bluuebunny/crossref_metadata_2025_split huggingface dataset:
341-OR: An Individualized, Simple, Patient-Centered Carb Counting Tool
Authors: WITKOW SHULAMIT , LIBERTY IDIT F. , GOLOUB IRINA , KAMINSKY MALKA , OTTO OLGA , RABIA YONES ABU , HARMAN BOEHM ILANA 
Published: June 2019

Aims: To introduce a simple carb counting tool (CC) in patients with type 1 diabetes mellitus (T1DM) making CC easy and accessible, overcoming barriers such as age, education, gender or tutoring language.
Methods: In a randomized control trial 82 patients (pts.) received either 1-the common CC guidance using calculation of insulin sensitivity (IS), Carb:insulin ratio (C:I) or 2- a simple personalized tool consisting of 2 tables: A) correction values derived from the individual's IS, B) calculated insulin dose for carb content (personal C:I) for the most consumed carbs derived from the individual’s personal food diary. The intervention comprised 6 tutoring visits to a dietician, diabetes educator. The primary outcome was Hba1c post training.
Results: On the common tool were 39 pts. and 43 on the simple tool. Both groups showed significant statistical and clinical improvement; A1C declined -1.31% in the common tool and -1.59% in the simple method. The positive effects of CC using either method were unaffected by gender (-1.65% vs. -1.22% in males and females respectively P=0.43). We hypothesized that older age, language barrier or people with &lt;12 years of education would benefit more from the simple tool compared to the common tool but no significant difference was found. Moreover, no significance was found among lower vs. higher education (&gt;12 ys) (-1.32% vs. -1.64% respectively p=0.58). Newly diagnosed T1DM (≤1 year) in both groups had a significant decrease in HbA1c (-4.67%) compared to T1DM &gt; 1 year (-.87%) (p&lt;0.001). As expected, better compliance decreased the HbA1c. Those attending ≤ 2 meetings decreased by -.46% vs. -1.56% (p=0.051) in those attending 3-6 CC training sessions.
Discussion: CC was beneficial for all pts.; barriers such as age, gender, tutoring or spoken language didn’t hinder the benefits. Teaching CC close to diabetes diagnosis yielded better clinical results emphasizing the importance of early CC education. Our method provides an additional effective tool to better deliver patient -centered diabetes education.

Disclosure
S. Witkow: None. I.F. Liberty: Other Relationship; Self; AstraZeneca, Novo Nordisk Inc., Sanofi. I. Goloub: None. M. Kaminsky: None. O. Otto: None. Y. Abu Rabia: None. I. Harman Boehm: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Merck Sharp & Dohme Corp., Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk Inc., Novo Nordisk Inc., Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novartis AG, Sanofi.
347-LB: MEA Technology as an Easy Electrophysiological Approach for Noninvasive Recordings of Intact Murine and Human Islets
Authors: SCHöNECKER SVEN , OZA MAULIK , KRAUSHAAR UDO 
Published: June 2019

Increase of blood glucose concentration leads to glucose-induced electrical activity of pancreatic beta-cells followed by insulin secretion. Electrical activity appears in glucose concentration-dependent oscillations easily recorded by microelectrode arrays (MEA). In comparison to other electrophysiological techniques MEAs can record non-invasively from intact islets and can be used for long term studies to investigate chronic effects of drugs.
Murine islets or islets isolated from human biopsies were used for recordings. Electrical activity was quantified as fraction of plateau Phase (FOPP) or number of single spike activity. Islets were placed via suction or cultivated on MEAs. The glucose concentration response curve recorded with murine islets plotted as FOPP revealed a half-maximal activity of 12 ± 2 mM which is in line with traditional methods like e.g., with intracellular electrodes. Glucose-induced activity of cultured islets remains stable over a month. Application of well-known substances (like e.g., diazoxide, tolbutamide) matched regular results. Human islets displayed typical glucose-induced activity (10 mM). Validation studies showed the existence of functional KATP channels and TTX reduced spike activity from 1047 ± 314 to 199 ± 90 spikes/5min after the application of 300 nM TTX. The washout led to an increased spike activity of 779 ± 301 spikes/minutes. The glucose concentration response curve revealed an EC50 value of 8 ± 3 mM glucose. The glucose responsiveness recorded with the MEA Technology is in line with other reports showing that the EC50 value of human beta-cells (∼ 6 mM) is lower than in mouse beta-cells.
MEA Technology allows medium throughput recordings from up to 40 intact islets simultaneously. While previous electrophysiological attempts failed MEAs offer large scale research in both academics and industry. The principle of function is not limited to rodent but is also applicable to human or stem cell derived islets of Langerhans.

Disclosure
S. Schönecker: None. M. Oza: Employee; Self; Multichannel Systems, Gmbh. U. Kraushaar: None.
36-LB: Mechanism of Neurotrophin-Mediated Neuroprotection in Diabetic and Hypoxic Conditions
Authors: LE YUN , QIU FANGFANG , ZHU MEILI 
Published: June 2019

To develop neuroprotective strategy for diabetic retinopathy (DR) and age-related macular degeneration (AMD), we studied the mechanism of trophic factor production/secretion by Müller cell (MC) and of MC viability in vivo and in vitro models under diabetic and hypoxic conditions. MC secreted a high level of brain-derived neurotrophic factor (BDNF) in high glucose media, which was elevated significantly by adding recombinant vascular endothelial growth factor (rVEGF) in a dose-dependent manner. This result was supported by VEGF upregulated BDNF synthesis in MCs and by reduced retinal BDNF in diabetic/hypoxic MC-specific VEGF receptor-2 (VEGFR2) knockout (KO) mice, which appeared to have an accelerated loss of retinal MCs and neurons. In addition, rBDNF and rVEGF promoted MC viability in a synergistic fashion. Targeting the main retinal BDNF receptor, tropomyosin receptor kinase B (TRK-B), with siRNA caused a significant reduction of activated ERK and MC viability. Parallel analyses for glial cell line-derived neurotrophic factor (GDNF) demonstrated a similar effect in GDNF production, MC protection, and survival pathway activation.
In conclusion, neurotrophins are capable of elevating MC viability under diabetic/hypoxic condition, which provide a critical support for MC to produce themselves and other trophic factors for neuroprotection. As a substantial portion of patients treated with anti-VEGF drugs for 5 years appeared to have very thin retinas (presumably severe retinal cell/neuron loss), which bears striking resemblance to that in our diabetic/hypoxic MC-specific VEGFR2 KO mice, it is likely that blocking VEGF signaling in MC may cause unwanted retinal neuronal degeneration in AMD patients subjected to long-term anti-VEGF treatment due to blocking VEGF signaling-mediated reduction of neurotrophin and other trophic factor production. Therefore, supporting MC viability with neurotrophins may be a feasible strategy for neuroprotection during anti-VEGF treatment.

Disclosure
Y. Le: None. F. Qiu: None. M. Zhu: None.
36-OR: Energy Stress Restores Muscle Insulin Action in High-Fat (HF)-Fed SIRT3 KO Mice
Authors: LANTIER LOUISE , HUGHEY CURTIS C. , WASSERMAN DAVID 
Published: June 2019

SIRT3 is a mitochondrial deacetylase that is necessary for insulin-stimulated muscle glucose uptake (MGU) in the setting of overnutrition, and its action is redox state-dependent (NAD/NADH). Energy stress induced by AICAR administration increases muscle insulin action and glucose uptake while enhancing the control of redox state. We hypothesized that acute energy stress would exacerbate the impairment in insulin-stimulated MGU in high fat-fed (HF) SIRT3 KO mice. To test this hypothesis, HF SIRT3 KO and WT littermates underwent 4h of either AICAR (1mg/kg/min) to induce an energetic stress or saline infusion followed by hyperinsulinemic (4mU/kg/min) euglycemic clamps. Experiments were conducted one week post jugular vein and carotid artery catheterization. Insulin clamps were combined with [3-3H] glucose to measure glucose fluxes and 2[14C]deoxyglucose to assess an index of MGU. AICAR significantly improved insulin sensitivity of liver, but not muscle of HF WT mice. Saline-SIRT3 KO mice were more insulin resistant than saline-WT mice, as glucose infusion rate (GIR) and MGU were reduced by ~50%. AICAR completely abolished the added insulin resistance in SIRT3 KO mice as GIR was similar to AICAR-WT. Consistent with this, AICAR increased muscle insulin-stimulated MGU in the SIRT3 KO mice to levels observed in WT mice. Results show that energy stress induced by AICAR infusion was sufficient to circumvent the defect in insulin-stimulated glucose uptake induced by SIRT3 KO, possibly by rescuing redox handling in skeletal muscle.

Disclosure
L. Lantier: None. C.C. Hughey: None. D. Wasserman: None.

Funding
National Institutes of Health (DK54902)
366-OR: TCF19 Promotes Functional Beta-Cell Mass and Proliferative Capacity by Regulating DNA Damage Repair Pathways
Authors: YANG GRACE H. , HAN JEE YOUNG , LODH SUKANYA , BLUMER JOSEPH T. , FONTAINE DANIELLE , DAVIS DAWN B. 
Published: June 2019

Transcription factor 19, TCF19, is a novel gene associated with type 1 and type 2 diabetes. We have previously shown that Tcf19 is involved in the regulation of proliferation and apoptosis in the INS1 β-cell line. To determine the role of Tcf19 in diabetes pathogenesis, we generated germline whole body Tcf19 knockout mice (wbTcf19KO). Lean wbTcf19KO mice have slightly increased fasting glucose and decreased in vivo glucose-stimulated insulin secretion. We focused on the pancreatic islet in further analysis of this model due to the high expression of Tcf19 in the mouse islet and our preliminary findings in a β-cell line. RNAseq from wbTcf19KO mouse islets identified significantly decreased expression of genes involved in maintaining β-cell identity, vesicle docking, and Ca2+ sensing (Nkx6.1, Nkx2.2, Pdx1, Sort1, Syt7). Additionally, the proliferative marker, Ki67, was downregulated by 3-fold. Similarly, with immunohistochemistry of pancreatic sections, there was a 20% decrease in Ki67+ β-cells in wbTcf19KO mice. Despite no difference in overall β-cell mass compared to control mice, wbTcf19KO mice have an altered islet size distribution with an increased quantity of small islets. In addition, wbTcf19KO mice fail to increase proliferative genes in the islet, such as cyclinD2 and Ki67, in response to a short term high fat diet (HFD). Islet RNA seq analysis also showed an upregulation of genes involved in the DNA damage pathway, inflammation, and pro apoptotic genes (Ddx60, Gadd45a, Dtx3l, Chop, Bak, Ifit1, Cxcl10). Baseline levels of DNA damage in the wbTcf19KO islets are increased, as measured by γH2AX on western blot. wbTcf19KO mouse islets also have increased DNA damage after in vivo challenge with extended HFD feeding or ex vivo after cytokine exposure. Taken together, we conclude that Tcf19 plays an important role in regulating β-cell DNA damage repair pathways to prevent apoptosis and allow proliferation.

Disclosure
G.H. Yang: None. J. Han: None. S. Lodh: None. J.T. Blumer: None. D. Fontaine: None. D.B. Davis: None.
370-P: Changes in Glutamate Dynamics in the Anterior Cingulate Cortex with Recurrent Hypoglycemia in Type 1 Diabetes
Authors: PARK YOUNG WOO , DEELCHAND DINESH , KUMAR ANJALI , MOHEET AMIR , ZHANG YUAN , EBERLY LYNN E. , SEAQUIST ELIZABETH R. , OZ GULIN 
Published: June 2019

The mechanisms of how recurrent hypoglycemia (HG) leads to impaired awareness of HG (IAH) remain elusive. Cortical glutamate (Glu) dynamics may be involved, as Glu levels were shown to decrease during HG in healthy controls and in patients with type 1 diabetes (T1D) and normal awareness of HG (T1D-NAH), but not in patients with IAH. While these data supported an association between blunted Glu response to HG and IAH, whether recurrent HG causes a blunting of the Glu response to HG remains unclear. We measured the neurochemical response to HG before and after induction of IAH in T1D-NAH patients undergoing four 2-hour HG clamps over 2 days. 1H-magnetic resonance spectroscopy at 7 tesla was used to measure Glu levels in the anterior cingulate cortex (ACC, 24x12x30 mm3) during the first (C1) and fourth clamps (C4), before and after induction of IAH, respectively. We focused on the ACC as differences in PET-measured glucose kinetics in ACC were associated with IAH. Epinephrine and symptom responses to HG during C1 and C4 confirmed induction of IAH. Glu levels significantly decreased in response to HG during C1, but not during C4. Glucose+Taurine (reported as sum due to cross-correlation) dropped by 40% with HG in C1, whereas it dropped by 32% in C4. We show that recurrent HG blunts the cortical Glu response to HG, which may be due to higher glucose or alternative fuel availability, eliminating the need to oxidize Glu.

Disclosure
Y. Park: None. D. Deelchand: None. A. Kumar: None. A. Moheet: None. Y. Zhang: None. L.E. Eberly: None. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company, Zucara Therapeutics Inc. Consultant; Self; 360 Consulting, MannKind Corporation. Research Support; Self; Eli Lilly and Company, JDRF, National Institutes of Health. Other Relationship; Self; American Diabetes Association, Sanofi, WebMD. G. Oz: None.

Funding
National Institutes of Health (R01NS035192, P41EB015894, P30NS076408)
377-P: Prospective Risk Assessment of Hypoglycemia in Type 1 Diabetes Mellitus Outpatient Pediatric Population
Authors: COSSEN KRISTINA , FIGUEROA JANET , MUIR ANDREW B. 
Published: June 2019

Objectives: The goal was to implement a risk profile that would prospectively identify youth with T1D at risk of severe hypoglycemia (SH) over the course of 1 year. We hypothesized that subjects with specific risk factors such as prior SH, a high frequency of nocturnal hypoglycemia (NH), and impaired hypoglycemia awareness would have a high rate of SH within the following year. If confirmed, an accurate assessment can lead to efficient application of interventions to reduce future risk of SH.
Methods: 404 subjects were followed for 14 months for SH, defined as a seizure, coma or loss of consciousness in the setting of presumed hypoglycemia (ISPAD guidelines). Subjects completed a survey that queried about SH, NH, and hypoglycemia unawareness. Comparisons were made using Chi-squared or Fisher’s exact tests for categorical variables and Wilcoxon Rank-Sum tests for continuous variables.
Results: Of the 404 enrolled, 18 subjects had SH in 14 months (4.46%). In the univariate analysis, those who had SH had indicated SH on the enrollment questionnaire (p-value 0.0015) and hypoglycemia unawareness as always or often (p-value 0.0259). Subjects with SH were more likely to wear CGMs (p-value 0.0369). Subject characteristics, T1D management, insurance, and NH were not statistically significant. In addition, we evaluated the 13 subjects who indicated on their initial questionnaire SH in the prior three months. In the univariate analysis, those subjects had more NH defined as ≥2 nights in a 3 month period (P=0.006) and less hypoglycemia awareness (P=0.030). With regards to insulin management, they had a lower insulin sensitivity factor (P=0.012) and higher proportion of basal insulin (P=0.003).
Conclusions: In a diverse cohort of T1D, this study shows the ability to identify pediatric subjects at risk for SH with hypoglycemia unawareness and prior SH. As SH is a rare event, as this study is expanded, there is the opportunity for a scored risk questionnaire to capture T1D youth at risk for SH.

Disclosure
K. Cossen: None. J. Figueroa: None. A.B. Muir: None.
383-P: The Potential Role of Il-6 in Defective Glucose Sensing following Recurrent Hypoglycaemia
Authors: MCNEILLY ALISON D. , GALLAGHER JENNIFER , MCCRIMMON RORY J. 
Published: June 2019

Hypoglycaemia is common in insulin-treated therapy in the management of type 1 and long duration type 2 diabetes. Hypoglycemia evokes a significant stress response stimulating the release of several inflammatory mediators including interleukin 6 (IL-6). Importantly, glial cells also release IL-6 in response to glucose deprivation. We have previously demonstrated a role for IL-6 in the induction of defective neuronal glucose sensing in vitro. Here we investigate the potential role of IL-6 in the development of defective counter-regulatory response (CRR) to hypoglycaemia in vivo.
IL-6Ra-/- mice were generated by crossing IL-6RaFlx/flx with Nestin-Cre+/-animals. Male IL-6Ra-/- and Cre+/- animals (Control) 18 weeks old, n=10/12 per group) were fed standard laboratory chow for 20 weeks. Hormonal response to hypoglycaemia was assessed in vivo by hyperinsulinaemic-hypoglycaemic clamps. Plasma epinephrine and glucagon were measured by ELISA in response to either acute (single hypo; AH) or recurrent (3 episodes per week for 4 weeks; RH) hypoglycaemia. Data are expressed as mean±SEM.
The epinephrine response to hypoglycaemia was significantly elevated (&gt;3 fold higher) in male IL-6Ra-/- animals following AH when compared to their control counterparts (0.38±0.09 vs. 1.31±0.28 delta; p&lt;0.05). Plasma glucagon levels were comparable between genotypes (p=ns). In contrast, there was a significant suppression of the CRR to hypoglycaemia in both Control and IL-6Ra-/- animals following RH. Indeed, both IL-6Ra-/- and Control animals had suppressed epinephrine (50% and 68% reduction) and glucagon (65% and 44% reduction) responses to following RH when compared to their non-RH counterparts.
These findings highlight an important role for central IL-6 signaling in response to acute hypoglycemia, however, additional mechanisms appear to contribute to the development of defective CRR following RH.

Disclosure
A.D. McNeilly: None. J. Gallagher: None. R.J. McCrimmon: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; The Leona M. and Harry B. Helmsley Charitable Trust.

Funding
Diabetes UK
393-P: Association of Hypoglycemia Prevention Measures with Quality of Life: A Retrospective Analysis of Electronically-Reported Patient Data
Authors: ALI KHAWLA F. , LAWRENCE LIMA , BUEHLER LAUREN A. , GAMBINO RONALD R. , HAMATY MARWAN 
Published: June 2019

Introduction: Hypoglycemia in patients with diabetes presents deleterious effects on quality of life (QoL). We aimed to utilize electronically patient-reported data to identify the correlation of patients’ behaviors, intended to prevent and manage hypoglycemia, with QoL scores.
Methods: In a retrospective single center cohort study, we identified adults with type 1 or 2 DM seen between January 2017 and March 2018 who completed two questionnaires. First, the ADA Low Blood Sugar Questionnaire which assessed the incidence of self-reported hypoglycemia and behaviors intended to prevent and manage hypoglycemia. Second, the Patient-Reported Outcomes Measurement Information System (PROMIS) Survey which evaluated self-reported physical and mental QoL scores. Associations between hypoglycemic behaviors and QoL scores were determined using Spearman correlations.
Results: We identified 538 subjects, with a mean (±SD) age of 53.1±15.3 years, a mean household income of $51,400 ±17,9384, 55% were female, and 66% were on insulin therapy. Patients with fewer severe hypoglycemic episodes had significantly better physical and mental QoL scores (p&lt;0.001, for both). Subjects who carried glucagon emergency kits had significantly higher physical QoL scores (p=0.001), while having a relative able to administer glucagon was associated with significantly higher physical and mental QoL scores (p=0.001 and p=0.003). Carrying snacks or glucose tablets and monitoring glucose before driving were associated with higher physical QoL scores (p&lt;0.001 and p=0.010).
Conclusion: Significant positive correlations were found between patients’ practices intended to reduce and treat hypoglycemia and QoL scores. People with diabetes and low QoL scores require special treatment considerations.

Disclosure
K.F. Ali: None. L. Lawrence: None. L.A. Buehler: None. R.R. Gambino: None. M. Hamaty: Consultant; Self; Applied Clinical Intelligence, LLC.

Funding
Merck & Co., Inc.
403-P: Cerebral Blood Flow Responses to Hypoglycemia in Healthy Humans Treated with Induction Protocol to Produce Impaired Awareness of Hypoglycemia
Authors: CANNA ANTONIETTA , GROHN HEIDI , MASCALI DANIELE , FILIP PAVEL , MOHEET AMIR , KUMAR ANJALI , LI XIUFENG , OLAWSKY EVAN A. , EBERLY LYNN E. , ESPOSITO FABRIZIO , SEAQUIST ELIZABETH R. , MANGIA SILVIA 
Published: June 2019

In this study, we sought to determine by 3T MRI the cerebral blood flow (CBF) responses to hypoglycemia (HG) in nondiabetic controls exposed to either two euglycemic or two hypoglycemic clamps on the day before the MRI (EU- or HYPO-preconditioning, respectively). Under the belief that HYPO-preconditioning induces hypoglycemia-associated autonomic failure (HAAF) with blunting of the counter-regulatory hormone and symptom responses to HG (Arbelaez et al, 2008), we hypothesized that CBF responses after HYPO-preconditioning would resemble those reported in T1D subjects with impaired awareness of hypoglycemia (IAH) (Weigers et al, 2017). CBF was measured by arterial spin labeling during a 2-step hyperinsulinemic clamp [step 1 = 95 mg/dL normoglycemia (NG), step 2 = 50 mg/dL (HG)]. Symptom and counter-regulatory hormone were also measured. Full CBF datasets were obtained from 10 participants who underwent EU-preconditioning (7F/3M, age 37 ± 14 years, BMI 27.2 ± 3.7 kg/m2) and 9 who underwent HYPO-preconditioning (5F/4M, age 40 ± 14 years, BMI 26.2 ± 2.6 kg/m2). In contrast with our assumption, the HYPO-preconditioning did not induce blunting of symptom or counter-regulatory hormone responses to HG other than for glucagon (33 ± 19 and 14 ± 21 pg/mL for EU- and HYPO-preconditioning, respectively, p=0.04 uncorr). CBF responses did not differ between the two pre-conditionings, and resembled those reported in the literature in naïve nondiabetic controls (Weigers et al, 2017). In particular, the cortical grey matter CBF did not change during HG vs. NG for either the EU- or HYPO-preconditioning settings (1 ± 10% and 2 ± 10%, respectively), while thalamic CBF increased in both settings (21 ± 20%, p=0.012 corr, and 27 ± 30%, p=0.06 corr, respectively). We conclude that the preconditioning protocols should be used with caution in nondiabetic controls for investigating IAH, as the mechanisms of HAAF in T1D patients may be specific to their disease condition.

Disclosure
A. Canna: None. H. Grohn: None. D. Mascali: None. P. Filip: None. A. Moheet: None. A. Kumar: None. X. Li: None. E.A. Olawsky: None. L.E. Eberly: None. F. Esposito: None. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company, Zucara Therapeutics Inc. Consultant; Self; 360 Consulting, MannKind Corporation. Research Support; Self; Eli Lilly and Company, JDRF, National Institutes of Health. Other Relationship; Self; American Diabetes Association, Sanofi, WebMD. S. Mangia: None.

Funding
National Institutes of Health