bluuebunny/crossref_metadata_2025_split huggingface dataset:
195-LB: How Does a Prepregnancy Weight Loss Program Affect Gestational Diabetes Risk?
Authors: LEBLANC ERIN S. , SMITH NING , VESCO KIMBERLY , ROSALES ANA G. , STEVENS VICTOR J. 
Published: June 2019

Although numerous organizations recommend that women with obesity or overweight lose weight prior to pregnancy, to our knowledge no data have addressed whether interventions that help women lose weight before pregnancy affect gestational diabetes risk in mothers. We successfully randomized 164 pregnant women to receive either a behavioral weight-loss intervention (n = 87) or usual care (n = 77) from prepregnancy through delivery. Intervention participants achieved significantly more weight loss before pregnancy than the usual care group (3.7 kg vs. 0.5 kg; p=&lt;0.001). A diabetologist who was blinded to intervention status used EMR data to determine whether women had a clinical diagnosis of GDM. We compared rates of GDM in the intervention and usual care groups using logistic regression. Higher weight at randomization, previous GDM diagnosis, Hispanic ethnicity, and lower income were associated with higher risk of GDM. After adjusting for these variables, women in the intervention group were less likely to develop GDM (Table), although the difference was not statistically significant. However, based on our sample size of 164, we only had a power of 37% to detect the observed difference of 11% in GDM rates. Future, fully powered studies should test the role of prepregnancy weight loss interventions in preventing gestational diabetes.

Disclosure
E.S. LeBlanc: None. N. Smith: None. K. Vesco: None. A.G. Rosales: None. V.J. Stevens: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK0099882)
1951-P: Prolonged (12-Hour) Glucagon Infusion Leads to Transient Elevation of Plasma Glucose but Sustained Elevation of Hepatic Glucose Production
Authors: CHEN XI , MEROVCI AURORA , CASE EMINA , DEFRONZO RALPH A. , TRIPATHY DEVJIT 
Published: June 2019

Recently, novel non-glycemic effects of glucagon have been described. Although short-term glucagon infusion is well known to elevate plasma glucose levels, long-term effect of increased plasma glucagon on glucose and lipid metabolism is unclear. The aim of the present study was to evaluate the effect of 12-hour glucagon infusion on hepatic glucose production and lipid metabolism in healthy NGT individuals. 8 NGT subjects (5M/3F, age=35± 5 years, BMI = 24 ± 1 kg/m2, HbA1c 5.2± 0.1%) received an 2-hour (75gram) OGTT. On a different day subjects received a 12-hour (6PM to 6 AM) glucagon infusion (3ng/kg/minutes) with the measurement of hepatic glucose production (HGP) with 3-3H-glucose on the following morning from 6-10 AM. HGP in glucagon infused subjects was compared to values in 20 age/gender/weight matched NGT subjects studied after an overnight fast from 6-10 AM. Plasma glucose, insulin, C-peptide, glucagon, and FFA concentrations were obtained every 15 minutes during OGTT. Plasma glucagon concentrations increased from 40 ± 4 to 120 ± 34 pg/ml at 6 AM. Plasma glucose increased 2 hours after the start of infusion from 95 ± 6 to 111 ± 6 mg/dl (p&lt;0.005); after 12 hours of glucagon infusion the plasma glucose concentration declined to the mean baseline levels. After 12-hour glucagon infusion (6 AM), plasma insulin and C-peptide were not significantly changed. Basal hepatic glucose production was significantly higher following prolonged (12-hour) glucagon infusion compared to NGT control subjects following 12-hour overnight fast (3.1 ± 0.1 vs. 2.2 ± 0.2 mg/kg/minutes, p&lt;0.05). Plasma FFA concentrations did not change following 12-hour glucagon infusion (0.629±0.1 vs. 0.670±0.2mml/l, p=ns). Thus 12-hour glucagon infusion led to higher basal rate of HGP, but unchanged plasma FFA levels. These results demonstrate that prolonged physiologic hyperglucagonemia results in a transient elevation of plasma glucose concentration but sustained increase in hepatic glucose production.

Disclosure
X. Chen: None. A. Merovci: None. E. Case: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. D. Tripathy: None.
1956-P: Increased Salt Intake Amplifies the Postprandial Glucagon-Like Peptide-1 Secretion
Authors: ASMAR ALI , CRAMON PER K. , SORENSEN CHARLOTTE MEHLIN , MADSBAD STEN , MORO CEDRIC , HARTMANN BOLETTE , HOLST JENS J. , JENSEN BOYE L. , ASMAR MEENA 
Published: June 2019

We have previously demonstrated that physiologically relevant changes in circulating glucagon-like peptide-1 (GLP-1) elicit a rapid increase in renal sodium excretion during intravenous sodium loading. The present study was designed to investigate the hypothesis that postprandial GLP-1 secretion is sensitive to dietary salt intake and is part of a feedforward natriuretic system. Under fixed sodium intake, 11 lean healthy males were examined twice in random order. Arterial blood samples were collected in 10-20 min intervals for 140 minutes after 75-g oral glucose load vs. 75-g oral glucose + 6-g oral salt load. Subjects remained supine during the experiments. Prior to each experiment, all subjects conducted a 4-day standardized diet with fixed salt intake and 24-h urine collections were completed successfully with urinary sodium excretions being similar between subjects (116±10 mmol). Arterial GLP-1 levels increased transiently in both studies and were higher around 80 min after the glucose+salt load compared to glucose alone (46 ± 4 pmol/L vs. 33 ± 3 pmol/L, p=0.011). The postprandial increase in arterial CCK levels was reduced by the glucose+salt load throughout the study (1.9 ± 0.1 pmol/L vs. 2.8 ± 0.2 pmol/L, p&lt;0.001), whereas arterial GIP and gastrin levels increased transiently and similarly in both studies. The transient increase in arterial glucose, insulin and c-peptide levels were similar on both study days. Arterial renin and aldosterone levels did not change within subjects and between study days, whereas angiotensin II was significantly reduced around 80 min after the glucose+salt load (10.9 ± 1.5 pg/mL vs. 14.4 ± 1.5 pg/mL, p=0.004). Arterial proANP, ANP, and BNP levels remained unchanged on both days. This study demonstrates that an increased salt intake amplifies the postprandial GLP-1 secretion in healthy individuals, supporting a possible GLP-1-mediated feedforward natriuretic system, likely via a suppression of angiotensin II.

Disclosure
A. Asmar: None. P.K. Cramon: None. C.M. Sorensen: None. S. Madsbad: None. C. Moro: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. B.L. Jensen: None. M. Asmar: None.
1965-P: Glucagon Receptor Agonism Stimulates Body Weight Loss in Antibiotic Treatment in Obese Mice
Authors: KIM TEAYOUN , ANTIPENKO JESSICA P. , NASON SHELLY , PRESEDO NATALIE , VAN DER POL WILLIAM J. , FINAN BRIAN , DIMARCHI RICHARD , MORROW CASEY D. , HABEGGER KIRK M. 
Published: June 2019

Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss in diet-induced obese (DIO) mice. Glucagon’s role as a primary counterregulatory hormone to insulin action has long received scientific attention, yet its broader therapeutic potential is an evolving research interest. We reported that chronic glucagon receptor (GCGR) activation increased energy expenditure and plasma bile acids (BA) in an farnesoid X receptor (FXR) dependent manner. Glucagon stimulates the conversion of cholesterol to BAs, with an increase in cholic and chenodeoxycholate species, critical regulators of FXR activity. Gut microbiota are known to alter the chemical structure of bile acids to produce secondary and tertiary BA. Thus, in these studies we tested the hypothesis that GCGR agonism regulates the gut microbiome to alter circulating BAs and stimulate FXR. GCGR agonism stimulated a profound change in the gut microbiome of DIO mice. These changes were largely associated with an increase in Actinobacteria and a decrease in Deferribacteria phylums. Assessment of functional microbiome composition via PICRUSt uncovered significant impacts on 130 out of 160 total KEGG pathways, including those involved in BA synthesis. To investigate the role of the gut microbiome on GCGR-stimulated weight loss we treated DIO mice with an antibiotic (AB) cocktail (ampicillin, vancomycin, metronidazole, neomycin, and amphotericin B) or vehicle. Mice were then treated with the GCGR agonist, IUB288, or vehicle for 14d to stimulate weight-loss. Surprisingly, AB-treated mice lost a similar amount of body-weight when treated with IUB288, suggesting that the gut microbiome may be dispensable for the weight loss effect. However, post hoc analysis of the cecal microbiome identified only a partial ablation of microbiota in AB-treated mice, with unexpected increases in Proteobacteria and Tenericutes. Thus, it is possible that GCGR-agonism acts via one of the resistant microbes to regulate weight loss.

Disclosure
T. Kim: None. J.P. Antipenko: None. S. Nason: None. N. Presedo: None. W.J. Van Der Pol: None. B. Finan: Employee; Self; Novo Nordisk A/S. R. DiMarchi: Employee; Self; Novo Nordisk Inc. C.D. Morrow: None. K.M. Habegger: Consultant; Self; Glyscend, Inc., Novo Nordisk Inc. Research Support; Self; Glyscend, Inc. Stock/Shareholder; Self; Glyscend, Inc.

Funding
National Institutes of Health
197-OR: IL-6 Protects Pancreatic ß Cells from Oxidative Stress via NRF2 Mitochondrial Translocation and Mitophagy
Authors: MARASCO MICHELLE , CONTEH ABASS M. , MURALIDHARAN CHARANYA , PFEIFER ELIZABETH , LINNEMANN AMELIA K. 
Published: June 2019

Glucose-stimulated insulin secretion by pancreatic β-cells results in a high level of metabolic activity and ROS production. Excess ROS can cause cellular damage leading to apoptosis. We recently reported that the cytokine interleukin 6 (IL-6) stimulates autophagy and protects β-cells from ROS-induced damage and apoptosis via the autophagic degradation of an antioxidant response repressor, KEAP1. This results in increased protein levels of the master antioxidant factor, NRF2. IL-6 also stimulates early markers of mitophagy in a NRF2-dependent manner. Interestingly, these effects are associated with noncanonical translocation of NRF2 to the mitochondria. Here, we set out to validate these findings and determine how NRF2 mitochondrial translocation is regulated. Using fluorescence imaging of mt-keima, we demonstrate that IL-6 stimulates mitophagy. This occurs without effects on mitochondrial function as measured by the Seahorse MitoStress Test. We also find that IL-6 rapidly stimulates NRF2 mitochondrial translocation, an effect that does not occur in response to treatment with hydrogen peroxide or a chemical inhibitor of KEAP1. These data indicate that liberating NRF2 from KEAP1 alone does not lead to NRF2 mitochondrial translocation, suggesting that IL-6 regulates NRF2 localization by additional mechanisms. NRF2 has extensive post-translational modifications, some of which are associated with nuclear localization. Therefore, we hypothesized that IL-6 induces specific NRF2 post-translational modifications that promote mitochondrial translocation. Indeed, we found that IL-6 stimulates serine phosphorylation on NRF2. Based on our findings described here, we propose that selective modification of NRF2 regulates its distinct subcellular localization and that selective translocation determines the mechanism of NRF2-mediated antioxidant response that functions to reduce ROS and restore cellular homeostasis in pancreatic β-cells.

Disclosure
M. Marasco: Employee; Spouse/Partner; Eli Lilly and Company. A.M. Conteh: None. C. Muralidharan: None. E. Pfeifer: None. A.K. Linnemann: None.

Funding
National Institutes of Health (K01DK102492), (R03DK115990 to A.K.L.)
1974-P: Identification of a Dual-Action Small Molecule with Potent Antidiabetic Activity
Authors: WANG YAO , LUO JING , ALKHALIDY HANA A. , XU BIN , LIU DONGMIN 
Published: June 2019

Type 2 diabetes (T2D) is a result of insulin resistance and pancreatic β-cell dysfunction. Therefore, identifying agents that simultaneously reverse these two defects could be a novel strategy leading to more effective prevention and treatment of T2D. Recently, we generated a small molecule elenolic acid moiety (EA). Here, we report that oral administration of EA normalized glycemia, glucose tolerance, insulin sensitivity, and hepatic glucose production in high-fat diet (HFD)-induced obese mice. These metabolic and antihyperglycemic effects of EA treatment were associated with increased circulating GLP-1 and peptide YY concentrations, but reduced blood insulin, leptin, and lipid levels. In addition, EA slowed gastric emptying and reduced food intake, body weight, and fat mass in HFD-fed obese mice. In vitro, EA directly induces glucagon-like peptide-1 (GLP-1) release from intestinal L-cells via a Gαq/phospholipase C-mediated mechanism. It also suppresses glucose production from HepG2 cells and stimulates glucose uptake in primary human skeletal muscle cells. These data suggest that EA may be a novel agent for developing drug to treat T2D.

Disclosure
Y. Wang: None. J. Luo: None. H.A. Alkhalidy: None. B. Xu: None. D. Liu: None.

Funding
National Institutes of Health (1R01AT007077, 1R01AT007566)
1976-P: Physiological Effects of GIP(1-30)NH2 in Healthy Subjects
Authors: KROGH LIVA S.L. , GASBJERG LÆRKE S. , STENSEN SIGNE , SKOV-JEPPESEN KIRSA , ROSENKILDE METTE MARIE , HARTMANN BOLETTE , VILSBØLL TINA , HOLST JENS J. , KNOP FILIP K. 
Published: June 2019

The gut-derived incretin hormone glucose-dependent insulinotropic polypeptide (GIP) circulates in at least two active forms: GIP(1-42), which besides its insulinotropic effect during hyperglycemia stimulates glucagon secretion at low plasma glucose (PG) levels and decreases bone resorption, and GIP(1-30)NH2. In vitro and rodent studies has shown similar physiological effects of GIP(1-30)NH2 and GIP(1-42), but effects in humans remain unexplored. Here, we infused GIP(1-42) and GIP(1-30)NH2 in humans to establish the physiological effects of GIP(1-30)NH2.
On three separate days, 10 healthy men (mean age 23 (range 20-28) years, BMI 22.4 (20.0-25.2) kg/m2) received intravenous infusions of GIP(1-42), GIP(1-30)NH2 and saline, respectively. Both peptides were infused at 4 pmol/kg/min during 200 minutes. After 20 minutes of infusion, PG was clamped at the fasting PG level (FPG) for 60 minutes, followed by 60 minutes at FPG × 1.5, and lastly 60 minutes at FPG × 2.
There were no differences in PG levels between the three interventions, but significantly more glucose was needed for the clamp with GIP(1-42) compared to saline (P = 0.022). Plasma levels of GIP(1-30)NH2 reached a mean (± SD) of 31.4 ± 29.9 pmol/l and GIP(1-42) of 97.8 ± 27.9 pmol/l. Despite this difference, both infusions resulted in robust and glucose-dependent insulin responses (as assessed by serum C-peptide) with no differences between the two peptide infusions (P = 0.187), and at FPG level only GIP(1-30)NH2 resulted in higher glucagon levels than saline (P = 0.0302). At 180 minutes, the bone resorption marker carboxy-terminal collagen I crosslinks (CTX) was suppressed to 61 ± 13% of baseline values during saline, 42 ± 16% during GIP(1-30)NH2, and 29 ± 6% during GIP(1-42) (P &lt; 0.001).
We conclude that, like GIP(1-42), GIP(1-30)NH2 is a potent insulinotropic (at high PG levels), glucagonotropic (at low PG levels) and bone resorption-inhibiting hormone in healthy subjects.

Disclosure
L.S.L. Krogh: None. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. S. Stensen: None. K. Skov-Jeppesen: None. M.M. Rosenkilde: Consultant; Self; Antag Therapeutics. 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.
198-OR: Role for the Cationic Amino Acid Transporter Slc7a2 in Alpha-Cell Proliferation and Islet Hormone Secretion
Authors: SPEARS ERICK , SHOU MATTHEW , SIV WALTER A. , DAI CHUNHUA , CHEN WENBIAO , POWERS ALVIN C. , DEAN DANIELLE 
Published: June 2019

Interrupting glucagon receptor signaling results in hyperaminoacidemia, which stimulates alpha cell hyperplasia. Arginine, a potent secretagogue for both insulin and glucagon, is required for hyperaminoacidemia-stimulated alpha cell proliferation. To investigate the role of arginine transport, we compared the expression of amino acid transporters in published datasets of sorted mouse and human islet cells and found that Slc7a2, cationic amino acid transporter, is the most highly expressed amino acid transporter in both mouse and human alpha cells and that its expression is three-fold higher in alpha cells than in beta cells. Following glucose/arginine injection, global Slc7a2 knockout mice (Slc7a2-/-) had 20% higher blood glucose (+/+ vs. -/-: 412±23 vs. 517±25mg/dL, n=11-12, p=0.004), 80% lower serum insulin (3.7±0.6 vs. 0.7±0.4nM, p=0.0008) and 59% lower serum glucagon (64.3±23.1pM vs. 26.3±11.4pM, p=0.009) than Slc7a2+/+ animals. Slc7a2+/- mice had 55% decreased insulin levels (+/+ vs. +/-: 3.7±0.6 vs. 1.7±0.3nM, n=8, p=0.012), but showed no difference in serum glucose or glucagon levels, indicating that Slc7a2 expression may be rate limiting for beta cell, but not alpha cell, function. Isolated islets from Slc7a2-/- mice had normal morphology, but reduced high amino acid-stimulated alpha cell proliferation by 90% and 58% in Slc7a2-/- and Slc7a2+/- islets, respectively (+/+ vs.-/-: 3.7±1.7 vs. 0.4±0.2%, p=0.007, n=4; +/+ vs. +/-: 3.7±1.7 vs. 1.5±0.6%, p=0.038, n=4). Knockdown with Slc7a2 shRNA in the aTC1-6 mouse alpha cell line also decreased proliferation. Taken together, these data indicate a central role for Slc7a2 in amino acid-stimulated alpha cell proliferation and glucagon and insulin secretion.

Disclosure
E. Spears: None. M. Shou: None. W.A. Siv: None. C. Dai: None. W. Chen: None. A.C. Powers: None. D. Dean: None.
1980-P: A Characterization of Postprandial Glucose Metabolism and Incretin Hormone Responses in Patients with Bile Acid Malabsorption
Authors: KÅRHUS MARTIN L. , SONNE DAVID P. , THOMASEN MARTIN L. , HOLST JENS J. , VILSBØLL TINA , BRØNDEN ANDREAS , KNOP FILIP K. 
Published: June 2019

Bile acid malabsorption (BAM) is characterized by an excessive spill-over of bile acids to the colon leading to bile acid-induced diarrhea; the condition is usually treated with bile acid sequestrants. Bile acids have been demonstrated to modulate the secretion of the incretin hormone glucagon-like peptide 1 (GLP-1) and the aim of this study was to characterize postprandial glucose metabolism and incretin hormone responses in patients with BAM. Twelve patients with BAM (6 women; mean age 39.1 (SD 13.2); mean BMI 28.4 kg/m2 (SD 1.2); HbA1c 31.4 (SD 3.7)) and 12 healthy gender, age, BMI and HbA1c-matched controls (6 women; mean age 39.3 (SD 15.6); mean BMI 29,1 kg/m2 (SD 1.1); HbA1c 31.0 (SD 2.8)) were subjected to two 4-hour standardized liquid meal tests with double-blinded single-dose administration of the bile acid sequestrant colesevelam (3.75 g) and placebo, respectively, performed on separate days, and in randomized order. Fasting and postprandial plasma GIP and GLP-1 concentrations were comparable among patients with BAM and control subjects and unaffected by colesevelam administration. Peak plasma glucose concentrations were higher in BAM patients vs. control subjects, but area under curve for plasma glucose did not differ between the two groups. Patients with BAM exhibited significantly higher postprandial serum C-peptide concentrations and hyperglucagonemia compared to controls. Single-dose colesevelam had no effect on postprandial glucose or glucagon excursions in any of the groups but decreased the postprandial C-peptide response in BAM patients. Patients with BAM are characterized by elevated serum C-peptide concentrations and hyperglucagonemia whereas postprandial glucose tolerance and GLP-1 and GIP responses are similar to healthy controls.

Disclosure
M.L. Kårhus: None. D.P. Sonne: None. M.L. Thomasen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. T. Vilsbøll: None. A. Brønden: Other Relationship; Self; AstraZeneca. 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.

Funding
Novo Nordisk Foundation
1984-P: Optic Atrophy 1 Deletion in Brown Adipose Tissue Induces Browning of White Fat by Inducing FGF-21
Authors: ALAMBERT RENATA PEREIRA , TADINADA SATYA MURTHY , ABEL E. DALE 
Published: June 2019

Optic Atrophy 1 (OPA1) is a mitochondrial inner membrane protein that regulates inner mitochondrial membrane fusion, cristae structure and respiratory capacity. Mitochondria are critical for the thermogenic activation of brown adipocytes. However, the role of OPA1 and mitochondrial dynamics in brown adipose tissue (BAT) physiology and in systemic metabolism is incompletely understood. We generated mice lacking OPA1 specifically in BAT by crossing mice floxed for the Opa1 genewith mice harboring the Cre recombinase under the control of the Ucp1promoter (OPA1 BAT-KO). Although mitochondrial respiratory capacity was reduced in mitochondria isolated from BAT of OPA1 BAT-KO, mitochondria respirations were elevated in the inguinal fat pad of these mice, which correlated with increased UCP1 protein levels and induction of thermogenic genes, consistent with browning of white adipose tissue (WAT). OPA1 BAT-KO mice also had elevated energy expenditure and reduced WAT mass. We, then, hypothesized that a BAT-derived secreted factor, or batokine, mediated these systemic effects. Upon mRNA expression analysis of a panel of batokines in OPA1-BAT KO mice, we found Fibroblast Growth Factor 21 (FGF-21) to be significantly elevated in BAT. We, therefore, generated OPA1/FGF-21 BAT-DKO mice. DKO mice had normalized WAT mass and lacked the induction of thermogenic genes in WAT.
In conclusion, OPA1 deletion in BAT results in increased FGF-21 expression, which induces browning of WAT to increase energy expenditure and promote leanness.

Disclosure
R. Pereira Alambert: None. S. Tadinada: None. E. Abel: None.

Funding
American Heart Association