bluuebunny/crossref_metadata_2025_split huggingface dataset:
Establishing Cost-Effectiveness of "Acceptable" T1D Care in Less-Resourced Countries
Authors: OGLE GRAHAM D. , GUO JINGCHUAN , AHMADOV GUNDUZ A. , FAWWAD ASHER , GREGORY GABRIEL A. , KLATMAN EMMA L. , ORCHARD TREVOR J. 
Published: June 2018

Aim: Cost-effective arguments are needed to help convince less-resourced governments to provide essential T1D services. We developed two scenarios - for Pakistan (Lower-Middle Income) (S1) and Azerbaijan (Upper-Middle Income) (S2).
Methods: We modelled the complications/costs/mortality/Disability Adjusted Life Years (DALYs) associated with achieving a mean HbA1c of 9.0% (75 mmol/mol) for S1 and 8.5% (69 mmol/mol) for S2 compared with those with a mean HbA1c level of 12.5% (113 mmol/mol). ’Acceptable care’ S1 involved human insulin by multiple daily injections (MDI), two blood glucose tests/day, education and complications screening etc. S2 was S1 with analog rather than human insulin and four tests/day. ’Minimal care’ was non-MDI insulin, syringes and routine clinic reviews. A discrete time Markov illness-death model with diabetes-duration-dependent transition probabilities was developed in R 3.3.1. Input parameters included 30 years (y) of University of Pittsburgh Epidemiology of Diabetes Complications (EDC) cohort statistics for T1D diagnosed &lt;17 y of age and DALYs and background mortality data from WHO. Eleven complications were included. Costs were determined from international and local estimations.
Results: Complications were markedly raised with HbA1c at 12.5% compared to 9.0% and 8.5%. For instance, blindness at 30y was 49.4%, 11.6% and 9.5% respectively. For S1, 30y total costs (maintenance and cost of acute and chronic complications) were $20,919/patient at 9.0% and $20,796 at 12.5%. For S2, costs were $61,429 at 8.5% and $60,826 at 12.5%. Thirty y survival rate for Pakistan was 87% at 9.0% and 64% at 12.5%, and for Azerbaijan 91% at 8.5% and 66% at 12.5%. Cumulative DALYs lost in 30 years in Pakistan were 2.6y at 9.0% and 6.0y (12.5%). Azerbaijan was 2.0y (8.5%) and 5.8y (12.5%).
Conclusion: ’Acceptable care’ is of similar cost to ’Minimal care’ in Pakistan and Azerbaijan, with improved survival and reduced DALYs. This model can be used in other less-resourced countries.

Disclosure
G.D. Ogle: None. J. Guo: None. G.A. Ahmadov: None. A. Fawwad: None. G.A. Gregory: None. E.L. Klatman: None. T.J. Orchard: None.
Visceral and Ectopic Fat Expansion and the Risk of Incident Type 2 Diabetes Mellitus
Authors: NEELAND IAN J. , AYERS COLBY , PATEL KERSHAW V. , JOSHI PARAG H. , MCGUIRE DARREN K. , GRUNDY SCOTT M. , ROHATGI ANAND , VEGA GLORIA L. 
Published: June 2018

Background: Excess visceral adipose tissue (VAT) is associated with an increased risk of prediabetes and type 2 diabetes (T2D) independent of body mass index (BMI). Whether expansion of VAT or other fat depots is associated with diabetes risk independent of weight gain is not fully known.
Methods: Among participants without prevalent diabetes or cardiovascular disease enrolled in the Dallas Heart Study, we measured body fat distribution by dual energy x-ray absorptiometry and biomarkers of glycemia at baseline (2000-2002) and repeated 7 years later. The incidence of prediabetes and T2D per ADA definitions were assessed at follow-up.
Results: The study included 1661 participants (mean age 44, 58% women, 45% black, 39% obese) with median weight gain of 3.0 (-1.1 to 7.2) kg. Eight percent of participants developed T2D and, among those with normal fasting glucose at baseline (n=1551), 36% developed prediabetes or T2D. Changes in fat depots are shown in the Table. VAT and SAT gain were associated with incident T2D and with prediabetes or T2D independent of traditional risk factors, baseline BMI, change in BMI, and baseline fat depot (Table). Increasing lower body fat was not associated with incident diabetes.
Conclusions: Expansion of VAT and SAT are both associated with incident T2D independent of weight gain. Abdominal adiposity may be a modifiable target for diabetes prevention even in the absence of generalized weight loss.

Disclosure
I.J. Neeland: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Novo Nordisk A/S, National Institute of Diabetes and Digestive and Kidney Diseases. Advisory Panel; Self; Advanced MR Analytics AB. C. Ayers: None. K.V. Patel: None. P.H. Joshi: Consultant; Self; Regeneron Pharmaceuticals, Inc. D.K. McGuire: Consultant; Self; AstraZeneca, Sanofi-Aventis, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Sanofi-Aventis, Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Lexicon Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Esperion Therapeutics. S.M. Grundy: None. A. Rohatgi: Research Support; Self; Merck Sharp & Dohme Corp., American Heart Association. Consultant; Self; CSL Behring. Research Support; Self; National Heart, Lung, and Blood Institute. G.L. Vega: None.
Lipid Accumulation Product and Sarcopenia in Korean Patients with Type 2 Diabetes
Authors: SHIN JANG YEL 
Published: June 2018

Lipid accumulation product (LAP), a new biomarker for lipid over accumulation in adults. has been suggested to show better relationships with insulin resistance (IR), metabolic syndrome (MS), and type 2 diabetes, and cardiovascular disease (CVD) than body mass index (BMI). Sarcopenia is proposed to risk factor for IR, MS, type 2 diabetes, and CVD. However, association between LAP and sarcopenia is not approved yet. We evaluated relationship between LAP and sarcopenia in patients with type 2 diabetes. Total of 481 subjects with type 2 diabetes were enrolled. LAP was estimated as follows: [waist circumference (WC)-65] X [triglycerides (TG)] in men and [WC-58] X [TG] in women. Appendicular skeletal muscle mass (ASM) was measured using dual energy X-ray absorptiometry (DEXA). Sarcopenia was defined as follows: ASM/ BMI&lt;0.789 in men and &lt;0.521 in women. Patients with the highest tertile of LAP were more likely to be hypertensive and current drinkers and less likely to have regular exercise than those with the lowest. They had higher values of BMI, systolic and diastolic blood pressure (BP), total cholesterol, HOMA-IR, and liver enzymes and lower values of age, HDL, and vitamin D3 (vitD3). Sarcopenic subjects gradually increased with increasing tertiles of LAP (p&lt;0.05). Odds ratios (ORs) in the highest tertile of LAP for sarcopenia after adjusted for age and gender were 1.884 (95% CI=1.128-3.146, p=0.015) in 2nd tertiles and 2.784 (95% CI=1.641-4.724, p&lt;0.001) in the highest. The association between LAP and sarcopenia remained significant after further adjustments for hypertension, currents drinking, regular exercise, total cholesterol, HDL, HOMA-IR, CRP, vitD3, and liver enzymes. LAP was significantly associated with sarcopenia in patients with type 2 diabetes independent of age, gender, hypertension, current drinking, regular exercise, BP, total cholesterol, HDL, HOMA-IR, CRP, vitD3, and liver enzymes. Further studies are required to investigate a causal relationship between LAP and sarcopenia.

Disclosure
J. Shin: None.
A Systems Approach to ER Stress Pathway Dynamics Reveals the Impact of Freeze-Dried Broccoli Extract to Mitigate Inflammation in Human Adipocytes through the Mevalonate Pathway
Authors: MURPHY ALICE , AZHARIAN SAHAR , TRIPATHI GYANENDRA , BARKER GUY , CHAPPELL MICHAEL J. , MCTERNAN PHILIP G. 
Published: June 2018

Background: Delivery of nutrient excess in obesity causes endoplasmic reticulum (ER) stress within adipose tissue; this activates the unfolded protein response (UPR) and contributes to type 2 diabetes mellitus (T2DM) risk. This study aimed to utilise freeze-dried broccoli extract (BE) as a nutrient to mitigate such cellular damage in human adipocytes, and create a mathematical model to understand pathway dynamics.
Methods: Differentiated human adipocytes (Chub-S7; n=6) were treated with BE (10ng/ml) alone or combined with tunicamycin (Tun; 750ng/ml), an inducer of ER stress. UPR proteins (BiP, PERK, P-PERK, eIF2α, P-eIF2α) were measured (18 time points; 0hr-72hr) using Western Blot and transcriptomics. Mass action kinetics was used to create ordinary differential equations (ODEs) to model the UPR for predictive analysis.
Results: Tun increased UPR proteins 9.5 fold (P&lt;0.05), whilst BE+Tun reduced ER stress proteins by 94% (P&lt;0.05). Transcriptomic analysis highlighted significant changes in the mevalonate pathway with BE (P&lt;0.05), whilst time series data identified oscillatory behaviour of UPR proteins. Finally, modelling pathway dynamics, time-series analysis improved the error between model output and experimental data by 23%, yielding a new enhanced qualitative model.
Conclusion: BE acts to alleviate ER stress in human adipocytes by reducing the UPR through the mevalonate pathway. Furthermore, modelling pathway dynamics using experimental data may provide insight into predicting nutrient capabilities to reduce inflammation.

Disclosure
A. Murphy: None. S. Azharian: None. G. Tripathi: None. G. Barker: None. M.J. Chappell: None. P.G. McTernan: None.
Altered Brain Resting-State Functional Connectivity in Obese Patients Is Associated with Plasma Levels of Leptin
Authors: DEVOTO FRANCANTONIO , FERRULLI ANNA , ZAPPAROLI LAURA , BONANDRINI ROLANDO , SCONFIENZA LUCA MARIA , BANFI GIUSEPPE , LUZI LIVIO , PAULESU ERALDO 
Published: June 2018

There is growing evidence for the role of the insular cortex in various types of cravings, including food craving. Here, we used resting-state functional brain connectivity (FBC) to explore system-level dysfunctions in the brain of obese (OB) individuals and their correlations with the leptin levels. We first used hierarchical clustering to identify the brain regions whose altered functioning was consistently reported by neuroimaging studies on food perception in OB subjects. We found that a cluster centred in left anterior insula and overlying frontal operculum (AI/fO) was specifically associated with hyper-responsivity in OB. This cluster was then used as a seed for a seed-based FBC analysis in 10 OB and 11 normal weight controls matched for sex, age and education. The analysis implied the calculation of the functional correlations of each brain voxel with the seed along the resting state fMRI time series. OB patients, compared to the control group, showed hyper-connectivity between the left AI/fO and key regions of the reward system, such as the left medial orbitofrontal cortex (OFC), in addition to the bilateral parahippocampal gyri and the posterior cingulate gyrus; conversely, they exhibited hypo-connectivity between the seed and the left dorsolateral prefrontal cortex, a key region involved in inhibitory control (all Ps &lt; .corrected for multiple comparisons). Finally, we found a substantial trend for a negative correlation between AI/fO-OFC hyper-connectivity and plasma levels of leptin (ρ = - .612, p = .06). Our results provide evidence for an imbalance between reward and inhibitory control systems in OB patients, which might be worsened by an altered response to food intake regulatory hormones (e.g., anorexigenic leptin), thus driving the overeating behavior. Moreover, our results suggest that the left AI could be a suitable target for drugs or neuro-modulatory treatment to recalibrate the FBC of a network involved in food intake, reward and cognitive control.

Disclosure
F. Devoto: None. A. Ferrulli: None. L. Zapparoli: None. R. Bonandrini: None. L. Sconfienza: None. G. Banfi: None. L. Luzi: Speaker's Bureau; Self; A. Menarini Diagnostics, AstraZeneca, Eli Lilly and Company. Research Support; Self; Gelesis. Consultant; Self; McKinsey & Company. Speaker's Bureau; Self; Menarini Group, Merck Sharp & Dohme Corp.. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sunstar Foundation. Speaker's Bureau; Self; Smith & Nephew. E. Paulesu: None.
Lower Ectopic Fat Accumulation in Obese Women May Help Explain Sex Differences in the Magnitude of Insulin Resistance
Authors: GILLEN JENNA B. , RYAN BENJAMIN J. , GIOSCIA-RYAN RACHEL A. , LUDZKI ALISON , CHENEVERT THOMAS L. , HOROWITZ JEFFREY F. 
Published: June 2018

Accumulating evidence suggests obese women maintain higher insulin sensitivity than obese men, but factors underlying this sex difference in insulin resistance remain unclear. We recently developed a semi-automated method for quantifying visceral and hepatic fat using advanced chemical shift-encoded magnetic resonance imaging (MRI). Using this method, we explored whether sex differences in ectopic fat accumulation may contribute to differences in insulin resistance. Twenty-one obese women (32 ± 6 year, 34.5 ± 3.1 kg/m2, 43.1 ± 5.5 kg fat mass (FM)) and a well-matched cohort of fifteen obese men (29 ± 6 year, 34.5 ± 3.3 kg/m2, 42.0 ± 7.8 kg FM) underwent an MRI scan during which 5mm axial slices were acquired from the abdominal region. Using 3D Slicer software, visceral fat area was quantified on three axial slices from the L2-L3 vertebrae region and averaged. Hepatic fat was quantified as the average percentage fat from three axial slices of the liver. On a separate day, subjects underwent a hyperinsulinemic-euglycemic clamp to quantify insulin sensitivity. Compared with men, women had lower hepatic (4.2 ± 5.5 vs. 13.1 ± 9.7%, p&lt;0.001) and visceral (114 ± 49 vs. 201 ± 87 cm2, p&lt;0.001) fat, which corresponded with higher insulin sensitivity (Glucose infusion rate during clamp [GIR]: 514 ± 330 vs. 263 ± 134 umol/kgFFM/SSI/min, p&lt;0.05). To further examine the relationship between ectopic lipid accumulation and insulin resistance, we stratified subjects into tertiles by hepatic fat content (n=12 per group). Interestingly, nearly all subjects in the lowest tertile for hepatic fat (1.1 ± 0.6%) were women, and when compared to the highest hepatic fat tertile (17.7 ± 8.2%), they also had lower visceral fat (101 ± 61 vs. 214 ± 83 cm2, p&lt;0.001) and importantly, were also more insulin sensitive (GIR: 626 ± 350 vs. 279 ± 238 umol/kgFFM/SSI/min, p&lt;0.05). Our findings suggest lower ectopic fat deposition may help explain the lower degree of insulin resistance in obese women compared with men.

Disclosure
J.B. Gillen: None. B.J. Ryan: None. R.A. Gioscia-Ryan: None. A. Ludzki: None. T.L. Chenevert: None. J.F. Horowitz: None.
Endobarrier® Gastrointestinal Liner in Obese Subjects with Type 2 Diabetes—Short- and Midterm Effects on Glucose Metabolism
Authors: TRIPOLT NORBERT J. , ABERER FELIX , URL JASMIN , PFERSCHY PETER N. , HÖGENAUER CHRISTOPH , SCHREIBER FLORIAN , EHERER ANDREAS , SVEHLIKOVA EVA , SOURIJ CAREN , OBERMAYER ANNA M. , STADLBAUER VANESSA , SOURIJ HARALD 
Published: June 2018

Background: A 60cm endoscopically implantable, duodeno-jejunal bypass liner (Endobarrier®) has been introduced as a therapeutic option for obese subjects with type 2 diabetes (T2DM). The aim of the study was to explore short and mid-term metabolic effects in the clamp setting.
Materials and Methods: This open, single-center trial investigated 10 obese, T2DM subjects with suboptimal glycemic control (HbA1c &gt;48mmol/mol). Prior to the implantation of the gastrointestinal liner (baseline), 4 weeks and 9 months (explantation) after, all subjects underwent Dual-energy X-ray absorptiometry (DXA) measurement, assessment of beta cell function and insulin sensitivity by a Botnia clamp procedure and a mixed-meal tolerance test.
Results: We investigated 10 patients with a mean age of 48±9 years and mean diabetes duration of 7±6 years. Detailed results and changes over the time are given in Table. No device has been removed prematurely.
Conclusion: Treating obese T2DM subjects by an endoluminally implanted Endobarrier® leads to moderate weight reduction with large inter-individual variation. Significant improvements in insulin sensitivity occurred already 4 weeks after the Endobarrier® implantation, which were maintained until the explantation of the device, accompanied by reductions in blood pressure.Baseline (mean±SD)4 Weeks (mean±SD)9 Monhts (mean±SD)p-value (Group comparison baseline vs. 4 weeks)p-value (Group comparison baseline vs. 9 months)Body weight (kg)121.2 ± 18.5116.3 ± 18.2115.7± 22.5&lt;0.0010.016Fat-Mass (kg)58.1 ± 12.055.0 ± 12.553.3 ± 16.10.0010.014HbA1c (mmol/mol)61 ± 1056 ± 955 ± 120.0160.139Blood pressure systolic (mmHg)143 ± 16129 ± 24125 ± 210.0590.007Blood pressure diastolic (mmHg)94 ± 1085 ± 1579 ± 160.1070.021Glucose infusion rate (mg/kg/min)0.50 ± 1.020.86 ± 0.990.81 ± 1.28&lt;0.0010.034C-peptide AUC (ng/mL/min)8.10 ± 3.017.27 ± 3.765.81 ± 2.090.4400.046

Disclosure
N.J. Tripolt: None. F. Aberer: None. J. Url: None. P.N. Pferschy: None. C. Högenauer: None. F. Schreiber: None. A. Eherer: None. E. Svehlikova: None. C. Sourij: None. A.M. Obermayer: None. V. Stadlbauer: None. H. Sourij: Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Novo Nordisk A/S, Amgen Inc., Sanofi, MSD K.K.. Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH, MSD K.K., GI Dynamics Inc..
Genetic Risk for Type 1 Diabetes Profoundly Influences the Core Gut Microbiome in Children
Authors: RUSSELL JORDAN , ROESCH LUIZ , ATKINSON MARK A. , SCHATZ DESMOND , TRIPLETT ERIC W. , LUDVIGSSON JOHNNY 
Published: June 2018

All of the gut microbiome associations with type 1 diabetes autoimmunity to date have been discovered in cohorts where all subjects are at high genetic risk for the disease. The design of such cohorts precludes an assessment of the influence HLA high risk alleles on gut microbiome composition. This question is addressed here by using stool samples from the general population All Babies in Southeast Sweden (ABIS) cohort where most children are at no genetic risk for type 1 diabetes. A proportion of ABIS children do possess high risk alleles including DR3/DQ2, DR4/DQ8, and DRB1. DNA from stool samples, collected at one year of age from 441 ABIS children (169 at high genetic risk), stored at -80°C, was extracted and 16S rRNA amplified, sequenced, and analyzed. The core microbiome for each category was computed by including only those reads from taxa found in at least 70% of all subjects within that group. The core microbiomes of the two groups were readily separated by PCoA (Fig. 1) and were significantly different (p=0.001). Each core microbiome comprised about 65% of the reads collected. Bifidobacterium was significantly higher in the no-risk group while Veillonella was higher in the risk group. Thus, HLA risk alleles appear to influence the core gut microbiome and posit a novel mechanism whereby the microbiome may influence the pathogenesis of type 1 diabetes.

Disclosure
J. Russell: None. L. Roesch: None. M.A. Atkinson: Other Relationship; Self; Patent Issued. D. Schatz: None. E.W. Triplett: None. J. Ludvigsson: None.
The Visceral Adiposity Index Predicts Cardiovascular Events Both in Cardiovascular Disease Patients With and in Those Without Diabetes
Authors: SAELY CHRISTOPH H. , VONBANK ALEXANDER , HEINZLE CHRISTINE , ZANOLIN DANIELA , LARCHER BARBARA , MADER ARTHUR , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ 
Published: June 2018

The visceral adiposity index (VAI) is a validated tool for the evaluation of visceral adiposity, using waist circumference, serum triglycerides, age and gender to diagnose this metabolic abnormality. It has recently been associated with cardiovascular risk in primary care patients. No data are available on the association of the VAI with mortality in patients with cardiovascular disease (CVD).
We therefore prospectively recorded the incidence of cardiovascular events over a mean follow-up period of 7.9± 3.1 years in a large cohort of 1858 consecutive patients with established cardiovascular disease (1599 patients with angiographically proven coronary artery disease and 259 patients with sonographically proven peripheral artery disease). The VAI was calculated according to the Amato formula; type 2 diabetes (T2DM) was defined according to the ADA definition.
At baseline, the VAI was significantly higher in CVD patients with T2DM than in those who did not have diabetes (347±331 vs. 228±200; p&lt;0.001). Prospectively, 585 vascular events occurred; the event rate was significantly higher in patients with T2DM than in those who did not have diabetes (46.8% vs. 31.3%; p&lt;0.001). After multivariate adjustment, the VAI significantly predicted cardiovascular events in CVD patients with T2DM (standardized adjusted hazard ratio (HR) 1.24 [1.09-1.42]; p=0.007) as well as in
those who did not have T2DM (HR 1.18 [1.06-1.31]; p=0.014).
We conclude that the VAI predicts cardiovascular events both in CVD patients with and in those without diabetes.

Disclosure
C.H. Saely: None. A. Vonbank: None. C. Heinzle: None. D. Zanolin: None. B. Larcher: None. A. Mader: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
Effect of Restricted Caloric Intake and Bariatric Surgery on PCSK9 Concentrations in Plasma
Authors: GHANIM HUSAM , ABUAYSHEH SANAA , MONTE SCOTT , DANDONA PARESH 
Published: June 2018

PCSK9 is a major modulator of LDLc through internalization and endosomal degradation of LDL receptor. It has been shown that PCSK9 plasma levels predict CVD risk. Bariatric surgery is known to reduce both LDLc and CVD. However, its exact effect on circulating PCSK9 levels has not been fully investigated. We have now investigated the effect of strict caloric restriction and Roux-en-Y bariatric surgery (RYGB) in 15 morbidly obese patients on plasma PCSK-9 levels. Subjects were instructed to follow a regimen of 4 liquid shakes (up to 16g carbohydrate, 0g fat, and 33g of protein, total daily intake was 550-785 calories) during the 2-weeks strict caloric restriction period prior to surgery and the usual dietary regime after surgery. Blood samples were obtained at 2 weeks before, at the time of surgery and 6 months after RYGB. There was a significant weight loss of 7.8±2.4 Kg during the 2 weeks prior to surgery and of additional 26.6±5.3 Kg 6 months after surgery. At completion of strict caloric restriction, subjects had a significant reductions in glucose, insulin and HOMA-IR (7.1±1.1 to 4.5± 1.0) which continued following surgery (HOMA-IR (4.5±1.0 to 2.1± 0.3). LDL(c) fell significantly by 11±7% (from 120±6 to 109±7mg/dl) following the strict caloric restriction and by 15±8% (from 109±7 to 95±6mg/dl) following surgery. There was a reduction of 38±11% (from 227±25 to 139±15 ng/ml) in plasma PCSK9 concentration in the 2 weeks of caloric restriction. Thereafter, PCSK9 levels increased to 166±22ng/ml over the next 6 months. Our data show that there is an impressive and concurrent fall in PCSK9, LDL(c) concentrations and insulin resistance following strict caloric restriction. The marked weight loss over 6 months has only a marginal effect on PCSK9 concentrations while metabolic improvements persisted. This reduction in PCSK9 may contribute to the known benefit in cardiovascular outcomes following bariatric surgery.

Disclosure
H. Ghanim: None. S. Abuaysheh: None. S. Monte: Stock/Shareholder; Self; Mobile Pharmacy Solutions (Community Pharmacy). Employee; Self; Synergy Bariatrics, a Department of ECMC. P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca.