bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diabetes Remission Clinical Trial (DiRECT)—Changes in Hepatic VLDL1-TG Production and Intrapancreatic Fat during Weight Maintenance Phase
Authors: AL-MRABEH AHMAD , ZHYZHNEUSKAYA SVIATLANA V. , PETERS CARL , BARNES ALISON C. , ARIBISALA BENJAMIN , HOLLINGSWORTH KIEREN G. , SATTAR NAVEED , LEAN MICHAEL E. , TAYLOR ROY 
Published: June 2018

Type 2 diabetes is characterized by excess hepatic and intrapancreatic fat deposition. Liver-derived Very Low Density Lipoprotein-Triglyceride (VLDL1-TG) delivers fat to all peripheral tissues. Relative changes in VLDL1-TG production and intrapancreatic fat were investigated in a sub-group of the prospective, randomized Diabetes Remission Clinical Trial (DiRECT). Individuals with complete datasets at 12 months (n=45) were included. Detailed metabolic tests were carried out at baseline, 4 months, and 12 months after low calorie diet (825-853 kcal/day). Intra-organ fat was quantified using 3-point Dixon MRI, VLDL1-TG production was quantified using a competitive blocking non-isotopic method, and insulin secretion was measured by the Stepped Insulin Secretion Test with Arginine (SISTA). Weight loss induced major changes in liver and intrapancreatic fat with 69% remission of diabetes (responders, defined as HbA1c &lt;6.5%). This was followed by weight regain between 4-12 months in responders (82.3±2.8 to 85.4±3.2kg, p=0.001) and non-responders (84.5±3.2 to 89.6±3.3kg, p&lt;0.0001). However, liver fat, VLDL1-TG production, and intrapancreatic fat remained stable in responders (2.5 ±1.9 to 2.9±0.6%, p=0.20; 386.7±30.2 to 428.5±21.2 mg/kg/day, p=0.14; and 8.0±0.5 to 7.7 ±0.4%, p=0.26, respectively). In contrast, these parameters increased in non-responders (2.7±0.5 to 6.2 ±1.8%, p=0.02; 460.2±39.8 to 596.2±36.6 mg/kg/day, p=0.001; and 6.7±0.3 to 7.0±0.4%, p=0.18, respectively). The recovered first phase insulin secretion in responders continued to improve between 4-12 months (0.13±0.02 to 0.17±0.04 nmol/min/m2, p=0.17). There was no change in the non-responders (0.03±0.01 to 0.03±0.01 nmol/min/m2, p=0.98). These data consistent with VLDL1-TG being the link between liver fat and intrapancreatic fat, and a major modulator determining remission of type 2 diabetes.

Disclosure
A. Al-Mrabeh: None. S.V. Zhyzhneuskaya: None. C. Peters: None. A.C. Barnes: None. B. Aribisala: None. K.G. Hollingsworth: None. N. Sattar: Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S, Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Mitsubishi Tanabe Pharma Corporation, Medscape, Sanofi-Aventis Deutschland GmbH. M.E. Lean: Advisory Panel; Self; Novo Nordisk Inc., Orexigen Therapeutics, Inc.. Research Support; Self; Cambridge Weight Plan. Consultant; Self; Counterweight Ltd. Stock/Shareholder; Self; Eat Balanced. R. Taylor: None.
Multinational, Multicenter, Prospective, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Efficacy of Cyclical Topical Wound Oxygen Therapy (TWO2) in the Treatment of Chronic Diabetic Foot Ulcers
Authors: FRYKBERG ROBERT , FRANKS PETER J. , EDMONDS MICHAEL E. , BRANTLEY JONATHAN N. , TÉOT LUC , WILD THOMAS , GAROUFALIS MATTHEW G. , LEE ALIZA M. , THOMPSON JANETTE , REACH GERARD , DOVE CYAANDI R. , LACHGAR KARIM , GROTEMEYER DIRK 
Published: June 2018

Non-healing DFUs lead to increased mortality, morbidity and health economic burden. Our RCT (NCT02326337) was undertaken to explore the efficacy of Topical Wound Oxygen (TWO2) homecare therapy in healing DFUs that had failed to heal with Standard of Care (SOC) alone. A Group Sequential Design was utilized with 2 interim analyses, requiring a significance of p&lt;0.022 at each. All subjects meeting the incl/excl criteria were enrolled into a run-in of SOC that included gold-standard offloading and sharp debridement. Only DFUs not on a proven healing trajectory with SOC alone (&lt;30% wound area reduction) were randomized into the active phase of the study, where they were assigned (double blind) to either active, or sham (placebo), TWO2 device treatment arms. The primary endpoint of the study was ulcers healed at 12 weeks. At the first interim analysis point of 73 subjects, the active TWO2 arm was shown to be significantly superior to the sham arm (Pearson Chi2 =7.2707, P=0.007). Multivariable analysis using logistic regression and Cox proportional hazards modelling of the secondary outcome measure of time to heal showed no other covariates achieved significance. The active TWO2 arm showed nearly 4 times the likelihood to heal DFUs in 12 weeks compared to the sham arm HR 3.88 (95% CI 1.40 to 10.71), p=0.009.

Disclosure
R. Frykberg: Research Support; Self; AOTI, Podometrics. P.J. Franks: Consultant; Self; AOTI. M.E. Edmonds: Advisory Panel; Self; Urgo Medical, Edixomed. J.N. Brantley: None. L. Téot: Advisory Panel; Self; Acelity, Integra LifeSciences. T. Wild: None. M.G. Garoufalis: None. A.M. Lee: None. J. Thompson: None. G. Reach: Other Relationship; Self; Abbott, AbbVie Inc., Janssen Pharmaceuticals, Inc., LifeScan, Inc., Eli Lilly and Company, Novo Nordisk Inc., Sanofi-Aventis, Servier, Becton, Dickinson and Company, AstraZeneca. C.R. Dove: None. K. Lachgar: None. D. Grotemeyer: Other Relationship; Self; AOTI Ltd.. Research Support; Self; Gore, Endologix.
Pro-apoptotic and Inflammatory Markers Enhance the Ability of MDA-LDL in Circulating Immune Complex to Predict Acute Myocardial Infarction in the VADT Study
Authors: LOPES-VIRELLA MARIA F.L. , HUNT KELLY J. , AGARWAL RASHI , BAKER NATHANIEL L. , VIRELLA GABRIEL , INVESTIGATORS VADT 
Published: June 2018

There is considerable interest in identifying biomarkers indicative of plaque instability and acute events. Previously we reported that MDA-LDL in circulating immune complex predicted acute myocardial infarction (MI) in the VADT study. Interleukin (IL)-6, Fas Ligand, tissue inhibitor of MMP (TIMP)-1 and monocyte chemotactic protein (MCP)-1 have been identified as potentially clinically relevant biomarkers related to plaque instability. Therefore, our objective was to examine the role of these biomarkers in conjunction with MDA-LDL in circulating immune complex as predictors of acute MI in type 2 diabetes. Biomarker levels were measured in 833 VADT patients, a median of 2.0 years after study entry and participants were subsequently followed a median of 3.7 years. Biomarkers were examined individually and as composite scores created by summing z scores across biomarkers. Hazard ratios (HRs) for acute MI were calculated by Cox proportional hazard models. During follow-up, 5.2% had an MI. After adjustment for conventional risk factors, results of composite biomarkers scores were promising with a hazard ratio for acute MI of 4.65 (95% CI: 1.56, 13.9) comparing the fourth to first quartile of our summary composite score which included MDA-LDL-IC, IL-6, Fas Ligand,TIMP-1 and MCP-1 (Table).

Disclosure
M.F.L. Lopes-Virella: None. K.J. Hunt: None. R. Agarwal: None. N.L. Baker: Research Support; Self; Bristol-Myers Squibb Company. G. Virella: None.
Different Augmentation of Left Ventricular Contractility of Mice during Myocardial Infarction following Gliptin and Sulfonylurea Treatment
Authors: HAJ-YEHIA ELIAS , DIEBOLD SEBASTIAN , MOELLMANN JULIA , KAHLES FLORIAN , KLEIN THOMAS , MARK MICHAEL , MARX NIKOLAUS , LEHRKE MICHAEL 
Published: June 2018

DPP-4 inhibitors are a class of antidiabetic drugs which act by augmentation of the GLP-1 system and insulin secretion. Despite similar glucose lowering efficacy within the class, only saxagliptin increased heart failure hospitalization in diabetic patients. This unexpected effect might relate to the metabolism of saxagliptin (saxa). Here, we directly compare linagliptin (lina, 3 mg/kg, p.o.), saxa (10 mg/kg, p.o.), and its metabolite 5-hydroxy-saxagliptin (OH-saxa, 10 mg/kg, p.o.) to the sulfonylurea glimepiride (glim, 2 mg/kg, p.o.) and control during acute myocardial infarction in mice. Millar catheter analysis under dobutamin stress 6h post (permanent) LAD ligation were performed. Drugs were given 3 days prior infarction. Active GLP-1 was significantly increased by Lina (1,69 fold), saxa (1,49 fold) and OH-saxa (2,27 fold) vs. control (each p &lt; 0.05), but not by glim. Despite similar GLP-1 levels, only lina and saxa but not OH-saxa or glim increased left ventricular contractility (Lina: 11.549 ± 795 dp/dt max; p &lt; 0.0001; n=9. Saxa: 10.121 ± 200 dp/dt max; p &lt; 0.05; n=12. OH-saxa: 8.201 ± 567 dp/dt max; n=7. Glim: 9.947 ± 813 dp/dt max; n=6 relative to control: 8.764 ± 284 dp/dt max; n=21). We further isolated mitochondria from non-infarcted myocardial tissue and found for lina 2.89 fold (p &lt; 0.0001; n=3), saxa 1.78 fold (p &lt; 0.05; n=8) and OH-saxa 2.2 fold (p &lt; 0.01; n=4) increase in mitochondrial respiration by Clark electrode, but not for glim.
In conclusion, only linagliptin and saxagliptin increased left ventricular contractility and myocardial mitochondrial respiration following LAD ligation; 5-hydroxy-saxagliptin had no effect on contractility despite increasing mitochondrial respiration. Glimepiride had no effect on contractility and mitochondrial function. Metabolism of saxagliptin might be linked to differences found in the DPP-4 class regarding heart failure.

Disclosure
E. Haj-Yehia: None. S. Diebold: None. J. Moellmann: None. F. Kahles: None. T. Klein: Employee; Self; Boehringer Ingelheim GmbH. M. Mark: Employee; Self; Boehringer Ingelheim GmbH. N. Marx: Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. M. Lehrke: Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Novo Nordisk A/S. Advisory Panel; Self; Sanofi, Amgen Inc., Bayer AG, MSD K.K..
Cold Atmospheric Pressure Plasma as a Novel Treatment Modality in Diabetic Foot Ulcers—A Pilot Study
Authors: PETERS EDGAR J. , LAGRAND RIMKE , SMITS PAULIEN , PEMEN A , SOBOTA ANA , ZEPER BAS , SABELIS LOUISE W. 
Published: June 2018

Introduction: Antimicrobial resistance is a growing problem in the treatment of diabetic foot ulcers. Plasma devices generate an ionized gas with a cocktail of highly reactive species, electric fields and UV light. Cold atmospheric plasma (CAP) treatment has advantages over antiseptic or antimicrobial infection prevention and control; it disinfects efficiently, painlessly and instantly, without development of antimicrobial resistance. Concurrently, plasma can stimulate human cell proliferation and migration as well as microcirculation. We studied the safety of a novel CAP device, that is simple to use and in the future can be applied at a patient’s home.
Method: We included subjects with diabetic foot ulcers (maximum depth 5 millimeters) without clinical signs of infection or exposed bone or joint in the wound base. Subjects were treated with CAP on a daily basis for ten days in a two-week period. Primary endpoint of this study was the occurrence of serious adverse events (SAE) as a result of treatment. Safety was defined as ≤ 10% of subjects experiencing SAE related to treatment other than infection, and ≤ 60% of subjects developing infection within 30 days after treatment. Standard protocols for wound treatment were deployed, including weekly debridement and offloading.
Results: Twenty subjects were enrolled. Three SAEs (infections) occurred at the site of application within one month of treatment, of which one occurred during treatment. Three SAEs unrelated to treatment occurred: pneumonia, toe amputation on the contralateral foot and a soft tissue infection of the ipsilateral leg. Transient adverse events (AE grade 1) during one or more applications were reported by 53% of subjects.
Discussion: No SAE other than infection occurred as a result of treatment and ≤ 60% of subjects developed an infection. The AEs were low graded and transient. The results of our study demonstrate that the application of CAP in diabetic foot ulcers is safe.

Disclosure
E.J. Peters: None. R. Lagrand: None. P. Smits: Employee; Self; Plasmacure BV. A. Pemen: None. A. Sobota: None. B. Zeper: Stock/Shareholder; Self; Plasmacure. L.W. Sabelis: None.
The Effect of Hypercholesterolemia on the Characteristics of Cerebral Microvasculature
Authors: TODATE YUSUKE , ISHIGAKI YASUSHI 
Published: June 2018

Aim: It remains unclear whether the increase of LDL cholesterol (LDL-C) is a risk factor for cerebral vascular disease (CVD). To clarify the effects of hypercholesterolemia on cerebral small vessel disease (SVD), we investigate the characteristics of microvasculature including lenticulostriate arteries (LSA) using high resolution brain magnetic resonance imaging (MRI) in subjects with familial hypercholesterolemia (FH).
Methods: Twenty-seven patients with FH and 25 patients with type2 diabetes (DM), 25 healthy controls underwent 7Tesla (7T) brain MRI. The prevalence of SVD and LSA structural changes, vessel wall plaque images were determined in each group.
Results: The prevalence of SVD, including white matter hyperintensities and lacunar infarctions, significantly increased in DM compared with both FH and controls. In addition, the average numbers of stems of LSA were significantly smaller in DM than FH as well as controls. Interestingly, both SVD prevalence and LSA structural changes showed no difference between FH and controls. Next, we examined the vessel wall imaging analyses of middle cerebral arteries (MCA) and vertebral-basilar arteries (VA-BA). The prevalence of vessel wall plaque on both horizontal segment of MCA (FH vs. controls; 51.8% vs. 20.0%, p&lt;0.05) and VA-BA (37.0% vs. 12.0%, p&lt;0.05) were significantly higher in FH than controls.
Conclusion: The prevalence of SVD and LSA structural impairment definitely increased in DM, suggesting that DM was strong risk for CVD compared to hypercholesterolemia. On the other hand, the prevalence of vessel wall plaque on MCA and VA-BA were significantly high in FH compared to controls. These results suggested long-term increase of LDL-C induced the plaque formation in cerebral microvasculature. Image analyses using 7T MRI enables us to investigate the characteristics of cerebral microvasculature prior to the development of SVD, leading to earlier interventions aimed at the prevention of atherosclerotic events.

Disclosure
Y. Todate: None. Y. Ishigaki: None.
Impaired Gastric Emptying Is Associated with a Higher Incidence of Coronary Heart Disease in Subjects with Diabetes
Authors: PARK SEON-YOUNG , CHUNG JIN OOK , CHO DONG HYEOK , CHUNG DONG JIN , CHUNG MIN YOUNG 
Published: June 2018

Results: Impaired gastric emptying is observed in long-standing diabetic patients. To date, there is limited information on cardiovascular events in diabetic subjects with upper gastrointestinal (UGI) symptoms according to the presence of impaired gastric emptying. The aim of this study was to identify cardiovascular events after gastric emptying study in diabetic subjects with UGI symptoms. This study collected data from 160 diabetic subjects (23 with type 1 diabetes and 137 with type 2 diabetes) with UGI symptoms who had undergone gastric emptying scintigraphy from 2001 to 2016. We gathered data on the incidence of cardiovascular events (coronary heart disease and ischemic stroke) after gastric emptying study. There were 66 diabetic subjects with normal gastric emptying and 94 diabetic subjects with impaired gastric emptying (58 with delayed gastric emptying and 36 with rapid gastric emptying). During 7.5 years of follow-up, 22.5% of subjects (36/160) developed the cardiovascular events (19 with coronary heart disease, 12 with ischemic stroke and 5 with both). The incidence of coronary heart disease was higher in the subjects with impaired gastric emptying (4.2% at 1 year, 10.6% at 3 years, and 12.7% at 5 years) than those with normal gastric emptying (2.4% at 1 year, 3.6% at 3 years and 4.8% at 5 years p=0.039). Our results showed that diabetic subjects with impaired gastric emptying had higher incidence of coronary heart disease than those with normal gastric emptying. This study may warrant a more careful cardiovascular assessment with a high index of suspicion for possible events in management of diabetic subjects with impaired gastric emptying.

Disclosure
S. Park: None. J. Chung: None. D. Cho: None. D. Chung: None. M. Chung: None.
Reducing Hypoglycemia through Increased Knowledge of an Evidence-Based Guideline
Authors: CLARK THAYER A. , BAK LEIGH 
Published: June 2018

Purpose: The purpose of this project is to increase compliance with a hypoglycemia guideline to improve patient care of those experiencing hypoglycemia in the emergency department at a large academic medical center.
Methods: In order to gain an understanding of current compliance to the hypoglycemia guideline, for four weeks all hypoglycemia events were analyzed looking at eight measures (Table) pre-intervention (n=43), and this step was repeated post intervention(n=39). The intervention period included one month dedicated to educating the staff about the guideline, implementing visual aids throughout the department, and having a staff member act as a glucose champion for all blood glucose related questions.
Results: Overall there was low compliance to the protocol initially, but after the intervention there was improvement in all eight areas analyzed (Figure). Areas that showed the most improvement included: immediate blood glucose recheck (9.1% to 23.1%), 15 minute recheck (29.5% to 51.3%), follow-up with a carbohydrate (40.9% to 71.8%), and hourly recheck x3.
Conclusion: Increasing awareness of the hypoglycemia guideline through education, and visual aids led to increased compliance. Anecdotally staff found having a glucose champion to be the most helpful in adhering to the guideline and delivering best care. Going forward having at least one assigned RN as a glucose champion is recommended.

Disclosure
T.A. Clark: None. L. Bak: None.
Gemigliptin Inhibits IL-1ß–Induced Endothelial-Mesenchymal Transition via BMP2/Smad/MAPK/Runx2 Pathway
Authors: KWON HYUK-SANG , HONG OAKKEE , KANG YANGGYO , KWON HEE SUN , YOO SOON JIB 
Published: June 2018

Objective: Endothelial-to-mesenchymal transition (EndMT) contributes to inflammatory conditions inducing conversion of endothelial cells (ECs) into activated fibroblasts, promoting fibrotic diseases. Pro-inflammatory cytokine interleukin (IL)-1ß is the most potent inducer of EndMT. We investigated inhibition of IL-1ß-induced EndMT by gemigliptin, a DPP-4 inhibitor.
Methods: We exposed human umbilical vein ECs (HUVECs) to 10 ng/mL IL-1ß/20 uM gemigliptin and analyzed the expression of endothelial, smooth muscle, mesenchymal, and osteoblastic markers, bone morphogenetic protein (BMP), Smad, and non-Smad signaling pathway proteins.
Results: Morphological changes showed gemigliptin blocked IL-1ß-induced EndMT, upregulated EC markers, and downregulated smooth muscle and mesenchymal markers. IL-1ß activation of HUVECs is initiated by the BMP/Smad and canonical BMP signaling pathways. Gemigliptin inhibited IL-1ß induction of BMP2 and 7, activin receptor type IA, BMP receptor type IA, and BMP receptor II. Reversal of IL-1ß-mediated inhibition of BMP-induced Smad 1/5/8, Smad2, and Smad3 phosphorylation by gemigliptin suggests involvement of the Smad pathway in gemigliptin action. In the canonical BMP pathway, gemigliptin treatment significantly increased the deactivation of ERK, p38, and JNK by IL-1ß. Gemigliptin treatment suppressed BMP-2-induced expression of key osteoblastic markers including osterix and runt-related transcription factor 2 during IL-1ß-induced EndMT.
Conclusions: We demonstrated a novel protective mechanism of gemigliptin against fibrosis by suppressing IL-1ß-induced EndMT.

Disclosure
H. Kwon: None. O. Hong: None. Y. Kang: None. H. Kwon: None. S. Yoo: None.
CRISPR-Cas9 Gene Editing Restores Beta-Cell Differentiation and Function in Patient-Specific iPSCs
Authors: MILLETTE KATELYN , VOGT KYLE R. , SALAS ANDREW , PITUKCHEEWANONT PISIT , AUSTIN JULIANA , MARTIN MARTIN , GEORGIA SENTA 
Published: June 2018

Genetic knockout studies in mice concluded that the differentiation of endocrine lineages in the pancreas and intestine requires the transcription factor neurogenin3 (NGN3). However, case reports of patients with NGN3 mutations show that most patients do not develop diabetes until later in childhood, suggesting that NGN3 may not be required for human beta cell differentiation in vivo. We have identified a patient with a previously undescribed NGN3 loss-of-function mutation and generated induced pluripotent stem cells from patient fibroblasts to analyze the role of NGN3 in human beta cell differentiation. We used established protocols to differentiate patient-specific iPSCs (PS-iPSCs) into pancreatic progenitor cells and beta-like cells in parallel with the H1 hESC line. The PS- iPSCs displayed significantly lower pancreatic progenitor cell differentiation with only 10.7% of the double positive PDX1+/NKX6.1+ cell population present, whereas the control H1s hESCs produce 60% double positive cells. After further differentiation into beta-like cells, H1 cells produced multiple endocrine cell types, while the PS-iPSC line was not able to make significant numbers of endocrine cells. To assess if the loss of NGN3 was the primary cause for the loss of pancreatic progenitor cells and beta-like cell differentiation, we used CRISPR-cas9 gene editing to correct the patient’s mutation in the PS-iPSCs (cPS-iPSCs). Correcting the patient’s mutation restored the PDX1+/NKX6.1+ cell population in the pancreatic progenitor stage. Beta-like cells differentiated from cPS- iPSCs were capable of glucose responsive insulin secretion at the end of the differentiation protocol.
In conclusion, our data suggests that NGN3 may have a previously unidentified role important for the differentiation of pancreatic progenitor cells and that there may be a relationship between NKX6.1 and NGN3 that is critical for pancreatic development.

Disclosure
K. Millette: None. K.R. Vogt: None. A. Salas: None. P. Pitukcheewanont: None. J. Austin: None. M. Martin: None. S. Georgia: None.