bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of Metreleptin for Weight Loss in Overweight and Obese Adults with Low Leptin Levels
Authors: DEPAOLI ALEX , LONG ALISON , FINE GREGORY M. , STEWART MURRAY , O'RAHILLY STEPHEN 
Published: June 2018

Leptin, an adipokine, regulates appetite, glucose and fat metabolism, and neuroendocrine function. A post-hoc pooled analysis of 4 studies (N=1064) in adults with BMI 27.0-40.0 kg/m2 showed that metreleptin (MTL), a leptin analogue, reduced weight in subgroups of adults with low baseline (BL) leptin levels (Fig. 1). A subsequent study (N=267) in adults with low BL leptin (females, ≤16 ng/mL; males, ≤5 ng/mL) and BMI 27.5-38.0 kg/m2 was conducted. Subjects (64% female; mean [SD] BL leptin, 14.2 [13.3] ng/mL) received QD subcutaneous MTL 10 mg, MTL 20 mg, or placebo. Both MTL doses decreased weight over time among subjects with low BL leptin (Fig. 2). MTL 20 mg showed statistically significant decreases by week 8. MTL was well tolerated. Thus, MTL 20 mg QD holds promise for weight loss among overweight and obese adults with low leptin levels.

Disclosure
A. DePaoli: Research Support; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp. A. Long: Employee; Self; Aegerion Pharmaceuticals. G.M. Fine: Employee; Self; Aegerion Pharmaceuticals. M. Stewart: Employee; Self; Novelion. Stock/Shareholder; Self; Novelion. S. O'rahilly: Advisory Panel; Self; Aegerion Pharmaceuticals, Pfizer Inc., AstraZeneca, MedImmune, Novo Nordisk Inc., ERX Pharmaceuticals, Inc..
Influence of Diabetes Complications on the Cost-Effectiveness of A1C Treatment Goals in Older U.S. Adults
Authors: SHAO HUI , ROLKA DEBORAH B. , GREGG EDWARD W. , ZHANG PING 
Published: June 2018

The American Diabetes Association (ADA) recommends glycemic management goals for older diabetes patients take into account the complexity of complications. Little information is available on how cost-effectiveness (CE) of glycemic control goals relates to a patient’s level of complications. We examined the CE of intensive glycemic control (A1c &lt;7.5%) compared to standard treatment (A1c &lt;8.5%) among adults aged 65 y with type 2 diabetes having various complications. 2011-2016 National Health and Nutrition Examination Survey data were used to generate nationally representative samples with various complications. The CDC-RTI diabetes simulation model was used to project the long-term health and cost consequences of intensive/standard glycemic control. The CE of the intensive glycemic control was measured in costs (2017 USD) per quality adjusted life year (QALY). Based on a $50,000/QALY threshold, intensive glycemic control was only marginally cost effective for patients with no complications or any microvascular complication (excluding renal failure) but was not cost-effective for patients with one or more macrovascular complications. Current ADA standards recommend intensive glycemic control among older adults with fewer than 3 complications. From a CE perspective, our results only support the intervention among those with no complications or only microvascular complication.

Disclosure
H. Shao: None. D.B. Rolka: None. E.W. Gregg: None. P. Zhang: None.
Postmenopausal Women with Endometrial Cancer Have Greater Metabolic Dysfunction and Higher BMI than Women with Benign Endometrium
Authors: COOKE KATHERINE M. , DUN ERICA , ANAM ANIKA K. , FLANNERY CLARE 
Published: June 2018

Obesity is an independent risk factor for endometrial adenocarcinoma (EC), yet it is unknown which attributes of obesity contribute to EC pathogenesis. We hypothesize that heterogeneity in metabolic health distinguishes which obese women are at risk for EC. We previously found that more premenopausal women with pre-malignant hyperplasia had type 2 diabetes and dyslipidemia than women with benign hyperplasia (BH), despite similar BMI. BH is the ideal control condition since presenting symptoms are similar, yet malignant transformation is negligible. Thus, we sought to compare metabolic abnormalities in postmenopausal women with EC and BH. We reviewed medical records of 284 women who received a biopsy/hysterectomy at our center over 3 years. We examined non-Hispanic white women age 50-65 years with BMI 25-50 kg/m2, to limit variability in factors known to affect metabolism. 122 women had histologically confirmed EC (n=74) or BH (n=48), and 60% had lab data. Variables were analyzed by chi-squared or Student’s T test. Women with EC were older (58 ± 0.5 vs. 53 ± 0.4 years, p&lt;0.0001) and had higher BMI (37 ± 1 vs. 32 ± 1 kg/m2, p&lt;0.0001) than women with BH. BMI distribution was markedly different between groups, with a higher frequency and greater severity of obesity among women with EC (p&lt;0.0001). More women with EC than BH had type 2 diabetes (19% vs. 4%, p&lt;0.05) and hypertension (54% vs. 25%, p&lt;0.01). Women with EC had higher triglycerides (140 ± 12 vs. 110 ± 13 mg/dL, p&lt;0.05) and lower HDL (55 ± 2 vs. 60 ± 4 mg/dL, p=NS). However, these differences can be explained by the skewed BMI distribution. LDL and total cholesterol as well as statin use (20% vs. 25%) were similar between groups (p=NS). The striking differences in BMI among postmenopausal women with EC and BH highlights the role of obesity in EC pathogenesis. Since BMI affects metabolism, a prospective study of BMI-matched women is necessary to determine whether metabolic dysregulation independently influences cancer development.

Disclosure
K.M. Cooke: None. E. Dun: None. A.K. Anam: None. C. Flannery: None.
Glycation and Deamidation Result in HDL Dysfunction in Patients with Type 2 Diabetes
Authors: KASUMOV TAKHAR , GOLIZEH MAKAN , KASHYAP SANGEETA 
Published: June 2018

Diabetes is associated with HDL dysfunction and perturbed iron metabolism. ApoAI, transferrin (Trf) and ceruloplasmin (Cp) are the key HDL proteins involved in cholesterol efflux and iron metabolism. We tested the hypothesis that hyperglycemia-induced glycation contributes to HDL dysfunction and altered iron metabolism in diet-controlled patients with T2D. HDL from patients with T2D and matched healthy controls (n=9/group) was isolated and it’s anti-oxidant and cholesterol efflux properties were quantified. HDL proteome composition and post-translational modification of proteins were quantified by proteomics aproach. Metabolic 2H2O-labeling was applied to quantify HDL proteome dynamics. Patients with T2D and controls had similar lipid (triglycerides, total cholesterol, and HDL cholesterol) profile. HDL from T2D patients had reduced anti-oxidant (PON1 activity) and macrophage-cholesterol efflux capacity (P&lt;0.05) and was enriched with glycated apoAI and transferrin (Tf), and deamidated ceruloplasmin (Cp), the key HDL proteins involved in cholesterol and iron transport. Both ApoAI and Trf glycation were directly correlated with HbA1c and the extent of glycations were associated with their increased degradation. ApoAI glycation was inversely correlated with cholesterol efflux activity of HDL. Trf glycations at Lys-2and Lys-534 sites involved in iron coordination, were 2-3 fold higher in T2D than in the controls. The PTM search on Cp revealed five asparagine deamidation sites in T2D patients with N-943 being located on one of the oxidation-prone motifs and may result in the loss of Cp’s ferroxidase activity. In vivo HDL flux study demonstrated that glycated apoAI and Tf, and deamidated Cp species were degraded 3, 10, and 2 fold faster than the respective non-modified native proteins. HDL dysfunction and oxidative stress in T2D is related to glycation- and deamidation-induced instability of HDL proteins, including ApoAI, Tf and Cp.

Disclosure
T. Kasumov: None. M. Golizeh: None. S. Kashyap: None.
Estrogen-Responsive Neurons in the Ventrolateral VMH Regulate Glucose Balance
Authors: HE YANLIN , XU PINGWEN , XIA YAN , YANG YONGJIE , CAI XING , HYSENI ILIRJANA , XU YONG 
Published: June 2018

Brain glucose-sensing neurons can detect glucose fluctuations and prevent severe hypoglycemia. We observed that estrogen receptor-α (ERα)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) are all glucose-sensing neurons, being either glucose-inhibited neurons (GI-ERαvlVMH) or glucose-excited neurons (GE-ERαvlVMH). In particular, hypoglycemia inhibits GE-ERαvlVMH neurons through opening the KATP channel, and activates GI-ERαvlVMH neurons via enhanced t-type voltage-gated calcium currents. GI-ERαvlVMH neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ERαvlVMH neurons preferentially project to the dorsal Raphe nuclei (DRN); selective activation of the ERαvlVMH◊mpARH circuit and inhibition of the ERαvlVMH◊DRN circuit both increase blood glucose. Importantly, loss of estrogen-ERα signals impairs glucose-sensing properties of ERαvlVMH neurons and attenuates hyperglycemic response to the central glucopenia in female mice. Depletion of estrogen impairs the AMP kinase pathway which accounts for the reduced glucose-sensing capability of these ERαvlVMH neurons; enhanced AMP kinase activity selectively in ERαvlVMH restores the glucose response in female mice depleted of estrogen. Thus, our results indicate that estrogen-ERα-AMP kinase signals in ERαvlVMH neurons are required for these neurons to detect hypoglycemia and therefore are indispensable for defending against severe hypoglycemia in female mice.

Disclosure
Y. He: None. P. Xu: None. Y. Xia: None. Y. Yang: None. X. Cai: None. I. Hyseni: None. Y. Xu: None.
The Role of Epicardial Adipose Tissue Lymphocytes in Low-Grade Inflammation and Coronary Artery Disease
Authors: MRAZ MILOS , CINKAJZLOVA ANNA , LACINOVÁ ZDENA , KLOUCKOVA JANA , KRATOCHVILOVA HELENA , LIPS MICHAL , KOPECKY PETR , PORIZKA MICHAL , LINDNER JAROSLAV , HALUZIK MARTIN 
Published: June 2018

Lymphocytes play a role in the development of adipose tissue inflammation. Epicardial adipose tissue was shown to be a potential source of inflammatory mediators contributing to coronary atherosclerosis. The aim of the study was to assess lymphocyte content in peripheral blood, subcutaneous (SAT) and epicardial adipose tissue (EAT) in subjects with coronary artery disease (CAD) along with the effects of elective cardiac surgery. Twelve subjects without CAD (non-CAD group) and 24 age-, BMI- and HbA1C-matched subjects with CAD were included into the study. Blood, SAT and EAT samples were obtained before and at the end of elective cardiac surgery. Lymphocyte populations were quantified as percent of CD45+ cells using flow cytometry. Subjects with CAD had higher total lymphocyte (CD45+) amount in EAT compared to SAT (32.24±7.45 vs. 11.22±1.34%, p=0.025) with a similar trend observed in non-CAD subjects (29.68±7.61 vs. 10.13±2.01%, p=0.067). CD3+ cells were increased and CD3- cells decreased in EAT of CAD relative to non-CAD group with no difference between EAT and SAT. In both groups EAT showed reduced percentage of NK cells (CD15/56+CD3-) and elevated B cells (CD19+) relative to SAT (NK cells: 5.96±1.32 vs. 13.22±2.10%, p=0.012 for CAD and 5.32±1.97 vs. 13.81±2.72%, p=0.022 for non-CAD; B cells: 5.22±2.43 vs. 0.96±0.21%, p=0.039 for CAD and 12.49±5.83 vs. 1.16±0.19%, p=0.016 for non-CAD). CD8+ and NKT (CD16/56+CD3+) cells in EAT correlated positively with fasting glucose and HbA1C, while showing no association in SAT. Cardiac surgery decreased total lymphocytes in peripheral blood, SAT and EAT of both groups, while having only minor effects on lymphocyte subpopulations. To conclude, epicardial adipose tissue in subjects with CAD shows increased amount of total and CD3+ lymphocytes as compared with SAT or non-CAD subjects. These changes could contribute to the development of local inflammation and coronary atherosclerosis.

Disclosure
M. Mraz: None. A. Cinkajzlova: None. Z. Lacinov : None. J. Klouckova: None. H. Kratochvilova: None. M. Lips: None. P. Kopecky: None. M. Porizka: None. J. Lindner: None. M. Haluzik: None.
Long Noncoding RNA Zfas1 in Diabetic Cardiomyopathy
Authors: FENG BIAO , CHEN SHALI , CHAKRABARTI SUBRATA 
Published: June 2018

Fibrosis is a significant problem in diabetic cardiomyopathy (DCM). Both long noncoding RNAs (LncRNAs) and miRNAs (miR) play important roles in cellular processes. miR-9 targets important extracellular matrix(ECM) protein, such as fibronectin(FN) and collagen(Col), which are upregulated in DCM. The role of ZNFX1-AS1 (Zfas1), a LncRNA targeting miR-9 in DCM is not clear. We investigated Zfas1 in vitro and in vivo and its regulatory mechanism on ECM protein through miR-9.
Microarrays were used to examine LncRNAs and miRNAs expression in ECs exposed to 25 mM glucose (HG) compare to 5 mM glucose and were validated by qPCR. Expression of ECM proteins targeted by miR-9 were examined. Luciferase assay was used to determine the interaction between miR-9 and its target genes. Cardiac tissues from streptozotocin-induced diabetic mice were examined similarly.
The array and qPCR analysis showed glucose-induced upregulation of LncRNA Zfas1 and downregulation of miR-9 in ECs. FN mRNA, Col1&4 mRNA and protein levels were increased in ECs treated with HG. Luciferase assay showed the binding of miR-9 to FN 3’-UTR and miR-9. Zfas1 silencing expression of its target genes expression in HG. Furthermore miR-9 mimics co-transfection with Zfas1 siRNA partially recovered these ECM protein expression. Interestingly, methylation blockade also reduced ECM protein expression. In the hearts of the diabetic animals, Zfas1 expression was increased and miR-9 was decreased and expression of transcripts regulated by miR-9 were increased.
These studies indicate a novel glucose-induced mechanism of increased ECM protein production, which is regulated by Zfas1 through miR-9 in diabetes. Identifying such mechanisms may lead to potential RNA based treatment for diabetic complications.

Disclosure
B. Feng: None. S. Chen: None. S. Chakrabarti: None.
Improving Quality of the Informed Consent Process—Developing an Easy-to-Read, Multimodal, Patient-Centered Format in Diabetes Research
Authors: LINDSLEY KAREN 
Published: June 2018

Objective: To develop a patient-centered informed consent and assessment written at a 6th grade-level that is multimodal, affordable, transportable, and readily modifiable for protocol updates.
Methods: This quality improvement initiative was performed in two phases on an actively-recruiting, familial study at a pediatric diabetes multi-site clinic. In phase I, 38 subjects completed the standard paper consent, a comprehension assessment and provided process feedback. Using feedback and the structure of the Plan-Do-Study-Act cycle a multimodal consent explanation and assessment were developed. In phase II, subjects were randomized to the standard (n=25) or the multimodal consent (n=25) and all completed the same comprehension assessment via touch-screen tablet. Primary outcomes were comparison of the individual and total comprehension assessment scores.
Results: Total comprehension scores were higher in the multimodal vs. the standard consent group (p&lt;0.001) and on the elements of benefits (p&lt;0.001), risks (p&lt;0.001), volunteerism (p&lt;0.012), results (p&lt;0.001), confidentiality (p&lt;0.004) and privacy (p&lt;0.001).
Conclusion: A multimodal consent explanation and assessment presented sequentially on a touch-screen tablet were patient-centered enhancements to standard consent.

Disclosure
K. Lindsley: None.
Increased Deacetylation of Proteins in Sensory Neurons by Sirtuin 1 Protein Overexpression Reverses T2D Peripheral Neuropathy
Authors: CHANDRASEKARAN KRISH , HO CHENG-YING , SALIMIAN MOHAMMAD , KUMAR PRANITH H. , REDDY KONDURU SAI SRUTHI , RUSSELL JAMES W. 
Published: June 2018

Sirtuin1 (SIRT1) protein uses NAD+ as a substrate to deacetylate transcription factors, cofactors, and histones to enhance mitochondrial function. We tested the hypothesis whether increased expression of SIRT1 protein in dorsal root ganglion (DRG) neurons would rescue mice from peripheral neuropathy induced by a high fat diet (HFD). Neuron-specific, doxycycline (DOX)-inducible, SIRT1 protein over expressing C57BL6 transgenic mouse (nSIRT1OE Tg) were generated. Expression of SIRT1 protein was observed in small to medium sized DRG neurons. nSIRT1OE was shut off by feeding, weaned Tg mice, with DOX in the diet for 12 weeks. The Tg mice were divided into 3 groups. Group # 1: nSIRT1OE Tg mice fed with standard diet (STD) plus DOX for 4 months; Group # 2: nSIRT1OE Tg mice fed with HFD plus DOX for 4 months; Group # 3: nSIRT1OE Tg mice fed with HFD plus DOX for 2 months until they develop neuropathy and then switched to HFD minus DOX for additional 2 months. Neuropathy was determined by mechanical allodynia thresholds (MAT) and nerve conduction velocity (NCV) at 0, 2 and 4 months. Intraepidermal nerve fiber density (IENFD) was measured at 4 months. MAT, NCV and IENFD were decreased in HFD-fed (Group # 2) mice compared to STD-fed mice (Group # 1) at 2 and 4 months. In Group # 3 mice, 2 months after turning on nSIRT1OE, we observed a reversal of mechanical allodynia, NCV and attenuation of IENFD (Group # 3 compared to Group # 2). Western blot of protein extracts from DRG neurons showed that HFD increased acetylation of proteins and SIRT1OE abolished the HFD-induced acetylation of proteins. The mitochondrial bioenergetics profile of cultured adult DRG neurons showed that hyperglycemia induced a decrease in the spare respiratory capacity in wild type (WT) DRG neurons. This was corrected in nSIRT1OE Tg DRG neurons. In type 2 diabetic neuropathy, altered acetylation of proteins and reduced mitochondrial function via a defective SIRT1 pathway may contribute to developing distal axonopathy.

Disclosure
K. Chandrasekaran: None. C. Ho: None. M. Salimian: None. P.H. Kumar: None. S. Konduru: None. J.W. Russell: None.
Comparison of Cognitive Function, Depression, and Sleep Quality among Type 2 Diabetes Mellitus Patients With and Without Diabetic Neuropathy
Authors: RADHAKRISHNAN CHANDNI , CR RINU R. , SREEJITH K , ANJUSHA UT 
Published: June 2018

Diabetic neuropathy is one of the most common complication of diabetes mellitus. Many studies had reported that type 2 diabetes mellitus increases the risk of cognitive impairement,depression and sleep impairement in patients with diabetes mellitus.
The main objective of the study is to determine whether any significant impairement in cognition function, sleep quality and depression status exist among diabetic neuropathy patients compared to patients with type 2 diabetes mellitus alone. A prospective observational study was conducted in a tertiary care teaching hospital. Patients who satisfied both inclusion and exclusion criteria were included in the study. A total of 59 type 2 diabetes mellitus patients with neuropathy and 55 patients with out neuropathy were enrolled in to the study after obtaining written informed consent. Cognitive status was assessed with the help of MOCA questionnaire. Sleep quality was assessed by using pittsburgh sleep quality index questionnare and depression, by using PHQ-9 questionnaire. The diabetic neuropathic patients showed a significant impairement in cognitive status (P value 0.003), sleep quality (P value 0.000) and depression status (p value 0.000). The study concluded that diabetic neuropathy increases the risk of cognitive impairement, impairement in sleep quality and depression in type 2 diabetes mellitus patients.

Disclosure
C. Radhakrishnan: None. R.R. Cr: None. S. K: None. A. Ut: None.
Effect of Ezetimibe Add-On Therapy on Non-HDL-C in Type 2 Diabetes Subjects—A Post-Hoc Analysis of RESEARCH Study
Authors: SAKAMOTO KENTARO , KAWAMURA MITSUNOBU , TAGAMI MOTOKI , TANAKA AKIRA , MORI YASUMICHI , HIRANO TSUTOMU , SHIBA TERUO ,   RESEARCH STUDY GROUP
Published: June 2018

Background: In RESEARCH study, we demonstrated the superiority of ezetimibe add-on therapy over statin-doubling in T2DM.Non-HDL-C is attracting attention as an index including TG rich lipoproteins reflecting insulin resistance in diabetics.
Methods: 109 T2DM adults with LDL-C &gt;=120 mg/dL (&gt;=100 mg/dL in secondary preventive) despite statin treatment were randomly assigned to statin doubling group (S) or adding ezetimibe (E) for 12 weeks.As a post-hoc analysis, non-HDL-C change and TG rich lipoproteins were analyzed.
Results: The rate of non-HDL-C reduction was significantly greater in E(20.9%) than in S(8.3%). Assuming the non-HDL-C target as &lt;150 mg/dl (&lt;130 mg/dl for secondary preventive), the achievement rate was significantly higher in E(88.7%) than in S(57.1%). The rates of apoB and apoE reduction were significantly larger in E (apoB 14.8% and apoE 7.7%) than in S (apoB 9.0% and apoE 2.9%). By regression analysis, apoE change rate showed correlation with sd-LDL change rate or RLP-C change rate, respectively, with larger correlation and regression coefficient in E. The percentage change in non-HDL-C was correlated with the percentage change in sd-LDL, with larger regression coefficient in E. Analysis was also made for 43 subjects with TG&gt;=150 mg/dl before treatment, and 73 subjects without achievement in the non-HDL-C target before treatment. Non-HDL-C reduction rates were greater in E (21.1% and 25.1%) than in S (8.9% and 8.7%), respectively. Target achievement rates were also significantly larger in E (77.8% and 83.9%) than in S (48.0% and 42.9%). ApoB reduction was 13.2% and 11.6% in S, and 12.5% and 17.1% E, and apoE reduction was 9.4% and 5.4% in S and 13.0% and 9.4% in E, respectively. The correlation of change rates showed almost the same tendency compared to the whole population.
Conclusion: Ezetimibe combination therapy effectively reduced non-HDL-C reflecting TG rich lipoproteins, compared with statin-doubling therapy.

Disclosure
K. Sakamoto: None. M. Kawamura: None. M. Tagami: None. A. Tanaka: Research Support; Self; Daiichi Sankyo Company, Limited. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., Kewpie Corporation. Y. Mori: None. T. Hirano: Speaker's Bureau; Self; Novo Nordisk Inc., AstraZeneca. T. Shiba: Speaker's Bureau; Self; Shionogi & Co., Ltd., Pfizer Inc., Merck Sharp & Dohme Corp., Kowa Company, Ltd., Daiichi Sankyo Company, Limited.