bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Mediator of Arsenic-Induced Pancreatic Beta-Cell Dysfunction
Authors: CARMEAN CHRISTOPHER M. , YOKOI NORIHIDE , KIRKLEY ANDREW G. , TAKAHASHI HARUMI , SARGIS ROBERT M. , SEINO SUSUMU 
Published: June 2018

With up to 140 million people living above arsenic (AS)-contaminated groundwater, AS exposure presents a major health risk worldwide. Studies have revealed a positive correlation between AS exposure and diabetes, where those suffering from symptoms of chronic AS toxicity have 5-6 times the local rates of diabetes. Recent mouse models of AS exposure suggested that this form of diabetes may be mediated by pancreatic β-cell dysfunction. To evaluate this possibility, the MIN6-K8 mouse β-cell line was utilized as a model. Three days of physiologically-relevant AS exposure decreased glucose-induced insulin secretion (GIIS) without effects on basal secretion. Three days of exposure to 1 µM AS decreased GIIS more than 60% without effects on cell count, total protein, total DNA, mitochondrial mass, or O2 consumption. RNAseq analysis of AS-exposed MIN6-K8 cells revealed 3 significantly regulated genes previously unassociated with β-cell function.
Each gene was individually knocked down by siRNA in the presence of AS. Knockdown of one of these genes, UDP-glucuronosyltransferase 1a6a (Ugt1a6a), partially recovered GIIS in AS-exposed cells. Ugt1a6a is a phase 2 detoxification enzyme for the conjugation of small aromatic compounds. The precursor and rate-limiting factor for serotonin production, 5-hydroxytryptophan (5-HTP), a known target of Ugt1a6a and modulator of GIIS, was decreased following AS exposure. Therefore, the AS-mediated increase in Ugt1a6a expression may deplete serotonin, and secondarily 5-HTP, decreasing GIIS. This work introduces a gene with a novel role in β-cell physiology and arsenic-mediated pathology.

Disclosure
C.M. Carmean: None. N. Yokoi: None. A.G. Kirkley: Consultant; Self; AbbVie Inc., Takeda Pharmaceuticals U.S.A., Inc.. H. Takahashi: None. R.M. Sargis: Advisory Panel; Self; CVS/Caremark. S. Seino: Research Support; Self; Merck Sharp & Dohme Corp., MSD K.K., Novo Nordisk Inc., Poxel SA, Sumitomo Dainippon Pharma Co., Ltd., Sanofi K.K.. Speaker's Bureau; Self; Sumitomo Dainippon Pharma Co., Ltd.. Research Support; Self; Daiichi Sankyo Company, Limited. Speaker's Bureau; Self; Novartis Pharma K.K.. Research Support; Self; Taisho Pharmaceutical Co., Ltd..
Analysis of ∼700 Human Tissue Samples Identifies microRNAs That Are Associated with, Predictive of, and Necessary for Insulin Gene Transcription
Authors: HARDIKAR ANAND , WONG WILSON , JOGLEKAR MUGDHA , DALGAARD LOUISE T. , JENKINS ALICIA , MA RONALD C. ,   THE MICRORNA ATLAS STUDY GROUP
Published: June 2018

There is growing evidence that microRNAs, a class of non-coding RNA molecules, are associated with regulation of gene expression in general. Here we profiled microRNAs and key endocrine pancreatic gene transcripts in 698 human tissues, including ∼200 human islet preparations. Figure 1 shows the tissue types in our biobank and circos plots showing correlation of key pancreatic genes and microRNAs. Using novel approaches involving penalized regression and bootstrapping in our discovery set of 507 tissue samples, we identified microRNAs that are highly associated with (pro-)insulin expression. Then, using two different de-identified validation sets (N=91 and N=100) of human cells/tissue samples, we demonstrate that the levels of insulin-associated microRNAs can predict the level of insulin transcript with high accuracy. Finally, we show that forced expression of insulin gene does not change the levels of insulin-associated microRNAs, but forced expression of selected microRNAs promotes insulin gene expression. More generally, these data identify key microRNA genes associated with, predictive of and promoting for insulin gene transcription.

Disclosure
A. Hardikar: None. W. Wong: None. M. Joglekar: None. L.T. Dalgaard: Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. A. Jenkins: Research Support; Self; Medtronic, Mylan, Sanofi-Aventis. R.C. Ma: Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp & Dohme Corp., Pfizer Inc.. Advisory Panel; Self; Boehringer Ingelheim GmbH, Nippon Boehringer Ingelheim Co. Ltd..
Newly Revealed Role for OGT in Obesity-Precipitated ß-Cell Hyperinsulinemia
Authors: LOCKRIDGE AMBER D. , JO SEOKWON , DAMBERG NIKLAS E. , MOHAN RAMKUMAR , ALEJANDRO EMILYN 
Published: June 2018

Highly expressed in the β-cell, the nutrient sensor O-GlcNAc transferase (OGT) couples metabolic environment to cellular behavior through dynamic protein modifications (O-GlcNAcylation) but the role of OGT in β-cell hyperlipidemia is unknown. Here, we observed changes in islet O-GlcNAcylation in obese humans and high-fat diet (HFD, 60%) fed mice vs. lean controls, leading us to hypothesize that OGT mediates β-cell adaptations to diet-induced obesity. In a mouse model of partial β-cell OGT loss, we found that Rip-Cre; OGT f/+ (OGT Het) mice failed to develop hyperinsulinemia over 12 weeks of HFD. Only Het islets isolated from HFD mice showed deficits in stimulated insulin secretion (30 mM KCl, vs. HFD Ogt f/+). Nutrient-driven ATP was not impaired, but islets with full β-cell OGT KO (Rip-Cre; OGT f/f) showed no acute secretory potentiation to palmitate (100 μM) implicating the amplification arm of the stimulus-secretion pathway. HFD β-cell mass was similar (OGT Het vs. WT) but increased Ins+/Gcg+ cells and Ngn3 gene expression in OGT Het islets suggested functional β-cell loss through enhanced dedifferentiation. HFD hypoinsulinemia was reiterated in a tamoxifen-induced OGT loss model (Mip-Cre; OGT f/f), which also showed elevated proinsulin/insulin serum ratios (6 weeks HFD). Transcriptome analysis by RNA-sequencing of OGT KO and WT mouse islets revealed differential gene expression of proteins involved in membrane depolarization (Kcnj11, Abcc8), ER calcium (Atp2a2), lipid uptake (Lpl) and β-cell differentiation (Ucn3). An upstream analysis suggested impairments in free radical scavenging, supported by elevated levels of 4-HNE lipid peroxidation staining in post-HFD OGT Het islets. However, antioxidant supplementation of HFD chow (0.2% alpha-lipoic acid) did not rescue OGT Het in vivo deficits. These data reveal OGT as a critical mediator of β-cell adaptation to diet-induced obesity and highlight protein O-GlcNAcylation as a potential therapeutic target to prevent prediabetic progression.

Disclosure
A.D. Lockridge: None. S. Jo: None. N.E. Damberg: None. R. Mohan: None. E. Alejandro: None.
Synchronized Microfluidic System to Dynamically Assess Pancreatic Islet Function beyond Glucose-Stimulated Insulin Secretion
Authors: NIEUWOUDT STEPHAN , MCDOWELL RUTH , ZHANG HUI , KIRWAN JOHN P. 
Published: June 2018

The endocrine function of pancreatic islets goes beyond glucose stimulated insulin secretion (GSIS). Besides glucose, dynamic regulation through a variety of incretin hormones, drugs, and metabolites have been shown to modulate insulin secretion. The most commonly applied ex vivo and in vitro methodologies to study islet function are static in nature; carried out in standard well formats for extended incubation times. This approach ignores the dynamic nature of secretion and regulation thereof, and limits the complexity of scientific questions that may be posed. In the last decade several groups have begun using microfluidic devices to assess islet function in a dynamic environment, which aims to mimic a physiological bolus of glucose followed by imaging and secretory analysis. Thus far no commercial research device has been made available to the scientific community, requiring the in-house development of microfluidic islet analysis systems by groups aiming to take a more in-depth view of pancreatic islet function. We have developed a fabrication processes for poly-methyl methacrylate (PMMA) microfluidic chips, with micromilled channels and pockets into which islets will be hydrostatically trapped. These optically clear chips allow for direct fluorescent imaging of the trapped islets, with real-time calcium flux (Fura-2-AM) and mitochondrial potential (Rhodamine 123) assays. Using the I2C (Inter-Integrated Circuit, NXP Semiconductors) protocol, we are able to synchronize several microcontrolled syringe pumps (and a fraction collector) to produce precise concentrations of glucose, hormones, metabolites, and factors of interest in a time-dependent manner. This system has applications in our study of the effects of bariatric surgery (in rodents) on pancreatic islet function, as well as the mechanisms by which myokines may directly regulate pancreatic endocrine function.

Disclosure
S. Nieuwoudt: None. R. McDowell: None. H. Zhang: None. J.P. Kirwan: None.
The microRNA 199a Family Is Regulated by Glucose Levels in Pancreatic Beta Cells
Authors: DE CASTRO JOAO PEDRO WERNECK , BLANDINO-ROSANO MANOEL , BERNAL-MIZRACHI ERNESTO 
Published: June 2018

The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient availability and hormone/growth factors signaling to regulate cell metabolism; being essential to beta-cell mass and function. The microRNA 199a-3p negatively regulates translation of mTORC1 mRNA and impacts beta-cell function. We investigated how miR-199a expression is regulated in beta-cells by examining expression responses of miR-199a precursors genes (primiR-199-a1, a2 and b) and its mature forms (miR-199a-3p and -5p) and promoter transcriptional activity assays in mouse islets and mouse insulinoma (MIN6) cells treated with different stimuli. We found that islets from male and female mice equally express the mature miR-199a-3p and -5p. However, the primiR expression is different: while primiR-199a1 expression is 2-fold greater than primiR-199a2, primir-199b is barely detected in mouse islets. The same primiR expression profile was found in MIN6 cells except that only the mature miR-199a-3p is expressed. A 2-fold increase in primiR-199a1 and -a2 mRNA levels was observed by 24 h culture of mouse islets in high glucose compared to 5.5 mM. Similar responses to high and low glucose were observed in MIN6 cells as early as 6 h. Interestingly, 30 mM of KCl treatment was sufficient to prevent the low glucose-induced decline in primiR-199-a2 expression but not in 199-a1 in MIN6 cells, indicating that calcium influx was involved. Transcriptional activity studies in MIN6 also reveal that low glucose or 2-DG glucose-induced starvation decreases the primir-199a2 promoter activity and this decrease was rescued by KCl and Tolbutamide (Potassium channel blocker), confirming that calcium influx is playing a role. Indeed, blocking calcium channels with 20 uM Nifedipine reduced primiR-199-a2 promoter activity in MIN6 cells under 25 mM glucose.
In conclusion, we uncover that glucose regulates microRNA 199a family expression in beta cells and that glucose metabolism and calcium influx are involved.

Disclosure
J. Werneck de Castro: None. M. Blandino-Rosano: None. E. Bernal-Mizrachi: None.
The Association of Dispositional Mindfulness and Adverse Childhood Experiences with Glycemic Control among Young Adults with Type 1 Diabetes
Authors: NAGEL KATHRYN , DEARTH-WESLEY TRACY , HERMAN ALLISON N. , SMITH HANNAH G. , GANDICA RACHELLE , GOLDEN LAUREN , WEIL HENRY F. , WHITAKER ROBERT C. 
Published: June 2018

To assess the potential of mindfulness practices to improve glycemic control in a diverse population of young adults with type 1 diabetes (T1D), we examined the cross-sectional association of hemoglobin (Hb)A1c levels with dispositional mindfulness and adverse childhood experiences (ACEs). In 2017 we conducted an online survey of all 19-31 year olds (y/o) with T1D receiving care at Columbia’s Naomi Berrie Diabetes Center. Responses were received from 423 of 752 (56%) patients and linked to medical record HbA1c. After adjusting for sociodemographic factors, HbA1c levels were compared between those with high and low mindfulness (median split) and those with (62%) and without ACEs (38%). The sample was 59% female and 69% non-Hispanic white, with a mean (SD) HbA1c of 8.0% (1.7). The relationship between HbA1c and mindfulness was moderated by age and ACEs. Among 27-31 y/o, those with high mindfulness had 0.7% lower HbA1c (95% CI:-1.2%, -0.2%) and this relationship was stronger in those with ACEs. The relationship between HbA1c and ACEs was also moderated by age. Among 23-26 y/o, those with ACEs had 0.4% higher HbA1c (-0.1%, 0.9%). Among 19-22 y/o, HbA1c levels were 0.5% higher in those with high mindfulness (-0.2%, 1.2%) and 0.8% lower in those with ACEs (-1.53%, -0.04%). The potential impacts of mindfulness practices for young adults with T1D may differ by age and history of ACEs.

Disclosure
K. Nagel: None. T. Dearth-Wesley: None. A.N. Herman: None. H.G. Smith: None. R. Gandica: None. L. Golden: None. H.F. Weil: None. R.C. Whitaker: None.
Sleep Disorders in Patients with Congenital Generalized Lipodystrophy
Authors: FERNANDES VIRGINIA O. , SILVA CARLA P. , MONTENEGRO ANA PAULA D.R. , PONTE CLARISSE M.M. , BATISTA LIVIA A.A. , PINTO THISCIANE F. , VASCONCELOS IZABELLA T. , KARBAGE LIA A.S. , FERNANDES PRISCILA M. , D'ALVA CATARINA B. , BRUIN PEDRO F.C. , MONTENEGRO RENAN M. ,   BRAZILIAN LIPODYSTROPHY STUDY GROUP (BRAZLIPO)
Published: June 2018

Background and Aims: Sleep disorders are often associated with the several metabolic complications. Congenital generalized lipodystrophy (CGL) is associated with severe insulin resistance, diabetes, dyslipidemia and hepatic steatosis in non-obese individuals, but there are no data evaluating the presence of sleep disorders in this condition.
The aim of this study was to describe the characteristics of sleep pattern in individuals with CGL and evaluate the presence of sleep disorders in these patients.
Materials and Methods: A cross-sectional study with 8 patients with CGL. It was performed a polysomnography following the guidelines of the American Academy of Sleep Medicine.
Results: There were 2 male and 6 female patients. The median age of these patients is 16,5 years old, ranging from 7 to 33 years old. All patients have hypertriglyceridemia and 6/8 had diabetes. Hepatic steatosis was observed in 4/8 cases (50%) and systemic arterial hypertension in 1/8 case (12,5%). Snore was observed in 7/8 (87,5%) of the sample. The diagnosis of obstructive sleep apnea syndrome was observed in 6/8 (75%) of the individuals, rapid eye movement sleep (REM) behavior disorder in 4/8 (50%), changes in sleep efficiency in 4/8 (50%), fragmented sleep in 8/8 (100%) and periodic leg movements in 7/8 (87,5%). There were no significant cardiovascular abnormalities in this study.
Conclusion: The patients with CGL evaluated showed a high frequency of sleep disorders. These findings in a young no-obese population, but with severe metabolic abnormalities, suggest its negative impact in sleep quality of these patients, increasing the cardiovascular risk in this population.

Disclosure
V.O. Fernandes: None. C.P. Silva: None. A.D.R. Montenegro: None. C.M.M. Ponte: None. L.A.A. Batista: None. T.F. Pinto: None. I.T. Vasconcelos: None. L.A.S. Karbage: None. P.M. Fernandes: None. C.B. D'Alva: None. P.F.C. Bruin: None. R.M. Montenegro: None.
Morphological Changes of Platelets as a Marker of Early Progression of Diabetic Nephropathy
Authors: PERTSEVA NATALIIA , DARIA CHUB , IGOR TVERDOKHLEB 
Published: June 2018

Aim: To study the main morphological changes of platelets in patients with type 1 diabetes mellitus (T1DM) depending on the level of estimated glomerular filtration rate (eGFR).
Materials and Methods: The study involved 37 patients with T1DM. Patients were divided to groups according to the level of eGFR (CKD-EPI, ml/min/1.73m²). Group 1 had eGFR ≥90; group 2 - eGFR 89-60; group 3 - eGFR 59-45. Control group consists of 10 healthy people. All patients were comparable for age and sex. The relative content of unactivated, aggregated, degranulated platelets and the density of packaging of α-granules in the platelet were determined using a transmission electron microscope120kV TEMs (JEOL USA).
Results: Changes were found in all three groups compared to the control. Decrease of unactivated platelets (%) 69.7 (62.4; 77), 64.6 (55.5, 73.7), 47.8 (39.6, 56.0), 75.5 (66.2; 84.8), respectively; increase of aggregated platelets (%) 7.4 (6.58; 8.22), 10.6 (9.4; 11.8), 15.4 (14.3; 16.5), 6.8 (5.98; 7.62), respectively; increase of degranulated platelets (%) 7.2 (6.22; 8.18), 10.4 (9.53; 11.27), 21.0 (18.88; 22.12), 6.3 (5.2; 7.4), respectively; decrease of the density of packaging of α-granules in the platelet (mkm³/mkm³) 0.0962 (0.0632; 0.0994); 0.093 (0.06; 0.126), 0.067 (0.038; 0.096), 0.1(0.077; 0.139), respectively. In the study group revealed a direct correlation between eGFR and: unactivated platelets (ρ=0.77; p&lt;0.001), density packing of α-granules (ρ=0.55; p &lt;0.001); the inverse correlation between eGFR and: aggregated platelets (ρ=-0.63; p&lt;0.001), degranulated platelets (ρ=-0.72; p&lt;0.001).
Conclusions: Morphological substrate of platelets damage is a complex of ultrastructural changes, which is an early predictor of the development of vascular complications. Morphological changes of platelets are detected with stored eGFR. Stronger changes correspond to low eGFR, that gives us to consider a complex of ultrastructural platelets changes, as an early sign of diabetic nephropathy.

Disclosure
N. Pertseva: None. C. Daria: None. T. Igor: None.
Retinal Thickness Is Not Associated with Renal Function in Diabetes
Authors: PATERSON EUAN N. , RAVINDRAN MEERA , GRIFFITHS KAYLEIGH , MCCARTER RACHEL V. , LE VELLY CLAIRE A. , MACGILLIVRAY THOMAS J. , HARBINSON MARK , MAXWELL ALEXANDER P. , HOGG RUTH E. , MCKAY GARETH J. 
Published: June 2018

Introduction: Spectral domain optical coherence tomography (SD-OCT) has made possible in vivo investigation of the segmented neural retinal layers of the eye. Following previous reported associations between retinal segmentation and choroidal thickness with renal function in a healthy population, we assessed associations in a cohort with multiple co-morbidities related to diabetes, kidney and cardiovascular disease.
Methods: Cross-sectional data was collected from adults attending nuclear cardiology and renal medicine clinics. All participants were imaged with SD-OCT (Heidelberg Spectralis) using Enhanced Depth Imaging. Measurements included macular, retinal nerve fibre layer and choroidal thickness, and macular volume. Blood and urinary measurements were taken, including estimated glomerular filtration rate (eGFR), urinary protein and plasma C-reactive protein (CRP). Linear regression was used to assess associations with adjustment for age, mean arterial blood pressure (MABP), gender, CRP, BMI, LDL, and retinopathy status.
Results: Of 241 participants, 93 (39%) had diabetes mellitus, a mean age of 65 years (standard deviation [SD] 9), MABP of 99 mmHg (SD: 13) and mean eGFR of 67 ml/min/1.73m2 (SD: 25). Diabetes was associated with lower retinal thickness across the macula and reduced choroidal volume (B = -0.07, 95% confidence interval (CI) -0.14, -0.01, p = 0.04) although failed to remain significant in the fully adjusted model. In individuals with diabetes, a thinner retina was associated with lower eGFR although this also did not remain significant following adjustment for confounders.
Conclusion: In this cohort of high disease burden, diabetes was associated with lower retinal thickness and choroidal volume but did not remain significant following adjustment for confounders. Similarly, lower retinal thickness was associated with reduced eGFR in individuals with diabetes, but these associations also did not remain significant following adjustment for associated confounders.

Disclosure
E.N. Paterson: None. M. Ravindran: None. K. Griffiths: None. R.V. McCarter: None. C.A. Le Velly: None. T.J. MacGillivray: None. M. Harbinson: None. A.P. Maxwell: None. R.E. Hogg: None. G.J. McKay: None.
Does Improving Glycemic Control Accelerate Healing of Diabetic Foot Ulcers?
Authors: PATIL MADHURI D. , GUNASEKARAN UMA , FONTAINE JAVIER LA , MENEGHINI LUIGI 
Published: June 2018

Diabetic foot ulcers (DFU) are common, complex and costly. Chronic hyperglycemia is associated with delayed wound healing and lower limb amputations. We performed a systematic review of literature looking for studies that assessed the impact of change in glycemic control on DFU healing.
Our search included key words such as ’glycemic control’, ’glycated hemoglobin (HbA1c)’, cross-linking them with text such as ’diabetic foot ulcer’, and ’wound healing’. We included published articles and studies in English with at least one component of observation or intervention that included effect of change in glycemic control and/or HbA1c on DFU healing; we excluded studies involving only DFU related amputations as outcome.
Six studies were identified- 1 randomized controlled trial (RCT), 2 observational studies, 1 pre-post study, 1 case report and 1 pooled analysis. All studies were heterogeneous in design, sample size, duration, patient characteristics, DFU characteristics, and end points or outcomes, including the manner in which glycemia was measured. While the RCT was inconclusive due to recruitment failure, the observational studies did show a relationship between wound healing and improvement in glycemic control. The pre-post study and case report described considerable improvement in healing rates of DFU that had been previously resistant to conventional care, after strictly controlling glycemia. The pooled analysis demonstrated that worsening glycemic control during DFU treatment significantly decreased the odds of wound healing.
Surprisingly, there exists a major gap of evidence with regards to whether prospectively lowering glycemic exposure improves DFU outcomes in patients with diabetes. The absence of a proper RCT, the heterogeneity of the existing studies, and the lack of consistency in their findings warrant a well designed prospective, randomized, controlled study to clearly establish whether aggressive glycemic control should be a standard in the management of diabetic foot ulcers.

Disclosure
M.D. Patil: None. U. Gunasekaran: None. J. La Fontaine: None. L. Meneghini: Advisory Panel; Self; Novo Nordisk Inc., Sanofi US. Consultant; Self; Sanofi US, Novo Nordisk Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Other Relationship; Self; American Diabetes Association.