bluuebunny/crossref_metadata_2025_split huggingface dataset:
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&lt;0.001); and this induction was abrogated by cell pre-treatment with apocynin or N-acetyl cysteine (P&lt;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&lt;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 &lt;70mg/dL, and 0% time in &lt;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&lt;0.05), Arg1 (p&lt;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&lt;0.001). c) Transplantation with 1000 IEQs resulted in restoration of normoglycemia with or without IgM therapy. Removal of islet graft-containing kidney at &gt;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&lt;0.05); by increasing transitional B cell proportions (p&lt;0.01) indicating normalization of B cell homeostatic defects; and inhibiting plasma insulin autoantibody levels (p&lt;0.0001). In NODVH125 mice, IgM eliminated insulin binding B cell population (p&lt;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