bluuebunny/crossref_metadata_2025_split huggingface dataset:
6-OR: Estimated Glucose Disposal Rate and Major Vascular Events in Type 1 Diabetes: A 10-Year Follow-Up Study
Authors: GAROFOLO MONIA , GUALDANI ELISA , GIANNARELLI ROSA , ARAGONA MICHELE , CAMPI FABRIZIO , LUCCHESI DANIELA , DANIELE GIUSEPPE , MICCOLI ROBERTO , FRANCESCONI PAOLO , PRATO STEFANO DEL , PENNO GIUSEPPE 
Published: June 2019

Estimated Glucose Disposal Rate (eGDR), a validated tool to estimate insulin sensitivity (IS) in T1DM [eGDR = 21.158 - (0.09 x WC, cm) - (3.47 x hypertension, yes = 1) - (0.551 x HbA1c, %)], has been associated to all-cause death. The relationship between eGDR and major vascular (CV) events was evaluated in 736 T1DM enrolled in an observational, single-centre study over a 10-year follow-up. Incidence of CV and coronary events were obtained by interrogating hospital discharge registers. Mean eGDR was 7.51±2.26 (M±SD) mg/kg/min (median 8.26; IQR 5.53-9.29). According to the “Swedish National Diabetes Register,” eGDR was stratified in: C1: ≥8.0 (N. 399, 54.2%, ref); C2: 6.0-7.99 (N. 121, 16.4%); C3: 4.0-5.99 (N. 144, 19.6%) and C4: &lt;4.0 mg/kg/min (N. 72, 9.8%). Compared to C1, C2-4 showed a worse risk profile. A total of 49 CV events (defined as first of MI, stroke, coronary, carotid or peripheral revascularization) occurred over a follow-up of 10.38±2.88 years (6.7%, 6.42 x1000 PYs). By Kaplan-Meier, incidence increased across eGDR categories: C1, 2.3%; C2, 4.1% (HR [95% CI] 1.79 [0.60-5.35]); C3, 11.8% (5.68 [2.53-12.75]); C4, 25.0% (12.76 [5.73-28.43], p&lt;0.0001). After adjustment for multiple confounders, risk of CV events was significantly increased in C4 (5.18 [2.11-12.72], p&lt;0.0001). Further adjustment for variables strictly related to IS (HDL, triglycerides, ACR) did not exclude C4 eGDR as an independent covariate. Over a follow-up of 10.47±2.74 years, 35 coronary events (first of MI or coronary revascularization) occurred (4.8%; 4.54 x 1000 PYs). Incidence increased across eGDR categories: C1, 2.3%; C2, 0.8% (0.35 [0.04-2.76]); C3, 7.6% (3.65 [1.51-8.81]); C4, 19.4% (9.64 [4.17-22.30], p&lt;0.0001). After adjustment for multiple confounders, risk of coronary events was significantly increased in C4 (4.78 [1.90-12.04], p=0.001). Even so after further adjustment for variables strictly related to IS. Thus, in our T1DM, eGDR was a long-term independent predictor of vascular events.

Disclosure
M. Garofolo: None. E. Gualdani: None. R. Giannarelli: None. M. Aragona: None. F. Campi: None. D. Lucchesi: None. G. Daniele: None. R. Miccoli: None. P. Francesconi: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Servier, Takeda Pharmaceutical Company Limited. Board Member; Self; AstraZeneca. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited. G. Penno: None.
608-P: High er Level of Angiopoietin-Like Protein-2 Is Associated with Diabetic Macular Edema in Patients with Type 2 Diabetes Mellitus
Authors: ZHANG NING , AN YAXIN , YIN RUILI , ZHAO DONG 
Published: June 2019

Background: Diabetic macular edema (DME) is characterized by hyperpermeability of retinal blood vessels and subsequent formation of hard exudates and macular edema. ANGPTL2 is associated with microvascularization and angiopoiesis, so we investigate the relationship between ANGPTL2 and occurrence of DME.
Methods: 222 patients with type 2 diabetic patients were enrolled and divided into 3 groups with matched gender, age and BMI: 1) DM group: patients without diabetic retinopathy (DR) and DME, 2) DR without DME group, and 3) DR with DME group. All subjects were performed optical coherence tomography scanning (OCT) and fundus photography. ANGPTL2 was measured by Elisa. We analyzed the OCT values of concentric circles of macular central fovea with average diameters of 1 mm (R1), 3 mm (R3) and 6 mm (R6) to diagnose DME. Multivariable regression analysis was performed to estimate association between ANGPTL2 and DME.
Results: Values of duration of diabetes, fasting C-peptide, postprandial C-peptide 1h, CRP, history of cataract and Statins treatment showed significant differences among three groups (p&lt;0.05). ANGPTL2 levels in DM, DR without DME, DR with DME groups were 3.55±1.56, 3.68±1.59, 4.45±1.8ng/ml, respectively (P=0.012). In multivariable linear regression, Angplt2 was significantly different among three groups after adjustment for age, gender, BMI, glycosylated hemoglobin, ALT, AST, GGT, and fasting C peptide (P=0.023).
Conclusions: Our findings suggest that ANGPTL2 is higher in patients both with DR and DME. Increased level of ANGPTL2 may take part in the progression of diabetic macular edema in type 2 diabetes mellitus.

Disclosure
N. Zhang: None. Y. An: None. R. Yin: None. D. Zhao: None.
609-P: Effect of Rosuvastatin on Lipoprotein Sphingolipids in Patients with Type 2 Diabetes
Authors: KELLY CLARE B. , HAMMAD SAMAR M. , KLEIN RICHARD L. , LOPES-VIRELLA MARIA F. , GOSMANOVA ALBINA , LEYVA MISTI J. , ASTON CHRISTOPHER E. , LYONS TIMOTHY 
Published: June 2019

Statin therapy reduces cardiovascular risk in type 2 diabetes (T2DM), partly by improving dyslipidemia, and partly through ‘pleiotropic’ effects. Sphingolipids, including ceramides, are amphiphilic components of lipoprotein surface monolayers. Sphingolipids regulate lipoprotein surface fluidity, and include key signaling molecules: ceramides are specifically associated with apoptosis and risk for premature coronary heart disease. Effects of statins on the sphingolipid content of lipoproteins are poorly defined.
Using liquid chromatography/electrospray ionization-tandem mass spectrometry, we determined fasting plasma concentrations of individual ceramides (Cer), sphingomyelins (SM), and glycosphingolipids (hexosyl- and lactosyl-Cer) in plasma from 19 men and 21 women with T2DM, before and after treatment with rosuvastatin (10 mg/day, 6 weeks). Exclusion criteria were use of ‘statins’ in the preceding 6 months, and any current use of lipid-modifying agents. Using existing lipoprotein compositional data, we calculated effects of rosuvastatin therapy on non-HDL sphingolipid content.
Results: Rosuvastatin reduced total cholesterol (C) (by 33%), triglycerides (20%), LDL-C (49%), and non-HDL particle number (34%); HDL-C was unaffected. It decreased total SM (15%), Cer (29%), and hexosyl- (30%) and lactosyl- (34%) Cer, independent of gender. Assuming HDL composition was unaffected, rosuvastatin reduced non-HDL SM by 42% and Cer by 61%: these reductions remained significant after correction for non-HDL-C and/or non-HDL lipoprotein surface area.
Conclusions: In T2DM, rosuvastatin lowers not only the number of non-HDL particles, but also the sphingolipid, and especially the Cer, content of each particle. This effect is independent of gender, potentially anti-atherogenic, and may represent a new pleiotropic effect of statins. Further studies are needed to confirm these findings in isolated lipoprotein classes, and to determine mechanism(s).

Disclosure
C.B. Kelly: None. S.M. Hammad: None. R.L. Klein: None. M.F. Lopes-Virella: None. A. Gosmanova: None. M.J. Leyva: None. C.E. Aston: None. T. Lyons: None.
61-LB: Voluntary Wheel-Running Improves Dynamic Glucose Disposal in Diet-Induced Obese Mice: A Stable-Isotope Approach
Authors: ALLERTON TIMOTHY , KOWALSKI GREG M. , FLOYD ELIZABETH , STEPHENS ELIZABETH 
Published: June 2019

Methods such as the hyperinsulinemic-euglycemic clamp have demonstrated improved insulin sensitivity in exercise-trained mice, but fail to recapitulate a dynamic physiological route of glucose metabolism. Therefore, we sought to test the effect of exercise (voluntary wheel running; VWR) on postprandial glucose dynamics by using a stable isotope labelled oral glucose tolerance test (SI-OGTT) incorporating complimentary deuterium glucose tracers at 1:1 ratio (2-2H-glucose and 6-6 2H-glucose; 2g/kg lean body mass) to distinguish between endogenous glucose concentrations (index of EGP; tracer less glucose) and meal (load) derived glucose which provides an index of whole-body glucose disposal. SI-OGTT was performed in C57/BL6J mice after 8 weeks on a high fat diet (45% fat). Mice were then randomized to either a wheel running cage (n=13, HFD Ex) or normal cage (n=13, HFD Sed) while maintaining the HFD for 4 weeks before performing a SI-OGTT. HFD Ex mice demonstrated improvements in whole blood glucose total AUC that was attributed primarily to a reduction in the endogenous glucose concentration (tracer less glucose) AUC. HFD Ex mice also demonstrated significantly lower 2-2H-glucose and 6-6 2H-glucose tracer excursions. Serum insulin levels measured at 0 and 15-minutes post glucose gavage were significantly elevated in the HFD Sed mice, whereas HFD Ex mice demonstrated the expected reduction at both time points. Overall, VWR appears to have improved postprandial hepatic insulin sensitivity and increased whole-body glucose disposal. Finally, these results demonstrate the benefits of VWR on hepatic insulin sensitivity by combining a more physiological route of glucose administration (oral glucose) with the resolution of stable isotope tracers. We clearly demonstrate the SI-OGTT to be a sensitive and cost-effective method to measure exercise adaptations in DIO-mice, which only requires as little as 2 µl of tail blood.

Disclosure
T. Allerton: None. G.M. Kowalski: None. E. Floyd: None. J.M. Stephens: None.

Funding
National Center for Complementary and Integrative Health (T32AT004094 to T.A.); Office of Dietary Supplements (P50AT002776)
61-OR: ADA Presidents' Select Abstract: Characterization of Beta-Cell Function with Autoantibodies, Islet Pathology, and Genetics after 50 Years of Insulin Dependence
Authors: YU MARC GREGORY , PEZZOLESI MARCUS G. , KEENAN HILLARY A. , POBER DAVID M. , HE ZHIHENG , TINSLEY LIANE J. , DORIA ALESSANDRO , BONNER-WEIR SUSAN , KING GEORGE L. 
Published: June 2019

Characterization of persistent beta-cell function in response to metabolic stimuli with HLA and monogenic genotypes and pancreatic morphology in a large group of people with long duration of type 1 diabetes (T1D) has not been reported. In the Joslin Medalist Study (“Medalists”), which enrolled people with ≥50 years of T1D (n=1019), we determined whether significant associations exist between beta-cell function, autoantibodies (AAb), islet morphology, and genetic risks for T1D and monogenic diabetes. In this cohort, 32% exhibited C-peptide&gt;0.05 ng/mL while 44% had GAD/IA2 AAb. In those with mixed meal tolerance test (MMTT, n=516), 6% responded with doubling of baseline C-peptide, without a related change in AAb status. Longitudinally (n=181, over a median of 4 years), C-peptide levels increased in 12% (n=22) and decreased in 37% (n=67). Among those with repeated MMTT, 5% (3/56) and 16% (9/56) had similar waxing and waning responses, respectively. Postmortem examination of 68 Medalist pancreases showed that all contained scattered insulin-positive cells, with three categories: A) only scattered singlets/doublets (n=9); B) scattered plus few insulin-positive cells in some islets (n=45); and C) scattered plus some lobes with islets having many insulin-positive cells (n=14). 30 Medalists with baseline C-peptide ≥0.1 ng/mL underwent a hyperglycemic/arginine clamp, to which 47% responded. Genetic screen for monogenic diabetes on all Medalists studied with the clamp showed 10 exhibiting monogenic variants, with HLA-/AAb- and HLA+/AAb- Medalists responding most to stimuli.
In summary, these results show that all Medalists retained insulin-positive beta-cells, with many responding to metabolic stimuli even after 50 years of T1D. Medalists are heterogeneous with respect to beta-cell function and many with HLA+ diabetes risk alleles also have monogenic variants, indicating the importance of genetic testing for clinically-diagnosed T1D.

Disclosure
M. Yu: None. M.G. Pezzolesi: None. H.A. Keenan: Employee; Self; Sanofi Genzyme. D.M. Pober: None. Z. He: None. L.J. Tinsley: None. A. Doria: Research Support; Self; Sanofi-Aventis. S. Bonner-Weir: Advisory Panel; Spouse/Partner; Semma Therapeutics, Inc. G.L. King: Research Support; Self; Sanofi.

Funding
Nunnally Foundation; Beatson Pledge Fund; National Institute of Diabetes and Digestive and Kidney Diseases
612-P: Eicosapentaenoic Acid (EPA) Inhibits Human HDL Oxidation in a Concentration-Dependent Manner at a Pharmacologic Dose In Vitro
Authors: SHERRATT SAMUEL , MASON R. PRESTON 
Published: June 2019

Aim: Prescription eicosapentaenoic acid (EPA) reduced cardiovascular events in the REDUCE-IT study population, including patients with diabetes. As EPA has been previously shown to reduce LDL oxidation, we investigated if it may prevent HDL oxidation at a pharmacologic dose. Atheroprotective properties of HDL are compromised in patients with diabetes due to oxidative damage and glycation.
Methods: Isolated human HDL at 200 µg/mL was incubated with vehicle or EPA at levels that match plasma concentrations (∼10 µM) at 4 g/d. All samples were subjected to oxidation over 6 hour under low and high glucose (200 mg/dL) conditions.
Results: EPA inhibited HDL oxidation in a highly dose- and time-dependent manner. At lower concentrations (≤ 3.5 µM), EPA inhibited oxidation until 4 hour or less. At higher concentrations (&gt;7.0 µM), EPA inhibited HDL oxidation 6 hour. At 10.0 µM, EPA inhibited HDL oxidation by 80% (p&lt;0.001) at 6 hour. Large effect shifts were observed with relatively small concentration shifts, with the critical concentration shifts being time-dependent. Similar antioxidant effects were observed with hyperglycemia.
Conclusions: These data support concentration-dependent antioxidant effects for EPA that require pharmacologic concentrations for sustained activity. These effects of EPA may provide one potential mechanism for cardiovascular benefits in patients with diabetes.

Disclosure
S. Sherratt: None. R. Mason: Consultant; Self; Amarin Corporation. Research Support; Self; Amarin Corporation, Amgen Inc., Novartis AG, Pfizer Inc. Speaker's Bureau; Self; Pfizer Inc.
616-P: Long-Term Statin Persistence Is Poor among High-Risk Patients with Baseline Diabetes: A Real-World Administrative Claims Analysis
Authors: TOTH PETER P. , PHILIP SEPHY , HULL MICHAEL , GRANOWITZ CRAIG B. 
Published: June 2019

Background: Statin persistence has been poor for over 2 decades, even in patients with a prior cardiovascular (CV) event. Data on longer-term statin persistence are lacking, particularly in patients with diabetes.
Methods: This retrospective administrative claims analysis (Optum Research Database) analyzed long-term data on statin persistence in patients with high CV risk by diabetes and triglycerides (TG). Patients aged ≥45 years with diabetes and/or atherosclerotic CV disease with an index date and statin prescription filled in 2010 were included. Patients with TG ≥150 mg/dL were propensity-matched to a comparator cohort with TG &lt;150 mg/dL and high-density lipoprotein cholesterol &gt;40 mg/dL. Cohorts were followed for ≥6 months to March 2016.
Results: In the elevated-TG and comparator cohorts (each n=23,181), mean follow-up was 41.4 and 42.5 months, mean age was 62.2 and 62.6 years, and 49.7% and 49.5% were female, respectively. In patients with and without baseline elevated-TG and/or baseline diabetes, statin persistence was poor, with ≤21% remaining on a prescription fill for index statin at 5 years (Figure).
Conclusions: Statin persistence remains poor, particularly in patients with high CV risk, elevated TG, and diabetes. Better public health programs and patient education initiatives on the benefits of statins and the danger of statin discontinuation are needed.

Disclosure
P.P. Toth: Consultant; Self; Amarin Corporation, Amgen Inc., AstraZeneca, Kowa Pharmaceutical Europe Co. Ltd., Novo Nordisk Inc. Speaker's Bureau; Self; Amarin Corporation, Amgen Inc., Merck & Co., Inc., Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi US. S. Philip: Employee; Self; Amarin Corporation. Stock/Shareholder; Self; Amarin Corporation. M. Hull: None. C.B. Granowitz: Employee; Self; Amarin Pharma Inc. Stock/Shareholder; Self; Amarin Pharma Inc.
618-P: Effect of Liraglutide Combined with Human Umbilical Cord Mesenchymal Stem Cells on Liver Injury of T2DM with NAFLD Rats by Mediating Toll-Like Receptor 4/Nuclear Factor-kappa B Signaling Pathway and Oxidative Stress
Authors: CHEN PIN 
Published: June 2019

Objective: To observe the effect of liraglutide combined with human umbilical cord mesenchymal stem cells on type 2 diabetes mellitus with nonalcoholic fatty liver disease rats liver injury. And then to investigate relation of the effect on the liver injury between the toll-like receptor 4/nuclear factor-kappa B inflammatory signal pathway and oxidative stress mechanism.
Methods: Animal model establishment and experimental grouping and intervention: The rats were randomly selected and divided into the following four groups: T2DM with NAFLD model group, hUC-MSCs treatment group, Liraglutide treatment group, Liraglutide combined with hUC-MSCs treatment group.
Results: 1. Rat serum levels of TNF-α, IL-6, 8-OHdG and SOD: Compared with MC+LIRA group, the levels of TNF-α, IL-6 and 8-OHdG were decreased in MC+LIRA+hUC-MSCs group (P &lt;0.05), SOD was increased (P&lt;0.05). 2. Pathological changes of rats liver tissue:Compared with MC+LIRA group, the NAS score were decreased in MC+LIRA+hUC-MSCs group (P &lt;0.05).3. Expression of TLR4 and NF-κB mRNA in rat liver tissue: Compared with MC+hUC-MSCs group, the expression of TLR4 and NF-κB mRNA were significantly decreased in MC+LIRA group and MC+LIRA+hUC-MSCs group (P&lt;0.05). Compared with MC+LIRA group, the expression of TLR4 and NF-κB mRNA were decreased in MC+LIRA+hUC-MSCs group (P &lt;0.05).
Conclusion: The mechanism of liraglutide combined with human umbilical cord mesenchymal stem cells on type 2 diabetes mellitus with nonalcoholic fatty liver disease is closely related to the down-regulation of TLR4/NF-κB inflammation pathway and oxidative stress.

Disclosure
P. Chen: None.
621-P: Cardiovascular Mortality and Orthostatic Hypotension in Type 2 Diabetic Patients (T2D) with Lower Limb Lesions—Italian Diabetic Patients' Association-Section of Treviso Project
Authors: SAMBATARO MARIA , SAMBADO LUISA , SPINETTI GAIA , SEGANFREDDO ELENA , TREVISIOL ENRICA , MARCON MARIALISA , STEFANI PIERO MARIA , FURLAN ANNA , CACCIATORE MATILDE , PACCAGNELLA AGOSTINO 
Published: June 2019

Introduction: Neuroischemic (NI) diabetic foot (DF) is an advanced complication leading to limb amputations and cardiac mortality. We contributed to demonstrate that bone marrow (BM) T2D neuropathy impairs vascular regenerative hematopoietic cell mobilization. We here hypothesize that autonomic neuropathy (DAN) and pathological orthostatic hypotension (reducing systolic and diastolic blood pressure -BP at least 30 and 10 mm Hg) convert to cardiovascular death in T2D patients with NI-DF.
Subjects and Methods: We performed DAN and postural hypotension tests in 204 surgical-treated neuropathic T2D without (87 N) or with (117 NI) critical limb ischemia (pO2 &lt;30 mm Hg). In peripheral blood (PB) (204) and BM (65) samples we evaluated: percentage of haematopoietic precursor CD34+, VEGF receptor KDR+ (PreC) and neurokinin-1 receptor on BM-CD34+ cells (BM-NK1R+preC) by flow cytometry; circulating P substance neuropeptide by ELISA.
Results: We observed 46 NI cardiac deaths (DD) and 158 alive patients (AD) after prospective 5 years. DD were older but comparable for diabetes age, BMI, HbA1c, post-revascularization oximetry and TUC lesion grade. All T2D had autonomic failure but only DD were orthostatically hypotensive (-BP -35±2 and -21± 3 mm Hg p&lt;0.01 vs. AD) with different BM/PB preC incremental ratio (8.8±4 vs. 1.5 ±0.3 106 events p&lt;0.0003 vs. AD), similar circulating P levels, reduced BM-NK1R+preC (14.5±8.5 vs. 36.4±5 % p&lt;0.04). Both -BP correlate with BM/PB preC (p&lt; 0.04) but not with BM-NK1R+preC.
Conclusions: We prospectively confirm that autonomic failure impacts on vascular homeostasis and cardiac mortality in T2D with prevalent NI-DF. Now we demonstrate that pathological orthostatic hypotension, a simple clinical measure, could contribute to persistent ischemic bone marrow signal in neuroreceptor reduced BM-derived stem cells, worsening BM vascular regenerative capacity and cardiac performance.

Disclosure
M. Sambataro: None. L. Sambado: None. G. Spinetti: None. E. Seganfreddo: None. E. Trevisiol: None. M. Marcon: None. P. Stefani: None. A. Furlan: None. M. Cacciatore: None. A. Paccagnella: None.

Funding
Italian Diabetic Patients' Association of Treviso and Oderzo
641-P: Relationship of Sarcopenia and Microcirculation Assessed by Skin Perfusion Pressure in Patients with Type 2 Diabetes
Authors: JUNG CHANHEE , CHOI DUGHYUN , KIM CHUL-HEE , MOK JI OH 
Published: June 2019

Sarcopenia is more prevalent in diabetes than controls and is related with higher cardiovascular events such as critical limb ischemia and mortality in T2DM. Microvascular dysfunction in diabetes plays a crucial role in the development of diabetic complications. Skin perfusion pressure (SPP) using laser Doppler technique is valuable in the evaluation of microcirculation function and limb ischemia. Although previous study reported that sarcopenia is independently associated with diabetic foot disease and even it is regarded as a chronic complication of T2DM, no studies have examined the relationship of sarcopenia and microcirculation. The current analysis is an attempt to evaluate the undisclosed relationship of sarcopenia and skin perfusion pressure. We analyzed the data of 188 patients with T2DM performing laser Doppler technique for measuring SPP. Sarcopenia was defined low appendicular muscle mass adjusted for height (Men &lt;7 kg/m2, women &lt; 5.7kg/m2) using bioelectrical impedance analysis. We divided into two groups based on SPP: ≤50 mmHg, &gt;50 mmHg. SPP below 50 mmHg was considered as impaired microcirculation. The mean age and SPP of total subjects were 51 years and 72 mmHg. A total of 26 patients (13.8%) were diagnosed with impaired function of microcirculation in limb on SPP. The prevalence of sarcopenia in total subjects was 8%. The prevalence of sarcopenia increased significantly in SPP ≤50 mmHg group than in SPP &gt;50 mmHg (23% vs. 5.3%, p=0.028). Significant positive correlation was found between SPP and appendicular muscle mass adjusted for height (p=0.008). Multiple logistic regression analysis showed that patients with sarcopenia had an odds ratio of 6.1 (95% CI =1.2-31.7) for having of SPP ≤50 mmHg even after adjustment for confounding factors (p=0.032). Our results suggest that the sarcopenia is significantly associated with the presence of impaired function of microcirculation on SPP in T2DM.

Disclosure
C. Jung: None. D. Choi: None. C. Kim: None. J. Mok: None.