bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between Glycated Lipoproteins and Vascular Function in African-American Diabetic Patients
Authors: ELUWOLE AYOBAMI , ADEDAYO AJIBOLA M. , TEDLA FASIKA , KREMER ARYE , MASTROGIOVANNI NICOLE , ROSENBERG CARL , DREIZEN PAUL , LAROSA JOHN , SALCICCIOLI LOUIS , BOUTJDIR MOHAMED , BANERJI MARY ANN , BROWN CLINTON , SALIFU MORO , LAZAR JASON , BAKILLAH AHMED 
Published: June 2018

Patients with type 2 diabetes mellitus exhibit non-enzymatic glycation of lipoproteins that are considered proatherogenic modification contributing to increased susceptibility of patients with diabetes to atherosclerosis. We postulated that glycated lipoproteins might be associated with vascular outcome. To explore this, we studied the relationship between glycated HDL (gHDL) and glycated LDL (gLDL) with vascular function in African American diabetic patients. Total of 146 diabetic were enrolled over a 6 month period. Levels of plasma gHDL and gLDL were measured by enzyme-linked immunosorbent assay (ELISA). Microvascular function was assessed by vascular reactivity index (VRI). Large artery stiffness was assessed by carotid-femoral pulse wave velocity (PWV). Carotid intima-media thickness (C-IMT) was assessed by B-mode ultrasound image analysis. Mean patient age was 60±8 years, 64% were female. 80% had hypertension, 90% had dyslipidemia and 15% had chronic kidney disease. Mean HbA1c levels were 8.1±2.2%. Pearson correlation analysis showed no significant correlation between gHDL and gLDL. Multi-regression analysis revealed that gHDL was negatively associated with VRI (β= -0.006, p= 0.012; r2 = 0.276 for model) in the entire population and in the group of patients with good glycemic control (HbA1c ≤ 7.0; β= -0.007, p= 0.031; r2 = 0.312 for model); whereas gLDL was positively associated with CIMT (β= 0.045, p= 0.051; r2= 0.568 for model) after adjustment for other independent variables such as age, gender, stroke, smoking, hypertension, dyslipidemia, HbA1c, diabetes duration, HDLc, and LDLc.
In this cohort, data showed that gHDL was associated with microvascular function, whereas gLDL was mainly correlated with carotid intima media thickness. Further large study is needed to clarify mediating factors of these relationships.

Disclosure
A. Eluwole: None. A.M. Adedayo: None. F. Tedla: None. A. Kremer: None. N. Mastrogiovanni: None. C. Rosenberg: None. P. Dreizen: None. J. LaRosa: None. L. Salciccioli: None. M. Boutjdir: None. M. Banerji: Speaker's Bureau; Self; Merck & Co., Inc.. C. Brown: None. M. Salifu: None. J. Lazar: None. A. Bakillah: None.
Real-World Implementation of Hybrid Closed-Loop (HCL) Insulin Delivery
Authors: FAULDS EILEEN R. , DUNGAN KATHLEEN M. 
Published: June 2018

Objective: Clinical trials demonstrate improved glycemic control with HCL insulin delivery systems, yet limited real-world data exists substantiating these findings. Data from the inaugural cohort of patients initiating a HCL system (Medtronic 670G) at a university medical center was used to examine real-world utilization, adherence, and glycemic control over the first 6-12 weeks of pump use.
Research Design and Methods: Data from 35 patients with type 1 diabetes (22-72 years of age) were obtained from insulin pump downloads at 4 time points: previous insulin pump, HCL start in manual-mode, 2-weeks after auto-mode transition, and between 6-12 weeks after HCL start. In person training by certified diabetes educators was performed for manual-mode, sensor initiation, and auto-mode with phone and electronic messaging following initiation of auto-mode.
Results: A total of 46 patients received HCL between June 1 and December 31 of 2017. Of these, 7 patients did not have sensors allowing them to initiate HCL, 3 did not have a 6-12 week download, and 1 never transitioned into auto-mode. Mean self-monitoring blood glucose (SMBG) per day increased from 5.15 baseline to 6.49 at 6-12 weeks (p&lt;0.05) with 3.26 sensor calibrations per day. Time in auto-mode was 79.3% at 2 weeks, and 71.7% by 6-12 weeks with 82% of patients spending &gt;50% of time in auto-mode. Over the 14-day final download there were 8.2 auto-mode exits. Time in target was 65.5% in manual-mode, 73.4% at 2-weeks (p=0.09), and 71.7% by 6-12 weeks (p=0.06). HbA1C decreased 0.51% (p=0.02), total daily dose increased (p=0.027), while basal-to-bolus ratio did not change over the study period. Baseline mean SMBG and HbA1C, but not basal:bolus ratio, bolus calculator use, or bolus frequency, were significant predictors of time in auto-mode and time-in-target at 6-12 weeks.
Conclusions: These data illustrate real-world implementation of HCL technology within a major medical center. Patients initiating HCL achieved acceptable time-in-auto mode and time-in-target range.

Disclosure
E.R. Faulds: Other Relationship; Self; A1Contro, LLC. K.M. Dungan: Research Support; Self; Novo Nordisk Inc.. Advisory Panel; Self; Sanofi-Aventis. Research Support; Self; Sanofi-Aventis, GlaxoSmithKline plc.. Consultant; Self; GlaxoSmithKline plc.. Research Support; Self; AstraZeneca. Other Relationship; Self; DKBmed, Horizon, Projects in knowledge, Rockpointe.
Identification of Pancreatic Elastase Inhibitors That Can Stimulate Beta-Cell Proliferation
Authors: BASILE GIORGIO , VETERE AMEDEO , HU JIANG , WAGNER BRIDGET , KULKARNI ROHIT 
Published: June 2018

The identification of novel small molecules that can target endogenous factors to regulate β-cell proliferation is a desirable goal to counter all forms of diabetes. Recently, we identified serpinB1 (SB1), an endogenous protease inhibitor, as a protein that promotes human β-cell proliferation by inhibiting elastase activity, and demonstrated that the elastase inhibitor sivelestat also induced β-cell proliferation. Here, we report high-throughput screening to identify novel elastase inhibitors and to evaluate their ability to induce human β-cell proliferation. We screened 16,320 compounds using a fluorescence-based porcine pancreatic elastase (pPE) assay, and confirmed inhibition of human neutrophil (hNE) and pancreatic (hPE) elastases using an absorbance-based assay. We observed that telaprevir and tebipenem each inhibited pPE with greater potency than sivelestat (IC50: telaprevir 33.9 nM, tebipenem 1.1 µM, sivelestat 2.4 µM; n=3). The results were confirmed on hPE (IC50: telaprevir 15.7 nM, tebipenem 3.6, sivelestat 2.3 µM; n=3), while neither telaprevir nor tebipenem blocked hNE activity. Interestingly, telaprevir and SB1 inhibited hPE and pPE at similar concentrations, enforcing the hypothesis of a shared mechanism of action between the protein and the compound. We then assessed the mitogenic properties of the compounds in in vitro cultures of mouse and human islets by immunofluorescence. Telaprevir and tebipenem each increased proliferating β-cells in rodent (∼6-fold and 1.5-fold increase, respectively; n=3) and human islets (∼4-fold and 1.5-fold increase, respectively; n=3) compared to vehicle-treated islets. Taken together, these data confirm the identification of two novel compounds with the ability to inhibit pancreatic elastase and enhance mammalian β-cell proliferation. These results highlight the therapeutic potential of using elastase inhibitors to stimulate β-cell proliferation to treat diabetes.

Disclosure
G. Basile: None. A. Vetere: None. J. Hu: None. B. Wagner: None. R. Kulkarni: None.
Hyposialylated Angiopoietin-4 Induces Podocyte Apoptosis via a3ß1 Integrin/FAK Signaling in Diabetic Nephropathy
Authors: CHEN HAIBING , GUO KAIFENG , PAN PAN 
Published: June 2018

Podocyte dysfunction, one of the major causes of proteinuria, leads to glomerulosclerosis and end stage renal disease, but its underlying mechanism remains poorly understood. Angptl4 has been reported to mediate proteinuria in some types of glomerulonephropathy. However, the underlying molecular mechanism remains unclear. This study aimed to investigate the role of Angptl4 in the pathogenesis of DN. In this study, we found that expression of ANGPTL4 in the kidney cortex was significantly increased in the diabetic mouse. Moreover, we demonstrated that ANGPTL4 induced podocytes apoptosis and actin cytoskeleton derangement via integrin pathway under high glucose. High glucose increased integrinα3β1 in podocytes. Our results showed ANGPTL4-induced podocytes apoptosis and actin cytoskeleton damage was effectively attenuated by blocking ANGPTL4 and integrin α3β1 by neutralizing antibody in vitro. Furthermore, we demonstrated that the effect of ANGPTL4 on podocyte damage is due to increased podocyte-secreted hyposialylated ANGPTL4 under high glucose, and these effects were effectively attenuated by conversion of hyposialylated ANGPTL4 to its sialylated form with ManNAc in both vivo and vitro. Taken together, these results indicate that targeting Angptl4 related signaling may represent a novel therapeutic strategy for proteinuric kidney diseases.

Disclosure
H. Chen: None. K. Guo: None. P. Pan: None.
Sweet-Taste Receptors Mediated ROS-NLRP3 Inflammasome Signaling Activation—Implications for Diabetic Nephropathy
Authors: ZHOU LUPING , HUANG WEI , XU YONG , GAO CHENLIN 
Published: June 2018

Previous studies demonstrated that ROS-NLRP3 inflammasome signaling activation were involved in the pathogenesis of diabetic nephropathy (DN). But the mechanism by which high glucose prime ROS-NLRP3 inflammasome signaling remains debatable. Recent research has shown that taste receptor type 1, member 2 (T1R2) and member 3 (T1R3), form heterodimers to act as sweet taste receptors (STRs), are widely expressed in the extraoral tissues, and emerging evidence suggests that STRs are important sentinels of innate immunity. As a natural ligand for STRs, whether high glucose prime ROS-NLRP3 inflammasome signaling via STRs is unclear. Therefore, diabetes mellitus (DM) mouse model was induced by streptozotocin (STZ) in vivo, mouse glomerular mesangial cells (GMCs) and human proximal tubular cells were stimulated by elevated concentrations of high glucose (10, 20, and 30 mmol/L) or mannitol as the osmotic pressure (OP) control in vitro, STRs inhibitor lactisole were used as an intervention reagent to evaluated the role and mechanism of the STRs in the pathogenesis of DN. Our results showed that the expression of STRs (T1R2 and T1R3) and associated signalling components (Gα-gustducin, PLCβ2, TRPM5) were obviously down-regulated under the condition of diabetes in vivo and in vitro. Further more, lactisole signifcantly mitigated the production of intracellular ROS and reversed the decrease of Ca2+ and the activation of NLRP3 inflammasome signaling in GMCs stimulated by high glucose (p&lt;0.05). These combined results support the hypothesis that high glucose induced ROS-NLRP3 inflammasome signaling activation in part via STRs, suggesting that STRs may act as new therapeutic targets of DN.

Disclosure
L. Zhou: None. W. Huang: None. Y. Xu: None. C. Gao: None.
Backcross db Gene into CD-1 Background Results in Novel Type 2 Diabetic Mouse Model with Progressive Kidney Fibrosis
Authors: MIZUNUMA YUIKO , NITTA KYOKO , TAKAGI SUSUMU , KANASAKI KEIZO , KOYA DAISUKE 
Published: June 2018

Kidney fibrosis is the final common pathway of progressive kidney disease including diabetic kidney disease (DKD). With the rapid increase of type 2 diabetes, DKD in type 2 diabetic patients has become a serious public health threat around the world. To establish novel therapy to combat DKD, human disease relevant animal model is essential. However, a type 2 diabetic mouse model with presenting progressive kidney fibrosis is not established yet. We have previously reported that kidneys of streptozotocin-induced diabetic CD-1 mice exhibited severe fibrosis compared to other backgrounds of mice associated with the suppression of anti-fibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline, fibroblast growth factor receptor 1, and their downstream target anti-fibrotic microRNAs (miRs) such as miR 29 and miR let-7. As the type 2 diabetic mice model, leptin receptor deficient mice in BKS background (BKSdb/db) are often utilized; the kidney fibrosis in BKSdb/db phenotype is minimum. Here we backcrossed db gene into potential fibrotic CD-1 background and found that male CD-1db/db exhibited severe kidney fibrosis when compared to male BKSdb/db. We have already performed the backcrosses for 11 generations. Body weight of CD-1db/db was comparable but drank up to 3 times more water compared to BKSdb/db. Blood glucose levels in CD-1db/db appeared to be higher when compared to BKSdb/db. When evaluated the per body weight ratio, kidney and heart weighed no significant differences between CD-1db/db and BKSdb/db. CD-1db/db exhibited severe tubulo-interstitial fibrosis, glomerulosclerosis, and tubular epithelial cells damage. Heart in CD-1db/db displayed fibrotic change as well.
In conclusion, here we provide novel fibrotic type 2 DKD mouse model. CD-1db/db could be excellent model to perform experimental therapy for DKD.

Disclosure
Y. Mizunuma: None. K. Nitta: None. S. Takagi: None. K. Kanasaki: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Eli Lilly and Company, Sanofi, Mitsubishi Tanabe Pharma Corporation. Research Support; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Astellas, Astellas. Research Support; Self; Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation. D. Koya: None.
Carbohydrate Response Element Binding Protein (ChREBP) Promotes Inflammation and Apoptosis of Mesangial Cells
Authors: CHEN YAN , ZHAO SHUJIE , WANG YANJUN 
Published: June 2018

Objective: Diabetic nephropathy (DN) is one of the most devastating complications of diabetes mellitus. Carbohydrate response element binding protein (ChREBP) is a basic helix-loop-helix leucine zipper transcription factor that primarily mediates glucose homeostasis in the body. The present study investigated the role of ChREBP in the pathogenesis of DN.
Materials and Methods: The expression of ChREBP was detected in patients with type 2 diabetes mellitus (T2DM), diabetic mice and mesangial cells. ELISA was used to measure cytokine production in mesangial cells. Flow cytometry analysis was performed to detect the apoptosis of mesangial cells in the presence of high glucose.
Results: The ChREBP and several cytokines (TNFα, IL-1β, and IL-6) were up-regulated in T2DM patients (P&lt;0.05). The mRNA and protein levels of ChREBP were significantly elevated in the kidneys of diabetic mice. Moreover, glucose treatment promoted mRNA levels of TNF-α, IL-1β and IL-6 in mesangial cells. Glucose stimulation induced significant apoptosis of SV40 MES 13 cells. In addition, transfection with ChREBP siRNA significantly inhibited ChREBP expression. Consequently, the inflammatory responses and apoptosis were inhibited in SV40 MES 13 cells.
Conclusions: These results demonstrated that ChREBP could mediate the inflammatory response and apoptosis of mesangial cells, suggesting that ChREBP may be involved in the pathogenesis of DN.

Disclosure
Y. Chen: None. S. Zhao: None. Y. Wang: None.
Generation of a Novel Mouse Model to Study Pancreatic Beta-Cell Dedifferentiation
Authors: MAK TRACY C.S. , LATREILLE MATHIEU 
Published: June 2018

Compromised β-cell identity triggered by metabolic stress has been revealed as a novel mechanism of insulin insufficiency in type 2 diabetes (T2D). Previous work from our group showed increased microRNA-7 (miR-7) expression in islets of mouse models of T2D and human islets exposed to an obesogenic environment. Murine β-cell-specific overexpression of miR-7 is sufficient to causes diabetes and is accompanied with decreased expression of β-cell identity markers, thus revealing miR-7 induction as a novel mechanism impairing β-cell identity. To address if insulin-producing cells can recover their function and identity in T2D, we engineered a novel mouse enabling us to temporally compromise the identity of β-cells through doxycycline-mediated miR-7 overexpression in vivo. We report that mutant mice exposed to doxycycline (Dox) displayed a severe diabetic phenotype characterized by hyperglycemia, glucose intolerance and reduced circulating insulin levels. Strikingly, four weeks after withdrawing Dox from the diet, we observed a complete normalization of glycemia, circulating insulin as well as the number of bihormonal cells in mutant mice. RNA seq analysis revealed that islets from miR-7-overexpressing mice exhibit a striking downregulation of β-cells identity markers and increased levels of α- and δ-cell specific genes. Interestingly, we measured upregulation of several genes involved in EMT, Inflammation and Stemness, pointing to a dedifferentiation of β-cells following induction of miR-7 expression. We provide novel evidence that miR-7 triggers an EMT process by repressing components of ATP-dependent chromatin remodelling complexes, altering nucleosome positioning at β-cell specific loci and ultimately causing dedifferentiation of β-cells. Together, our data reveal the mechanism underlying β-cell dedifferentiation by miR-7 and provide a proof of concept for the therapeutic efficacy of anti-miR-7 molecules in reversing β-cell dedifferentiation and improving β-cell function.

Disclosure
T.C.S. Mak: None. M. Latreille: None.
Advanced Glycation End Products (AGEs)-Role in Development and Progression of Kidney Disease in Type 1 Diabetes in DCCT/EDIC
Authors: BEISSWENGER PAUL J. , BEBU IONUT , HOWELL SCOTT , LACHIN JOHN 
Published: June 2018

Introduction: Early diagnostic measures that predict development of complications in individuals with type 1 diabetes would be clinically relevant. Our goal was to determine if glycative and oxidative stress biomarker levels are independent risk factors in the development of advanced diabetic kidney disease (DKD) prior to detection of overt disease in the DCCT and follow-up EDIC.
Methods: Using a case-cohort design, we measured plasma and urine levels of 5 Advanced Glycation (AGEs) and 2 oxidation end-products by LC-MS/MS in 109 DKD cases (&gt;40% eGFR decline from baseline confirmed on two consecutive visits) and 350 non-progressor controls. Sampling, done at study baseline and three other time points during DCCT and early EDIC prior to later GFR decline, was analyzed by Cox models adjusted for risk covariates (Age, HbA1c, BMI, HDL, LDL, Sex, SBP, and DBP) to assess the association between the AGEs and risk of DKD.
Results: Significant associations between GFR decline and plasma biomarkers occurred for three specific AGEs: Carboxymethyllysine (CML, p=0.003), 3-deoxyglucosone hydroimidazolone (3DG-H, p=0.0007), and carboxyethyllysine (CEL, p=0.021) using multi-variate adjusted analyses. Prediction by AGEs was independent of HbA1c at the same time points. Urinary AGEs were not predictive. Calculation of c-statistics also showed that plasma 3DG-H significantly increased predictive value for progression of DKD above traditional risk factors.
Conclusions: Two predictive AGEs, CML and CEL, previously shown to predict DKD
(Diabetes Care, 36, 3234-9, 2013) were found to independently identify progression in DCCT/EDIC. DKD prediction by 3DG-H also confirms prior data showing that
DKD is associated with increases in its precursor, 3-deoxyglucosone. Early identification of those at high risk of progression to DKD by measuring specific AGEs may provide predictive power above traditional risk factors and allow the institution of preventive therapies.

Disclosure
P.J. Beisswenger: Employee; Self; PreventAGE Health Care, LLC.. I. Bebu: None. S. Howell: None. J. Lachin: Board Member; Self; AbbVie Inc., Celgene Corporation.
Significant Association of TGF-Beta1 C-T Transition in Codon 10 of the Gene with Posttransplant Diabetes
Authors: JAHROMI MOHAMED M.J. 
Published: June 2018

Post-transplant Diabetes (PTD) is a serious complication of transplantation. We hypothesize that transforming growth factor-beta (TGF-β1), a multifunctional growth factor which plays a key role in the development of tissue fibrosis, may be involved in the pathophysiology of PTD.
Our purpose was to examine the functional polymorphism within the TGF-β1 gene in codons 10 of promoter region of the gene association with Kuwaiti PTD post kidney transplantation.
Method: We conducted a large case-control study using cases with kidney transplantation who have developed diabetes post transplantation, 152. Controls were renal recipient patients who did not present diabetes a year post-kidney transplantation, 150. Neither cases nor controls had previous history of diabetes. Genotyping was by amplification refractory mutation system polymerase chain reaction. Fisher’s exact test was used to analyze the data. Our diagnosis criteria incorporated with the international consensus guidelines regarding the definition of PTD.
Results: There was a significant difference in the frequency of the TGF-β1 codon 10 genotype in the PTD cases compared with controls. There were neither gender nor age at onset specificity statistical differences among the PTD cohort compared to non-PTD cohort. Individual with the TT (TGF- β1 gene in codons 10) was strongly susceptible to PTD (p=0.001); whereas, the CC of the same gene showed protection against PTD progression. Although T allele was strongly associated with progression of PTD, p=1.4 * 10-5, it could not exert its impact during CT genotype, p=0.6.
Discussion: In our study the TGF-β1 codon 10 polymorphism is associated with PTD post-kidney transplantation. Variation in this gene may contribute to the genetic predisposition to this complication in kidney transplantation. Further subgroup analyses are underway to find out if there is any correlation between bone mass indexes, familial history of diabetes, hepatitis C infection among both cohorts.

Disclosure
M.M.J. Jahromi: None.
SAD-A Promotes Pancreatic ß-Cell Proliferation by Regulating ß-Cell Cycle as a Downstream Target of mTORC1 Signaling
Authors: NIE JIA , MUSI NICOLAS , SHI YUGUANG 
Published: June 2018

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and β-cell dysfunction, which leads to the depletion of β-cell mass. Understanding the molecular mechanisms driving islet β-cell dysfunction is paramount for developing therapies to increase β-cell function. The mammalian target of rapamycin complex 1 (mTORC1) plays a key role in regulating β-cell function by integrating growth factors and mitogens to direct cell cycle and survival; yet, mechanistically this process is not fully understood. Synapses of amphids defective protein kinase A (SAD-A) is a member of AMP-activated protein kinase (AMPK)-related family kinases, with high expression in the pancreas. My earlier work demonstrated that SAD-A is a β-cell specific mediator of insulin secretion and islet β-cell size. Furthermore, glucose dramatically stimulated SAD-A protein translation in islets that was potently inhibited by rapamycin, an inhibitor of mTORC1. My recent preliminary studies showed that 1) SAD-A overexpression increases β-cell proliferation in the MIN6 β-cell line and islets; 2) Ablation of SAD-A in pancreas of mice (pSADKO) promotes β-cell apoptosis and attenuates compensatory islet growth in obese mice; 3) SAD-A depletion in the pancreas increases mRNA expression of cyclin D2 in islets of pSADKO mice. Based on these observations, I hypothesize that SAD-A promotes pancreatic β-cell proliferation by regulating β-cell cycle as a downstream target of mTORC1 signaling.

Disclosure
J. Nie: None. N. Musi: None. Y. Shi: None.