bluuebunny/crossref_metadata_2025_split huggingface dataset:
Individual and Combined Glucose-Lowering Effects of Glucagon Receptor Antagonism and Sodium-Glucose Cotransporter 2 Inhibition
Authors: HAEDERSDAL SOFIE , LUND ASGER B. , MAAGENSEN HENRIK , NIELSEN-HANNERUP ELISABETH , HOLST JENS J. , KNOP FILIP K. , VILSBØLL TINA 
Published: June 2018

Studies suggest that sodium-glucose cotransporter 2 inhibitors (SGLT2i) induce hyperglucagonemia, which might counteract its glucose-lowering ability in type 2 diabetes. In a randomized, placebo-controlled, double-dummy, double-blinded, cross-over study, 12 middle-aged patients with type 2 diabetes (BMI [mean (SD)]: 30.3 (5.8) kg/m2; HbA1c: 50.3 (10.5) mmol/mol) underwent four 4-hour liquid mixed meal tests preceded by single-dose administration: 1) Placebo, 2) SGLT2i (25 mg empagliflozin), 3) glucagon receptor antagonist (GRA) (300 mg LY2409021), and 4) GRA + SGLT2i. The SGLT2i and GRA individually lowered fasting plasma glucose (FPG) compared to placebo and the combination further decreased FPG. SGLT2i reduced postprandial glucose excursions as assessed by baseline-subtracted area under curve (bsAUC) whereas GRA increased bsAUC compared to placebo (Figure). The paradoxical GRA-induced increment in bsAUC was annulled by a potent SGLT2i-induced reduction of bsAUC during the combination of SGLT2i and GRA (Figure).
In conclusion, SGLT2i and GRA combined reduce FPG beyond their individual capacity in patients with type 2 diabetes, and in the context of GRA, SGLT2i’s beneficial effect on postprandial glucose excursions seems to be potentiated.

Disclosure
S. Haedersdal: None. A.B. Lund: Other Relationship; Self; Novo Nordisk A/S. H. Maagensen: None. E. Nielsen-Hannerup: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. T. Vilsbøll: None.
Risk of Breast Cancer According to Glycaemia and HbA1c Concentration—A Meta-analysis of Prospective Studies
Authors: MACACU ALINA , PIZOT CECILE , BOYLE PETER , AUTIER PHILIPPE 
Published: June 2018

Some observational studies have suggested that women with diabetes may be at increased risk of breast cancer. Blood levels of fasting glucose (FG) and of glycated hemoglobin (HbA1c) are major diagnostic tools for diabetes. The aim of this study was to investigate the association between HbA1c, FG and breast cancer occurrence. A systematic literature search identified prospective studies which reported a quantitative estimate of the association between HbA1c or FG and breast cancer. Summary relative risks (SRR) of breast cancer, comparing high vs. low levels of HbA1c or FG, were computed using random-effect meta-analysis. Ten studies for HbA1c (116,035 women and 3,095 breast cancer cases) and 13 studies for FG (971,071 women and 14,579 breast cancer cases) were selected. High levels of HbA1c (FG) ranged from &gt;4.5% to &gt;9% (&gt;5 to &gt;7.8 mmol/L), and low level ranged from &lt;4.3% to &lt;6.7% (&lt;4.4 to &lt;6.1 mmol/L). Overall, the SRR of breast cancer was 0.97 (95% CI: 0.76, 1.24) for HbA1c and 1.15 (95% CI: 1.00, 1.33) for FG, with moderate heterogeneity between studies (I²=44% and 45%, respectively). When the analyses were restricted to women with HbA1c &lt;6.5% and FG &lt;7mmol/L, the SRR was 0.97 (95% CI: 0.81, 1.15) for HbA1c (six studies) and 1.15 (95% CI: 1.01, 1.31) for FG (seven studies) without heterogeneity in both analyses (I²=0%). In 3 studies conducted in diabetic women, the SRR for the association between HbA1c levels and breast cancer was 0.95 (95% CI: 0.79, 1.15) with no heterogeneity (I2=0%). No study was found on FG among diabetic women only. No association was found between HbA1c and breast cancer occurrence, while fasting glucose might be associated with a slight increased risk. The lack of clear association suggests that the increased risk of breast cancer observed among diabetic women appears to be driven by factors other than the blood glucose concentration disorders.

Disclosure
A. Macacu: None. C. Pizot: None. P. Boyle: Other Relationship; Self; Sanofi. P. Autier: Other Relationship; Self; Sanofi.
Endo Soc-3-Decrease in AMP Kinase Expression and Activity in Diabetic Patients with Hypogonadism—Increase following Testosterone Supplementation
Authors: DHINDSA SANDEEP , GHANIM HUSAM , BATRA MANAV , CHAUDHURI AJAY , ABUAYSHEH SANAA , DANDONA PARESH 
Published: June 2018

AMP kinase is a key enzyme involved with energy regulation, the intake of macronutrients, the uptake of glucose and fatty acids by cells and the metabolic combustion of fatty acids. We hypothesized that in patients with hypogonadism associated with diabetes, its expression and activity are diminished since there is a quantitative and qualitative loss of skeletal muscle function. Twenty-two men with HH and T2DM were compared with 20 eugonadal men with T2DM at baseline. From the HH patients, 12 were treated with testosterone 200mg every 2 weeks injected intramuscularly for 24 weeks, during which their plasma concentrations were maintained in the physiological range. Hyperinsulinemic, euglycemic clamps (HEC) were carried out prior to and after testosterone replacement and fat (abdomen) and muscle (quadriceps) biopsies were carried out prior to and after HEC procedure on each occasion. In the hypogonadal state, the expression and the activity (measured as phoso-T172-AMPK-α) of AMP kinase-α was significantly lower in HH patients than eugonadal diabetics both in adipose tissue and skeletal muscle by 37% and 29%, respectively, for expression and by 22.1% and 28%, respectively for activity. Following testosterone, there was no change in expression but there was a significant increase in AMP kinase activity by 69±31% (from 14.9±2.8 to 22.8±2.2U/ml, p&lt;0.05) in the muscle but not in the adipose tissue. At the end of the treatment and following the hyperinsulinemic euglycemic clamp, there was a significant increase in AMP kinase expression by 41±9% and 46±11% in adipose tissue and muscle, respectively, while there was only a modest increase (NS) in activity in both tissues. Clearly, therefore, testosterone is an important modulator of AMP kinase activity. This effect of testosterone may contribute to the increase in glucose uptake and an improvement in insulin sensitivity since AMP kinase also induces an increase in Akt-2 and GLUT-4 expression.

Disclosure
S. Dhindsa: None. H. Ghanim: None. M. Batra: Speaker's Bureau; Self; Eli Lilly and Company. A. Chaudhuri: Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc.. S. Abuaysheh: None. P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca.
Gastrin—A Potential Predictor of Glucoregulation in Newly Diagnosed Type 2 Diabetes Patients
Authors: BERKOVIC MAJA CIGROVSKI , MAHECIC DAVORKA HERMAN , BILIC-CURCIC INES 
Published: June 2018

Background and Aims: Experimental data demonstrated that activation of GLP-1 and gastrin signaling induces beta cell neogenesis, resulting in a promotion of glucose-induced insulin secretion. In addition, treatment with proton pump inhibitors is associated with greater glycemic control in patients with type 2 diabetes (T2DM), particularly in those on insulin- or GLP-1-based therapy. The aim of this study was to assess gastrin as a potential predictor of beta cell function and glucoregulation in newly diagnosed T2DM patients.
Materials and Methods: In this cross sectional study 190 patients (64 males and 126 females) with new onset T2DM were included. Patients treated with IPPs were excluded. Fasting plasma glucose (FPG), postprandial PG, HbA1c, fasting insulin, pancreatic B cell function (HOMA-B), insulin resistance index (HOMA-IR), fasting c-peptide and gastrin levels were measured at the time of diagnosis.
Results: Baseline HbA1c was 7.53±2.08%, average age of patients was 61.8±10.years and body mass index (BMI) was 31.25±5.73 kg/m2. Parameters of glucoregulation were not significantly correlated with gastrin (all p&gt;0.05), while there was moderate negative correlation with HOMA-B (HbA1c, FPG and PPG; p &lt;0.01 for all) and positive correlation with HOMA-IR (HbA1c, FPG and PPG; p&lt;0.01 for all). Patients with higher baseline measures of glucose regulation had lower HOMA-B and higher HIMA-IR as was expected. There was no association between gastrin and HOMA-B (p&gt;0.05) or HOMA-IR. Furthermore, no association was established between c-peptide, insulin levels and gastrin (p&gt;0.05).
Conclusion: Baseline gastrin levels are not sufficient to have a significant effect on glucoregulation or HOMA-B and HOMA-IR in newly diagnosed T2DM, therefore it could be postulated that further stimulation of gastrin secretion (e.g., with IPPs or GLP-1 based therapy) is needed in order to influence beta cell function and glycemic control.

Disclosure
M. Cigrovski Berkovic: None. D. Herman Mahecic: None. I. Bilic-Curcic: None.
Anti-inflammatory Cholinergic Signals Inhibit Islet Resident Macrophage Responses to ATP in Living Pancreatic Tissue Slices
Authors: WEITZ JONATHAN , DIAZ RAYNER RODRIGUEZ , ALMACA JOANA , MAKHMUTOVA MADINA , CAICEDO ALEJANDRO 
Published: June 2018

When stimulated by high glucose concentrations, beta cells release ATP together with insulin. Under these conditions, the ATP concentration in the islet reaches levels that would induce inflammatory responses in other tissues. Yet inflammation does not occur during normal islet physiology. We therefore postulated that there is a local anti-inflammatory circuit that prevents pathological immune responses. Our studies focused on resident macrophages, which are the local immune cells in the pancreatic islet. We recently showed that islet macrophages detect ATP to gauge the level of beta cell activation. We hypothesized that the potentially inflammatory responses to ATP are inhibited in macrophages by cholinergic input from parasympathetic nerves, as reported for other organs. Using immunohistochemistry, we found that most islet resident macrophages were indeed contacted by local cholinergic nerves, with an innervation density that was equivalent to that of beta cells. To study the impact of local cholinergic nerves on resident macrophages, we used living tissue pancreatic slices, where activity of islet cells, nerves, and macrophages can be visualized in a preserved local microenvironment. We determined that Ca2+ responses to ATP were inhibited in islet macrophages by nicotine, an agonist of nicotinic acetylcholine receptors. These results indicate that macrophages receive cholinergic input from parasympathetic nerves. We expect our studies to identify parasympathetic nerves as a source of anti-inflammatory signals that efficiently dampen the potentially pro-inflammatory environment in the islet.

Disclosure
J. Weitz: None. R. Rodriguez Diaz: None. J. Almaca: None. M. Makhmutova: None. A. Caicedo: None.
Association Between Body Fat Mass and Plasma Insulin Level in the Male Patients with Idiopathic Hypogonadotropic Hypogonadism and Normal Glucose Tolerance
Authors: YANG XUBIN , LIN QIONGYAN , HU XILING , XU WEN , DENG HONG R. 
Published: June 2018

Male patients with idiopathic hypogonadotropic hypogonadism (IHH) characterized with low serum testosterone(T) might have higher risks of diabetes and coronary heart disease partly due to the high level of plasma insulin. Low serum T might also affect the body fat mass(BFM) in patients with IHH. However, the relationship between BFM and plasma insulin level in IHH patients has not been clearly clarified.
A total of 22 patients who were admitted to our hospital with IHH and normal glucose tolerance(NGT) confirmed by oral glucose tolerance test and 10 healthy subjects as controls were enrolled into our study. Glucose, insulin, serum T levels, HOMA-IR, HOMA-B and percentage of BFM were determined.
When compared with controls subjects, patients with IHH had significantly lower T concentrations(1.80nmol/L vs. 19.82nmol/L, P&lt;0.001), whereas they had significantly higher BFM(31.38% vs.21.11%, P=0.004), fasting insulin level (15.86 mu/L vs. 7.65 mu/L, P=0.018), HOMA-B(293.19 vs. 120.26, P=0.016) and HOMA-IR(3.18 vs. 1.64, P=0.018). Pearson correlation revealed that BFM was correlated with fasting insulin level(r=0.63, P=0.002), HOMA-B(r=0.53, P=0.014) and HOMA-IR(r=0.47, P=0.031). Multiple linear regression revealed BFM was an independent factor of fasting insulin level(B=0.57, 95% CI:0.24∼0.90, P=0.002), HOMA-B(B=0.096, 95% CI:0.01∼0.18, P=0.030) and HOMA-IR(B=17.09, 95% CI:3.81∼30.37, P=0.014).
BFM was an independent factor of plasma insulin level in IHH patients with NGT.

Disclosure
X. Yang: None. Q. Lin: None. X. Hu: None. W. Xu: None. H.R. Deng: None.
Effects of Epinephrine on Atherothrombotic Responses and In Vivo Endothelial Function in Healthy Humans
Authors: MIKELADZE MAIA , HEDRINGTON MAKA , DUMBADZE SOFIO , BRISCOE VANESSA J. , TATE DONNA , THAYER EVAN , DAVIS STEPHEN 
Published: June 2018

In this study we have tested the hypothesis that levels of epinephrine simulating those occurring during hypoglycemia of 70, 60, or 50 mg/dl will result in pro-coagulant and pro-atherothrombotic responses and endothelial dysfunction.
32 healthy humans (16M/16F) participated in 4 separate, single blind, randomized, 1-day studies: Placebo (Protoco1 1) and epinephrine infusions of 0.015, 0.03 and 0.06µg/kg/min (Protocols 2-4) respectively. Studies consisted of 2-hour hyperinsulinemic (133±7µU/ml) euglycemic clamps of 92±1mg/dl. 2D Doppler imaging determined flow mediated dilation (FMD) of the brachial artery.
Increases of IL-6, P-selectin, E-selectin, ICAM-1, and VCAM-1 were higher and reductions in FMD and ET-1 greater during all epinephrine infusions compared to Placebo (p&lt;0.05). (Table 1)Table 1. Changes from baseline to final 30 minProtocol 1Protocol 2Protocol3Protocol 4Δ IL-6 (pg/ml)-3.0±1.22.8±2.9*3.6±2.7*8.1±2.9*Δ P-selectin (pg/ml)-13.7±6.51.3±0.8*2.0±2.0*5.6±1.8*Δ ICAM-1 (ng/ml)-18.7±12.324.1±13.3*65.5±36.9*114.3±69.6*Δ ET-1 (pg/ml)-0.2±0.05-0.4±0.05*-0.5±0.12*-0.6±0.09*Δ FMD (mean maximum%)0.8±0.7-2.0±0.5*-2.6±0.6*-3.7±0.7*Δ Epinephrine (pg/ml)18±2299±38*532±41*1011±12*Mean±SEM * p&lt;0.0007-0.compared to Protocol 1
Epinephrine activated pro-coagulant, inflammatory and pro-atherothrombotic mechanisms while impairing endogenous and exogenous nitric oxide mediated endothelial function.
In conclusion, during hyperinsulinemic euglycemia, epinephrine levels simulating those occurring during hypo of only 70mg/dl produced significant inflammatory effects. Increasing doses of epinephrine resulted in greater inflammatory responses and in-vivo endothelial dysfunction (p&lt;0.001). Epinephrine may be an important mechanism responsible for adverse vascular biologic effects during hypo in healthy humans.

Disclosure
M. Mikeladze: None. M. Hedrington: None. S. Dumbadze: None. V.J. Briscoe: None. D. Tate: None. E. Thayer: None. S. Davis: None.
Anorexic Peptide Nesfatin-1 Exerts Vasoprotective Effects in Injured Arteries of Mice
Authors: MORI YUSAKU , SHIMIZU HIROYUKI , KUSHIMA HIDEKI , TERASAKI MICHISHIGE , HIROMURA MUNENORI , KOSHIBU MASAKAZU , KOHASHI KYOKO , HIRANO TSUTOMU 
Published: June 2018

Background: Nesfatin-1 (Nes), an anorexic peptide hormone, has recently gained attention as a potential therapeutic target for obesity and its related metabolic abnormalities, including type 2 diabetes. Recently direct cardioprotective effects of Nes have demonstrated; however, its vasopressor effects at very high dose are also reported, which potentially limit its clinical application. Here, we evaluated vascular actions of Nes in vivo and in vitro.
Methods: Male C57BL/6 and nucleobindin-2, a precursor of Nes, transgenic (NUCB-Tg) mice (9 w) were employed. C57BL6 mice were randomly assigned to treatment with vehicle (control) or Nes at the low or high doses (Nes-L, 0.2 mg/kg/d; Nes-H, 2 mg/kg/d). Subsequently, the mice were subjected to femoral artery wire injury to induce arterial remodeling.
Results: In the Nes-H group, food intake was decreased compared to that in the controls by 10% (p&lt;0.05) without affecting blood pressure (BP) and plasma glucose and lipid levels. Furthermore, Nes-H reduced neointimal hyperplasia in injured arteries by 30% (p&lt;0.05). In contrast, Nes-L did not affect any metabolic or vascular parameters including food intake. In NUCB-Tg mice, BP was slightly elevated, but neointimal area was lower than that observed in littermate controls (50% reduction, p&lt;0.05). Additionally, associated reductions in vascular cell proliferation were observed (r=0.46, p&lt;0.05). In in vitro studies using human umbilical vein endothelial cells, Nes treatment (1-100 nmol/L) dose-dependently increased nitric oxide (NO) production and AMP-activated protein kinase (AMPK) phosphorylation by 1.5- to 3-fold (p&lt;0.05). In contrast, Nes treatment did not directly suppress proliferation of human aortic smooth muscle cells.
Conclusions: We demonstrated that Nes at the dose exerting anorexic, but not vasopressor effects, suppresses arterial remodeling in injured arteries of mice, possibly through the activation of AMPK and enhancement of NO production in vascular endothelial cells.

Disclosure
Y. Mori: None. H. Shimizu: Speaker's Bureau; Self; Eli Lilly and Company, MSD K.K., Daiichi Sankyo Company, Limited, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc.. H. Kushima: None. M. Terasaki: None. M. Hiromura: None. M. Koshibu: None. K. Kohashi: None. T. Hirano: Speaker's Bureau; Self; Novo Nordisk Inc., AstraZeneca.
ILDR2 Alters Hepatic Phospholipid Composition via MBOAT7—Effects on Liver Fat
Authors: WATANABE KAZUHISA , NAKAYAMA KAZUHIRO , YOSHIDA KEN , MILLINGS ELIZABETH J. , LEDUC CHARLES A. , LEIBEL RUDOLPH , IWAMOTO SADAHIKO 
Published: June 2018

Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes, and increases the risk for liver cirrhosis and cancer. A diabetes susceptibility gene, ILDR2, encodes a transmembrane protein localized to the ER membrane whose primary physiological functions are unclear. We previously purified ILDR2-containing protein complexes using the tandem affinity purification tags and identified MBOAT7, which mediates acyl-chain remodeling of phosphatidylinositols (PIs). The MBOAT7 variant rs641738 T allele is associated with decreased hepatic PI (36:4) and PI (38:3) and an increase in severity of NAFLD. We hypothesized that ILDR2 may influence hepatic Pl composition in NAFLD. We used two mouse models fed a methionine- and choline-deficient (MCD) diet: 1. liver-specific ILDR2 knockout (LKO-ILDR2) using an AAV-Cre/loxP system; and 2. AAV-overexpressing ILDR2 (OX-ILDR2) mice.
In LKO-ILDR2 mice compared to AAV-GFP injected ILDR2 floxed (GFP-flox) mice, liver triglyceride (TG) content was significantly increased by 1.6-fold with a significant 1.2-fold increase in plasma TG. In LKO-ILDR2 mice compared to GFP-flox mice, hepatic PI (38:4) was significantly decreased. The livers of LKO-ILDR2 mice showed significantly increased JNK activation, collagen gene expression, and increased in hydroxyproline, suggesting that ILDR2 depletion leads to inflammation and the development of fibrosis. In OX-ILDR2 mice compared to AAV-GFP injected WT (GFP-WT) mice, hepatic PI and PC species were significantly increased. The liver in OX-ILDR2 mice showed decreased expression of JNK and ER stress-related genes, and hydroxyproline, with a slight (9%) decrease in hepatic TG compared to GFP-WT mice. Thus, ILDR2 overexpression attenuated hepatic inflammation, ER stress, and fibrogenesis.
Manipulation of hepatic ILDR2 expression is associated with changes in PI and PC molecular species in the liver. Patterns of hepatic phosphatidyl fatty acid composition are associated with NAFLD development.

Disclosure
K. Watanabe: None. K. Nakayama: None. K. Yoshida: None. E.J. Millings: None. C.A. LeDuc: None. R. Leibel: None. S. Iwamoto: None.
The Role of a Glucagon-Like Peptide-1 Receptor Agonist in Visceral and Subcutaneous Fat Redistribution
Authors: ZHAO LI , ZHU CHUNFANG , LU MENG , CHEN CHI , CHEN YI , WANG NINGJIAN , LU YINGLI 
Published: June 2018

Glucagon-like peptide-1 receptor agonists (GLP-1RA) are an ideal therapy for type 2 diabetes and recently, for obesity. In contrast to visceral fat, subcutaneous fat accumulation appears to be protective against metabolic syndrome. Here, we reported that liraglutide, a GLP-1RA redistributed visceral and subcutaneous fat via the tissue-specific modulation of lipid metabolism and stimulation of subcutaneous white adipose tissue (WAT) browning. We showed that liraglutide decreased visceral fat and relatively increased subcutaneous fat. Lipogenesis was reduced in visceral WAT but elevated in subcutaneous WAT treated with liraglutide. Lipolysis was also attenuated, and fatty acid oxidation was enhanced. The mRNA expression levels of adipose-related genes displayed similar trends. Liraglutide down-regulated the expression levels of lipogenesis- and lipolysis-related genes but up-regulated the expression levels of β-oxidation-related genes in visceral WAT. In subcutaneous WAT, the expression levels of lipogenesis-related genes were up-regulated in both inguinal and cluneal WAT. However, the lipolysis-related gene expressed higher in inguinal WAT but lower in cluneal WAT, while the β-oxidation-related gene expressed lower in inguinal WAT but higher in cluneal WAT after liraglutide treatment. In addition, the uncoupling protein-1 was up-regulated in subcutaneous WAT. Thus, liraglutide potentially redistributes body fat and promotes browning remodeling in subcutaneous WAT to improve metabolic disorders.

Disclosure
L. Zhao: None. C. Zhu: None. M. Lu: None. C. Chen: None. Y. Chen: None. N. Wang: None. Y. Lu: None.