bluuebunny/crossref_metadata_2025_split huggingface dataset:
1827-P: Higher Glucagon-Like Peptide-1 Response and Lower Beta-Cell Glucose Sensitivity Are Associated with Increased Glycemic Variability among Individuals with Prediabetes
Authors: CHOW ELAINE , LUK ANDREA , LING JAMES , KONG ALICE P. , MA RONALD C. , FERRANNINI ELE , CHAN JULIANA C. 
Published: June 2019

Background: Increased glycemic variability (GV) is thought to represent abnormalities of glucose homeostasis in the progression from prediabetes to diabetes. We evaluated the association between GV, beta-cell function and glucagon-like peptide 1 (GLP-1) response among individuals with prediabetes.
Methods: 61 individuals with prediabetes (age Mean±SD 56±9 years, 31 male) each wore a blinded continuous glucose monitor (Medtronic iPro2) for 72 hours. Standard deviation (SD) and coefficient of variation (CV) were calculated from CGM glucose. Participants underwent a 2-hour mixed-meal tolerance test with measurement of insulin, C-peptide, GLP-1 for modelling of beta-cell function.
Results: Early and late GLP-1/glucose ratio were positively correlated with CGM sensor glucose SD (r = 0.29, p=0.02 and r= 0.28 p = 0.048 respectively). Beta-cell glucose sensitivity (βCGS) was negatively correlated with SD (r = -0.28, p = 0.03). In multivariate analyses, only βCGS and GLP-1 response were significant predictors of SD, while early phase insulin and insulin secretion rate predicted average sensor glucose but not indices of GV.
Conclusions: Higher GLP-1 response and reduced βCGS are associated with greater glucose fluctuations in the prediabetic range.

Disclosure
E. Chow: Research Support; Self; Powder Pharmaceuticals Inc., Sanofi-Aventis. A. Luk: None. J. Ling: None. A.P. Kong: Advisory Panel; Self; Lilly Diabetes. Research Support; Self; AstraZeneca, Lilly Diabetes. Speaker's Bureau; Self; Abbott. Other Relationship; Self; AstraZeneca, Novartis Pharmaceuticals Corporation, Sanofi. R.C. Ma: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; AstraZeneca, Bayer AG, Pfizer Inc. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca. E. Ferrannini: None. J.C. Chan: Board Member; Self; Asia Diabetes Foundation. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Merck Sharp & Dohme Corp., Sanofi-Aventis. Research Support; Self; Amgen Inc., AstraZeneca, Lee Powder, Lilly Diabetes, Pfizer Inc., Sanofi-Aventis. Speaker's Bureau; Self; Ascensia Diabetes Care. Stock/Shareholder; Self; GemVCare.
183-LB: The Gut Microbiome and Puberty in Girls at Risk for Type 2 Diabetes (T2D)
Authors: JOBIRA BEZA , FRANK DANIEL N. , PYLE LAURA , GROSS SUSAN , IR DIANA , PENDLETON WESLEY , ROBERTSON CHARLES E. , NADEAU KRISTEN J. , KELSEY MEGAN M. 
Published: June 2019

Objectives: Pediatric-onset T2D is twice as common in girls vs. boys and is tightly linked with puberty and obesity. Alterations in gut microbiota, specifically the Firmicutes:Bacteroidetes ratio (F:B), may be associated with insulin sensitivity (Si) and may play a role in the pathophysiology of T2D. We aimed to evaluate associations between gut microbiome composition and Si and insulin secretion in obese prepubertal (PP) vs. late-pubertal (LP) girls.
Methods: Obese PP (N=9, age 8.5 ±0.8 year, BMIz 2.0±0.5) and LP (Tanner 4-5, N=9, age 13.0±2.0 year, BMIz 2.0±0.5) obese girls underwent stool collection and intravenous glucose tolerance testing after an overnight fast. High-throughput sequencing of the bacterial 16S rRNA gene V3-V4 region was used to profile fecal bacterial communities. Bergman's minimal model was used to estimate Si and insulin secretion (acute insulin response to glucose, AIRg) and disposition index (DI). T-tests assessed group differences in Si, AIRg and DI. Spearman’s correlation examined relationships between microbiota relative abundance (%RA) and Si, AIRg and DI.
Results: PP vs. LP girls had significantly higher Si (8.0±1.0 vs. 2.0±0.5 x10-4/min-1/μIU/ml, p&lt;0.001) and DI (3,525 ± 636 vs. 1,687 ± 385 x10-4/min-1, p=0.03). AIRg was not different between PP and LP girls (568 ± 132 vs. 840 ± 174 μIU/ml, p=0.23). F:B ratio related to insulin secretion and DI, (r=-0.32, p=0.20; r=-0.39, p=0.11) but not Si. At the genus level, Si was correlated to Ruminococus and Lachnospira %RA (r=0.53, p=0.02; r=0.50, p=0.036). AIRg was correlated to Peptostreptococcaceae %RA (r=-0.48, p=0.045). DI was correlated with Prevotella and Bifidobacterium %RA (r=0.57, p=0.01; R=- 0.54, p=0.02).
Conclusion: These pilot study results suggest possible relationships among the gut microbiome, glucose metabolism, and puberty in girls at risk for T2D that merit further exploration.

Disclosure
B. Jobira: None. D.N. Frank: None. L. Pyle: None. S. Gross: None. D. Ir: None. W. Pendleton: None. C.E. Robertson: None. K.J. Nadeau: None. M.M. Kelsey: None.

Funding
University of Colorado Center for Women’s Health; National Institutes of Health/Colorado Clinical Translational Science Award (UL1TR002535)
1834-P: Pancreatic Fat Associates with Impaired Insulin Secretion in Genetically Predisposed Individuals
Authors: JAGHUTRIZ BENJAMIN , HENI MARTIN , MACHANN JÜRGEN , SCHICK FRITZ , ULLRICH SUSANNE , HAERING HANS-ULRICH , FRITSCHE ANDREAS , WAGNER ROBERT 
Published: June 2019

Background: Pancreatic fat (PF) related beta-cell failure might play a role in the pathophysiology of type 2 diabetes (T2D). We hypothesized that the effect of PF on beta-cell function can be modeled as a gene x environment interaction. To this end, we investigated the association of PF with insulin secretion in subjects with different genetic predisposition for T2D.
Methods: A genome-wide polygenic risk score (gwPRS) was computed combining summary statistics from a genome-wide association study with ∼900.000 participants and 480.000 genetic variants in our cohort. The interaction of MRI-measured PF with gwPRS was investigated in 376 nondiabetic participants.
Results: PF interacted with gwPRS on insulin secretion after adjustment for confounders (p=0.001). In participants with low gwPRS, PF associated positively with insulin secretion. In participants with high gwPRS, there was a negative association with insulin secretion.
Discussion: PF is a pathophysiologic factor potentially contributing to both primary insulin hypersecretion and impairment of insulin secretion, dependent on genetic predisposition.

Disclosure
B. Jaghutriz: None. M. Heni: Research Support; Self; Boehringer Ingelheim International GmbH, Sanofi. Speaker's Bureau; Self; Lilly Diabetes, Merck Sharp & Dohme Corp., Sanofi. J. Machann: None. F. Schick: None. S. Ullrich: Advisory Panel; Spouse/Partner; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck Sharp & Dohme Corp., Mylan, Novo Nordisk A/S. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc. H. Haering: None. A. Fritsche: None. R. Wagner: Other Relationship; Self; Lilly Diabetes, Novo Nordisk A/S.

Funding
German Federal Ministry of Education and Research
1837-P: Central IL-6 Receptor Deficiency Impairs Pancreatic Insulin Secretion
Authors: MCNEILLY ALISON D. , GALLAGHER JENNIFER , MCCRIMMON RORY J. 
Published: June 2019

Inflammation has become a major mechanism linking obesity to type 2 diabetes (T2D). The pleiotropic cytokine, Interleukin 6 (IL-6) is pro-inflammatory and widely thought to negatively impact on obesity-induced insulin resistance. However, recent evidence challenges this concept. IL-6-deficient (IL-6−/−) mice develop mature onset obesity, glucose intolerance, insulin resistance, and increased liver inflammation in response to a high-fat diet. Here we investigate the CNS role of IL-6 in the manifestation of T2D using a neuronal-specific IL-6 receptor null mouse model.
IL-6Ra-/- mice were generated by crossing IL-6RaFlx/flx with Nestin-Cre+/-animals. Male IL-6Ra-/- and Cre+/- animals (18 weeks, n=12/group) were fed standard laboratory chow for 20 weeks. Body composition and energy homeostasis were assessed using EchoMRI and CLAMS systems. Insulin secretion by glucose-stimulated insulin secretion (GSIS) was measured both in vivo and ex-vivo in isolated β-cell preparations. Circulating insulin was measured by ELISA. Data are expressed as mean±SEM.
Body weight was comparable between IL-6Ra-/- and Cre+/- animals. Fat mass however was significantly reduced (20% reduction; p&lt;0.05) despite animals being hyperphagic (28% increase; p&lt;0.01). Energy expenditure was reduced (12% reduction) and the respiratory exchange ratio were significantly increased (18% increase) in IL-6Ra-/- animals (p&lt;0.01 for both). Glucose and insulin tolerance were comparable. In vivo insulin secretion was markedly diminished in IL-6Ra-/- animals (GSIS AUC; 2.5±0.6 vs. 17.1±5.1, p&lt;0.01). Histological analysis and stimulation of isolated pancreatic islets ex vivo however, showed similar islet morphology and GSIS or glucagon secretion (p=ns for all). Administration of hexamethonium, an Ach receptor blocker to IL-6Ra-/- animals restored GSIS in vivo (p=ns).
These finding suggest that classical IL-6 signaling within the CNS plays an important role in regulating insulin secretion via direct effect on β-cell function in vivo.

Disclosure
A.D. McNeilly: None. J. Gallagher: None. R.J. McCrimmon: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; The Leona M. and Harry B. Helmsley Charitable Trust.

Funding
Diabetes UK
1839-P: GLP-1 Receptor Antagonism Using Exendin-9,39 in the Fasting State Modulates a-Cell Function in Humans with Type 2 Diabetes
Authors: HURTADO MARIA D. , EGAN AOIFE M. , LAURENTI MARCELLO C. , ADAMS J.D. , RIZZA ROBERT A. , COBELLI CLAUDIO , MATVEYENKO ALEKSEY , MAN CHIARA DALLA , VELLA ADRIAN 
Published: June 2019

Glucagon-Like Peptide-1 (GLP-1) potentiates insulin secretion in response to an oral challenge. Exendin-(9,39) a competitive antagonist of GLP-1, has been used to quantify the contribution of endogenous GLP-1 to glucose tolerance. In nondiabetic subjects, Exendin-(9,39) infused for three hours altered the subsequent β-cell response to an i.v. glucose challenge. Similar results were observed using perifused human islets from nondiabetic donors. We hypothesized that the effects of fasting GLP-1 secretion on β-cell response would be similar in people with type 2 diabetes (T2D). We studied 9 subjects with T2D in random order. Glucose containing [3-3H]-glucose was infused to mimic the systemic appearance of glucose after a meal. On one occasion, saline, was infused for 3 hours prior (-180 to 0 minutes) to the I.V. challenge, while on the other Exendin-(9,39) was infused at 750pmol/kg/minutes. Exendin-(9,39) infusion prior to the i.v. challenge increased fasting (8.7 ± 0.6 vs. 7.8 ± 0.5 mmol/l, p &lt; 0.01) and peak (13.3 ± 0.8 vs. 12.5 ± 0.6 mmol/l, p = 0.05) glucose concentrations. These differences were not explained by altered insulin secretion: insulin and C-peptide concentrations did not differ between study days. On the other hand, fasting glucagon concentrations were increased (70 ± 8 vs. 53 ± 1 ng/l, p = 0.01) by Exendin-(9,39) and this was accompanied by increased endogenous glucose production (23 ± 1 vs. 20 ± 1 μmol/kg/minutes, p = 0.02). In separate experiments using perifused isolated human islets from diabetic donors, pretreatment with Exendin-(9,39) did not alter integrated insulin secretion in response to hyperglycemia (0.6 ± 0.2 vs. 0.9 ± 0.4 nmol/Islet/30 minutes, p = 0.49). Taken together these results suggest that in T2D fasting GLP-1 receptor activation may augment glucagon suppression in response to subsequent challenges. This may represent an adaptive mechanism not seen in nondiabetic subjects that restrains α-cell function to decrease postprandial hyperglycemia.

Disclosure
M.D. Hurtado: None. A.M. Egan: None. M.C. Laurenti: Employee; Self; GlySens Incorporated. J. Adams: None. R.A. Rizza: Advisory Panel; Self; Lilly Diabetes, Metavention, Novo Nordisk A/S, vTv Therapeutics. C. Cobelli: None. A. Matveyenko: None. C. Dalla Man: None. A. Vella: Advisory Panel; Self; vTv Therapeutics. Research Support; Self; Novo Nordisk Inc.

Funding
Endocrine Fellows Foundation; National Institutes of Health
184-LB: Pancreatic Hypoplasia Patients Experience Poor Weight Gain and Labile Diabetes without Diabetic Ketoacidosis (DKA)
Authors: DENSON ANNA M. , FREEMARK MICHAEL , THOMAS INAS H. , ABDULLATIF HUSSEIN , NOGUEIRA JANAINA B. , BENJAMIN ROBERT , LETOURNEAU LISA R. , NAYLOR ROCHELLE N. , GREELEY SIRI ATMA W. 
Published: June 2019

Mutations in GATA6, GATA4 and PDX1 cause congenital diabetes and pancreatic hypoplasia (PH) or agenesis. We investigated clinical features and treatment of 10 PH patients through the University of Chicago National Monogenic Diabetes Registry. Data was self-reported or extracted from medical records. Similar to previous cohorts, congenital heart defects, gallbladder agenesis, and exocrine pancreatic insufficiency were often present, whereas features such as recurrent infections and epilepsy have not been reported previously (Figure 1). Weight gain and glycemic control were often poor, yet there were no episodes of DKA over 110 patient-years (Figure 2). Close multi-subspecialty follow-up of these complex patients may improve frequent difficulties with weight gain and highly labile blood sugars.

Disclosure
A.M. Denson: None. M. Freemark: Research Support; Self; Rhythm Pharmaceuticals, Inc. I.H. Thomas: None. H. Abdullatif: None. J.B. Nogueira: None. R. Benjamin: None. L.R. Letourneau: None. R.N. Naylor: None. S.W. Greeley: None.

Funding
American Diabetes Association (1-17-JDF-008 to S.A.W.G.); National Institutes of Health (R01DK104942, P30DK020595, UL1TR002389)
1867-P: The Role of Ketone Bodies in Diabetes Pathogenesis Using Untargeted Metabolomics
Authors: PUCHALSKA PATRYCJA , LENGFELD JUSTIN E. , STAGG DAVID B. , CRAWFORD PETER A. 
Published: June 2019

The pathogenesis of human T2D is linked to the progression of nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH). In the normal fed state, impairments of hepatocyte ketogenesis and Kupffer cell mitochondrial metabolism of ketone bodies conspire to drive hepatic injury, and lobular fibrosis - key features increasing insulin resistance and T2D. Preliminary data suggest that a local circuit of intrahepatic ketone metabolism may protect the liver from lobular injury, which involves distribution of ketone body carbon into numerous metabolic pathways. Nonetheless, the metabolic products of local hepatic ketone body metabolism that confer protection to the liver, and which are therefore linked to insulin resistance and T2D, remain unknown. Here, we use stable isotope tracing untargeted metabolomics (ITUM) to reveal the chemical space penetrated in vivo by D-[13C]β-hydroxybutyrate (D-βOHB) and its oxidized redox partner [13C]acetoacetate (AcAc). A kinetic study revealed rapid clearance (∼30 min) of both ketones from the bloodstream when introduced as intraperitoneal boluses into wild type mice. Many 13C-labeled metabolites were tissue-specific, particularly distinctly acetylated amino acids. Labeling of TCA cycle intermediates by 13C-labeled ketone bodies also varied by tissue, and by the specific labeled ketone body delivered. Finally, recurrent administration of unlabeled AcAc protected mice from high fat, fibrogenic diet-induced hepatic injury and fibrosis, while unlabeled D-βOHB exacerbated injury and fibrosis.
In conclusion, the two ketone bodies AcAc and D-βOHB, strikingly exhibit distinct metabolic and phenotypic effects in the context of NAFLD/NASH, and insulin resistance.

Disclosure
P. Puchalska: None. J.E. Lengfeld: None. D.B. Stagg: None. P.A. Crawford: Consultant; Spouse/Partner; Medtronic.
1872-P: Hepatic miR-582-5p Is Programmed by Maternal Diet-Induced Obesity in Male Mice and Contributes to Nonalcoholic Fatty Liver Disease
Authors: PANTALEAO LUCAS , FERNANDEZ-TWINN DENISE , CARPENTER ASHA , LOCHE ELENA , DEARDEN LAURA , GUIMARAES DANIELLA DUQUE , PENFOLD NAOMI C. , ASHMORE THOMAS J. , BUSHELL MARTIN , OZANNE SUSAN 
Published: June 2019

Obesity during pregnancy is associated with increased risk of nonalcoholic fatty liver disease (NAFLD) in the offspring; however, the underlying molecular mechanisms remain largely unknown. The aim of the current study was to explore the contribution of microRNAs (miRs) as mediators of programming by maternal obesity. To achieve this, we used a mouse model of maternal-diet induced obesity where dams develop gestational diabetes and offspring demonstrate increased hepatic triglyceride content. We carried out small RNA next generation sequencing analysis of liver from twelve-week-old male offspring and identified miR-582-5p as the most dysregulated, showing a threefold increase. Binding site prediction (TargetScan 7.2) and pathway enrichment analysis (Reactome v67) suggested a number of miR-582-5p target genes related to lipid metabolism including Insulin Induced Gene 2 (INSIG2) and Translocase of Inner Mitochondrial Membrane 23 (TIMM23). Overexpression of miR-582-5p in AML12 (mouse) and HEPG2 (human) cell lines caused increased triglyceride accumulation, downregulation of INSIG2 and TIMM23, increased nuclear localization of Sterol Regulatory Element-Binding Protein 1 (SREBP-1), and overexpression of lipogenic genes. These findings suggest that overexpression of miR-582-5p induces hepatic intracellular lipid accumulation through mechanisms that involve mitochondrial malfunction and activation of de novo lipogenesis. We therefore conclude that an epigenetically programmed increase in hepatic miR-582 is a likely contributing mechanism underlying the programming of fatty liver disease in the offspring of obese gestational diabetic mothers.

Disclosure
L. Pantaleao: None. D. Fernandez-Twinn: None. A. Carpenter: None. E. Loche: None. L. Dearden: None. D. Duque Guimaraes: None. N.C. Penfold: None. T.J. Ashmore: None. M. Bushell: None. S. Ozanne: Advisory Panel; Self; Nestlé.

Funding
Brazilian National Council for the Improvement of Higher Education (BEX 10594/13-2); Brazilian National Council for Scientific and Technological Development (PDE/204416/2014-0)
1882-P: Liver-Specific Deletion of the Mitochondrial Quality Control E3 Ligase Parkin Is Associated with Increased Hepatic Steatosis and Markers of NAFLD in Diet-Induced Obese Mice
Authors: EDMUNDS LIA R. , MILLS AMANDA , JURCZAK MICHAEL J. 
Published: June 2019

PARKIN, an ubiquitin E3 ligase, regulates mitochondrial homeostasis through a process called mitophagy, where damaged mitochondria are selectively targeted and removed via autophagy. Diminished hepatic mitophagy may play a role in mitochondrial dysfunction that occurs alongside insulin resistance and hepatic steatosis in association with obesity. Reduced hepatic mitophagy was observed in obese mice with fatty liver, raising the question as to whether loss of mitophagy contributes to the pathogenesis of fatty liver or is merely associated with the disease. To understand how loss of hepatic mitophagy affects obesity-associated liver disease, we developed a liver-specific PARKIN knockout mouse (LKO). There was no difference in body weight in LKO compared with WT mice fed regular chow (RC) or high-fat diet (HFD; 60% kcal, 12 weeks). There was also no difference in liver steatosis between RC groups, however, liver steatosis was 45% greater in HFD-LKO compared with WT mice (p&lt;0.05). Liver histology demonstrated presence of microvesicular steatosis in zones 2-3 in both HFD groups, but only LKO mice presented with micro and macrosteatosis in zones 1-3. HFD-LKO samples showed presence of an inflammatory cell infiltrate that was less apparent in WT samples. Unbiased transcriptomic analysis by RNA-Seq demonstrated 113 significant differentially expressed genes (82 up, 31 down) in HFD-LKO mice. Unsupervised gene ontology and pathway analysis revealed significant changes in extracellular matrix accumulation, lipid metabolism, metabolic and ROS processes in HFD-LKO mice.
In summary, the increased steatosis and presence of macrovesicular steatosis and inflammation in HFD-LKO mice, alongside changes in gene expression suggesting collagen deposition and extracellular matrix remodeling, suggest that loss of PARKIN-mediated mitophagy increases susceptibility to HFD and may predispose mice to NAFLD.

Disclosure
L.R. Edmunds: None. A. Mills: None. M.J. Jurczak: None.

Funding
American Diabetes Association (1-19-PDF-102 to L.R.E.)
1887-P: The GLP-1 Receptor Agonist Liraglutide Improves Hepatic Inflammation and Fibrosis in a Mouse Model of NASH
Authors: MONTANDON SOPHIE A. , SOMM EMMANUEL , VITO CLAUDIO DE , JORNAYVAZ FRANÇOIS R. 
Published: June 2019

Nonalcoholic fatty liver disease (NAFLD) is a common complication of type 2 diabetes (T2D). In fact, NAFLD affects up to 70% of diabetic patients and 90-95% of obese individuals. NAFLD can progress to nonalcoholic steatohepatitis (NASH) which can itself lead to cirrhosis and hepatocellular carcinoma. Despite the life-threatening aspects of these hepatic disorders, validated pharmacologic treatments are still lacking. As GLP-1 receptor agonists (GLP-1 RAs) are now widely used in the treatment of T2D, our study aimed to assess their potential beneficial effects on NAFLD/NASH. Wild type C57BL/6 male mice were fed a methionine-choline deficient (MCD) diet to induce the liver manifestations of NASH (steatosis, hepatocyte ballooning, inflammation, fibrosis). After 3 weeks on MCD diet, mice were subcutaneously infused with either liraglutide (16 μg/d) or saline solution for 4 weeks using osmotic minipumps before being euthanazied for analysis. Liver tissues were studied using qPCR and histological stainings and pathological scores were evaluated by a certified pathologist. Liraglutide-infused mice had similar body and liver weights than saline controls. Histological scores revealed a significant decrease in hepatic inflammation in the liraglutide-infused mice compared to controls, despite a similar degree of steatosis. These observations were associated with a significant downexpression of profibrogenic genes (Col1a1, Col1a2, Col3a1, Timp1, Mmp13, Serpine1, Tgfb1) and inflammatory/immune markers (Tnfa, Itgax, Adgre1) in the liver of liraglutide-treated mice. In addition, genes involved in hepatic stellate cells activation (Acta1, Vim) were also downregulated in liraglutide-treated mice.
In conclusion, the long-acting GLP-1 RA liraglutide reduces liver inflammation and fibrosis despite no major action on steatosis. These results suggest anti-inflammatory and anti-fibrotic actions of liraglutide that are independent of lipid metabolism.

Disclosure
S.A. Montandon: None. E. Somm: None. C. De Vito: None. F.R. Jornayvaz: None.

Funding
Novo Nordisk