bluuebunny/crossref_metadata_2025_split huggingface dataset:
326-OR: A Novel Machine Learning Analysis of Brain Multimodal Magnetic Resonance Imaging Classifies Painful Diabetic Neuropathic Pain Severity with High Accuracy
Authors: SELVARAJAH DINESH , TEH KEVIN , SLOAN GORDON P. , SHILLO PALLAI RAPPAI , WILKINSON IAIN D. , TESFAYE SOLOMON 
Published: June 2019

Using advanced MR neuroimaging we have demonstrated altered brain structure and functional connectivity that could serve as a potential Central Pain Signature (CPS) for painful diabetic neuropathy (DN). However, the key challenge is how to apply this potential biomarker for routine diagnostic purposes. The aim of this study was to examine if the CPS can accurately classify painful DN patients based on a patient’s pain severity.
Methods: 53 painful DN patients underwent detailed clinical and neurophysiological assessments. The NTSS-6, a validated questionnaire that measures both the frequency and the intensity of neuropathic pain was used to assess pain severity. Patients were divided into high pain (NTSS-6 score &gt;7) and low pain (&lt;7). All subjects underwent brain volume and resting state functional MRI at 3T. We used novel and validated machine learning algorithms [support vector machines] to differentiate pain severity based on functional connectivity and structural/volume data. A nested cross validation method was used to determine the accuracy (sensitivity and specificity).
Results: There was no age or gender difference (p &gt; 0.05) between the high and low pain groups. The CPS classified painful DN patients based on their pain intensity with 94% accuracy (AUC 0.98). The positive and negative predictive values were 0.80 and 1.00 respectively. The F1 scores for predicting high pain and low pain were 0.89 and 0.96 respectively. Brain regions identified as the best classifier were the left and right postcentral gyri, thalami, and anterior and posterior cingulate cortices.
Conclusions: This novel study demonstrates that a simple, 15-minute MR brain scan can accurately classify painful DN patients according to pain intensities with high accuracy. This assessment tool has a great potential as a biomarker of diabetic neuropathic pain and may serve as a target for future trials of analgesic compounds for painful DN.

Disclosure
D. Selvarajah: None. K. Teh: None. G.P. Sloan: None. P. Shillo: None. I.D. Wilkinson: None. S. Tesfaye: Advisory Panel; Self; Mitsubishi Tanabe Pharma Corporation, WÖRWAG Pharma. Speaker's Bureau; Self; AstraZeneca, Merck & Co., Inc., NAPP Pharmaceuticals Limited, Neurometrix, Novo Nordisk Inc., Pfizer Inc. Other Relationship; Self; Impeto Medical.

Funding
European Foundation for the Study of Diabetes
328-LB: Characteristic Features in the Intraislet Ductal Cells of Diabetic C414A-CRY1 Transgenic Mice
Authors: OKANO SATOSHI , YASUI AKIRA , KANNO SHIN-ICHIRO , SATOH KENNICHI , IGARASHI MASAHIKO , NAKAJIMA OSAMU 
Published: June 2019

The transgenic mice ubiquitously expressing the zinc-binding site-mutant CRY1 (C414A-CRY1) show early onset diabetes mellitus similar to human MODY characterized by β-cell dysfunction. In the Tg mice with age, atypical ductal structures emerged inside islets, suggesting that islet cells can transdifferentiate to duct-like cells as we have reported at ADA Scientific Sessions in 2017 and 2018. To explore further molecular features of intra-islets ducts, we conducted staining experiments for Dolichos biflorus agglutinin (DBA) lectin in the pancreatic sections of well-matured mice. The results showed that high levels of staining for DBA lectin were observed in normal ducts of both wild type and Tg mice. In contrast, majority of intra-islet ductal structures especially still not fully developed small ones were weakly positive for DBA lectin, suggesting immaturity for ductal functions of the intra-islet ductal cells. Furthermore, the variation of the staining levels for DBA lectin in intra-islet ductal cells was evidently larger than that in other ductal cells, indicating heterogeneity in the cell functions among intra-islet ductal cells. We also found that remarkably high accumulation of FAM98A, an RNA-binding protein whose functions are still not decisive, was observed in the intra-islet ducts in the Tg mice. In normal ducts, moderate staining of FAM98A was observed. As for pancreatic endocrine cells, although as a whole the immunostaining levels were much weaker than those of acini and ductal cells, discernable staining of FAM98A is detected in both α and β cells of islets. Taken together, our results indicate that intra-islet ductal cells have unique feature distinct from normal ductal cells, and suggest that FAM98A may play important roles in the generation of atypical ductal cells from non-ductal cells in the islet.

Disclosure
S. Okano: None. A. Yasui: None. S. Kanno: None. K. Satoh: None. M. Igarashi: None. O. Nakajima: None.

Funding
Japan Society for the Promotion of Science; Tohoku University
330-LB: Using Human Induced Pluripotent Stem Cell-Derived Organoids to Identify New Pathologies in Patients with PDX1 Mutations
Authors: KRISHNAMURTHY MANSA , BRODA TAYLOR R. , ZHANG XINGHAO , PALERMO JOSEPH J. , THOMAS INAS H. , HEIDER AMER , STEIEN DANA B. , DAUBER ANDREW , WELLS JAMES 
Published: June 2019

Pancreas and gastrointestinal (GI) tract development is guided by several transcription factors, including Pancreatic and duodenal homeobox gene-1 (PDX1). While it is well known that PDX1 is essential for pancreas development, its role in GI development and function in humans has not been investigated. We have identified two patients with a homozygous point mutation in PDX1 (c.188delC(p.P63fs)), causing total loss of protein function. These patients have additional GI complications however endoscopy and histological analysis of gastric and ?intestinal biopsies did not? reveal any pathologies. We used patient derived GI organoids from induced pluripotent stem cells (iPSCs) as a novel diagnostic approach and identified a myriad of undiagnosed GI pathologies. Analyses of human antral gastric organoids (HAGO) using immunofluorescence staining demonstrated a loss of gastric marker? claudin18 (CLDN18) and increased intestinal villin expression in PDX1-null? organoids, signifying that regions of the antrum are converting to an intestinal?phenotype. Similarly, human intestinal organoids (HIO) demonstrated a loss of intestinal marker ?Cadherin17 and an increase in gastric marker? CLDN18, indicating that regions of the intestine are undergoing gastric metaplasia. We also observed an increase in parietal cells in HAGOs, a lack of gastrin hormone in HAGO, and an increase in mucin production in HIOs. Based on this data we re-analyzed antral and duodenal biopsies of both patients and confirmed gastric and intestinal metaplasia increased parietal cells, decreased gastrin and increased mucin production. Because of our findings, these patients will have additional screening to monitor for development of gastric and intestinal cancer. This clearly demonstrates the utility of organoids in improving patient diagnoses and developing new clinical treatment plans.

Disclosure
M. Krishnamurthy: None. T.R. Broda: None. X. Zhang: None. J.J. Palermo: None. I.H. Thomas: None. A. Heider: None. D.B. Steien: None. A. Dauber: Consultant; Self; Novo Nordisk Inc. Research Support; Self; Novo Nordisk Inc. J. Wells: None.

Funding
American Diabetes Association (1-19-PDF-036 to M.K.)
331-OR: Glycemic Index and Postprandial Blood Glucose Excursions, Insulin Requirements, and Hunger in T1D
Authors: LENNERZ BELINDA S. , SIMONSON DONALD C. , STEIL GARRY M. , LUDWIG DAVID S. 
Published: June 2019

High compared to low glycemic index (GI) foods elicit larger glycemic and insulinemic excursions, and are associated with lower satiety. However, it is unclear whether the satiety effect is attributable to differences in glycemia or insulinemia, and whether insulin delivery in individuals with T1D could be optimized for satiety per se. Fifteen men with T1D, BMI 25 (SD 3) kg/m2, aged 23 (5) years, HbA1c 7.4 (0.7)% underwent three experimental conditions in a randomized cross-over design: High GI, high insulin (HGI/HI): meal GI of 84 with intravenous insulin (IVI) to maintain euglycemia; Low GI (LGI): meal GI of 37 with IVI to maintain euglycemia (comparison condition); High GI, low insulin (HGI/LI): high GI meal as above with IVI matched to LGI. Test meals provided 25% of daily calories (60% carbohydrate, 15% protein, 25% fat). IVI was adjusted using a PID algorithm with blood glucose measurements every 5 minutes for 4.5 hr. When using matched insulin doses, blood glucose area under the curve (AUC) was 789 (145) vs. 493 (48) mg/dl*h (p&lt;0.001) for HGI/LI vs. LGI. To maintain euglycemia (HGI/HI vs. LGI), 25 (9) vs. 17 (5) units of insulin were needed (p=0.005). Late postprandial (3.5-4.5 hr) free fatty acid (FFA) concentrations were higher for HGI/HI (0.62 [0.31] mmol/L) vs. LGI (0.26 [0.09] mmol/L p=0.008). Hunger was lower at peak glycemia (1 hr) for HGI/HI vs. LGI (2.3 vs. 3.2 on a 0-10 scale, p=0.01), but was greater in the late postprandial phase after either HGI/HI or HGI/LI vs. LGI (6.3 [p=0.05] or 6.3 [p=0.03] vs. 5.3, respectively). In a controlled feeding study, a high GI meal was associated with a 1.5-fold higher insulin requirement to obtain similar glycemia, or a 1.6-fold higher glucose AUC when using the same insulin dose. The high GI meal also increased late postprandial hunger regardless of insulin dose, and resulted in a greater rise in FFA (high insulin condition). These meal effects, with or without aggressive insulin management, may predispose to cardiovascular risk, metabolic dysfunction or weight gain.

Disclosure
B.S. Lennerz: None. D.C. Simonson: Stock/Shareholder; Self; GI Windows, Inc. Stock/Shareholder; Spouse/Partner; Phase V Technologies, Inc. G.M. Steil: Consultant; Self; Eli Lilly and Company, Profusa, Inc. D.S. Ludwig: Other Relationship; Self; Various publishers.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (K12DK094721, K24DK082730)
332-OR: Determining the Impact of Additional Macronutrients on the Glycemic-Insulin Dynamic Model
Authors: JIANG BOYI , ZHONG YUXIANG , AGRAWAL PRATIK , CORDERO TONI L. , VIGERSKY ROBERT 
Published: June 2019

Background and Aims: Though many studies report that macronutrients such as lipids and protein significantly impact the absorption rate of carbohydrates and insulin requirement, there has not been wide adoption of simulators that take macronutrients into account. This may likely be due to lack of access to macronutrient records. This study evaluated the introduction of additional macronutrient components to a carbohydrate-only simulator.
Methods: Data uploaded between 05/15/2018-10/15/2018 by 114 individuals aged 38.1±14.2 years who used the Guardian Connect continuous glucose monitoring system with the Sugar.IQ application were analyzed. Information on 10 major macronutrients was collected on 4213 meals. Models fitting using 1) Only carb as input (“Carb-only”) and 2) Carbohydrate, lipids and protein as inputs (“Multi-macro”) were conducted and compared using the Mean Average Percent Error (MAPE) and Error Grid Analysis (EGA).
Results: The “Multi-macro” model predicts sensor glucose (SG) outcome 15% more accurately than the “Carb-only” model (MAPE: 11.3% vs. 13.5%, p&lt;0.05). The “Multi-macro” model also improved points within the Clarke A region by 6.1% (EGA: 81.6% vs. 75.5%, p&lt;0.05).
Conclusion: Lipids and protein are macronutrients that should be considered when creating glycemic-insulin dynamic models, as both appear to significantly impact the absorption of carbohydrates and improve SG prediction accuracy surrounding meal intake.

Disclosure
B. Jiang: Employee; Self; Medtronic. Y. Zhong: None. P. Agrawal: Employee; Self; Medtronic MiniMed, Inc. Stock/Shareholder; Self; Medtronic. T.L. Cordero: Employee; Self; Medtronic. R. Vigersky: Employee; Self; Medtronic MiniMed, Inc.
34-OR: Maladaptive Increases in Skeletal Muscle Ketone Body Oxidation Contribute to Dysglycemia in Mice Subjected to Experimental Obesity
Authors: BATRAN RAMI AL , GOPAL KESHAV , CHAHADE JADIN J. , USSHER JOHN R. 
Published: June 2019

Type 2 diabetes (T2D) is a rapidly growing health epidemic, with intense investigation on whether perturbations in skeletal muscle carbohydrate and fatty acid metabolism contribute to obesity-induced insulin resistance and/or T2D. Conversely, whether perturbations in skeletal muscle ketone body oxidation take place in the pathology of obesity-induced insulin resistance/T2D remains unclear. Therefore, our goal was to investigate potential alterations in ketone body metabolism during the pathology of obesity-induced T2D, and to elucidate whether such changes are adaptive or maladaptive. C57BL/6J mice were subjected to low-fat (lean) or high-fat (obese) diet supplementation for 12 weeks. Obese mice exhibited glucose intolerance, which was associated with decreased circulating βOHB and elevated circulating glucose levels. In addition, obese mice demonstrated a marked increase in mRNA and protein expression of succinyl CoA:3-ketoacid CoA transferase (SCOT), the rate limiting enzyme of ketone body oxidation, within gastrocnemius muscles, which was associated with an increase in SCOT enzymatic activity. Of interest, SCOT activity requires succinyl-CoA as a substrate, which is also required for protein succinylation. Accordingly, siRNA knockdown of Oxct1 augmented lysine succinylation, whereas Oxct1 overexpression abolished lysine succinylation. Additionally, Oxct1 knockdown in C2C12 myotubes increased AMPK phosphorylation, which was recapitulated in mice with an Oxct1 skeletal muscle-specific deficiency (Oxct1SkM-/-). Intriguingly, Oxct1SkM-/- mice were protected against obesity-induced dysglycemia and insulin resistance. Our results suggest that ketone body metabolism is augmented in skeletal muscle during the pathology of obesity, which may contribute to dysglycemia and insulin resistance in T2D via potentially modifying protein succinylation and/or AMPK activity.

Disclosure
R.Al batran: None. K.Gopal: None. J.J.Chahade: None. J.R.Ussher: None.
342-OR: The Feasibility and Acceptability of a Diabetes Survival Skills Intervention for Incarcerated Persons Transitioning to the Community
Authors: REAGAN LOUISE A. , LAGUERRE RICK A. , GALLAGHER COLLEEN 
Published: June 2019

Community evidenced-based diabetes self-management education (DSME) models have not been examined for feasibility, acceptability or effectiveness among incarcerated persons transitioning to independent DSM. In a non-equivalent control group design with repeated measures, we examined the feasibility, acceptability and preliminary effect of a 6-week 1-hour per week diabetes survival skills (DSS) intervention on diabetes knowledge, distress, self-efficacy and outcome expectancy for transitioning incarcerated males. Of the 92 participants (84% T2D, 83% using insulin, 40% black, 20% white,30% Latino, 66% high school or less, mean age 47.3 years, 84% length of incarceration ≤4 years), 41 completed the study (22 Control/19 intervention (TX). One-way repeated measures ANOVAs revealed significant changes in diabetes knowledge within each group (C, p=.002; TX, p=.027) at all time points; however, a two-way repeated measures ANOVA showed no differences between groups. Additionally, both groups showed improvement in diabetes-related distress and outcome expectancy with the treatment group experiencing greater and sustained improvement at the 12-week time point. Analysis of focus group data (Krippendorf) revealed acceptance of and enthusiasm for the DSS training and low literacy education materials, and the need for skill demonstration, and ongoing support throughout incarceration and before release. Our results highlight the complexity of working with incarcerated populations. We observed information-gathering strategies among incarcerated persons that may account for overall increases in diabetes knowledge. Due to high attrition, the power to detect effects was limited. Yet, results suggest that the intervention is feasible and acceptable with an increased sample size and refined recruitment procedure.

Disclosure
L.A. Reagan: None. R.A. Laguerre: None. C. Gallagher: None.

Funding
American Nurses Foundation
348-OR: Impact of Endocrinology ECHO on Utilization in Medicaid Patients with Complex Diabetes
Authors: BLECKER SAUL , LEMIEUX EMILY , PAUL MAGGIE , BERRY CAROLYN , BOUCHONVILLE MATTHEW F. , HAGER BRANT , ARORA SANJEEV , BILLINGS JOHN 
Published: June 2019

Background: Poorly controlled diabetes can be difficult to manage, particularly in high-risk patients and in settings without an endocrinologist. Project ECHO is a case-based learning and tele-mentoring model that connects primary care providers (PCPs) with specialists. We evaluated the impact of the ECHO model on healthcare utilization and care for Medicaid patients with diabetes in New Mexico (NM).
Methods: Between January 2015 and April 2017, patients with complex diabetes from 10 federally qualified health centers in NM were recruited to receive diabetes care from a PCP and community health worker upskilled via weekly Endo ECHO sessions. We included patients with 6 months of continuous enrollment in the NM Medicaid claims database and performed 5:1 propensity matching of participants to comparison Medicaid beneficiaries. We used a difference-in-difference (DID) approach to compare utilization and processes of care between study participants and controls.
Results: Of 539 Medicaid patients enrolled in Endo ECHO, 235 met inclusion criteria and were successfully matched to comparison patients. Outpatient visits increased for study participants in the pre- versus post-enrollment period (801 vs. 1056 per 1,000 patients/month) but not for comparators (785 vs. 680 per 1000 patients/month, DID p&lt;0.01). We observed no difference in inpatient (131 vs. 134 per 1,000 patients/month) or ED utilization (24 vs. 26 per 1,000) in the pre- versus post-enrollment period for study participants. The intervention was associated with increased metformin utilization (DID 15.2%, p=0.01), but had no effect on expenditures, statin utilization, or ACE inhibitor/ARB utilization for hypertension.
Discussion: Patient enrollment in Endo ECHO was associated with increased outpatient utilization and increased compliance with some, but not all, process measures. No impact was observed on hospitalizations or ED visits. Ongoing evaluation will determine the impact of the ECHO model on clinical outcomes.

Disclosure
S. Blecker: Advisory Panel; Self; Medtronic. E. Lemieux: None. M. Paul: None. C. Berry: None. M.F. Bouchonville: None. B. Hager: None. S. Arora: None. J. Billings: None.

Funding
The Leona M. and Harry B. Helmsley Charitable Trust
349-OR: Major Cardiovascular Outcomes among At-Risk High-Deductible Health Plan Members
Authors: FRANK WHARAM J. , ZHANG FANG , LU CHRISTINE , HERNANDEZ ADRIAN F. , WALLACE JAMIE , ROSS-DEGNAN DENNIS , NEWHOUSE JOSEPH P. 
Published: June 2019

High-deductible health plan (HDHP) effects on major cardiovascular outcomes are unknown. We studied a 2004-2014 national sample of 63,363 HDHP members aged 40-64 years with diabetes, cardiovascular disease, hypertension, or hyperlipidemia, who were continuously enrolled for 1 year in a low-deductible (≤$500) plan followed by 3 years in a HDHP (≥$1000) after an employer-mandated switch. We matched HDHP members to 539,445 contemporaneous controls who had the same cardiovascular risk factors and whose employers offered only low-deductible plans. Using a controlled interrupted-time-series design, we analyzed cumulative rates of myocardial infarction, stroke, and amputation. We modelled weighted cumulative event rates using aggregate-level segmented regression. HDHP members experienced no detectable absolute change in myocardial infarction (-0.9 events per 10,000 members, 95% confidence interval: -2.7, 0.8) at 3 years of follow-up relative to the end of the baseline year compared to controls. Stroke and amputation declined by 3.4 (-4.0, -2.9) and 6.7 (-9.0, -4.4) events per 10,000 members, respectively, among HDHP members versus controls over the same period. At-risk patients who were switched to HDHPs did not experience increases in major cardiovascular outcomes over 3 follow-up years. Future research should follow patients longer and examine outcomes among low-income populations.

Disclosure
J. Wharam: None. F. Zhang: None. C. Lu: None. A.F. Hernandez: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation. Research Support; Self; AstraZeneca, GlaxoSmithKline plc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation. J. Wallace: None. D. Ross-Degnan: None. J.P. Newhouse: Board Member; Self; Aetna Inc.

Funding
National Institutes of Health
35-OR: Physiological Insulin Regulates Alternative mRNA Splicing in Liver and Muscle at Multiple Levels
Authors: BATISTA THIAGO M. , CAI WEIKANG , BRANDAO BRUNA , KAHN C. RONALD 
Published: June 2019

Alternative splicing of mRNAs contributes importantly to proteome diversity and tissue identity. Work by us and others have suggested that alternative splicing and the spliceosome are dysregulated in diabetes, but the role of this under physiological conditions is not known. To gain more insight into alternative splicing regulation by physiological insulin in vivo, we performed RNA-seq of mRNAs in skeletal muscle and liver from mice undergoing euglycemic clamp with physiological insulin for 3h. In both tissues, insulin significantly regulated over 1000 transcripts, including known pathways related to glucose and fatty acid metabolism. In addition, insulin also regulated many components involved in mRNA splicing, including mRNAs of ribonucleoprotein particles (RNP) spliceosome components, splicing factors and CLK splicing kinases, many of which were down-regulated by insulin. This was associated with significant changes in 102 and 63 alternatively spliced mRNAs in muscle and liver in a variety of gene classes including those encoding proteins involved in tissue-structure, mitochondrial function, autophagy and transcription. Insulin also regulated the spliceosome at the post-translational level, with a 1.5- to 2-fold increase in the phosphorylation of the U2-RNP component SF3B1 and the splicing factor SRSF5. Phosphorylation of the splicing factors SRSF4, SRSF5 and SRSF6 was also increased by insulin in C2C12 myotubes, and this was prevented by pretreatment with the CLK inhibitor TG003. Myotubes treated with TG003 also showed dose-dependent decrease of insulin-stimulated glucose uptake and increased FCCP-uncoupled respiration. Taken together, these data demonstrate that regulation of alternative splicing at multiple mechanistic levels integrates the physiological response to insulin. Disruption of insulin signaling to the spliceosome could potentially shift isoform balance of metabolically relevant proteins and contribute to insulin resistance.

Disclosure
T.M. Batista: None. W. Cai: None. B. Brandao: None. C. Kahn: Advisory Panel; Self; MedImmune. Board Member; Self; Kaleido Biosciences. Consultant; Self; AntriaBio, Inc., Cobalt Therapeutics, Flagship Pioneering. Research Support; Self; Alnylam.

Funding
National Institutes of Health