bluuebunny/crossref_metadata_2025_split huggingface dataset:
183-OR: Allogenic Adipose-Derived Mesenchymal Stem Cells (ASCs) and Vitamin D Supplementation in Patients with Recent-Onset Type 1 Diabetes Mellitus: A 6-Month Follow-Up Pilot Study
Authors: DANTAS JOANA R. , ARAUJO DEBORA B. , BAPTISTA LEANDRA S. , SOUTO DEBORA L. , PEREIRA KARINA , PEREIRA MARIA F. , CLAUDIO-DA-SILVA CESAR S. , MANTUANO MATHEUS S. , DAGA DEBORA R. , SENEGAGLIA ALEXANDRA C. , REBELATTO CARMEN K. , COURI CARLOS EDUARDO B. , OLIVEIRA JOSE E. , ZAJDENVERG LENITA , RODACKI MELANIE 
Published: June 2020

Objective: To evaluate safety and efficacy of ASCs infusion from healthy donors and daily cholecalciferol (VitD) supplementation in patients with recent-onset T1D, after a 6-month follow-up.
Methods: This is a phase II, prospective, one center, open trial, in which patients with recent onset T1D received one infusion of ASCs (1x106 cells/kg) and VitD 2000UI/day for 6 months. They were compared to controls with standard insulin therapy. C-peptide (CP) after mixed meal, insulin dose(UI/kg), HbA1c and CD45+CD3+CD4+FoxP3+T-cells frequencies (flow cytometry) were measured at baseline (T0) and after 3 (T3) and 6 months (T6).
Results: Eleven patients were included. Mean age and disease duration were 24.2 ± 5.2 years and 3.11 ± 0.88 months, respectively. Group 1 (n=7) received ASCs+VitD and group 2 (n=4) standard insulin therapy. Age, insulin dose, HbA1c and area under the curve (AUC) of CP were similar at T0 between groups (p=0.23, 0.23, 0.98 and 0.73, respectively). After intervention, group 1 had lower insulin requirement than group 2 at T3 (0.24±0.18 vs. 0.53±0.23IU/Kg, p=0.04) and T6 (0.24±0.15 vs. 0.66±0.33 UI/kg, p=0.04). Two patients in group 1 became transiently insulin free. HbA1C was lower in group 1 at T6 (6.77±0.79 vs. 8.75±0.95%; p=0.01). CP AUC was higher in group 1 at T3 (211.20 ± 100.42 vs. 106.05±47.25 ng/ml.min;p=0.04) and T6 (220.58 ± 97.06 vs. 63.37±37.96ng/ml.min, p=0.006). At T6, 6 patients in group 1 (85.7%) were in honeymoon phase (insulin dose ≤ 0.5IU/kg and HbA1c &lt;7.5%) vs. none in group 2 (p=0.01). At T6 there was an inverse correlation between serum VitD and HbA1C (p=0.03; r=-0.66) and a positive correlation between VitD and CP AUC (p=0.02, r=0.67). CD45+CD3+CD4+FoxP3+ T-cells increased at T1 in group 1 (p=0.04), without differences at T3 and T6.
Conclusion: Allogenic ASCs infusion + VitD without immunosuppression was safe and may be an effective approach for the treatment of patients with recent onset T1D.

Disclosure
J.R. Dantas: None. D.B. Araujo: None. L.S. Baptista: None. D.L. Souto: None. K. Pereira: None. M.F. Pereira: None. C.S. Claudio-da-Silva: None. M.S. Mantuano: None. D.R. Daga: None. A.C. Senegaglia: None. C.K. Rebelatto: None. C.B. Couri: None. J.E. Oliveira: None. L. Zajdenverg: None. M. Rodacki: None.

Funding
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior; Fundação de Amparo a Pesquisa do Rio de Janeiro
1842-P: Modeling Nonalcoholic Steatohepatitis in Aged C57BL/6J Mice
Authors: SERRANO JASON , FRENCH RICHARD D. , LEIGHTON KRYSTAL , SANMIGUEL ADAM , ELLIS MICHAEL , IMAI DENISE , SCHILE ANDY 
Published: June 2020

Nonalcoholic steatohepatitis (NASH) is usually diagnosed in 40-60 year old patients with metabolic syndrome, but many common mouse models involve dietary or chemical interventions that begin at young ages. We established 3 NASH models using year-old C57BL/6J (B6J) males with approximate human age equivalence of 40 years. In one model, aged mice ate Gubra Amylin NASH (GAN) diet (40 kcal% fat with 18 kcal% palm oil; 20% fructose; 2% cholesterol; N=12) or chow diet (6% fat by weight; N=10) for 5 months. Aged mice fed GAN had rapid signs of liver damage: by 1 month, serum alanine aminotransferase (ALT) rose from 53 ± 20 to 309 ± 188 IU/L (Repeated measures ANOVA; P &lt; 0.0001) and aspartate aminotransferase (AST) increased from 77 ± 33 to 399 ± 420 IU/L (P &lt; 0.0001); values were stable in aged B6J fed chow. In contrast, liver damage progressed more slowly when B6J were started on GAN as young adults (6 weeks old; N=11); ALT increased from 27 ± 5 to 231 ± 96 IU/L and AST from 53 ± 18 to 177 ± 88 IU/L after 5 months. After 1 month, GAN-fed aged B6J serum cholesterol rose from 166 ± 24 to 290 ± 65 mg/dL (P &lt; 0.0001) but not in aged B6J fed chow or young B6J fed GAN. Triglycerides and glucose did not change after 5 months in any group, while ALT, AST and cholesterol remained high in aged GAN mice throughout. Histopathology of aged B6J fed GAN for 5 months showed severe submassive to diffuse steatosis; perivascular, bridging, and perisinusoidal fibrosis; necrosis and hepatocyte degeneration. A second model was created by treating year-old B6J mice with 3 daily doses of 50 mg/kg streptozotocin (STZ) and 60 kcal% high fat diet (STZ-HFD). Serum glucose, ALT, AST and cholesterol rose in STZ-HFD mice. Steatosis and fibrosis were less severe in STZ-HFD mice compared to aged mice fed GAN. In a third model, young and aged B6J responded similarly to a choline-deficient, reduced-methionine diet with elevated ALT and AST; reduced glucose, cholesterol and body weight; and comparable histopathology scores. The results show the value of studying mice at a life stage that more closely resembles age of clinical diagnosis.

Disclosure
J. Serrano: None. R.D. French: None. K. Leighton: None. A. SanMiguel: None. M. Ellis: None. D. Imai: None. A. Schile: None.
1846-P: Low-Dose Dihydrotestosterone Increased Lipogenic Proteins Resulting in Increased NAFLD via Regulation of SREBP1c in Liver Tissue of Normal Weight Female Mice
Authors: ANDRISSE STANLEY 
Published: June 2020

Hyperandrogenemia (HA) and insulin resistance are hallmarks of polycystic ovary syndrome (PCOS). These hallmarks are also integral elements of nonalcoholic liver disease (NALFD). Administering low dose dihydrotestosterone (DHT) induced a lean female mouse model with a PCOS-like phenotype. The molecular mechanism of HA-induced NAFLD has not been determined. We hypothesized that low dose DHT would interrupt hepatic lipid metabolism leading to NAFLD. We extracted white adipose tissue (WAT), liver, and skeletal muscle from control and low dose DHT female mice; and performed Western blot and real-time quantitative PCR (qRT-PCR) analysis of lipogenic intermediates. Low-dose DHT lowered the active form of cytosolic SREBP1 in the liver and WAT compared to controls. Additionally, low dose DHT increased inactive SREBP1 in the liver. However, DHT did not alter the levels of the active and inactive forms of SREBP2 in the liver and WAT. DHT increased SCAP protein expression and SCAP-SREBP1 binding, which helps activate SREBP. Regarding lipogenic enzymes, FAS mRNA and protein expression was increased in liver of DHT mice. p-ACC levels were unaltered in liver but decreased in WAT. Other lipid metabolism pathways were examined in liver and WAT but no changes were observed. Taken together, our findings support the hypothesis that cytosolic SREBP1 decreased due to its translocation to the nucleus, where it upregulated lipogenic mRNA expression. We showed that low-dose DHT increased SCAP-SREBP-1 association promoting the activation and translocation of SREBP1 from the cytosol to the nucleus to influence lipogenic gene expression leading to increased lipogenesis contributing to NAFLD.

Disclosure
S. Andrisse: None.

Funding
Robert Wood Johnson Foundation (74250); Eunice Kennedy Shriver National Institute of Child Health and Human Development (K23HD095075)
1849-P: Fructose Induces Hepatic Steatosis via ME1-Mediated Cytosolic Redox Status
Authors: JIANG HAOWEN , LI JIA 
Published: June 2020

Increased consumption of fructose-rich beverages has emerged as an important risk factor for development of hepatic steatosis, type 2 diabetes and metabolic syndrome. As is well-known, fructose robustly stimulates de novo lipogenesis in vivo; but how this occurs is less clarified and may involve multiple mechanisms. To determine the mechanism of fructose-induced hepatic steatosis and associated metabolic disease, we fed mice with chow diet and 30% fructose in drinking water. Fasting blood glucose level was elevated and insulin sensitivity was impaired in fructose fed group. Also, mice fed with fructose showed exaggerative lipid accumulation in the liver. To find out how fructose induced hepatic steatosis, we performed liver proteomic analysis following fructose fed. Compared with chow fed, Fructose fed significantly increased malic enzyme 1 (ME1), which is NADP-dependent and responsible for NADPH generation. Consistently, the ratio of NADPH/NADP+ in liver was increased by fructose fed, suggesting that fructose increased hepatic redox status. NADPH performed as a hydrogen donor for the synthesis of fatty acids, nucleic acids, etc. We also found that the multiple metabolites depending on NADPH production was dramatically enriched in our metabolome analysis. Then, we use selective ME1 inhibitor to decrease NAPDH production and redox status. The accumulation of triglyceride (TG) in primary hepatocytes by fructose was dose-dependently reduced by ME1 inhibitor. Similarly, the increasing of intracellular TG accumulation and NADPH/NADP+ ratio by fructose was inhibited upon ME1 knockdown by the application of siRNA. Taken together, our preliminary results suggested that ME1 mediated cytosolic redox status might play an important role in fructose induced hepatic steatosis and associated metabolic disease.

Disclosure
H. Jiang: None. J. Li: None.
185-LB: Does Having Coexisting Diabetes Mellitus Improve Outcomes of Hospitalizations for Rheumatoid Arthritis?
Authors: EDIGIN EHIZOGIE , YAP SARA ELIZABETH T. , SHAKA HAFEEZ , XU JING , PADILLA SORTO MARIA ELENA 
Published: June 2020

Background: Diabetes mellitus (DM) is a common metabolic disorder, which has negative outcomes on various medical conditions.
Objectives: This study aims to determine if DM has an impact on the outcomes of patients primarily admitted for rheumatoid arthritis (RA). The primary outcome is inpatient mortality, and secondary outcomes are hospital length of stay (LOS) and total hospital charge.
Methods: Data were extracted from the Nationwide Inpatient Sample (NIS) Database for 2016 and 2017. This database contains the largest collection of inpatient hospitalization data in the USA. NIS was searched for hospitalizations for RA as the principal diagnosis, with and without DM as a secondary diagnosis, using ICD-10 codes. Hospitalizations for adults from the above groups were included. Multivariate logistic and linear regression analysis was used to adjust for possible confounders for the primary and secondary outcomes respectively.
Results: Over 71 million hospitalizations were included in the combined 2016 and 2017 NIS database. There were 18,905 hospitalizations for those 18 years or older, who had RA as the principal diagnosis. Of these, 14,822 (78.4%) had no secondary diagnosis of DM and 4,083 (21.6%) had co-existing DM. RA hospitalizations had 175 inpatient deaths (0.93%), of which, 25 occurred in hospitalizations with DM (0.61%). The adjusted odds ratio (AOR) of inpatient mortality for RA with DM compared to without DM was 0.342 (95% CI: 0.137 - 0.85, P=0.021). In hospitalizations for RA with DM, there was a decreased mean adjusted LOS of 0.76 days (95% CI -1.26 - {-0.26}, P=0.003) compared to without DM. The adjusted mean total hospital charge for hospitalizations for RA with DM was lower by $6243 compared to without DM (95% CI -12250 - {-236}, P=0.042).
Conclusions: Hospitalizations for RA with co-existing DM had less inpatient mortality, LOS and total hospital charge compared to without DM. More studies are needed to determine if indeed DM is protective in hospitalizations for RA.

Disclosure
E. Edigin: None. S.T. Yap: None. H. Shaka: None. J. Xu: None. M. Padilla Sorto: None.
1853-P: Neutrophils Play a Pivotal Role in Obesogenic Diet-Induced Nonalcoholic Steatohepatitis
Authors: ZHOU QIONG L. , KHAN SHOAIB , RIGOR MICHAEL , BEERAM INDEEVAR , JIANG ZHEN Y. 
Published: June 2020

Lipid deposition, inflammatory damage, and fibrotic remodel are the hallmarks of nonalcoholic steatohepatitis (NASH). However, the molecular and cellular mechanisms by which obesogenic diet-induced progression from steatosis to NASH remains elusive. Here, we report that neutrophils play a significant role in mediating NASH in the liver. Remarkably, high-fat high-fructose diet (HFHFD) feeding increased expression of chemokines in the liver leading to a dramatic upsurge of neutrophil infiltration into the liver with a concomitant increase of macrophages and Th17 cell accumulation and collagen deposition in the liver. In contrast, inhibition or deletion of neutrophil elastase (NE) significantly reduced lipid deposition, metabolic stress, and inflammation in the liver in mice fed obesogenic diets. Inhibition of NE dramatically reduced the expression of chemokines, accumulation of neutrophils, macrophages, and Th17 cells, and progress of fibrosis in the liver. Together, our data suggest that NE contributes to NASH progression through regulating metabolic signaling and inflammatory damage in the liver.

Disclosure
Q.L. Zhou: None. S. Khan: None. M. Rigor: None. I. Beeram: None. Z.Y. Jiang: None.

Funding
National Institutes of Health (1R56DK121142)
1865-P: SGLT2 Inhibition Compared with Iso-energetic/Low-Carbohydrate Diet Reprograms Systemic Substrate Oxidation in Type 2 Diabetes
Authors: IGARASHI HIROYUKI , UCHINO HIROSHI , FURUTA MASASHI , MIYAGI MASAHIKO , KUMASHIRO NAOKI , HIROSE TAKAHISA 
Published: June 2020

Introduction: Pharmacologic inhibition of the renal sodium/glucose cotransporter-2 (SGLT2i) facilitates lipid oxidation. Iso-energetic/low-carbohydrate diet (i-Carbo) eliminates the same amount of glucose as SGLT2 inhibition (∼ 50 g/day of glucose). We examined whether i-Carbo and SGLT2i may have any impact, on 1) fasting and postprandial energy expenditure (EE) and substrate oxidation, 2) the basal-bolus dose of insulin that achieve euglycemia.
Method: Twenty four T2D (M/F = 15/9, age 53.6 ± 14.2, BMI 26.9 ± 4.8 kg/m2, HbA1c 12.5 ± 1.6 %) were enrolled to this 12 weeks, randomized, 3 arms open-label, prospective study with basal-bolus insulin titration algorithm, control diet (CON) or adding canagliflozin 100 mg/day to CON (SGLT2i) and the i-Carbo. We measured indirect calorimetry to provide EE and respiratory quotient (RQ) during fasting and postprandial before and after the intervention.
Results: In spite of similar carbohydrate amount in the i-Carbo, compared to the SGLT2i, the total daily dose of insulin was significantly higher (p=0.02). Compared to the CON, fasting EE were similar on both SGLT2i and i-Carbo, however, postprandial EE were elevated, respectively (p=0.03, 0.04). Fasting RQ was marginally higher in SGLT2i compared to the CON (p=0.049). Postprandial RQ was elevated by means of increased carbohydrate substrate utilization on both SGLT2i (p=0.04) and i-Carbo (p=0.03) groups compared to the CON.
Conclusion: Iso-energetic/low-carbohydrate in i-Carbo, which matches urinary carbohydrate loss in SGLT2i, had similar fasting and postprandial energy expenditure and substrate oxidation rate. Increased insulin requirement in i-Carbo indicates that relative high lipid and protein ratio, compared to SGLT2i, may have any effect to insulin requirement.

Disclosure
H. Igarashi: None. H. Uchino: None. M. Furuta: None. M. Miyagi: None. N. Kumashiro: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker’s Bureau; Self; Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. T. Hirose: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; AstraZeneca, Lilly Diabetes, Novo Nordisk Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd.
1872-P: Metabolomic Profiling during Diabetic Ketoacidosis (DKA) Demonstrates Unique Defects Underlying the Pathophysiology of Ketosis-Prone Diabetes
Authors: HSU JEAN W. , MEHTA PARAS , KEENE KELLY R. , MULUKUTLA SURYA N. , CADUCOY EUNICE I. , PEACOCK WILLIAM , BALASUBRAMANYAM ASHOK , JAHOOR FAROOK 
Published: June 2020

Obese patients with ketosis-prone type 2 diabetes (“A-β+ KPD”) have increased catabolism of the ketogenic amino acids leucine/isoleucine (Leu/Ile) and impaired ketone oxidation when stable and normoglycemic (Patel et al, Diabetes 2013). We performed comparative serum metabolomics on patients at presentation with hyperglycemic crisis without (N = 29) or with (N = 73) DKA compared to healthy controls (N = 17). The diabetic groups included normal weight and overweight/obese subgroups. DKA patients had higher plasma cortisol and catecholamines and lower C-peptide than the other groups. Three metabolite patterns distinguished the DKA patients from the other groups: 1) Elevated levels of Leu/Ile and of their respective ketoacids, no difference in isovaleryl carnitine (C5) but markedly lower ratio of C5 to C2 (acetyl carnitine) - implying accelerated shunting of Leu/Ile into their catabolic pathways but impaired oxidation because defective TCA cycle activity restrains acetyl CoA entry and metabolism. These changes were most pronounced in obese DKA patients, recapitulating the pattern of A-β+ KPD patients when stable; 2) Markedly decreased levels of glutamate, ammonia and many non-essential amino acids including citrulline, in the presence of increased glutamine, suggesting a defect in glutaminase activity; 3) Low levels of 3-methyl histidine, suggesting a surprising decrease in muscle protein breakdown. The pattern of amino acids and their metabolites among the DKA (especially obese) patients indicate that both increased ketone production from Leu/Ile and their blunted oxidation contribute to the proclivity to develop DKA; elevated leucine and low citrulline could contribute to beta cell dysfunction via mTOR hyperactivity and diminished intracellular arginine availability. Thus serum metabolomic profiling during an acute DKA episode helps define a unique pathophysiology underlying the phenotype of obese ketosis-prone T2D.

Disclosure
J.W. Hsu: None. P. Mehta: None. K.R. Keene: None. S.N. Mulukutla: None. E.I. Caducoy: None. W. Peacock: None. A. Balasubramanyam: None. F. Jahoor: None.

Funding
National Institutes of Health (R01DK101411)
1882-P: The Comparative Effects of Atorvastatin, a Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor (PCSK9i), and Estrogen on Oxidative Muscle Mitochondria in a Rat Model of Obesity with Menopause
Authors: THONUSIN CHANISA , ARUNSAK BUSARIN , AMPUT PATCHAREEYA , PALEE SIRIPONG , PRATCHAYASAKUL WASANA , CHATTIPAKORN NIPON , CHATTIPAKORN SIRIPORN C. 
Published: June 2020

The aim of this study was to compare the effects of atorvastatin, a PCSK9i, and estrogen on oxidative muscle mitochondria in a rat model of obesity and menopause. Female Wistar rats consumed either a normal diet (ND: n = 12) or a high-fat diet (HFD: n = 60). At week 13, ND-fed rats received a sham-operation, while HFD-fed rats were undergone either a sham-operation (n = 12) or an ovariectomy (n = 48). At week 19, all sham-operated rats were treated with vehicle, while ovariectomized HFD-fed rats were separated into 4 groups (n = 12/group) to receive either vehicle, 40 mg/kg/day of atorvastatin, 4 mg/kg/day of PCSK9i (SBC-115076), or 50 µg/kg/day of estrogen for 3 weeks. Metabolic panel and soleus muscle were investigated at the end of week 21. Sham-operated and ovariectomized HFD-fed rats developed obesity, insulin resistance, and hyperlipidemia. Increased MDA level, OXPHOS proteins, ratio of p-Drp1/total Drp1 protein, mitochondrial ROS, and mitochondrial membrane depolarization in soleus muscle were observed in both groups of HFD-fed rats. Both drugs and estrogen equally decreased insulin resistance, MDA level, OXPHOS proteins, and ratio of p-Drp1/total Drp1 protein. However, only atorvastatin and PCSK9i attenuated hypertriglyceridemia. Estrogen showed greater efficacy in weight loss than both drugs. In addition, estrogen decreased mitochondrial ROS and mitochondrial membrane depolarization in soleus muscle of ovariectomized HFD-fed rats. Interestingly, only atorvastatin increased cytochrome C protein and ratio of active caspase 3,8/caspase 3,8 proteins in soleus muscle. Our findings suggested that atorvastatin and PCSK9i are superior to estrogen in the reduction of hypertriglyceridemia. However, estrogen is more effective than both drugs in weight loss and exhibits the least harmful impact on oxidative muscle. PCSK9i displays less skeletal muscle toxicity than atorvastatin.

Disclosure
C. Thonusin: None. B. Arunsak: None. P. Amput: None. S. Palee: None. W. Pratchayasakul: None. N. Chattipakorn: None. S.C. Chattipakorn: None.
1894-P: Interruption of Glucagon Signaling Increases Pancreas Mass
Authors: DAI CHUNHUA , BRADLEY AMBER , COATE KATIE C. , POFFENBERGER GREG , SPEARS ERICK , WRIGHT JORDAN J. , SHRESTHA SHRISTI , DEAN DANIELLE , BRISSOVA MARCELA , POWERS ALVIN C. 
Published: June 2020

Interruption of glucagon signaling by glucagon receptor gene inactivation or treatment with a glucagon receptor blocking monoclonal antibody (GCGR-Ab) stimulates alpha cell proliferation and expansion. Surprisingly, pancreas weight is also increased in mice with GCG gene inactivation. To investigate mechanisms linking glucagon signaling and pancreas size, we treated C57BL/6J mice with GCGR-Ab or a control IgG. Eight weeks of treatment (N=4-15 mice/treatment) increased absolute pancreas weight (0.42±0.013 vs. 0.32±0.008; p&lt;0.0001), pancreas weight normalized to body weight (1.39±0.03% vs. 1.11±0.02%; p&lt;0.0001), and serum levels of 15 amino acids (AA), including glutamine (1.7-4.67 fold, p&lt;0.0001). GCGR-Ab treatment promoted acinar cell proliferation (Ki67+, 0.65±0.14% vs. 0.20±0.03%; p=0.0058), increased acinar cell size (peri-islet region: 438.4±12.77 vs. 341.7±22.05μm2; p=0.0045; peripheral region: 431.1±9.34 vs. 334.2±25μm2, p=0.0055; central region: 437.0±10.45 vs. 338.7±13.6 μm2, p=0.0006), and increased pancreas protein content (248.3±9.84 vs. 194±8.67μg/mg tissue; p=0.0003). By electron microscopy, GCGR-Ab treatment increased acinar cell zymogen granule number (129±9 vs. 49±6; p&lt;0.0001; n=28-37 cells/treatment) and led to acinar cell ER dilatation, but did not induce pancreatitis or alter acinar cell apoptosis or pancreatic macrophage number. Serum cholecystokinin and total glucagon-like peptide-1, trophic hormones linked to exocrine growth, were not changed by GCGR-Ab treatment. GCGR-Ab treatment upregulated mRNA and protein levels of the glutamine transporter, Slc38a3, and increased mTOR-related ribosomal protein S6 phosphorylation in acinar cells. Together, these data indicate that interruption of glucagon signaling increases pancreas mass by inducing acinar cell hyperplasia and hypertrophy and activates protein synthesis and mTOR signaling; whether this is mediated by elevated glutamine or AA levels is not known.

Disclosure
C. Dai: None. A. Bradley: None. K.C. Coate: None. G. Poffenberger: None. E. Spears: None. J.J. Wright: None. S. Shrestha: None. D. Dean: None. M. Brissova: None. A.C. Powers: None.

Funding
National Institutes of Health (DK117147)