bluuebunny/crossref_metadata_2025_split huggingface dataset:
1163-P: Exercise as a Strategy to Decrease Pancreatic ß-Cell Senescence
Authors: CARAPETO PRISCILA , AGUAYO-MAZZUCATO CRISTINA 
Published: June 2021

Age increases the prevalence of type 2 diabetes (T2D) and insulin resistance (IR) accelerates the appearance of senescent β-cells, one of the hallmarks of aging. This suggests that senescence could contribute to the development of T2D and be a novel therapeutic target. In addition to improving blood glucose levels, exercise has been shown to attenuate all hallmarks of aging. However, the effects of exercise upon β-cell senescence remain to be determined. Our hypothesis is that exercise can decrease β-cell senescence and we aim to verify the effects of exercise upon senescence prevention and reversibility under control and IR conditions. Retired breeder male C57Bl/6 mice (6-8 months of age) were randomly assigned into groups (n=5/group): sedentary, exercised (treadmill running, 1 h, 5 times per week, for 2 weeks, at 17 cm/s and 5% incline) and IR (S961, 40nM/week for 2 weeks); exercise was performed at the same time, before or after IR to assess prevention and reversibility. ANOVA Brown-Forsythe and Welch were used to compare groups. Under control conditions, exercise decreased β-cell senescent markers (-58.1% p21Cip1 mRNA and -29% β-Galactosidase activity through FACS sorting), improved glucose tolerance (-13.6% in total area under the curve during intraperitoneal glucose tolerance test) and preserved suppression of basal insulin secretion when compared to sedentary (+39.3% insulin). Exercise performed before and during IR decreased mRNA levels of senescence marker and effector p16Ink4a by 41.7% and 80% respectively. Basal insulin secretion was decreased, and glucose-stimulated insulin secretion restored. When performed after IR, exercise decreased p16Ink4a mRNA by 62.4% and restored basal insulin secretion with no change in the stimulation index.
In conclusion, exercise decreased the load of senescent cells in insulin resistant animals. Its effects were more effective before and during IR but it was also able to reverse some of the deleterious effects of IR converting it into a novel β-cell anti-aging strategy.

Disclosure
P. Carapeto: None. C. Aguayo-mazzucato: Consultant; Self; eGenesis.

Funding
Joslin Diabetes Center (to C.A-M.); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (to P.C.)
1165-P: Alterations of Hepatic Mitochondrial Respiration in Murine Models of Diabetes and Nonalcoholic Fatty Liver Disease (NAFLD)
Authors: DEWIDAR BEDAIR , REINADOFUNDO MICHELLE , ENGLISCH CORNELIA , MASTROTOTARO LUCIA , PESTA DOMINIK , RESS CLAUDIA , ESPOSITO IRENE , RODEN MICHAEL 
Published: June 2021

Diabetes mellitus (DM) accelerates progression of fatty liver to nonalcoholic steatohepatitis (NASH) and fibrosis. Mitochondrial function is also frequently impaired in DM, but maybe differently regulated in NAFLD. Thus, we examined hepatic mitochondrial respiration during DM and NAFLD development.
Two-days old male C57BL/6j mice received streptozotocin (STZ) or vehicle (placebo, PLC) and then high-fat diet (HFD) or continued regular chow diet (RCD) from week 4 to 12, yielding 4 models (n=8 each): obesity [PLC+HFD], DM [STZ+RCD], NASH [STZ+HFD] and control [PLC+RCD]. Histology and immunohistochemistry were performed to describe NAFLD, including the NAFLD activity score (NAS) derived from steatosis, lobular inflammation and hepatocellular ballooning. High-resolution respirometry and hyperinsulinemic-euglycemic clamps were used to measure mitochondrial respiration and insulin sensitivity.
DM and NASH showed &gt;200% higher blood glucose levels (p&lt;0.0001 vs. control). The NAS (mean±SEM) was not different in obese (1.38±0.32; p&gt;0.99), gradually higher in DM (2.50±0.42; p=0.063) and markedly increased in NASH (3.25±0.45; p&lt;0.01) compared to control (1.00±0.27). Main contributors to NAS were steatosis and hepatocellular ballooning in NASH (p&lt;0.001 and p&lt;0.05 vs. control) and hepatocellular ballooning in DM (p&lt;0.01 vs. control). Maximal uncoupled β-oxidation-associated respiration was 1.6-, 1.7-, and 1.9-fold higher in obesity, DM and NASH compared to control (all p&lt;0.01). Mitochondrial density was decreased in both DM and NASH (p&lt;0.05 vs. control), whereas β-oxidation-dependent mitochondrial leak control ratio was not different between all groups. Insulin-stimulated glucose disposal was 44% and 66% lower in obesity and NASH (both p&lt;0.001 vs. control).
In conclusion, hyperglycemia and high-fat diet feeding associate with higher respiration but lower content of hepatic mitochondria, which may both contribute to progression of NAFLD.

Disclosure
B. Dewidar: None. M. Reinadofundo: None. C. Englisch: None. L. Mastrototaro: None. D. Pesta: None. C. Ress: None. I. Esposito: None. M. Roden: Advisory Panel; Self; Allergan plc, Bristol-Myers Squibb Company, Novo Nordisk A/S, Research Support; Self; Boehringer Ingelheim International GmbH, Danone Nutricia, Sanofi-Aventis Deutschland GmbH.
1168-P: Serum MicroRNA-122 and -192 Are Increased in Adolescents with NAFLD: Potential Role as Biomarkers
Authors: SHORT KEVIN R. , PALLE SIRISH KUMAR , HELLMAN DIANA S. AMAYA , JIANG SHAONING , TRYGGESTAD JEANIE B. , GARCIA ESTEFANIA FEMATT 
Published: June 2021

The best available blood biomarker for nonalcoholic fatty liver disease (NAFLD) is alanine aminotransferase (ALT), though it does not reliably distinguish NAFLD severity. Alternate biomarkers have been tested in adults, but fewer in children. We tested serum microRNA-122 (miR-122) as a biomarker for NAFLD in adolescents since it inhibts hepatic lipogenesis in animals and is exported from liver to blood with disease progression. The only prior study of miR-122 in children produced mixed results. We also measured miR-192, -130b, and -155 as they have roles in hepatic lipogenesis. Participants were boys and girls, 12-20 y, with biopsy-confirmed NAFLD (n=23), and peers without NAFLD who were either obese (Ob, n=22), or normal weight (NW, n=24). RNA was extracted from serum from all participants and from liver biopsies from the NAFLD group. Serum miR-122 and -192 were 12- and 10-fold higher (p&lt; 0.01), respectively, in NAFLD patients compared to both Ob and NW controls. Within the NAFLD group, serum abundances of miR-122 and -192 were inversely correlated with their liver values (r = -0.51, p = 0.002 and r = -0.40, p = 0.067, respectively), and positively correlated with histological scores for steatosis (r = 0.39 and 0.28, respectively) and fibrosis (r = 0.56 and 0.54, respectively). mIR-122 and -192 content were also positively correlated with ALT (r = 0.78 for both) and with each other in both serum (r = 0.92) and liver (r = 0.74), suggesting similar regulation. Areas under the receiver operating curve for distinguishing NAFLD was 0.95 for miR-122 and -192. Serum miR-130b, which regulates PGC-1 alpha, was 2.6-fold higher in serum from NAFLD patients versus both control groups, while serum miR-155, which regulates lipogenesis and inflammation, did not differ in NAFLD. Serum miR-130b and miR-155 values were not correlated with their corresponding values in liver biopsies. These results support the potential use of miR-122 and -192 as biomarkers for the presence and severity of NAFLD in adolescents.

Disclosure
K. R. Short: None. S. Palle: None. D. S. Amaya hellman: None. S. Jiang: None. J. B. Tryggestad: None. E. Fematt garcia: None.

Funding
Oklahoma Shared Clinical & Translational Resource
1170-P: Dapagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, Attenuates the Development of Nonalcoholic Steatohepatitis-Associated Hepatocellular Carcinoma
Authors: LEE MINYOUNG , KIM YOUNG-EUN , LEE SEJEONG , KIM HAE KYUNG , LEE SOOK JUNG , KIM JIWON , KIM SUN-WOO , KIM RYEONG-HYEON , PARK HYUNKI , LEE HAYNGKYU , KANG EUN SEOK 
Published: June 2021

Nonalcoholic steatohepatitis (NASH) is the most prevalent chronic liver disease worldwide and increases the risk for hepatocellular carcinoma (HCC) in developed countries. However, no medications have been approved to protect against NASH-driven HCC. Dapagliflozin, a sodium glucose cotransporter-2 (SGLT-2) inhibitor, improves hyperglycemia by promoting glycosuria. We investigated whether dapagliflozin prevents NASH-driven HCC using a mouse model. Diethylnitrosamine (25 mg/kg) was intraperitoneally injected into 2-week-old C57BL6/J male mice, followed by either normal chow diet or 60% high-fat diet (HFD) for 30 weeks with or without dapagliflozin, 0.003% (w/w). HFD-fed mice without dapagliflozin had an increased number of tumor on liver surface compared with chow-fed mice (77.0 vs. 12.5/per mouse; n=6 per group; p=0.01). The number of liver tumors was significantly lower in dapagliflozin treated group (19.5/per mouse in dapagliflozin-treated HFD-fed mice; n=6) than that in HFD-fed mice without dapagliflozin (p=0.03). Dapagliflozin treatment numerically reduced body weight and fasting blood glucose compared with HFD-fed mice without dapagliflozin (41.0 vs. 40.2 g, p=0.94 for body weight, and 196.3 vs. 170.8 mg/dL, p=0.34 for fasting blood glucose). In addition, several human HCC cell lines (Huh 7, HepG2, and Hep3B) expressed SGLT-2 protein. Thus, it is possible that dapagliflozin might directly modulate HCC development via SGLT-2 inhibition.
In conclusion, dapagliflozin attenuates NASH-associated HCC development possibly via its direct effect on HCC.

Disclosure
M. Lee: None. H. Lee: None. E. Kang: None. Y. Kim: None. S. Lee: None. H. Kim: None. S. Lee: None. J. Kim: None. S. Kim: None. R. Kim: None. H. Park: None.
1190-P: Diabetes Activates Pancreatic Stellate Cells through RAGE Signaling in Pancreatic Ductal Adenocarcinoma
Authors: UCHIDA CHIAKI , MIZUKAMI HIROKI , KUDO KAZUHIRO , YAMAMOTO YASUHIKO 
Published: June 2021

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive carcinoma with poor prognosis. Its poor prognosis is ascribed to the extensive fibrotic stroma. Pancreatic stellate cells (PSCs) are major contributors to PDAC fibrosis. Type 2 diabetes (T2D) is an established risk factor for PDAC. The common mechanistic link might be the accumulation of advanced glycation end-products (AGEs) and the signaling through receptor for advanced glycation end-products (RAGE), the receptor for AGEs. Nevertheless, the role of RAGE in PSCs activation was not evaluated in PDAC with T2D. First, PSCs were isolated from male obese T2D model, db/db (db) and db/m (C) mice at 12 weeks of age. mRNA expression of the makers for PSCs activation like TGF-β1, αSMA and collagen type1A1 were significantly increased in PSCs isolated from db compared to C (p&lt;0.01, respectively). To evaluate the implication of RAGE, PSCs isolated from C57BL/6 (WT) and RAGE deleted mice (RKO) were stimulated with 12.5-100 μg/ml AGEs. AGEs increased mRNA expression of TGF-β1, αSMA and collagen type1A1 in WT-PSCs with dose dependent manner (p&lt;0.01, respectively) despite no increase in mRNA expressions in RKO-PSCs. Furthermore, PSCs were isolated from high fat diet induced obese WT and RKO for 8 weeks. The mRNA expressions of TGF-β1, αSMA and collagen type1A1 were comparable between two groups. We evaluated surgically resected human PDAC subjects with T2D (PDT2D, 33 cases) and without T2D (PDNT2D, 83cases). αSMA-labeled PSCs significantly surrounded the ducts with dysplasia in PDT2D compared to PDNT2D (p&lt;0.05). The nuclear expression of NF-κB in stromal cells, which was downstream molecules of RAGE, was significantly higher in PDT2D than PDNT2D (p&lt;0.05). Collectively, RAGE signaling was activated in PSCs in T2D, which could be implicated in severe stromal fibrosis in PDAC. Inhibition of RAGE signaling in PSCs may link to a new therapy, in which the stromal fibrosis and cytokine production are reduced in PDAC with T2D.

Disclosure
C. Uchida: None. H. Mizukami: None. K. Kudo: None. Y. Yamamoto: None.

Funding
Japan Society for the Promotion of Science (JP17K17579)
1193-P: Investigating the Role of Intestinal L-Cell Secretagogin in Circadian GLP-1 Secretion in a Mouse Model of Type 2 Diabetes
Authors: BIANCOLIN ANDREW , BRUBAKER PATRICIA L. 
Published: June 2021

The intestinal L-cell hormone Glucagon-like Peptide-1 (GLP-1) increases glucose-dependent insulin secretion and is thus used in the treatment of T2D. GLP-1 secretion from the L-cell exhibits a circadian pattern in rodents and varies by time-of-day in humans. We have shown that KD of the SNARE-regulatory protein, secretagogin (SCGN) prevents time-dependent GLP-1 release. SCGN KD in ß-cells also decreases insulin secretion and SCGN levels are reduced in T2D islets. We thus hypothesized that SCGN is decreased in the L-cell in T2D, causing alterations in the physiological pattern of GLP-1 secretion. High-fat diet, low-dose streptozotocin (HFD-STZ) mice, a model of T2D, exhibited increased fasting glucose (5.5 vs. 15.6 mmol/L; p&lt;0.001) and decreased ß-cell area (by 75%, p&lt;0.001). Unexpectedly, oral glucose tolerance tests conducted in 4-hour intervals through the 24-hr day showed that HFD-STZ mice exhibit a 10x increase in GLP-1 responses (400 vs. 4000 pg/ml*60 min, p&lt;0.001) and exhibit an anti-phasic rhythm to controls. Basal GLP-1 levels remained unchanged between HFD-STZ and controls. Unexpectedly, insulin responses were not reduced in HFD-STZ mice, suggesting that increased GLP-1 levels could act as a compensatory mechanism. HFD-STZ mice also exhibited hyperglucagonemia compared to control, with increased glucagon secretion across timepoints following glucose administration (–243 vs. 800 pg/ml*60 min, p&lt;0.001). RT-qPCR of intestinal mucosa showed an anti-phasic Scgn rhythm in the HFD-STZ model, with a 1.5-fold increase in average expression across timepoints (p&lt;0.05), which could explain the drastically increased GLP-1 secretion. These data show that GLP-1 secretion is both increased and arrhythmic in a murine model of T2D, and that this occurs in association with an unanticipated increase in Scgn expression. Further investigation into the role of SGCN in the L-cell may serve as an avenue for therapeutics aimed at increasing endogenous GLP-1 release.

Disclosure
A. Biancolin: None. P. L. Brubaker: None.

Funding
Canadian Institutes of Health Research (PJT-15308)
1203-P: High-Dose Erythropoietin and Cardiac Function in Mice
Authors: LEE JEEYOUNG , NOGUCHI CONSTANCE T. 
Published: June 2021

Erythropoietin (EPO) is the cytokine required for erythropoiesis. EPO stimulated increase in hematocrit elevates blood viscosity that may cause hemodynamic risks in the cardiovascular system, promote ischemic heart disease, and stroke. Herein, we studied the physiological effect of high dose exogenous EPO (i.p. 3000 U/kg, 3 times/week for three weeks) with high fat diet (HFD) on cardiac function using echocardiographic measurements in young wild-type (WT) male and female mice and older obese WT male mice with fat mass &gt;45%. In young male mice, but not in female and older obese male mice, EPO treatment with HFD decreased body weight and fat mass accumulation compared with saline, although all groups showed similar EPO stimulated increases in hematocrit. EPO reduced ejection fraction and fractional shortening of left ventricle (LV) in both young male and female mice. This is consistent with the previous report that mice with chronic overexpression of human EPO have decreased fractional shortening of LV. In contrast, older obese male mice have reduced basal ejection fraction and fractional shortening that remain unchanged with EPO treatment indicating that the changes in basal ejection fraction and fractional shortening with EPO treatment in younger mice were not due to EPO stimulated increase in red cell mass. EPO decreased peak velocity of blood flow in the pulmonary artery in all groups indicative of increased hematocrit promoting higher blood viscosity. In addition, EPO increased LV posterior wall thickness in diastole in older male obese mice. This is consonant with observations that high hematocrit is related to concentric left ventricular hypertrophy in human. These data suggest that high dose EPO treatment may be associated with possible cardiac dysfunction with decreased ejection fraction and fractional shortening of LV, and alteration of left ventricular geometry.

Disclosure
J. Lee: None. C. T. Noguchi: None.
1205-P: Baricitinib Inhibition of Jak/STAT Pathway Changed Immune Composition in Adipose Tissue and Improved Metabolism in Diet-Induced Obese Mice
Authors: LIAN ZEQIN , PERRARD XIAOYUAN , BALLANTYNE CHRISTIE M. , WU HUAIZHU 
Published: June 2021

Jak/STAT pathway plays key roles in inflammation and is highly activated in adipose tissue (AT) in obesity. Recently, inhibition of the Jak/STAT pathway with baricitinib, a Jak1/Jak2 inhibitor, has been demonstrated to accelerate clinical improvements in a trial of hospitalized patients with COVID-19, who had a mean BMI of 32. Currently, we aimed to examine effects of long-term treatment with baricitinib on AT inflammation and metabolism in diet-induced obese mice. Starting from 3 months old, male C57BL/6J mice were fed high fat diet (HFD) and concurrently received daily oral gavage of baricitinib (10mg/kg) or vehicle for 12 weeks. Compared to vehicle control, baricitinib treatment significantly improved insulin resistance examined by insulin tolerance test and increased UCP1 (a key browning marker) expression in perigonadal (pAT) and inguinal AT (iAT), but did not affect weight gain and AT mass. Strikingly, total T cells were reduced by ~50% in iAT and pAT in baricitinib group vs. control group. CD4+ IFNγ-expressing Th1 cells, IL5-expressing Th2 cells, and TNFα-expressing T cells were decreased in pAT, but not in iAT, of mice from baricitinib group vs. control group. Unexpectedly, percentage of TNFα-expressing cells in CD8+ T cells were higher in iAT of baricitinib-treated mice than controls. Finally, baricitinib compared to control reduced M1/M2 ratio in pAT, but not iAT, and reduced eosinophils in iAT and pAT. Baricitinib inhibition of Jak/STAT pathway in diet-induced obese mice improved insulin sensitivity and changed immune cells in AT, with dramatic reductions of T cells in particular, indicating an important role of Jak/STAT-mediated inflammation in metabolism in obesity. Given the fact that obesity and insulin resistance are associated with increased severity of COVID-19, our data also point to the need for further studies on AT immune cells, COVID-19, and baricitinib.

Disclosure
Z. Lian: None. X. Perrard: None. C. M. Ballantyne: Advisory Panel; Self; Amarin Corporation plc, Arrowhead Pharmaceuticals, Inc., Pfizer Inc., Consultant; Self; Amgen Inc., CSL Behring, Intercept Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Regeneron Pharmaceuticals Inc., Research Support; Self; Abbott, Amgen Inc., Ionis Pharmaceuticals, Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals Inc., Roche Diagnostic USA. H. Wu: None.
1208-P: Caloric Restriction Modified Factors Regulating Lipid Storage and Apoptosis in Inguinal but Not Epididymal Adipose Tissue of 24-Month-Old Male Rats
Authors: VARSHNEY PALLAVI , SCHLEH MICHAEL W. , AHN CHEEHOON , ZHENG AMY , ARIAS EDWARD B. , CARTEE GREGORY D. , HOROWITZ JEFFREY F. 
Published: June 2021

Calorie restriction (CR) and the resultant weight-loss are known to improve metabolic health, but the effects of CR on factors regulating white adipose tissue (WAT) metabolic function and remodeling remain unclear. The purpose of this study was to examine the effects of 8 weeks of CR on markers of lipid storage/release, endoplasmic reticulum (ER) stress, and apoptosis in inguinal and epididymal WAT collected from aged rats. We harvested inguinal and epididymal adipose tissue from 24-month-old male Fischer-344 x Brown Norway rats that were either fed an ad libitum chow diet (AL, n=6) or subjected to CR (consuming 35% below AL intake) of the same diet (n=6) for 8 weeks. Using standard immunoblotting methods, inguinal WAT from CR had a greater abundance of phosphorylated hormone sensitive lipase (pHSL) than AL (11.1±6.6 vs. 4.5±3.3 arbitrary units (AU); P=0.05) indicative of elevated lipase activity in CR, and a lower protein abundance of the esterification marker, diacylglycerol acyltransferase (DGAT; 1.0±0.2 vs. 2.4±0.6 AU; P&lt;0.001). Interestingly, protein abundance of the ER stress marker, CCAAT-enhancer-binding protein homologous protein (CHOP) was also significantly lower in CR vs. AL (0.7±0.3 vs. 1.7±0.5 AU; P&lt;0.01), and the protein abundance of Beclin, a marker of autophagy, tended to be lower in CR vs. AL (1.9±0.4 vs. 2.6±0.7 AU, for CR vs. AL; P=0.08). In contrast to these findings for inguinal WAT, there were no detectable differences in protein abundance for any of these markers in epididymal WAT from CR vs. AL.
In summary, CR-mediated responses in WAT of aged rats appeared to be depot-specific and CR may contribute to important metabolic modifications and may impact cellular remodeling of inguinal adipose tissue.

Disclosure
P. Varshney: None. M. W. Schleh: None. C. Ahn: None. A. Zheng: None. E. B. Arias: None. G. D. Cartee: None. J. F. Horowitz: None.

Funding
National Institutes of Health (R01DK077966, P30DK089503, R01AG010026)
1212-P: Adipose Tissue Mitochondrial Function in Humans with Varying Liver Histology
Authors: PAFILI KALLIOPI , KAHL SABINE , PESTA DOMINIK , STRASSBURGER KLAUS , MASTROTOTARO LUCIA , PUETZER-FURMANCZAK JENNIFER , DEWIDAR BEDAIR , SARABHAI THERESIA , ESPOSITO IRENE , SCHLENSAK MATTHIAS , RODEN MICHAEL 
Published: June 2021

Adipose dysfunction may drive the development of insulin resistance, type 2 diabetes (T2D) and nonalcoholic (NA) fatty liver disease (NAFLD), comprising NA fatty liver and steatohepatitis (NAFL and NASH). Possible underlying mechanism comprise impaired lipid storage or mitochondrial oxidation favoring increased fatty acid flux to other tissues. Thus, we examined subcutaneous (SAT) and visceral adipose tissue (VAT) mitochondrial capacity in humans with different degrees of insulin resistance and histologically proven NAFLD. Obese people without NAFL (OBE-CON, n=20, 38±8 years, body mass index 53±6 kg/m2, 10% T2D), with NAFL (OBE-NAFL, n=20, 40±8 years, 51±5 kg/m2, 25% T2D) or NASH (OBE-NASH, n=20, 42±10 years, 51±6 kg/m2, 40% T2D) underwent metabolic phenotyping and tissue biopsies. O2 flux rates from different substrates were measured with high resolution respirometry in SAT and VAT. In VAT, maximal uncoupled respiration was lower in OBE-NAFL (least square means (LSM): 0.46 pmol*mg wet weight–1*s–1 [95% confidence interval 0.21;0.71], p&lt;0.05) and OBE-NASH (LSM: 0.51 [0.26;0.76], p&lt;0.001) compared to OBE-CON. Similar differences were seen for state 3 respiration related to complex I (glutamate) or combined complex I and II activity (succinate). In Pearson correlation analysis, combined complex I and II activity in VAT positively correlated with whole-body insulin sensitivity (M value; r= 0.29, p&lt;0.05). VAT mitochondrial content, as assessed from mitochondrial DNA copy number, was not different between the groups. Protein expression of electron transport chain complexes was similar in VAT and SAT of all groups, except for complex IV that tended to be lower in VAT in OBE-NASH than in OBE-CON (p=0.065). Of note, in SAT, oxidative capacity was comparable between groups despite a higher mitochondrial mass in OBE-NASH than in OBE-CON (p=0.045).
In conclusion, oxidative capacity is downregulated in VAT, but not in SAT of obese humans with NAFLD, which may be related to the degree of insulin resistance.

Disclosure
K. Pafili: None. M. Schlensak: None. M. Roden: Advisory Panel; Self; Allergan plc, Bristol-Myers Squibb Company, Novo Nordisk A/S, Research Support; Self; Boehringer Ingelheim International GmbH, Danone Nutricia, Sanofi-Aventis Deutschland GmbH. S. Kahl: None. D. Pesta: None. K. Strassburger: None. L. Mastrototaro: None. J. Puetzer-furmanczak: None. B. Dewidar: None. T. Sarabhai: None. I. Esposito: None.