent glycemic control, minimal glycemic variability, and reduction in hypoglycemia over 2 years. Strategies to improve oxygen delivery and neo-vascularization and minimize immunosuppression are needed to improve long-term outcomes at this site.

Disclosure

D. Baidal: None. D.M. Berman: None. C. Ricordi: Advisory Panel; Self; Zone Labs. A.M. Alvarez Gil: None. N. Padilla: None. G. Ciancio: None. E. Linetsky: None. R. Alejandro: None.

Funding

JDRF; The Leona M. and Harry B. Helmsley Charitable Trust; Diabetes Research Institute Foundation, State of Florida; University of Miami Clinical and Translational Science Institute; Sanofi Genzyme
260-OR: Encapsulation of Islets with Tannic Acid Enhances Islet Function
Authors: BARRA JESSIE , KOZLOVSKAYA VERONIKA , KHARLAMPIEVA EUGENIA , KORBUTT GREG , TSE HUBERT M.
Published: June 2019

Islet transplantation can restore glucose homeostasis in patients with type 1 diabetes (T1D), however, limited islet availability, toxicity of immunosuppressants, and poor graft survival impede clinical application. We hypothesize that islet encapsulation with coatings consisting of tannic acid (TA), an immunomodulatory antioxidant, and poly(N-vinylpyrrolidone) (PVPON), will provide immunoprotection and maintain β-cell function after transplantation. (PVPON/TA)-encapsulated syngeneic islets (n=13) significantly delayed graft failure without immunosuppression after transplantation under the kidney capsule into diabetic non-obese diabetic (NOD) mice by more than 30 days compared to non-encapsulated grafts (n= 13; p=0.0021). Histology of islet engrafted kidneys demonstrated increased insulin, glucagon, and somatostatin positivity within encapsulated grafts compared to non-encapsulated grafts and was corroborated with enhanced glucose responsiveness following an intraperitoneal glucose tolerance test (n=9, p=0.0032). To define the immunoprotective properties of (PVPON/TA) coatings, flow cytometric analysis of islet grafts at day 7 post-transplantation displayed fewer MHC-II expressing cells compared to non-encapsulated controls. Gene expression of islet grafts at 5 days post-transplant displayed a significant increase in Ins2 (p<0.05), Arg1 (p<0.0001), and a decrease in Ccl5 (p=0.0006), Cxcl10 (p=0.043), and Grzmb (p=0.032) mRNA accumulation in encapsulated islet grafts in contrast to controls, suggesting that (PVPON/TA)-encapsulation reduces proinflammatory immune responses and elicits a shift toward an anti-inflammatory phenotype. To address limited islet availability, encapsulation of neonatal porcine islets restored euglycemia in diabetic NOD.scidmice for more than 200 days after xenotransplantation. Our results support the hypothesis that (PVPON/TA) coatings are immunomodulatory and may prolong islet graft function following transplantation.

Disclosure

J. Barra: None. V. Kozlovskaya: None. E. Kharlampieva: None. G. Korbutt: None. H.M. Tse: None.

Funding

American Diabetes Association (7-12-CD-11 to H.M.T.); JDRF (1-SRA-2015-42-A-N)
263-OR: IgM Therapy Reverses Autoimmune Diabetes and Prevents Islet Allo- and Xenotransplant Rejection
Authors: MA MINGYANG , BRAYMAN KENNETH L. , CHHABRA PREETI
Published: June 2019

Purpose: To determine if IgM therapy promotes islet allo- and xenograft survival.

Methods: a) 200ug IgM was injected into new onset diabetic NOD mice (n=14) and blood glucose monitored. b) 2000 human islet equivalents (IEQs) were transplanted under the kidney capsule of diabetic BL/6s with and without IgM therapy (IgM (M) n=5; saline (S) n=6). c) 1000 IEQs were transplanted in NOD/scids (M n=4; S n=4). d) 400 Balb/C islets were transplanted under the kidney capsule (M n=6; S n=6); and 350 islets in the portal vein of diabetic BL/6 mice (M n=6; S n=3). e) 5 weeks-old BL/6 and NODs, BL/6- and NOD-VH125 mice and humanized BLT mice received IgM or Saline (5X) following which spleen and bone-marrow cells were analyzed by Flow cytometry.

Results: a) IgM reversed hyperglycemia in 70% of diabetic mice. b) With 2000 IEQS, 5/5 mice in the IgM group returned to normoglycemia, while controls became diabetic in 11±5.5 days (p<0.001). c) Transplantation with 1000 IEQs resulted in restoration of normoglycemia with or without IgM therapy. Removal of islet graft-containing kidney at >60days post-transplant reinstated T1D. d) Following allotransplantation, IgM restored normoglycemia permanently in 6/6 mice. Graft removal at 100 days posttransplant resulted in T1D. Hyperglycemia in controls returned in 10.8±4.7 days. Following intraportal transplantation, all IgM-treated mice were cured. Controls turned diabetic in 6.3±2.5 days. e) IgM mitigated autoimmunity in NODs by reducing % age of marginal zone B cells that perpetuate autoimmunity (p<0.05); by increasing transitional B cell proportions (p<0.01) indicating normalization of B cell homeostatic defects; and inhibiting plasma insulin autoantibody levels (p<0.0001). In NODVH125 mice, IgM eliminated insulin binding B cell population (p<0.0001) and in humanized BLT mice, hIgM therapy expanded the Helios+Foxp3+Treg population.

Conclusion: IgM therapy reversed T1D and promoted permanent islet graft survival indicating its clinical relevance for T1D.

Disclosure

M. Ma: None. K.L. Brayman: None. P. Chhabra: None.

Funding

American Diabetes Association (1-17-IBS-244 to K.L.B.); University of Virginia
265-OR: Myeloid CREBZF Couples Inflammatory Signals to Systemic Insulin Resistance by Regulating Immune Response of the Adipose Tissue
Authors: HU ZHIMIN , LIU YUXIAO , LIU ZHENGSHUAI , ZHAO ZEHUA , CUI AOYUAN , MA FENGGUANG , XUE YAQIAN , HAN YAMEI , ZHANG FEIFEI F. , FAN JIANGAO , LI YU
Published: June 2019

Obesity and type 2 diabetes are associated with chronic inflammation response in the adipose tissue, in which macrophage activation and infiltration are hallmark characteristics. However, the molecular mechanism of this association remains largely unknown. Here, we show that CREB/ATF bZIP transcription factor CREBZF as a critical regulator of the adipose macrophage sensing inflammatory signals to cause systemic insulin resistance in obesity. We found that CREBZF was markedly induced in bone-marrow-derived macrophages and J774 macrophage cell lines in response to lipopolysaccharide treatment. To elucidate the function of CREBZF, we generated a myeloid cell-specific CREBZF knockout (CREBZF MKO) mouse by crossing floxed CREBZF mice with LysM-Cre transgenic mice. Myeloid cell-specific CREBZF deficiency in mice largely attenuated high-fat high sucrose (HFHS) diet-induced obesity and insulin resistance and hyperglycemia. CREBZF MKO mice showed a dramatic reduction of infiltrated macrophages in the white adipose tissue and an induction of whole-body energy expenditure. Ablation of CREBZF in myeloid cells caused a potent reduction of M1 macrophages and a concomitant induction of M2 macrophages in the adipose tissue of mice fed with HFHS diet, suggesting an important role of CREBZF in regulating adipose tissue macrophage polarization. Interestingly, CREBZF is capable of potentiating NF-κB signaling as evidenced by increased phosphorylation of IκB and p65 in the macrophage, whereas CREBZF deficiency resulted in opposite effects. These data indicate that CREBZF plays an important role in the regulation of innate immune response in the macrophage, and maintains whole-body energy metabolism and glucose homeostasis. Pharmacologic manipulation of CREBZF activity in the macrophage may provide novel opportunities for treating obesity, insulin resistance and type 2 diabetes.

Disclosure

Z. Hu: None. Y. Liu: None. Z. Liu: None. Z. Zhao: None. A. Cui: None. F. Ma: None. Y. Xue: None. Y. Han: None. F.F. Zhang: None. J. Fan: None. Y. Li: None.

Funding

National Key Research and Development Program of China (2017YFC0909601); National Natural Science Foundation of China (31471129, 31671224); Chinese Academy of Sciences (KJZD-EW-G20-02); K.C. Wong Education Foundation (to Y.L.)
266-LB: Evidence for a Hexosamine Biosynthesis Pathway-Mediated Sp1 Cholesterolgenic Response Being an Early Etiological Factor of Insulin Resistance
Authors: GRICE BRIAN A. , COVERT JACOB D. , KREILACH ALEC M. , THORNBURG MATTHEW , TACKETT LIXUAN , MCCLAIN DON , ELMENDORF JEFFREY S.
Published: June 2019

Excess plasma membrane cholesterol-mediated cellular insulin resistance has been shown to result from increased hexosamine biosynthesis pathway (HBP) O-GlcNAcylation of the transcription factor Sp1 in 3T3-L1 adipocytes and L6 skeletal muscle myotubes. Here we tested the causal relationship between excess skeletal muscle membrane (SMM) cholesterol and insulin resistance, as well as probed the potential HBP/Sp1 link, in mice fed a Western-style high-fat diet for one week or in mice with targeted skeletal muscle overexpression of glucosamine-fructose aminotransferase (GFAT, the rate-limiting enzyme of the HBP). HF feeding increased SMM cholesterol and impaired GLUT4 regulation, glucose tolerance and insulin sensitivity within one week. These early skeletal muscle and systemic metabolic abnormalities were fully prevented in HF-fed mice treated during the one-week diet challenge with two subcutaneous injections of the cholesterol-depleting agent methyl-β-cyclodextrin. Consistent with in vitro data, an HBP-mediated Sp1 cholesterolgenic response contributing to SMM cholesterol accumulation, the transcription of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, was increased in skeletal muscle from HF-fed mice. Furthermore, treating HF-fed mice during the one-week HF-feeding challenge with mithramycin, an agent that blocks Sp1 binding to DNA, prevented the SMM cholesterol buildup, glucose intolerance, and insulin resistance. Skeletal muscle GFAT overexpression also caused accumulation of SMM cholesterol, glucose intolerance, and insulin resistance.These data suggest that early skeletal muscle insulin resistance in the setting of HF feeding are a consequence of a HBP-mediated Sp1 cholesterolgenic transcriptional response and that targeting this pathway has therapeutic potential for preventing insulin resistance and the development of T2D.

Disclosure

B.A. Grice: None. J.D. Covert: None. A.M. Kreilach: None. M. Thornburg: None. L. Tackett: None. D. McClain: None. J.S. Elmendorf: None.

Funding

American Diabetes Association (1-15-BS-053 to J.S.E.); National Institutes of Health (R01DK114222-01A1, UL1TR001108T32, DK064466, T32GM077229, P30DK097512); Indiana University-Purdue University; Indianapolis Research Support Funds
267-LB: Diabetes-induced Insulin Resistance and DPP-4 Activity Can Be Alleviated through the Reduction of M1 Polarization of Adipose Tissue
Authors: CHEN LEE-WEI
Published: June 2019

Dysregulation of M1/M2 polarization in adipose tissues is emerging as a central mechanism underlying the pathogenesis of obesity and comorbidities such as insulin resistance and nonalcoholic fatty liver disease. To define the involvement of dysregulation of M1/M2 polarization of adipose tissues in diabetes and the effect of nondiabetic plasma on M1/M2 polarization of adipose tissue and liver as well as dipeptidyl peptidase-4 (DPP-4) activity in plasma, we purified stromal vascular fractions (SVFs) from diabetic and nondiabetic mice and analyzed their M1/M2 polarization with or without the treatment of nondiabetic plasma. SVF of diabetic mice (Lep-/-) demonstrated a significant increase of M1 but decrease of M2 signature as compared with nondiabetic mice (Lep+/-). Treatment of SVF from adipose tissue of Lep-/- mice with plasma of Lep-/- mice in vitro significantly increased M1 gene signature. Treatment of SVF from adipose tissue of Lep-/- mice with plasma of nondiabetic mice (Lep+/- mice) increased M2 gene signature. Moreover, injection of plasma of nondiabetic mice (Lep+/-) to adipose tissue of diabetic mice (Lep-/-) induces M2 expression of SVF and decreases inflammation of liver and DPP-4 activity of diabetic (Lep-/-) mice. These data suggest that plasma of diabetic mice can induce M1 expression and plasma of nondiabetic mice can induce M2 expression of adipose tissue of diabetic mice.

In conclusion, diabetes and obesity-induced insulin resistance, glucose intolerance, and systemic inflammation can be alleviated through the reduction of M1 polarization of adipose tissue.

Disclosure

L. Chen: None.

Funding

Taiwan Ministry of Science and Technology (MOST 107-2314-B-010-043-MY3)
27-OR: Simplifying Detection of Large Scale Deletions Causing MODY5
Authors: BERBERICH AMANDA J. , WANG JIAN , CAO HENIAN , MCINTYRE ADAM D. , ROBINSON JOHN F. , YANG PING , KNOLL JOAN , HEGELE ROBERT
Published: June 2019

Maturity Onset Diabetes of the Young (MODY) 5, also known as renal cysts and diabetes syndrome, is a rare autosomal dominant form of monogenic diabetes caused by mutations in the HNF1B gene encoding hepatocyte nuclear factor 1 homeobox beta. Whole gene deletions of one copy of HNF1B are the most common mutation underlying MODY5, with more extensive deletions encompassing HNF1B and several surrounding genes, known as 17q12 deletion syndrome, present in a sub-set of individuals with MODY5, who present with additional clinical features. Historically, these large scale deletions are not identified using Sanger or targeted next generation sequencing (NGS) panels, and require other tools, such as microarray-based genomic hybridization or multiplex ligation probe amplification to detect. Incorporating such tests to targeted sequencing adds significantly to cost and labor.

Recent advances in bioinformatics allow for identification of large-scale copy number variation (CNV) from NGS output data without requiring additional laboratory methods. The NGS data from 57 patients suspected to have MODY by their physicians but who were negative for pathogenic mutations using a targeted NGS approach were thus re-examined using a CNV calling tool (CNV Caller, VarSeq v1.4.3).

Three unrelated patients were found to have large scale deletions spanning HNF1B. These deletions were verified using whole exome sequencing data as well as microarray analysis (CytoScan, Affymetrix), which confirmed the presence of 17q12 deletion in all three individuals. The deletions varied in size from 1.46 to 1.85 million base pairs. Clinical correlation revealed a history of genitourinary abnormalities in all three probands.

These results confirm the utility of the CNV Caller tool in identifying large-scale deletions causing MODY5, as well as 17q12 deletion syndrome. This may represent an easier, more cost-effective approach to making this diagnosis, ultimately improving case detection and allowing for more personalized care for affected individuals.

Disclosure

A.J. Berberich: None. J. Wang: None. H. Cao: None. A.D. McIntyre: None. J.F. Robinson: None. P. Yang: None. J. Knoll: Stock/Shareholder; Self; Cytognomix Inc. R. Hegele: Consultant; Self; Aegerion Pharmaceuticals, Akcea Therapeutics, Amgen Inc., Regeneron Pharmaceuticals, Sanofi.
270-LB: Amelioration of Hepatic Insulin Resistance by Brown Adipocyte Secretion
Authors: BHUSHAN ABHINAV , TANATAWEETHUM NIDA , LEE CHAEEUN , ZHONG FRANKLIN , TRANG ALLYSON , BUDIMAN ANDREW
Published: June 2019

Insulin resistance (IR) is a hallmark of T2D. In the IR state, insulin fails to inhibit hepatic glucose production yet promotes lipogenesis. Although thiazolidinediones can partially reinstate insulin sensitivity, there are concerns about long-term usage. Recent studies have shown positive effects of paracrine signaling from BAT transplant on metabolic homeostasis. Transplant of embryonic BAT into diabetic mice can improve glucose tolerance. However, the mechanisms are unclear. In this study, we show that brown adipocyte secretions can partially resolve hepatic IR. We cultured primary hepatocytes in a microfluidic organ-on-chip device. IR was induced by cytokine exposure and the cells were treated with brown adipocyte secretions among other controls. The group treated with brown adipocytes had restored insulin sensitivity. This was verified by an increased Akt phosphorylation (Figure 1), lowered glucose production, increased glucose uptake, and increased glycogen synthesis. We finally confirmed that genes important for glucose production (G6pc, PEPCK) and lipogenesis (SREBP1) were downregulated in the treated cells. We will present results from ongoing mechanistic studies. Our data imply that brown adipocyte secretions contain factors that regulate hepatic insulin sensitivity and could be potential targets for drug development.

Disclosure

A. Bhushan: None. N. Tanataweethum: None. C. Lee: None. F. Zhong: None. A. Trang: None. A. Budiman: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (DK095984NIH, P30DK020595)