bluuebunny/crossref_metadata_2025_split huggingface dataset:
Significant Bone Loss in Obese Patients with Acanthosis Nigricans after LSG—One-Year Follow-Up Study
Authors: ZHANG YOUYANG , ZHANG ZHIYIN , ZHU CUILING , SUN SIQI , YIN YING , CUI RAN , SHENG HUI , QU SHEN 
Published: June 2018

The aim of the study was to investigate the longitudinal bone mineral density(BMD) and bone metabolic related markers changes in obese patients with acanthosis nigricans (AN) and without AN(OB) after Laroscopic Sleeve Gastrectomy (LSG). 41 obese patients (AN group:n=29,OB group:n=12) were recruited in this study. Areal BMD (aBMD) and lumbar spine volumetric BMD (vBMD)were measured by dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT). Insulin and markers of bone metabolism including 25-OHD, calcium, intact parathyroid hormone (iPTH), osteocalcin (OC), and type I collagen cross-linked C-terminal telopeptide (CTX) ] were assessed; Insulin area under the curve(AUCins) and HOMA-IR were computed. Results showed that the AN group had a higher fasting serum insulin (42.80±28.52 vs. 22.55±8.94mU/L,p=0.006), AUCins (522.42±280.32 vs. 263.87±195.75mU/L,p=0.008)and BMI(40.6±5.1 vs. 36.7±4.1kg/m2,p=0.024) compared to the OB group at baseline. The both groups did a obvious decrease in HOMA-IR after LSG; In AN group, there was a significant decrease in Lumbar vBMD(-4.4%,p=0.011), pelvic aBMD (-6.48%,p&lt;0.001) and femoral neck aBMD (-6.7%,p=0.045) after LSG compared with baseline, whereas no detectable BMD changes in the OB group. CTX and OC increased in both AN (97.69%,79.65%,respectively)and OB(115.21%,62.28%,respectively) groups; No significant alteration of 25-OHD, serum calcium, or iPTH was observed.
In conclusion, Insulin resistance was improved, and bone turnover was activated one year after LSG in both groups, but the bone loss was more likely to occur in the obese patients with acanthosis nigricans.

Disclosure
Y. Zhang: None. Z. Zhang: None. C. Zhu: None. S. Sun: None. Y. Yin: None. R. Cui: None. H. Sheng: None. S. Qu: None.
Increased Bile Acids and FGF-19 after Sleeve Gastrectomy and Roux-en-Y Gastric Bypass Correlate with Improvement in Type 2 Diabetes in a Randomized Trial
Authors: MURPHY RINKI , NEMATI REZA , DOKPUANG DECH , LU JUN 
Published: June 2018

Background: Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), are both effective bariatric procedures to treat type 2 diabetes (T2DM) and obesity. The contribution of changes in bile acids (BAs) and fibroblast growth factor19 (FGF-19) to such metabolic improvements is unclear.
Methods: We examined associations between changes in BAs, FGF-19 (fasting and prandial), with changes in body weight, glycemia and other metabolic variables in 61 obese patients with T2DM before and one year after randomisation to SG or RYGB.
Results: Weight loss and diabetes remission (defined by HbA1c &lt;39mmol/mol [&lt;5.7%] in absence of glucose lowering therapy) after RYGB and SG was similar (mean weight loss -29kg vs. -31kg, p=0.50; diabetes remission proportion 37.5% vs. 34%, p=1.0). Greater increments in fasting and prandial levels of total, secondary and unconjugated BAs were seen after RYGB than SG. Fasting and prandial increases in total (r=-0.3, p=0.01; r=-0.2, p=0.04), secondary (r=-0.3, p=0.01; r=-0.4, p=0.01) and unconjugated BA (r=-0.3, p=0.01; r=0.4, p&lt;0.01) correlated with decreases in HbA1c, but not weight. Changes in 12α-OH/non 12α-OH were positively associated with prandial glucose increments (r=0.2, p=0.03), HbA1c (r=0.3, p=0.01) and negatively associated with changes in insulinogenc index (r=-0.3, p=0.01). Only changes in prandial FGF-19 were negatively associated with HbA1c (r=-0.4, p&lt;0.01) and visceral fat (r=-0.3, p=0.04).
Conclusions/Interpretation: The modest association between increases in secondary, unconjugated BAs and improvements in HBA1c, (but not weight) achieved after both RYGB and SG suggest augmentation of BA signalling as one potential strategy for controlling T2DM through weight independent means.

Disclosure
R. Murphy: None. R. Nemati: None. D. Dokpuang: None. J. Lu: None.
Lactational Programming of Offspring Glucose Homeostasis and Body Composition by Early Postnatal Metformin Exposure
Authors: GREGG BRIGID 
Published: June 2018

Background: The early postnatal period is a critical window for programming of long-term metabolic health. Our previous studies have shown that gestational metformin exposure increases pancreatic beta-cell fraction at birth and improves glucose homeostasis in adulthood.
Hypothesis: We hypothesized that metformin administration to dams during the critical window of lactation would alter neonatal nutrient exposure and the acquisition of the gut microbiome from the mother leading to a permanent change in offspring metabolic tissues.
Methods: We used C57BL/6J mice for the developmental programming studies in this experiment. Metformin was delivered in drinking water to dams from postnatal day 1 (P1) and continued through the lactation period to P21 (Met PN group). Offspring were examined during lactation and as adults. Dams were examined during lactation and upon weaning. Gut microbe composition was determined by 16s sequencing in dams and offspring.
Results: Dams on metformin showed improved glucose tolerance at weaning. Met PN pups had lower body weights that began during the first 3 weeks of life and persisted to 6 months. On intraperitoneal glucose tolerance testing male but not female offspring had improved glucose responses at 2 months and increased glucose stimulated insulin secretion. Met PN offspring had a lower body fat percentage at necropsy. Stool microbiome studies showed that Met PN pups had an altered intestinal colonization that persisted into adulthood with an increase in the bacteroidetes:firmicutes ratio at the time the lower weight trajectory was established. A lower bacteroidetes:firmicutes ratio has been associated with obesity.
Conclusions: These findings suggest that limited early postnatal exposure to a dam on metformin results in long-term programming of offspring weight, insulin secretion and intestinal microbiome.

Disclosure
B. Gregg: None.
Caveolin-1 Deficiency Inhibits Palmitate-Induced Intracellular Lipid Accumulation and Enhances Autophagy in Pancreatic ß Cells via AMPK/mTOR Pathway
Authors: ZENG WEN , LIU KUNYING , TANG JIANSONG , PENG HANGYA , LIN CHUWEN , LIN SHUO , LIN KEYI , JIANG YAN , ZENG LONGYI 
Published: June 2018

Lipotoxicity induced intracellular lipid accumulation in pancreatic β cells, one of the strongest predictors for T2DM. The objective of this study is to explore the role of Cav-1 in intracellular lipid accumulation of β cells under lipotoxicity condition. Our data showed that Cav-1 silencing significantly reduced PA-induced intracellular triglyceride (TG) accumulation, enhanced autophagy and insulin secretion in NIT-1 cells and murine pancreatic islets. Further investigation found that Cav-1 depletion facilitated AMPK phosphorylation, decreased the expression of downstream lipogenic makers (SREBP-1c, FAS and ACC) and increased the expression of fatty acid oxidation maker (CPT-1), leading to the ultimate enhancement of lipid metabolism. Meanwhile, Cav-1 depletion also suppressed mTOR phosphorylation, decreased the expression of p62 protein and increased the expression of LC3-II proteins, resulting in the ultimate increase of autophagy. Subsequent inhibition of AMPK and mTOR pathways abolished Cav-1 depletion mediated autophagy enhancement and TG content reduction, leading to the reduction of insulin secretion. Our findings suggest the potential application of the Cav-1 molecule as a target for effective T2DM treatment through preservation of lipotoxicity-induced β-cell intracellular lipid accumulation and dysfunction.

Disclosure
W. Zeng: None. K. Liu: None. J. Tang: None. H. Peng: None. C. Lin: None. S. Lin: None. K. Lin: None. Y. Jiang: None. L. Zeng: None.
Liraglutide Inhibits Endoplasmic Reticulum Stress in Pancreatic Beta Cells via Regulation of the Homeodomain Transcription Factor Nkx6.1
Authors: LI YUKUN , DONG YANAN , SHILUN LI , XUE PENG 
Published: June 2018

The GLP-1 mitigates the endoplasmic reticulum (ER) stress in β cells. Nkx6.1 plays an important role in the development and survival of β cells. This study aims to investigate the relation of Nkx6.1 and liraglutide in the protection effect of endoplasmic reticulum stress in INS-1-3 cells. INS-1-3 cells were divided into different groups for treatment: control group, thapsigargin (TG)-treated group, TG and GLP-1 co-treated group. Knockdown of Nkx6.1 was established by lentivirus infection. RT-PCR was used to verify the expression changes of target genes. MTT and flow cytometry analysis were used to detect cell viability and apoptosis rates. Glucose stimulates insulin secretion (GSIS) was used to measure β cell function. In TG-treated cells, liraglutide significantly increased cell viability and GSIS by 1.53 and 1.89 folds. These were associated with the suppression of the PERK, IRE1 and ATF-6 pathways. Knock down of Nkx6.1 partially diminished protective effect of liraglutide. The cell viability and GSIS were decreased by 24.7% and 54.0%. And both of the early and late apoptosis were increased by 1.55, 1.10 folds. Liraglutide protected INS-1-3 cells from TG-induced ER stress by suppressing the PERK, IRE1 and ATF-6 pathways. And its protective effects on ER stress was partially via transcription factor Nkx6.1.

Disclosure
Y. Li: None. Y. Dong: None. L. Shilun: None. P. Xue: None.
Effects of Extra Virgin Olive Oil Polyphenols on Pancreatic Beta-Cell Function and Survival
Authors: NATALICCHIO ANNALISA , SPAGNUOLO ROSARIA , MARRANO NICOLA , BIONDI GIUSEPPINA , DIPAOLA LUCIA , CIGNARELLI ANGELO , PERRINI SEBASTIO , LAVIOLA LUIGI , GIORGINO FRANCESCO 
Published: June 2018

Extra virgin olive oil (EVOO) is one of the major components of the Mediterranean diet and is appreciated worldwide because of its nutritional benefits in metabolic diseases, including type 2 diabetes. In addition to high levels of fatty acids, EVOO contains significant amounts of micronutrients such as polyphenolic compounds that may positively influence the metabolic status. In this study, we have evaluated the effects of such EVOO polyphenolic compounds on beta-cell function and survival. INS-1E cells were exposed to different doses (10-50-100 microM) of the main polyphenols of EVOO for 24 h. Under these conditions, glucose-stimulated insulin secretion (GSIS), insulin content, proinsulin mRNA expression and cellular apoptosis were evaluated. At the concentration of 10 microM, which is closest to that in EVOO, hydroxytyrosol, tyrosol and apigenin augmented proinsulin mRNA levels and insulin content; moreover, apigenin and luteolin enhanced GSIS. On the other hand, vanillic acid and vanillin were pro-apoptotic for beta-cells, even if they increased GSIS. Finally, ferulic and sinapic acids significantly worsened GSIS. Furthermore, although most of the polyphenol compounds at the concentration of 50 microM did not induce apoptosis, some of them (e.g., caffeic, vanillic and ferulic acids) caused a marked reduction in proinsulin gene expression. At the concentration of 100 microM, most polyphenolic compounds caused a reduction in proinsulin mRNA levels and enhanced apoptosis.
In conclusion, this study, comparing for the first time the effects of the main polyphenols contained in EVOO, shows that, at low concentrations, hydroxytyrosol, tyrosol, luteolin and apigenin exert positive effects on both the function and survival of beta-cells, suggesting that EVOO enriched with these compounds may improve insulin secretion and promote glycemic control in type 2 diabetic patients.

Disclosure
A. Natalicchio: None. R. Spagnuolo: None. N. Marrano: None. G. Biondi: None. L. Dipaola: None. A. Cignarelli: Advisory Panel; Self; Aegerion Pharmaceuticals. Consultant; Self; Roche Diagnostics Corporation, Eli Lilly and Company. S. Perrini: None. L. Laviola: Advisory Panel; Self; AstraZeneca, Animas Corporation. Speaker's Bureau; Self; A. Menarini Diagnostics. Advisory Panel; Self; Boehringer Ingelheim GmbH, Eli Lilly and Company. Speaker's Bureau; Self; Medtronic, Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk Inc., Roche Diabetes Care Health and Digital Solutions, Sanofi-Aventis, Takeda Development Centre Europe Ltd. F. Giorgino: Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim GmbH. Research Support; Self; Eli Lilly and Company, Johnson & Johnson Services, Inc.. Consultant; Self; MedImmune, Merck Sharp & Dohme Corp., Roche Diabetes Care Health and Digital Solutions, Sanofi. Research Support; Self; Takeda Development Centre Europe Ltd..
Discovery and Replication of HDL-Associated Loci in the Korean Population Using 35,000 Individuals
Authors: KIM BONG-JO , KIM YOUNG JIN , HWANG MI YEONG , MOON SANGHOON 
Published: June 2018

Low levels of HDL are known to be associated with increased risk of type 2 diabetes. It has been suggested as a new therapeutic approach that increase HDL levels in plasma. Previously, to identify lipids traits associated loci, we performed large-scale genome-wide meta-analyses comprising 25,923 East Asian individuals from 11 studies from Korea, Japan, Philippines, China, Singapore, and Taiwan in the discovery stage. With subsequent replication study, we have revealed seven novel loci associated with HDL including loci at CD163-APOBEC1, NCOA2, and NID2-PTGDR. However, previous study was limited in sample size in the discovery stage and low association mapping resolution due to HapMap based imputation analysis. In this study, we performed genome-wide association analyses (GWAS) on HDL using about 35,000 Korean samples and imputed based on 1,000 Genomes project phase 3 and Korean Reference Genome. We focused on imputed (imputation quality score &gt;0.4) and genotyped common variants with minor allele frequency &gt;= 1%. In this discovery study, 17 known loci were replicated at the genome-wide significance level (P&lt;5x10-8). However, no novel association meet the genome-wide significance. We further examined associated loci at suggestive statistical significance (P&lt;5x10-6). As a result, 11 known loci were additionally replicated and 10 possible novel candidate loci were identified including a variant near GATA4. It is noteworthy that the variant near GATA4 was previously reported to be associated with triglyceride level.
In summary, we performed a GWAS on HDL using about 35,000 Korean samples. The GWAS confirmed 28 known loci and discovered 10 possible novel candidate loci responsible for variation of HDL level. However, a replication study in an independent cohort is warranted for validating the results. Taken together, the possible novel candidates discovered from this study may provide potential novel therapeutic targets for diseases associated with HDL.

Disclosure
B. Kim: None. Y. Kim: None. M. Hwang: None. S. Moon: None.
Exploring the Role of Calcium-Activated Potassium Channels in Alpha-Cell Function
Authors: DICKERSON MATTHEW , ALTMAN MOLLY K. , DADI PRASANNA , VIERRA NICHOLAS C. , JACOBSON DAVID 
Published: June 2018

Calcium influx into pancreatic α-cells through voltage-dependent calcium channels (VDCCs) is required for glucagon (GCG) secretion and the mechanisms that mediate this process become defective during the pathogenesis of diabetes. Potassium channels are key regulators of membrane potential (Vm), and thus, modulate VDCC activity. However, the role of calcium-activated potassium (KCa) channels in α-cell calcium handling and GCG secretion have not been determined.
The aim of this study was to investigate the importance of KCa channels to α-cell electrical excitability, calcium handling, and GCG secretion. α-cells display a KCa current, which is partially inhibited by blocking small conductance KCa (SK) or big conductance KCa (BK) channels. Inhibition of P/Q-type VDCCs, sarco/endoplasmic reticulum (ER) calcium-ATPases (SERCAs), and KATP channels also partially inhibit this current. It is likely that calcium influx through VDCCs triggers calcium-induced calcium release (CICR) from ER calcium stores activating α-cell KCa channels. The inhibition of SK channels transiently increases calcium influx into α-cells at 1 mM glucose; however, over time intracellular calcium decreases. This may be due to voltage-dependent inactivation of α-cell VDCCs. Interestingly, SK channel inhibition reduces GCG secretion at 1 mM glucose while SST secretion is unaffected. Thus, it is likely that this is an intrinsic α-cell effect. These findings demonstrate that α-cells possess a KCa current and that its activation is important for α-cell electrical activity, Ca2+ handling, and GCG secretion.

Disclosure
M. Dickerson: None. M.K. Altman: None. P. Dadi: None. N.C. Vierra: None. D. Jacobson: None.
STIM1/Orai1 Inhibition Reduces Store-Operated Ca2+ Entry and Modulates a-Cell Glucagon Secretion
Authors: ALTMAN MOLLY K. , DADI PRASANNA , JACOBSON DAVID 
Published: June 2018

In type 2 diabetic patients glucagon secretion becomes dysregulated under elevated glucose conditions worsening hyperglycemia. However, the mechanisms of glucose inhibition of glucagon secretion remain incompletely understood. Therefore, we sought to uncover the glucose dependent mechanisms that modulate pancreatic α-cell glucagon secretion. One mechanism that regulates α-cell Ca2+ influx in a glucose dependent manner is store-operated Ca2+ entry (SOCE). Therefore, in our studies we used a small molecule (AnCoA4) that inhibits the STIM1/Orai1 protein interaction and prevents store-operated Ca2+ channel activation. In whole mouse islet α-cells inhibition of SOCE with AnCoA4 reduced Ca2+ influx in 1 mM glucose (8.4% ± 1.1%). We went on to test the influence of SOCE on glucose modulation of glucagon secretion, in 1 mM glucose AnCoA4 reduced glucagon secretion in mouse pancreatic islets (53.5% ± 11%). However, there was no significant change in glucose inhibition of glucagon secretion by inhibition of SOCE at 11 mM glucose. To follow-up on this, we used transgenic mice without STIM1 in α-cells and showed that AnCoA4 does not influence Ca2+ fluctuations in knockout islet α-cells. This proves in our hands that AnCoA4 works selectively. Additionally, we used transgenic GCAMP3 mice without STIM1 in α-cells for whole islet confocal studies to measure SOCE in 1 mM and 11 mM glucose conditions. We found that in whole islet α-cells without functional STIM1, Ca2+ influx due to SOCE was reduced in 1 mM glucose. Next, we wanted to test this molecule in human islet calcium homeostasis studies. Human dispersed α-cells show inhibition of SOCE with AnCoA4 treatment in 1 mM glucose conditions. Thus, our findings identify that inhibition of STIM1/Orai1 reduces SOCE in low glucose conditions leading to decreased α-cell glucagon secretion.

Disclosure
M.K. Altman: None. P. Dadi: None. D. Jacobson: None.
Impact of Past and Current Smoking on Mortality Risk in Angiographied Coronary Patients with Type 2 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 impact of smoking on mortality risk in angiographied coronary patients is unclear and is addressed in the present study. We enrolled 1804 consecutive patients undergoing coronary angiography for the evaluation of established or suspected stable coronary disease (CAD). Patients who had smoked within 30 days prior to angiography were considered current smokers. Prospectively, mortality was recorded over a mean follow-up time of 7.6±2.8 years. At baseline, both in patients with T2DM (n=522; 28.9% of the study cohort) and in nondiabetic subjects the prevalence of a past (44.1 and 39.5%; p=0.035) and, albeit less so, of current smoking (18.0 and 17.7%; p = 0.247) was high. Prospectively, current smoking independently predicted cardiovascular events after multivariate adjustment including baseline CAD in patients with diabetes (HR 1.78 [1.16-2.74]; p=0.009) as well as in nondiabetic patients (HR 1.68 [1.12-2.52]; p=0.013), whereas past smoking neither in patients with T2DM nor in nondiabetic subjects was associated with cardiovascular events (HRs 0.77 [0.54-1.10]; p=0.152 and HR 1.16 [0.87-1.53]; p=0.313, respectively). An interaction term diabetes x current smoking was not significant (p=0.564), indicating that current smoking was equally predictive of mortality in patients with T2DM and in nondiabetic subjects. We conclude that current but not past smoking strongly increases mortality risk angiographied coronary patients with T2DM independently from the baseline CAD state.

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.
Hyperbaric Oxygen Therapy Is Associated with Improved Six-Year Survival in People with Chronic Diabetic Foot Ulcers
Authors: LONDAHL MAGNUS , FAGHER KATARINA , NILSON ANDERS , KATZMAN PER 
Published: June 2018

Both micro- and macrovascular components probably mutually contribute to the increased mortality in people with diabetic foot ulcers (DFU). We have previously shown that QTc-time is an important risk factor for mortality and that hyperbaric oxygen therapy (HBO) seems to reduce QTc-time prolongation. The aim of this study based on our randomized clinical trial was to evaluate the effect of HBO on 6-year survival in people with hard-to-heal DFU as well as a possible relation to QTs-time on survival.
Methods: People with DFU of ≥3 months duration without any indication or possibility of vascular surgical intervention were randomized to either HBO (2.5 ATA, 90 minutes) or hyperbaric air (Ctrl) treatment. Only those who fulfilled the pre-specified criterion of completing at least 36 out of 40 treatments sessions were included in the evaluation.
Results: No statistical differences in baseline characteristics were seen between groups. The 6-year survival was 58% (22/38) in the HBO, and 35% (13/37) in the Ctrl group (LogRank p&lt;0.048). Survival in those with a baseline QTc-time &gt; 420 ms are given in Figure 1. In a Cox Regression analysis including treatment allocation, presence of coronary heart disease and age, only treatment allocation was a statistically significant factor associated with survival (p=0.038).
Conclusion: HBO might be associated with improved 6-year survival in people with chronic DFU.

Disclosure
M. Londahl: Speaker's Bureau; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk A/S. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; ReApplix AS. K. Fagher: Speaker's Bureau; Self; AstraZeneca, Sanofi, Novo Nordisk A/S, Merck Sharp & Dohme Corp. A. Nilson: Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. P. Katzman: None.