bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low Income Predicts Mortality Independently from the Presence of Type 2 Diabetes and Preexisting Coronary Artery Disease
Authors: SAELY CHRISTOPH H. , VONBANK ALEXANDER , HEINZLE CHRISTINE , ZANOLIN DANIELA , LARCHER BARBARA , MADER ARTHUR , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ 
Published: June 2018

A low socioeconomic status has been associated with increased mortality. Whether low income predicts mortality risk independently from the presence of type 2 diabetes (T2DM) and preexisting coronary artery disease (CAD) is not known and is addressed in the present study. We assessed the annual net income through a standardized questionnaire in a consecutive series of 438 patients referred to coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD). Prospectively, we recorded mortality over a mean follow-up period of 10.0±2.3 years. Annual net income was &lt;€20.000 in 58.0%, €20.000-35.000 in 33.1% and &gt;€35.000 in 8.9% of our patients. It was significantly lower in women (&lt;€20.000 in 70.4%, €20.000-35.000 in 25.6%, &gt;€35.000 in 4.0%) than in men (&lt;€20.000 in 53.0%, €20.000-35.000 in 36.1%, &gt;€35.000 in 10.9%; p&lt;0.001) but did not differ significantly between patients with T2DM (n=116) and nondiabetic subjects (p=0.147) nor between patients with CAD (n=353) and those who did not have CAD at angiography (p=0.391). During follow-up, mortality significantly increased with decreasing income: it was 7.7%, 17.9%, and 25.6% in patients with net incomes of &gt;€35.000, €20.000-35.000 and &lt;€20.000, respectively; p=0.009). Annual net income significantly predicted the incidence of cardiovascular events both univariately (HR 0.59 [0.41-0.85]; p=0.004) and after adjustment for age, gender, smoking, LDL cholesterol, HDL cholesterol, hypertension, BMI, waist circumference, T2DM and angiographically determined baseline CAD (HR 0.61 [0.40-0.96]; p=0.033). We conclude that a low net income predicts cardiovascular event risk independently from the presence of T2DM and preexisting CAD.

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.
Hypoglycemia and Glycemic Variability in Singaporean Subjects with Type 1 Diabetes
Authors: YUNG KOH ANGELA FANG , FUN SHARON N. , YEOH ESTER 
Published: June 2018

Tight glycemic control in type 1 diabetes (T1D) is limited by hypoglycemia, while glycemic variability (GV) confers independent risk for the development of diabetes-related complications. We aimed to establish the values for indices of hypoglycemia and GV in T1D Singaporean subjects. One-hundred and thirty one subjects (73% Chinese, 11% Malay, 12% Indian; 48% male) were recruited from a single center. Eighty subjects submitted glucose records performed over 4 weeks. Ryan lability index and HYPO score were calculated in subjects with at least 3 glucose readings/day. Key characteristics, indices of hypoglycemia and GV are summarized in the table.
Hypo score and LBGI were significantly correlated (r=0.63). ADRR and mLI correlated with each other (r=0.79), and with LI (ADRR r=0.72, mLI r=0.93), S.D.(r=0.78 and 0.79), %CV (r=0.45 and 0.56) and HbA1c (r=0.53 and 0.44). LI correlated with S.D. (r=0.58) but not %CV or HbA1c
Our results indicate differences compared to other populations. There were fewer subjects with hypoglycemia than Edmonton (85%), or Korean T1D subjects (71%), with much lower Hypo scores in our cohort (90th percentile of 76 vs. 1047 in Edmonton and 377 in Korean subjects). Ryan LI was comparable to the Edmonton cohort, but ADRR, LI and mLI were lower than Korean T1D subjects. Population-specific values should be established, to determine appropriate cut-offs for access to treatments such as islet transplantation.
Clinical characteristics and glycemic indicesCharacteristicResultsGlycemic parametersResultsHypoglycemia awareness ScoresResultsGlycemic variability IndicesResultsAge of diagnosis, years19 (12 – 27)Average HbA1c (%)8.2 (7.3 – 9.2)Clarke score ≥424.6%Average daily risk range (ADRR) (n=53)Median (Interquartile range), 90th percentile25.0 (17.7 – 37.0), 40.6Duration of diabetes, years14 (8 – 19)Average Glucose (mmol/L)9.2 (8.0 – 11.2)Gold score ≥428.3%Ryan lability index (n843)Median (Interquartile range), 90th percentile168.5 (93.3 – 333.6), 432.8Insulin use (units/kg/day)0.77 (0.61 – 0.91)S.D. (mmol/L)4.4 (3.5 – 5.2)Hypoglycemia IndicesRyan lability index/no. of BG readings/day (modified Li, mLI)Median (Interquartile range), 90th percentile44.6 (27.0 – 63.1), 83.7Type of insulin regimen (twice daily, 3 times/day, 4 or more/day, insulin pump) (%)6.5/17.7/59.7/16.1%CV37.9 (9.9 – 44.5)Ryan Hypo score (n=43)Median (Interquartile range), 90th percentile 13 (0 – 25), 76Low blood glucose index (LBGI) (n=80)Median (Interquartile range), 90th percentile1.1 (0.5 - 2.1), 3.5% patients with at least 1 episode of hypoglycemia &lt; 3 mmol/L38.8

Disclosure
A. Koh: None. S.N. Fun: None. E. Yeoh: None.
The Exocyst Complex in Insulin-Stimulated Glucose Uptake in Skeletal Muscle Cells
Authors: FUJIMOTO BRENT , LEE AMANDA , WONG ADRIAN M. , CARTER LAMAR T. , FOGELGREN BEN , POLGAR NOEMI 
Published: June 2018

Objectives: Skeletal muscle cells are responsible for 80-90% of the insulin-induced glucose uptake in the body. Insulin activation of muscle cells triggers a signaling cascade that results in the exocytosis of membrane-bound glucose transporter type 4 (GLUT4) to the plasma membrane. The eight-protein complex called the exocyst is recognized as having an essential role in the insulin-induced exocytosis of GLUT4 vesicles in cultured adipocytes. We hypothesize that Sec10, a central component of the exocyst complex, is essential for the insulin-induced exocytosis of GLUT4 vesicles in skeletal myoblasts and that the exocyst is a master regulator of glucose homeostasis in metabolic tissues.
Methods/Results: To analyze exocyst-mediated intracellular trafficking in skeletal muscle in vitro, we used L6 GLUT4-myc rat skeletal myoblasts, and CRISPR/Cas9 to create Sec10 knockout (Sec10-KO) clones from these cells. Immunofluorescent staining shows co-localization of exocyst Sec10 and GLUT4 upon insulin signal in L6 myoblasts. Cellular fractionation reveals that GLUT4 delivery to the plasma membrane in response to insulin is impaired in Sec10-KO cells. Also, glucose uptake rates are significantly decreased in Sec-10-KO L6 myoblasts compared to wild type cells upon insulin stimulus. We have also generated a tamoxifen-activated skeletal muscle-specific Sec10-knockout mouse strain to assess the exocyst’s role in glucose homeostasis in vivo. Sec10 knockout mice demonstrate impaired glucose tolerance compared to littermate controls.
Conclusion: Based on our findings, Sec10 and the exocyst are necessary for insulin stimulated glucose uptake in skeletal muscle. Ongoing work will further investigate the molecular mechanism of exocyst-mediated GLUT4 trafficking in skeletal muscle.

Disclosure
B. Fujimoto: None. A. Lee: None. A.M. Wong: None. L.T. Carter: None. B. Fogelgren: None. N. Polgar: None.
Association of ATF5 Gene with Metabolic Syndrome and Insulin Resistance in Mediterranean Populations
Authors: HAYDAR SARA , GRIGORESCU FLORIN , LAUTIER CORINNE , NORMAND CHRISTOPHE , HADI JEAN CHRISTOPHE , VINTILA MADALINA , GHEORGHIU MONICA , FOUNTAS ATHANASIOS , TSATSOULIS AGATHOCLES , COPOLA ANDREA , LAURO DAVIDE , YLLI DORINA , YLLI AGRON , BRUGNARA LAURA , HANZU FELICIA , GOMIS RAMON 
Published: June 2018

Insulin resistance (InsR) characterizes the metabolic syndrome (MetS) for which many genes were involved by GWAS. To further explore genetic susceptibility involving rare SNPs with major effect we genotyped patients from MEDIGENE collection using Affymetrix MEDISCOPE chip. Screening of French, Romanians and Albanians in Italy and Greece (n = 605) for metabolic pathways detected a new SNP associated with MetS in exon 3/4 of ATF5 (activating transcription factor 5) gene (Chr19q13.33). Genuine association was completed by imputation (BEAGLE4.1) at 1000 Genome Project adding new 6 SNPs and submitted to sliding window (SW) procedure for haplotypes detection. The strong association signal was found for rs61742136 with MetS (P &lt; 1.8x10-7, Bonferroni 2.7x10-6, OR 9.37, 95% CI[3.3-26.8]), InsR (P &lt; 0.00049, OR 3.4, 95% CI[1.7-8.4]) and with HOMA index (P &lt; 0.023). Among MetS components, the strongest association concerned high blood pressure (HBP) (P &lt; 2.1x 10-4, OR 4.8, 95% CI[1.8-12.4]) while HDL, TG and obesity were associated with OR &lt; 3. In women, MetS association signal was much stronger with OR 10.9, 95% CI[3.2-36.6] (P &lt; 8.5x10-7). SW detected associated haplotypes between 3 to 8 SNPs, the best value being that of ATGGGGTC haplotype with OR 12.2, 95% CI[3.2-46.65] (P &lt; 1.98 x10-7, Bonferroni 1.13x10-5). Association of rs61742136 was replicated in MEDIGENE cohort (n = 948) with MetS, albeit with P &lt; 2.0x10-3 (Bonferroni 0.026) and solely with low HDL (P &lt; 0.05). Other SNPs were associated with HBP (rs75273180 and rs1152230 with P &lt; 0.03 and 0.04, respectively) and with potential interactions in Haploreg V4 database. Overall fixation index (Fst = 0.001) indicates a minimal differentiation suggesting adaptive selection in Mediterranean populations. This is a first time report of implication of ATF5 in MetS and gives a new insight on its pathogenesis in view of this CREB valine/leucine zipper transcriptional factor in stress-induced anti-apoptosis or neuroprotective effects.

Disclosure
S. Haydar: None. F. Grigorescu: None. C. Lautier: None. C. Normand: None. J. Hadi: None. M. Vintila: None. M. Gheorghiu: None. A. Fountas: None. A. Tsatsoulis: None. A. Copola: None. D. Lauro: None. D. Ylli: None. A. Ylli: None. L. Brugnara: None. F. Hanzu: None. R. Gomis: None.
HLA Genotype in Ketosis-Prone Type 2 Diabetes
Authors: SHIMADA AKIRA , OIKAWA YOICHI , SATOMURA ATSUSHI , HAISA AKIFUMI 
Published: June 2018

In ketosis prone type 2 diabetes with A-beta+ phenotype (= autoantibodies absent, beta cell function present; KPD), we found insulin peptide reactive T cell response, and reported in ADA meeting 2017. This time, we examined not only T cell response but also HLA genotype because characteristics of HLA in KPD is unknown. This study was approved by institutional review board. Peripheral blood was obtained from enrolled subjects with informed consent, and stimulated with insulin peptides (insulin B9-23, B10-24, B11-25, B12-26) for 24 hours, then IFN-gamma spots were counted (duplicate). Forty three point three percent (13 out of 30) of KPD (28 male, 2 female, mean age 41.1 years, mean duration 2.6 years) was found to be positive for the spots; we confirmed the previous data even we increased the patient numbers. This was similar level in acute onset type 1 diabetes (=T1D, 45.3% (24 out of 53), 19 male, 34 female, mean age 45.7 years, mean duration 5.7 years), but only 1 out of 35 (0.03%) was positive in controls (26 male, 9 female, mean age 61.8 years). On the other hand, the frequency of susceptible HLA in Japanese type 1 diabetes (DRB1*04:or DRB1*09:01) examined was 39.1% in KPD, 89.4% in T1D, and 45.7% in controls (KPD vs. T1D, p&lt;0.001). Moreover, frequency of protective HLA in type 1 diabetes (DRB1*15:01 or DRB1*15:02) was 21.7% in KPD, 2.1% in T1D, and 20.0% in controls (KPD vs. T1D, p&lt;0.05). Therefore, although insulin peptide T cell response was detected in KPD as same degree in T1D, characteristics of HLA genotype in KPD was different from T1D. These results suggest that even though autoreactivity exists in KPD, “less susceptible” and “protective” HLA genotype of type 1 diabetes in KPD may contribute to the suppression of the disease progression, and may explain the different clinical course after onset of ketoacidosis between KPD and T1D.

Disclosure
A. Shimada: Speaker's Bureau; Self; Eli Lilly and Company, Sanofi-Aventis, Novo Nordisk A/S. Y. Oikawa: None. A. Satomura: None. A. Haisa: None.
Correlations of Type 2 Diabetes Mellitus with Gastrointestinal Related Tumor Markers and Tumor Recurrence Risk
Authors: CHEN MING , YANG SHAOLING , LI NAN , WANG YANRU , XU LU , DONG JIAQI , ZHOU XUE , LI HONG , QU SHEN 
Published: June 2018

The relationship of type 2 diabetes mellitus (T2DM) with the prognosis of gastrointestinal (GI) tumor remains unclear. Here we studied the correlations of T2DM with GI related tumor markers and recurrence risk among 370 patients with gastric cancer and colorectal cancer underwent radical surgery in our hospital from 2011 to 2014. Recurrence was evaluated during postoperative follow-up till 2017. The differences in GI related tumor markers (CEA, CA199, CA724, CA50 and CA242) between T2DM and non-DM group were compared. The correlation of T2DM with GI tumor recurrence risk were analyzed using Cox regression analysis. Moreover, patients with T2DM were divided into subgroups according to duration (0-5 years, 6-10 years, and &gt;10 years) and HbA1c (&lt;6.5%, 6.5-7.49%, and ≥7.5%). Of 370 patients, 68 (18.4%) were type 2 diabetics. After a median follow-up time of 47 months, 76 cases (30.7%) had recurrence. The CEA (Ln-transformed, 1.89±1.37 vs. 1.06±1.20, P&lt;0.001), CA199 (2.68±1.57 vs. 2.43±1.30, P=0.021) and CA724 (1.66±1.47 vs. 1.01±1.08, P=0.001) in T2DM group were remarkably higher than those in non-DM group, and no significant differences were observed in CA50 and CA242 between two groups (P&gt;0.05); FPG was positively correlated with CEA (r=0.182, P&lt;0.001) and CA199 (r=0.143, P=0.007). Univariate Cox regression analysis indicated that the recurrence risk was positively correlated with T2DM, age, BMI, CEA, CA199, CA724, TNM stages, lymphatic metastasis, perineural invasion (all P&lt;0.05), which increased with the increases in T2DM duration (OR1=1.738, OR2=2.314, OR3=3.325, all P&lt;0.05) and HbA1c (OR1=1.909, OR2=2.331, OR3=2.362, all P&lt;0.05). Besides, multivariate analysis revealed that T2DM remained the independent risk factor of recurrence after adjusting the above confounding factors (OR=1.701, 95% CI: 0.980-2.951, P=0.039). Hence, T2DM contributes to higher levels of CEA, CA199, CA724 and increased recurrence risk of GI tumor in China.

Disclosure
M. Chen: None. S. Yang: None. N. Li: None. Y. Wang: None. L. Xu: None. J. Dong: None. X. Zhou: None. H. Li: None. S. Qu: None.
Deletion of REDD1 Prevents Hyperglycemia-Induced Reactive Oxygen Species Accumulation and Retinal Cell Death
Authors: MILLER WILLIAM P. , TORO ALLYSON , DENNIS MICHAEL D. 
Published: June 2018

Apoptosis of retinal neurons is accelerated by diabetes and the onset of increased cell death occurs early in disease progression. The present study was designed to evaluate molecular defects that contribute to diabetes-induced neuroretinal apoptosis and visual dysfunction. We recently demonstrated that the stress response protein REDD1 is induced by hyperglycemia in the retina of diabetic mice in a manner that contributes to neuronal cell death and visual dysfunction. One potential mechanism whereby REDD1 promotes neuronal apoptosis is through upregulation of reactive oxygen species (ROS), as the protein forms a pro-oxidant complex. In the retina of streptozotocin-induced diabetic mice, ROS levels, neuronal cell death, and REDD1 expression were increased concomitant with attenuation of contrast sensitivity thresholds, as assessed by behavioral optomotry. In R28 retinal cells in culture, hyperglycemic conditions increased REDD1 expression, ROS levels, and cell death. However, addition of the antioxidant N-acetyl-L-cysteine (NAC) to culture medium was sufficient to prevent the increase in ROS and cell death in response to hyperglycemic conditions. Moreover, REDD1-deficient cells did not exhibit increased ROS or cell death in response to hyperglycemic conditions. Similarly, in REDD1-deficient diabetic mice, ROS levels and cell death in retina were similar to that observed in nondiabetic mice. Finally, oral administration of NAC improved contrast sensitivity in diabetic mice relative to vehicle treated diabetic controls, demonstrating a key role for ROS levels in diabetes-induced visual dysfunction. Overall, the findings support therapeutic approaches targeting REDD1 and ROS production in the prevention of diabetes-induced visual dysfunction.

Disclosure
W.P. Miller: None. A. Toro: None. M.D. Dennis: None.
Elevated Nonesterified Fatty Acids (NEFA) Are Associated with Blunted Hyperglycemia-Induced Increments in Brain Glucose Levels
Authors: LAM WAI , JIANG LIHONG , BUTRICO GINA MARIE , CLINE GARY , RANGEL ELIZABETH SANCHEZ , HAMZA MUHAMMAD , PARIKH LISA , BELFORT-DEAGUIAR RENATA , ROTHMAN DOUGLAS L. , MASON GRAEME F. , SHERWIN ROBERT , HWANG JANICE 
Published: June 2018

Recently, we have demonstrated that obesity and T2DM are associated with blunted brain glucose transport capacity during acute hyperglycemia in humans, which was also associated with higher total NEFA levels. Palmitic acid has been shown in vitro to suppress brain glucose uptake by downregulating GLUT1 expression in brain endothelial cells. Thus, this current study was undertaken to determine whether specific NEFA composition is associated with blunted human brain glucose transport capacity. Plasma NEFA composition was assessed using Gas-Chromatography Mass-Spectroscopy in 8 healthy lean (HC) (4F/4M, age 33±11 years, BMI 23±2 kg/m2, HbA1C 5.0±0.2), 10 obese (OB) (6F/4M, age 34±11 years, BMI 39±6 kg/m2, HbA1C 5.3±0.3), and 6 T2DM individuals (5F/1M, age 52±5 years, BMI 33±2 kg/m2, HbA1C 9.5±1.3) at the end of a 2-hour hyperglycemic clamp (220mg/dl) and correlated with previously measured changes in intracerebral glucose levels. Blunted rise in brain glucose levels was observed in OB and T2DM vs. HC individuals (p&lt;0.05). Plasma long-chain non-esterified fatty acids (LCFA) including saturated (myristic acid, palmitic acid, stearic acid), monounsaturated (palmitoleic acid, oleic acid) and polyunsaturated (linoleic acid, an essential fatty acid) were different across all 3 groups (p&lt;0.05). Moreover, these LCFAs negatively correlated with hyperglycemia-induced change in brain glucose levels (myristic r=-0.45; p=0.03, palmitic: r=-0.49, p=0.02; stearic r=-0.44, p=0.04; palmitoleic r=-0.49, p=0.02; oleic r=-0.49, p=0.02; linoleic r=-0.41, p=0.05). Our results demonstrate an inverse relationship between elevated LCFA levels and blunted brain glucose uptake in humans, which appears to be non-specific for NEFA composition. As the ability to transport glucose into the brain is crucial for energy homeostasis, these findings highlight a potential role for NEFAs to modulate brain glucose transport and metabolism and in turn cognitive function.

Disclosure
W. Lam: None. L. Jiang: None. G. Butrico: None. G. Cline: None. E. Sanchez Rangel: None. M. Hamza: None. L. Parikh: None. R. Belfort-DeAguiar: Research Support; Self; GlaxoSmithKline plc.. D.L. Rothman: None. G.F. Mason: Consultant; Self; UCB, Inc., Sumitomo Dainippon Pharma Co., Ltd. R. Sherwin: Other Relationship; Self; QuintilesIMS, MannKind Corporation. Research Support; Self; Regeneron Pharmaceuticals, Inc.. Other Relationship; Self; ICON plc.. J. Hwang: None.
Epsin Deficiency Promotes Lymphangiogenesis through Regulation of VEGFR3 Degradation in Diabetes
Authors: CHEN HONG 
Published: June 2018

Lymphangiogenesis occurs in adult tissues of chronic complex diseases, including diabetes. Whether lymphangiogenesis is altered owing to diabetic complication remains unknown. VEGF-C/VEGFR-3 signaling axis fuels the growth of lymphatic vessels. How VEGF-C/VEGFR3 signaling is regulated under pathological conditions, such as diabetes, however, is poorly understood. Here, we report that mice with inducible lymphatic endothelial cell-specific deficiency of epsins 1 and 2 (LEC-iDKO) display enhanced lymphangiogenesis compared to wild type (WT) in diabetic condition. A profound increase in VEGF-C-induced lymphatic vessel growth is exhibited in corneas and subcutaneous Matrigel implanted in diabetic LEC-iDKO mice compared to diabetic WT mice. Conversely, lymphatic endothelial cells isolated from diabetic WT mice show marked impairment in proliferation, migration, and tube formation in response to VEGF-C relative to those from diabetic LEC-iDKO in vitro. Mechanistically, reactive oxygen species (ROS) generated from hyperglycemia induces c-Src-dependent VEGFR3 phosphorylation independent of VEGF-C, which parallels c-Src-dependent epsin upregulation through the transcription factor AP-1. Heightened epsin expression induced by ROS facilitates epsin binding to VEGFR3 within Golgi compartment, promoting degradation of newly synthesized VEGFR3, and progressively reducing availability of VEGFR3 at the cell surface. Consequentially, lymphatic-specific epsin loss strengthens insufficient lymphangiogenesis and improves the resolution of tail edema in diabetic mice. Collectively, our data indicate that inhibiting epsin expression protects VEGFR3 against degradation and ameliorates diabetes-triggered downregulation of lymphangiogenesis, providing a plausible original therapeutic strategy to treat diabetic complication.

Disclosure
H. Chen: None.
Disruption of the Autophagy-Regulatory Becn1-Bcl2 Complex Impairs Insulin Storage and Secretion in Mice
Authors: YAMAMOTO SOH , WANG NAN , ZHANG WEIRAN , HE CONGCONG 
Published: June 2018

Autophagy, a stress-induced lysosomal degradation pathway, has thought to exert similar metabolic effects in different organs. Yet the function and tissue-specific requirement of autophagy in metabolic regulation remain enigmatic. Here we establish a new model in which autophagy plays different roles in insulin-producing β cells vs. insulin-responsive cells, utilizing a point mutant (Becn1F121A) mouse model manifesting constitutively active autophagy under non-autophagy-inducing conditions. In response to high-fat diet challenge, we found unexpectedly that the autophagy-hyperactive mice show impaired glucose tolerance, but improved insulin sensitivity, compared to mice with normal levels of autophagy. We further demonstrated that autophagy hyperactivation increases insulin sensitivity in insulin-responsive cells, but decreases insulin load and secretion by sequestrating and degrading secretory vesicles containing insulin granules in β cells, a process we characterized as vesicophagy. The reduction in insulin secretion was not due to islet degeneration; instead, the β cell mass was expanded in the mutant mice, suggesting higher β cell regeneration. The reduction in insulin storage, insulin secretion, and glucose tolerance in autophagy-hyperactive mice can be reversed by transient treatment of an autophagy-blocking ULK1 kinase inhibitor. Thus, we conclude that β cells and insulin-responsive tissues require different levels of autophagy for their optimal functions. Importantly, our findings suggest that acute or intermittent, rather than chronic, activation of autophagy should be considered in therapeutic development against type 2 diabetes, to improve insulin sensitivity without negatively affecting insulin secretion.

Disclosure
S. Yamamoto: None. N. Wang: None. W. Zhang: None. C. He: None.