bluuebunny/crossref_metadata_2025_split huggingface dataset:
198-LB: Maternal Plasma AGEs and Preeclampsia in Women with Type 1 Diabetes
Authors: KARANCHI HARSHA , KELLY CLARE B. , HAMMAD SAMAR M. , KLEIN RICHARD L. , LOPES-VIRELLA MARIA F. , LEYVA MISTI J. , YU JEREMY , JENKINS ALICIA J. , NANKERVIS ALISON J. , HANSSEN KRISTIAN F. , ASTON CHRISTOPHER E. , HOWELL SCOTT , BEISSWENGER PAUL J. , LYONS TIMOTHY 
Published: June 2019

Preeclampsia (PE) occurs four times more frequently in pregnant women with type 1 diabetes (T1D) than in nondiabetic women. We hypothesized that elevated plasma advanced glycoxidation products (AGEs) predict PE in T1D women. In a prospective T1D pregnancy cohort (study visits at 12, 22, 32 weeks' gestation), we used liquid chromatography/mass spectrometry, with internal stable heavy isotope substituted standards, to determine plasma levels of nine AGE and oxidation products (carboxymethyl-lysine [CML], carboxyethyl-lysine [CEL], methylglyoxal-hydroimidazolone [MGHI], 3-deoxyglucosone hydroimidazolones [3DGH], methionine sulfoxide [MetSO], glyoxal hydroimidazolone [GHI], 3-nitrotyrosine [3NT], dityrosine [DT], 2-aminoadipic acid [2AAA]) in 23 women with T1DM who developed PE vs. 24 who did not, and in 19 nondiabetic normotensive pregnant women. These products have been associated with CVD and renal failure in non-pregnant cohorts. All women were free of microalbuminuria and hypertension at enrolment, and all visits preceded clinical PE onset. GFR was estimated (Chronic Kidney Disease Epidemiology Collaboration equation).
Results: Plasma CML, CEL, MGHI, 3DGH, MetSO, GHI, and 2AAA did not differ between the three groups at any study visit, and thus did not predict preeclampsia in T1D. In T1D women who later developed PE, eGFR was inversely associated at V3 with CML (p=0.008), CEL (p=0.03), MGH1 (p=0.03), 3DGH (p=0.03), GHI (p&lt;0.001), and 2AAA (p&lt;0.05); and at V2 with CEL (p=0.04), MGHI (p=0.02), and GHI (p=0.02). No such associations were observed in normotensive T1D or in nondiabetic pregnant women. Plasma levels of 3NT and DT were undetectable in all participants.
Conclusions: Plasma AGEs did not predict PE in well-controlled, previously healthy T1D women, and levels did not differ from healthy nondiabetic controls. Uniquely, in T1D women who developed PE, plasma AGEs were associated with renal function, consistent with the notion that subclinical alterations in renal function precede PE.

Disclosure
H. Karanchi: None. C.B. Kelly: None. S.M. Hammad: None. R.L. Klein: None. M.F. Lopes-Virella: None. M.J. Leyva: None. J. Yu: None. A.J. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. A.J. Nankervis: None. K.F. Hanssen: None. C.E. Aston: None. S. Howell: Employee; Self; PreventAGE Health Care, LLC. P.J. Beisswenger: Other Relationship; Self; PreventAGE Health Care, LLC. T. Lyons: None.
1982-P: Glucagon-Like Peptide-2 Inhibits Postprandial Gallbladder Emptying in Healthy Male Individuals—A Randomized, Double-Blinded, Placebo-Controlled Study
Authors: HANSEN NINA L. , NEXØE-LARSEN CHRISTINA CHARLOTTE , BRØNDEN ANDREAS , CHRISTENSEN ALEXANDER S. , SONNE DAVID P. , HARTMANN BOLETTE , VILSBØLL TINA , HOLST JENS J. , KNOP FILIP K. 
Published: June 2019

A recent study in mice has demonstrated that the gut-derived hormone glucagon-like peptide-2 (GLP-2) may be involved in the regulation of gallbladder motility and induces gallbladder refilling. This study evaluated the effect of exogenous GLP-2 on postprandial gallbladder motility in humans. On three experimental days, 15 young healthy males ([mean±SEM] age 24.3±1.9 years, BMI 22.5±0.9 kg×m-2, HbA1c 4.8±0.1% (29.3±1.5 mmol/mol)) were subjected to a 3.5-hour 300 kcal mixed liquid meal-test. Continuous 4-hour intravenous infusions of placebo (saline), low-dose GLP-2 (1 pmol×kg-1×min-1) or high-dose GLP-2 (10 pmol×kg-1×min-1) were initiated 30 min before meal ingestion. Gallbladder volume was determined by ultrasonography, and gallbladder ejection fraction was calculated. Postprandial maximum gallbladder ejection fraction during saline infusion (76.3±2.8%) was significantly reduced by low-dose GLP-2 (65.5±3.5%, P=0.026) and completely abolished during high-dose GLP-2 infusion (4.0±3.7%, P&lt;0.0001) (Figure). Postprandial peak plasma glucose was lower during high-dose GLP-2 infusion (6.4±0.2 mmol/l) compared to low-dose GLP-2 (6.9±0.2mmol/l, P=0.0004) and placebo infusion (7.2±0.2 mmol/l, P=0.008).
In conclusion, exogenous GLP-2 dose-dependently inhibits postprandial gallbladder emptying in healthy male subjects.

Disclosure
N.L. Hansen: None. C.C. Nexøe-Larsen: None. A. Brønden: Other Relationship; Self; AstraZeneca. A.S. Christensen: None. D.P. Sonne: None. B. Hartmann: None. T. Vilsbøll: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S.
1983-P: WNT Pathway and Bone Fragility in Postmenopausal Women with Type 2 Diabetes
Authors: PICCOLI ALESSANDRA , CANNATA FRANCESCA , RUSSO FABRIZIO , GRETO VALENTINA L. , ISGRÒ CAMILLA , LEANZA GIULIA , STROLLO ROCKY , MASSARONI CARLO , PEDONE CLAUDIO , SILVESTRI SERGIO , VADALÀ GIANLUCA , DENARO VINCENZO , BISOGNO TIZIANA , PAPALIA ROCCO , POZZILLI PAOLO , MACCARRONE MAURO , NAPOLI NICOLA 
Published: June 2019

Fragility fractures are major complications in type 2 diabetes (T2D), but mechanisms underlying bone fragility are still poorly clarified. Bone mineral density (BMD) underestimates T2D fracture incidence, since a normal or even higher BMD is associated with a greater fracture risk than healthy population. We hypothesized that bone fragility in T2D results from poor bone microarchitecture and bone quality caused by WNT signaling impairment and lower bone formation. We aimed to evaluate the association between bone gene expression of WNT pathway and features of bone microarchitecture and strength. We enrolled T2D (n=13) and nondiabetic (controls, n=75) postmenopausal women undergoing standard hip arthroplasty. Serum and proximal femur samples from recruited subjects were collected at the moment of surgical procedure. Gene expression of sclerostin (SOST), WNT5a, WNT10b, SFRP5, GSK3β, osteocalcin and RUNX2 was analyzed by real-time PCR. Total-body, lumbar and femoral BMD were assessed by bone densitometry. A trabecular core from bone samples was analyzed by Micro X-ray computed tomography and by compression tests. Age (75.23 ± 8.47 vs. 73.24 ± 5.77) and BMI (29.92 ± 5.38 vs. 27.68 ± 5.62 Kg/m2) did not differ between T2D and controls respectively. Glycated hemoglobin was 6.48 ± 1.7 mmol/mol. We found that T2D subjects had no differences in BMD and in bone microarchitecture parameters compared to controls. Neither bone turnover nor WNT serum markers differed among groups. SOST gene expression was increased (p=0.003) whereas RUNX2 expression was decreased in T2D vs. controls (p=0.017), independently by BMI and age. Osteocalcin and other WNT related genes expression did not differ among groups. Compression tests did not show impairment in bone strength in T2D vs. controls.
In conclusion, although a good glycemic control and no alterations in bone density, microarchitecture and strength, we found an increase in SOST and a decrease in RUNX2 gene expression, implying a lower bone formation in T2D.

Disclosure
A. Piccoli: None. F. Cannata: None. F. Russo: None. V.L. Greto: None. C. Isgrò: None. G. Leanza: None. R. Strollo: None. C. Massaroni: None. C. Pedone: None. S. Silvestri: None. G. Vadalà: None. V. Denaro: None. T. Bisogno: None. R. Papalia: None. P. Pozzilli: None. M. Maccarrone: None. N. Napoli: None.

Funding
Campus Bio-Medico University
199-LB: Low Prevalence of Small-for-Gestational-Age in Women with Type 1 Diabetes and Chronic Hypertension
Authors: HELMAN SARIT , JAMES-TODD TAMARRA , BROWN FLORENCE M. 
Published: June 2019

Objective: To evaluate delivery outcomes in women with concurrent type 1 diabetes and chronic hypertension (cHTN) treated with anti-hypertensive pharmacotherapy to target blood pressure (BP) 110-129/65-79 mmHg throughout pregnancy per ADA 2008-2016 guidelines.
Research Design and Methods: We abstracted clinical data from the medical records of 752 pregnancies derived from 550 women seeking prenatal care at the Joslin Diabetes Center and Beth Israel Deaconess Medical Center’s Diabetes in Pregnancy Program from 2004-2017. We calculated means and percentages, used t test or ?2 test, and linear regression to compare trimester specific BP values, birth weight and prevalence of small for gestational age (SGA) in pregnancies of women with type 1 diabetes and cHTN to those with type 1 diabetes and no cHTN.
Results: Type 1 diabetes and cHTN occurred in 51 (6.7%) of pregnancies and the mean BP values were 128/76 in the first trimester; 122/72 in the second trimester; 124/76 in the third trimester; 137/82 prior to delivery. BP values were significantly higher in women with type 1 diabetes and cHTN for each trimester compared to women with type 1 diabetes and no cHTN (p&lt;0.001). Women with type 1 diabetes and cHTN were older (33.4 vs. 31.5 years p=0.04), had higher BMI (28.3 vs. 26.6 kg/m2 p=0.03), were more likely to have diabetic nephropathy (10.4% vs. 2%, p&lt;0.001) and use insulin pumps (75.5% vs. 60%, p=0.04). There were no significant differences in gestational age at delivery and birth weight. SGA in both groups was rare, with 0 (0%) in the type 1 diabetes with cHTN group and 5 (0.9%) in the group without cHTN (p=0.54).
Conclusion: SGA is rare in pregnancies complicated by type 1 diabetes and cHTN and did not differ from those without cHTN, even when BP targets of 110-129/65-79 mmHg are used. This may provide reassurance to reestablish these lower BP targets rather than the recently adopted higher targets of 120-160/80-105 mmHg followed by ACOG since 2013 and ADA since 2017.

Disclosure
S. Helman: None. T. James-Todd: None. F.M. Brown: None.
199-OR: Time-Restricted Feeding Ameliorates Metabolic Dysfunction through the Restoration of Circadian Beta-Cell Function and Transcriptional Identity
Authors: BROWN MATTHEW , HER TRACY K. , MATVEYENKO ALEKSEY 
Published: June 2019

There are clear associations between circadian disruption (CD), induction of pancreatic β-cell failure and T2DM. However, the underlying mechanisms driving these associations remain unclear. CD is behaviorally characterized by the dysregulation of circadian feeding patterns, which play a key role in the regulation of glucose homeostasis. Therefore, we set out to test the hypothesis that disrupted circadian feeding patterns mediate CD-induced metabolic dysfunction by promoting β-cell failure and reprogramming of the circadian islet transcriptome. To address this, C57B6 mice were assigned into 3 protocols for 12 weeks: 1) LD: exposed to standard light-dark cycle on ad libitum chow; 2) CD: Constant light exposure, to disrupt endogenous circadian rhythms, on ad libitum chow; 3) CD-tRF: Constant light exposure with time-restricted access to chow (tRF) during the first 8h of the circadian “active/feeding” phase. CD led to a loss of circadian rhythmicity in feeding, activity and energy expenditure (p&lt;0.05 vs. LD). These behavioral abnormalities corresponded with loss of circadian regulation of glucose tolerance and insulin response (p&lt;0.05 vs. LD). Moreover, time-dependent RNA-seq of islets revealed that CD significantly altered 98% of genes that were differentially expressed under LD conditions. Restoration of circadian feeding patterns (without altering daily energy intake) in CD-tRF led to reversal of metabolic defects by enhancing circadian glucose tolerance and insulin secretory response (p&lt;0.05 vs. CD). Importantly, CD-tRF normalized circadian expression patterns of 707 genes enriched for KEGG pathways regulating key aspects of β-cell function such as insulin secretion, protein processing in ER, and NF-kB signaling (all FDR&lt;0.05). This study suggests that the deleterious metabolic effects of CD on the β-cell are a consequence of disrupted circadian feeding patterns and imply that tRF may attenuate β-cell failure in T2DM.

Disclosure
M. Brown: None. T.K. Her: None. A. Matveyenko: None.

Funding
National Institutes of Health (R01DK98468)
1996-P: Paternal Gastric Bypass Surgery Confers Protection from Metabolic Syndrome and Hepatic Steatosis in Offspring Mice
Authors: YUCHI YIXING , HAO ZHENG , TAKAGI TOKIYO , BERTHOUD HANS-RUDOLF , PATTI MARY E. 
Published: June 2019

Bariatric surgery is increasingly recognized as a potent approach for obesity and T2D. While bariatric surgery in females yields variable effects on offspring, the impact of bariatric surgery in males on metabolism of their offspring is unknown. To determine whether paternal RYGB could induce intergenerational effects, male C57BL/6 mice with Roux-en-Y gastric bypass 5 months earlier (RYGB, n=4) or weight/age-matched controls (CON, n=5) were bred with healthy females of the same strain; 3 pregnancies were achieved by RYGB and 6 by CON males. Birth weight of offspring from RYGB or CON fathers did not differ. Seven offspring (2 litters) of RYGB fathers and 12 (2 litters) of CON fathers survived to weaning. On chow diet, male offspring of RYGB fathers reduced weight gain over time (p&lt;0.05 vs. CON) but there was no significant difference in insulin sensitivity or glucose tolerance at 3 months of age. At 6 months of age, male offspring of RYGB fathers had significantly lower fasting glucose and improved oral glucose tolerance (17% lower AUC, p&lt;0.05). When fed a 45% high-fat diet (HFD) for 15 weeks, RYGB offspring had significantly lower weight gain than control offspring, with lower body weight (37±5.7g vs. 51±1.1g), and reduced fat percentage (36±6.8 vs. 48±1.1%), in turn potentially linked to reduced food intake. Moreover, RYGB offspring had lower fasting glucose, improved insulin sensitivity (intraperitoneal insulin tolerance), and increased respiratory exchange ratio in fed state. In addition, HFD-fed RYGB offspring had dramatic improvement in hepatic steatosis, with 70% of RYGB offspring having no steatosis, as compared with 100% of CON offspring with severe steatosis (p&lt;0.0001).
In conclusion, RYGB surgery in fathers prior to breeding can provide protection against metabolic syndrome and hepatic steatosis in offspring, and suggests that interventions to improve the health of fathers could interrupt intergenerational cycles of obesity and diabetes risk.

Disclosure
Y. Yuchi: None. Z. Hao: None. T. Takagi: None. H. Berthoud: None. M.E. Patti: Consultant; Self; Eiger BioPharmaceuticals. Research Support; Self; Dexcom, Inc., Janssen Pharmaceuticals, Inc., MedImmune, Xeris Pharmaceuticals, Inc.

Funding
The Medical Foundation; National Institutes of Health (DK047348)
200-OR: Role of Delta Cell Gpr120 in the Regulation of Islet Function and Glucose Control
Authors: CROZE MARINE L. , GRANZIERA SABRINA , VIVOT KEVIN , SZPIGEL ANAIS , GHISLAIN JULIEN , POITOUT VINCENT 
Published: June 2019

Gpr120 is a long-chain fatty acid receptor expressed in pancreatic islets, where it inhibits the secretion of somatostatin (SST) by the δ cell. SST is a negative regulator of glucoregulatory hormone secretion. However, the precise role of Gpr120 in the regulation of insulin and glucagon secretion is still unclear, as well as the specific islet cell(s) type(s) involved.
Objective: This study aimed at defining the role of pancreatic δ-cell Gpr120 signaling in the regulation of islet function and glucose homeostasis.
Methods: Insulin and SST secretion was measured in isolated islets from WT, Gpr120 KO and Gpr40 KO mice in 1h static incubation in the presence of 2.8 or 16.7 mM glucose with or without synthetic (Compound A, Cpd A) or endogenous (alpha-linolenic, eicosapentaenoic or docosahexaenoic acid) Gpr120 agonists. Glucagon and SST secretion was measured after 1h static incubation in response to arginine with or without Cpd A. Cpd A was administered orally to WT male mice before an oral Glucose Tolerance Test or an Arginine Test, and blood glucose and insulin or glucagon plasma levels were measured.
Results: In isolated islets from WT mice, activation of Gpr120 with either Cpd A or endogenous agonists dose-dependently inhibited glucose-stimulated SST secretion, and concomitantly increased glucose-stimulated insulin secretion. Cpd A also inhibited SST secretion and potentiated glucagon secretion in response to arginine in low glucose conditions. The effects of Cpd A were unaltered in Gpr40 KO islets but disappeared in Gpr120 KO islets. Oral administration of Cpd A improved glucose tolerance and potentiated both glucose-induced insulin secretion and arginine-induced glucagon secretion.
Conclusion: The results demonstrate that Gpr120 activation in islets inhibits SST secretion, potentiates insulin and glucagon secretion, and improves glycemic control.

Disclosure
M.L. Croze: None. S. Granziera: None. K. Vivot: None. A. Szpigel: None. J. Ghislain: None. V. Poitout: None.

Funding
Société Francophone du Diabète; Montreal Diabetes Research Center; Natural Sciences and Engineering Research Council of Canada
2002-P: A Long-Acting GLP-1 and Y2-Receptor Dual Agonist Improves Body Weight and Glucose Control in Obese and Diabetic Rodent Models
Authors: OLDHAM STEPHANIE , HOWARD VICTOR G. , WILL SARAH , HORNIGOLD DAVID C. , RHODES CHRISTOPHER J. , MADALLI SHIMONA , SERMADIRAS ISABELLE , NAYLOR JACQUELINE , RIVERA CHRSITAN 
Published: June 2019

Bariatric surgery can result in profound weight loss and remission of type 2 diabetes. Following meal consumption post-surgery, patients exhibit an exaggerated increase in the circulating levels of the enteroendocrine L-cell peptides peptide YY (PYY) and glucagon-like peptide-1 (GLP-1). We have developed a long-acting PYY Y2 and GLP-1 receptor agonist (GLP-1-Fc-PYY), which exerted potent effects on improving glucose metabolism and body weight loss in diabetic db/db mice and diet-induced obese (DIO) mice. Administration of GLP-1-Fc-PYY to diabetic db/db mice for 28 days normalized HbA1c levels (4.3%) compared to vehicle controls (9.1%), and exceeded that observed with Fc-GLP-1 monotherapy treatment (7.2%). GLP-1-Fc-PYY administration also preserved circulating insulin levels and increased pancreatic insulin content in db/db mice, which was not observed in mice treated with Fc-GLP-1. Administration of GLP-1-Fc-PYY for 21 days in DIO mice resulted in a 28% (p&lt;0.0001) decrease in body weight, whereas vehicle-treated mice gained 13% and Fc-GLP-1-treated mice only exhibited a 13% reduction in body weight. To further characterize the GLP-1-Fc-PYY molecule, DIO GLP-1R knockout (KO) mice were treated for 13 days, and effects on body weight loss were partially attenuated in GLP-1R KO mice (10% BW loss), compared to wild type mice (32% BW loss). Additionally, when GLP-1R KO DIO mice were challenged with an IP glucose bolus following sub-chronic GLP-1-Fc-PYY treatment, the improvement in glucose excursion was lost compared to wild type mice. DIO Y2R KO mice treated for 11 days with GLP-1-Fc-PYY had attenuated BW loss (9%) compared to wild type mice (32%). These data suggest that GLP-1-Fc-PYY is a balanced dual agonist with in vivo activity at both the GLP-1 and Y2 receptors. GLP-1-Fc-PYY therefore represents a PYY/GLP-1 long-acting dual agonist that produces robust bariatric surgery-like weight loss and antidiabetic efficacy in relevant rodent models.

Disclosure
S. Oldham: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. V.G. Howard: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. S. Will: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. D.C. Hornigold: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. C.J. Rhodes: Employee; Self; AstraZeneca, MedImmune. S. Madalli: None. I. Sermadiras: None. J. Naylor: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. C. Rivera: None.
2011-P: Totum-63 Lowers Adipose Tissue Inflammation and Reverses Both Hepatic Steatosis and Insulin Resistance in High-Fat Diet-Induced Obese Mice
Authors: DER ZANDE HENDRIK JOHANNES VAN , ZAWISTOWSKA-DENIZIAK ANNA , OTTO FRANK , CHAVANELLE VIVIEN , PELTIER SEBASTIEN , SIRVENT PASCAL , GUIGAS BRUNO 
Published: June 2019

The worldwide prevalence of obesity, metabolic syndrome and type 2 diabetes (T2D) is reaching epidemic proportions that urge the development of new therapeutic strategies. Obesity-associated meta-inflammation contributes to nonalcoholic fatty liver disease (NAFLD) and plays a central role in the development of insulin resistance and T2D. Totum-63 has recently been developed for the management of prediabetes and shown to prevent high-fat diet (HFD)-induced metabolic disorders in mice. In the present study, we investigated whether Totum-63 could also improve metabolic homeostasis in insulin-resistant obese mice. For this purpose, C57Bl6/J male mice were fed a low- (LFD) or HFD for 12 weeks followed by supplementation with or without Totum-63 (2.7% w/w) for 4 additional weeks. Although no metabolic phenotype was observed in LFD-fed mice, Totum-63 decreased body weight in HFD-fed mice, an effect exclusively due to reduced fat mass and associated with a transient reduction in food intake confined to the first days of supplementation. The liver and brown adipose tissue weights were significantly reduced, whereas adipose tissue (AT) mass and adipocyte size distribution were not affected. Totum-63 markedly reduced hepatic macrovesicular steatosis and liver triglyceride content. Furthermore, potent decreases in fasting plasma glucose, insulin and leptin levels, and improvements in systemic insulin sensitivity and glucose tolerance were observed. Remarkably, a significant reduction in AT M1-like pro-inflammatory macrophages was found, indicating that Totum-63 can modulate macrophage recruitment/polarization and lower HFD-induced AT inflammation. Altogether, our results strongly suggest that Totum-63 reverses hepatic steatosis and insulin resistance in obese mice at least partly by dampening meta-inflammation, constituting a promising new approach for alleviating NAFLD and metabolic dysfunctions in established T2D.

Disclosure
H.J. van der Zande: None. A. Zawistowska-Deniziak: None. F. Otto: None. V. Chavanelle: Employee; Self; Valbiotis. S. Peltier: Board Member; Self; Valbiotis. P. Sirvent: Board Member; Self; Valbiotis. B. Guigas: Advisory Panel; Self; Valbiotis. Research Support; Self; Valbiotis.