bluuebunny/crossref_metadata_2025 huggingface dataset:
1789-P: Inactivation of Acyl-Protein Thioesterase 1, a Major Mediator of Palmitoylation Cycling, Promotes Insulin Secretion and ß-Cell Failure
Authors: DONG GUIFANG , WEI XIAOCHAO , YIN LI , FENG CHU , ADAK SANGEETA , SHYR ZEENAT A. , ZHANG QIANG , MORIKAWA SHUNTARO , ASADA RIE , URANO FUMIHIKO , REMEDI MARIA S. , SEMENKOVICH CLAY F.
Published: June 2020

Palmitoylation cycling involves successive addition and removal of lipid from proteins to regulate cell structure and membrane interactions. Cycling requires depalmitoylation, mediated mostly by the enzyme acyl-protein thioesterase 1 (APT1). To test the hypothesis that depalmitoylation is critical for normal glucose metabolism, we generated global and islet-specific (using tamoxifen-inducible Pdx1 Cre) APT1 knockout mice. Both models on a chow diet had enhanced glucose tolerance due to increased insulin secretion. Pancreatic insulin content was unaffected by APT1 deficiency. Isolated islets from APT1-deficient models demonstrated increased glucose-stimulated insulin secretion under static and dynamic conditions. Quantitative histomorphometry demonstrated β cell hypertrophy in islets from global APT1 KO mice. Calcium dynamics in isolated islets were unaffected by APT1 deficiency, suggesting that increased insulin secretion is mediated downstream of depolarization-dependent calcium influx. APT1 knockdown in replicates of human islets from two donors showed increased insulin secretion. At 4 weeks of age, global APT1 KO db/db mice had improved glucose tolerance due to increased insulin secretion compared to littermate db/db mice. However, by 16 weeks of age APT1-deficient db/db mice had severe glucose intolerance, hypoinsulinemia, and β cell atrophy compared to littermate db/db mice. Islet palmitoylation proteomics identified putative APT1 substrates including Scamp1, -2 and -3. Scamp1 was validated as a palmitoylated protein, APT1 deficiency would be predicted to impair Scamp1 function, and Scamp1 knockdown in insulinoma cells increased insulin secretion. These results suggest that deficiency of APT1, an enzyme susceptible to post-translational regulation in the setting of insulin resistance, causes hypersecretion of insulin that leads to β cell failure, modeling the clinical evolution of human type 2 diabetes.

Disclosure

G. Dong: None. X. Wei: None. L. Yin: None. C. Feng: None. S. Adak: None. Z.A. Shyr: None. Q. Zhang: None. S. Morikawa: None. R. Asada: None. F. Urano: Stock/Shareholder; Self; CytRx Corporation. Other Relationship; Self; AETAS Pharma, Amylyx Pharmaceuticals, Mitochon, National Center for Advancing Translational Sciences, Novus Biologicals?. M.S. Remedi: None. C.F. Semenkovich: None.
179-OR: Mitochondrially Targeted Tamoxifen Improves Diet-Induced Obesity and Diabetes and Reduces Adipose Tissue Senescence in Experimental Mice
Authors: TRNOVSKA JAROSLAVA , DAVIDOVA ELISKA , SVOBODA PETR , KRATOCHVILOVA HELENA , MRAZ MILOS , HUBACKOVA SONA , NEUZIL JIRI , HALUZIK MARTIN
Published: June 2020

Diabetes and ageing are mutually linked and senescent cells might be involved in the development of obesity and type 2 diabetes mellitus (T2DM). Recent studies have shown that senolytic agents may improve diabetes-related pathologies. To this end we have tested our novel anti-cancer agent with senolytic properties, mitochondrially targeted tamoxifen (MitoTam), in a mouse model of T2DM. Obesity and diabetic metabolic profile were induced by high fat diet (HFD) feeding in 20 C57BL/6J male mice for 6 months with another group fed a standard diet (SD) serving as controls. Subsequently, both groups were divided into 2 subgroups (n=10 each) treated either with MitoTam (2µg/1g of body weight dissolved in 4% ethanol in corn oil) or the excipient given i.p. twice a week for a period of 4 weeks. In HFD animals, MitoTam decreased body weight already after 2 weeks of treatment, with most pronounced reduction of visceral adipose tissue (VAT, P<0.001), whereas it had no effect on body weight in SD group. MitoTam also reduced fasting glucose (P<0.001) as well as postprandial glucose AUC (P<0.001) of HFD mice to levels comparable with SD group. This glucose-lowering effect was accompanied by a decrease in serum triglycerides (P<0.002), insulin (P<0.002), leptin (P<0.001) and glucose-dependent insulinotropic peptide (GIP, P<0.03) together with reduction of mRNA expression of leptin in epididymal adipose tissue (EAT, P<0.001), EAT adipocyte size and lipid accumulation in the liver (P<0.002). HFD-induced obesity and T2DM phenotype was associated with elevated levels of senescent markers p16 and β-gal in EAT (P<0.001 for p16 and P<0.03 for β-gal vs. SD), both of which were markedly reduced by MitoTam treatment (P<0.001 for p16 and P<0.002 for β-gal vs. HFD).

In conclusion, our results suggest that MitoTam significantly improves HFD-induced obesity and diabetes in mice and that this effect might be in part mediated by alleviated senescence in adipose tissue.

Disclosure

J. Trnovska: None. E. Davidova: None. P. Svoboda: None. H. Kratochvilova: None. M. Mraz: None. S. Hubackova: None. J. Neuzil: None. M. Haluzik: Advisory Panel; Self; Lilly Diabetes, Sanofi. Consultant; Self; Ethicon US, LLC. Speaker’s Bureau; Self; AstraZeneca, Mundipharma International, Novartis AG, Novo Nordisk A/S.

Funding

Institute for Clinical and Experimental Medicine (00023001); Czech Science Foundation (GA 18-02550S)
1791-P: The Threshold for Fasting Insulin Secretion Is Independent of the Beta-Cell Secretory Response to Glucose in Nondiabetic Humans
Authors: KOHLENBERG JACOB D. , LAURENTI MARCELLO C. , EGAN AOIFE M. , MAN CHIARA DALLA , RIZZA ROBERT A. , COBELLI CLAUDIO , VELLA ADRIAN
Published: June 2020

The transition from normal fasting glucose (NFG) and normal glucose tolerance (NGT) to type 2 diabetes is characterized by impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Graded Glucose Infusion (GGI) has been used to measure β-cell function in response to glucose and to extrapolate the β-cell threshold for insulin secretion. However, this assumes a linear relationship between fasting insulin secretion and the response to a GGI. This may not be the case in e.g., humans with IFG/NGT who have normal β-cell function despite IFG. As part of a series of experiments examining the pathogenesis of prediabetes, we examined the relationship of fasting insulin secretion with the subsequent β-cell response to GGI. To do so, we studied nondiabetic, weight-stable individuals (53 ± 2 yrs, BMI 27.5 ± 1.2 kg/m2). At the time of screening, subjects underwent a 75 g oral glucose tolerance test. On the study day, after an overnight fast, at 0700 (-120 min) a variable insulin infusion was used to maintain glucose at ∼80 mg/dL (until 0845). At 0900, GGI commenced (0-240 min total, starting at 1 mg/kg/min and doubling every 60 min). Insulin Secretion Rate (ISR) was estimated by deconvolution of frequently sampled peripheral C-peptide concentrations. The rate of change of ISR in response to increasing glucose concentrations was used to calculate β-cell responsivity to glucose and the set-point of insulin secretion. As expected, ISR rose throughout the study (0.07 ± 0.01, 0.21 ± 0.05, 0.30 ± 0.07, 0.55 ± 0.13, 0.94 ± 0.15 nmol/min; 0, 60, 120, 180, and 240 min respectively). The individual glucose threshold for insulin secretion (4.8 ± 0.1 mmol/l) was independent of β-cell function during the screening glucose tolerance test (R2 = 0.07, p = 0.67) and during the GGI (R2 = 0.06, p = 0.68). These data imply that the glucose threshold for insulin secretion is independent of β-cell function.

Disclosure

J.D. Kohlenberg: None. M.C. Laurenti: None. A.M. Egan: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. R.A. Rizza: None. C. Cobelli: None. A. Vella: Advisory Panel; Self; vTv Therapeutics, Zealand Pharma A/S. Research Support; Self; Novo Nordisk A/S, Xeris Pharmaceuticals, Inc.

Funding

Endocrine Fellows Foundation; National Institutes of Health (R01DK78646, R01DK116231)
1793-P: C-Peptide Kinetics: The Van Cauter Population Model May Not Be Applicable to Post–Gastric Bypass Adults with Postprandial Hyperinsulinemic Hypoglycemia
Authors: SCHIAVON MICHELE , HERZIG DAVID , HEPPRICH MATTHIAS , DONATH MARC Y. , STETTLER CHRISTOPH , BALLY LIA , MAN CHIARA DALLA
Published: June 2020

Insulin secretion is key to understand postprandial hyperinsulinemic hypoglycemia (PHH), an increasingly recognized and potentially debilitating complication of gastric bypass (GB) surgery. To assess it noninvasively, the Oral C-peptide Minimal Model (OCMM) can be used. This requires to know C-peptide (CP) metabolic clearance rate (MCR) usually fixed to the values predicted by the Van Cauter (VC) population model, but this has never been assessed in PHH individuals. Here, the aim is to fill this gap. Two groups of post-GB adults with PHH underwent either a 75g oral glucose (11F/5M; age=43±8 y; BMI=28.2±7.1kg/m2) or a 60g mixed-meal (9F/3M; age=44±10y; BMI=27.4±3.9kg/m2) tolerance test with sampling for plasma glucose and CP over 3.5 and 3h, respectively. The OCMM was used to describe CP concentration with CP kinetics fixed to VC or estimated based on data (DB). Model performance was assessed by its ability to predict CP data. In both groups, the VC approach underestimated CP-peak and overestimated CP-tail, while the DB one well predicted CP data in all subjects (Figure 1A). As a consequence, MCR resulted significantly higher with DB than VC approach (Figure 1B). The present findings question the validity of the VC population model to predict CP kinetics in PHH patients and call for CP bolus experiments to develop a reliable kinetic model in this population.

Disclosure

M. Schiavon: None. D. Herzig: None. M. Hepprich: None. M.Y. Donath: Advisory Panel; Self; AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Roche Pharma, Sanofi-Aventis. C. Stettler: None. L. Bally: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH.

Funding

Italian Ministry of Education (232/2016); Swiss National Science Foundation (PCEGP3_186978); University of Padova
1795-P: Proinsulin-Insulin Pancreatic Islets In-situ Expression Mirrors Metabolic Defects Observed in Type 2 Diabetic and Glucose Intolerant Living Donors
Authors: BRUSCO NOEMI , SEBASTIANI GUIDO , LICATA GIADA , GRIECO GIUSEPPINA E. , NIGI LAURA , FIGNANI DANIELA , MOFFA SIMONA , SORICE GIAN PIO , DI GIUSEPPE GIANFRANCO , ASSUNTA CEFALO CHIARA MARIA , MARI ANDREA , DOTTA FRANCESCO , GIACCARI ANDREA , MEZZA TERESA
Published: June 2020

Increased circulating levels of proinsulin (PI) and proinsulin-to-insulin ratio (PI/INS) is a well-known abnormality in type 2 diabetes (T2D). The exact mechanism behind this increase in T2D, as well as in T1D, is unknown. The aim of this study was to analyze proinsulin and insulin expression in pancreatic islets of tissue biopsies of patients undergoing partial pancreatectomy (PP) with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and T2D, in order to explore the alterations that occur in islets during metabolic stress. Frozen sections of pancreatic tissue biopsies (n=17) classified following OGTT into n=5 NGT, n=9 IGT and n=3 T2D were stained for INS and PI through double immunofluorescence staining. β-cell glucose sensitivity (calculated as the ratio of insulin secretion and glucose increments), basal insulin secretion, and glucose levels 2-hours following OGTT were analyzed. Image analysis was performed on each individual islet through Volocity software. In-situ staining measurements were correlated with patients’ clinical parameters. PI-INS colocalization as well as the area (µm2) of PI positivity and PI/INS ratio gradually increased from NGT to IGT and T2D pancreatic islets (p<0.0001), suggesting an altered localization and processing of PI in INS which potentially cause the release of immature granules with a higher relative content of PI. We demonstrated that the increase of PI/INS ratio was associated with higher basal INS (r=0.65 p<0.004) and glucose levels 2-hours following OGTT (r=0.75 p<0.0008). Finally, we also observed that the reduction of β-cell glucose sensitivity is linked to increase of in-situ PI-INS ratio (r=-0.6 p<0.02).

In conclusion, our results suggest that the increase of PI/INS ratio in pancreatic islets is directly related to metabolic defects in dysfunctional β cells, highlighting the importance of correct PI processing and folding in the maintenance of glucose homeostasis.

Disclosure

N. Brusco: None. G. Sebastiani: None. G. Licata: None. G.E. Grieco: None. L. Nigi: None. D. Fignani: None. S. Moffa: None. G. Sorice: None. G. Di Giuseppe: None. C. Cefalo: None. A. Mari: Consultant; Self; Lilly Diabetes. Research Support; Self; Boehringer Ingelheim International GmbH. F. Dotta: None. A. Giaccari: Speaker’s Bureau; Self; Amgen, AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi-Aventis. T. Mezza: None.

Funding

European Foundation for the Study of Diabetes; AstraZeneca
1797-P: Effect of LCZ696 and Its Components Sacubitril and Valsartan on Insulin Secretion and Glucose Homeostasis in Mice
Authors: ESSER NATHALIE , SCHMIDT CHRISTINE R. , BARROW BREANNE , CRONIC LAURA , HACKNEY DARYL J. , MONGOVIN STEVE M. , HULL REBECCA L. , ZRAIKA SAKENEH
Published: June 2020

In type 2 diabetes, HbA1c decreases upon treatment of heart failure with the angiotensin receptor-neprilysin (NEP) inhibitor LCZ696 (LCZ). We sought to determine whether the components of LCZ, the NEP inhibitor sacubitril (SAC) and angiotensin receptor blocker valsartan (VAL), enhance insulin secretion and if so, their effects are additive when combined in LCZ. C57BL/6 mice fed high fat diet (HFD) received injections of vehicle (VEH) or low-dose streptozotocin (3 × 30 mg/kg; STZ), the latter to induce diabetes. Mice were continued for 8 weeks on HFD alone (CTL) or supplemented with LCZ (114 mg/kg/d), SAC (48 mg/kg/d) or VAL (54 mg/kg/d). All drugs significantly reduced body weight gain in both VEH and STZ groups, with LCZ being more effective than SAC (Table). SAC and VAL, but not LCZ, lowered fed and fasting plasma glucose and increased insulin release during an IV glucose tolerance test (IVGTT) in STZ mice only (Table). In VEH and STZ mice, insulin sensitivity was similar among the 4 treatment groups; however, SAC enhanced glucose disposal during IVGTT (Table). None of the treatments altered pancreatic ß- and α-cell mass or lipolysis (not shown). In sum, SAC and VAL exert beneficial anti-obesity, glycemic and insulinotropic effects when given alone in obese and/or diabetic mice. Additional studies are needed to understand why, when SAC and VAL are combined in LCZ, only anti-obesity effects are observed.

Disclosure

N. Esser: None. C.R. Schmidt: None. B. Barrow: None. L. Cronic: None. D.J. Hackney: None. S.M. Mongovin: None. R.L. Hull: None. S. Zraika: Research Support; Self; Novartis Pharmaceuticals Corporation.

Funding

Novartis Pharmaceuticals Corporation (LCZ696BUSNC09T)
1798-P: Chronic Administration of a Long-Acting Glucagon Analogue Results in Enhanced Insulin Secretory Activity in a Directly-Observed Murine Model
Authors: SUBA KINGA , PATEL YATEEN S. , ALONSO ALDARA MARTIN , SCOTT REBECCA , MINNION JAMES S. , LECLERC ISABELLE , OWEN BRYN , DISTASO WALTER , TAN TRICIA M. , MURPHY KEVIN , BLOOM STEPHEN , RUTTER GUY A. , SALEM VICTORIA
Published: June 2020

Aims: GLP-1 (GLP-1R) and glucagon (GCGR) receptor co-agonists are in development to treat type 2 diabetes. The effect of chronic GCGR agonism on weight loss is well-documented, but its direct influence on islet function remains poorly understood. We investigated the effects of a long-acting glucagon analogue G778 on pancreatic islet calcium dynamics.

Methods: C57Bl/6 (n=9 per group) mice with diet-induced obesity (DIO) received daily subcutaneous injections of G778 100nmol/kg or saline (and calorie restricted to achieve weight matching) for 40 days. All mice had syngeneic islets with beta-cell specific expression of the calcium fluorophore GCaMP6f implanted in the anterior chamber of the eye, providing a direct, longitudinal readout of beta-cell function in vivo using confocal microscopy. Such islets were tested in vitro to measure the effects of G778 on whole islet calcium dynamics. Another experiment measured the effects of G778 administration on oxygen consumption in a CLAMS system.

Results: G778 produced a small but significant rise in energy expenditure (EE) in mice. At 40 days, there was non-significant difference in body weight loss between the saline and G778-treated groups (0.9g ±1.1 vs. 3.4g ±0.7 p=0.07), but a marked improvement in glucose tolerance in mice treated long term with the glucagon analogue (15 min glucose on a 2mg/kg IPGTT 15.9 mmol/L vs. 9.2 mmol/L p<0.001). Islet readouts over the course of the experiment revealed that glucagon receptor agonism was able to restore calcium activity of islets in DIO mice in vivo. In vitro findings confirmed that G778 promoted calcium waves of longer duration and heightened connectivity above 7mM glucose (p=0.05).

Summary: Our data suggest that the glucagon element of a glucagon/GLP-1 analogue contributes to weight-loss partly through an elevation in EE but also has independent effects on insulin secretory function, promoting more robust and sustained beta-cell calcium responses.

Disclosure

K. Suba: None. Y.S. Patel: None. A. Martin Alonso: None. R. Scott: None. J.S. Minnion: None. I. Leclerc: Consultant; Spouse/Partner; Sun Pharmaceutical Industries Ltd. Research Support; Spouse/Partner; Servier. B. Owen: None. W. Distaso: None. T.M. Tan: None. K. Murphy: None. S. Bloom: None. G.A. Rutter: Consultant; Self; Sun Pharmaceutical Industries Ltd. Research Support; Self; Servier, Sun Pharmaceutical Industries Ltd. V. Salem: None.

Funding

Diabetes UK (15/0005317)
1803-P: Antifibrotic Effect of a Novel Long-Acting GLP-1/GIP/Glucagon Triple Agonist (HM15211) in BDL-Induced Liver Fibrosis Mice
Authors: KIM JUNG KUK , LEE JONG SUK , KWON HYUNJOO , LEE JONGSOO , KIM DAEJIN , BAE SUNGMIN , LEE SANG HYUN , CHOI IN YOUNG
Published: June 2020

Fibrosis due to nonalcoholic steatohepatitis (NASH) remains a major cause of liver-related mortality. However, no medication has been approved despite accelerated drug development. Since multiple biological pathways are involved, strategy simultaneously targeting multiple pathways might be required to effectively treat fibrosis. To address this, we developed a novel long-acting GLP-1/GIP/Glucagon triple agonist, HM15211. Previously, HM15211 significantly improved fibrosis as well as steatosis and inflammation in MCD-diet mice. In addition to the diet-induced models, bile duct ligation (BDL) has also been extensively used as an animal model of fibrosis. Here, we further investigated the anti-fibrotic effects of HM15211 in BDL-induced fibrosis mice. Two days post BDL (single ligation), the mice were administered either with HM152111 or obeticholic acid (OCA) for 2 weeks, followed by histological analysis. HM15211 treatment showed greater reduction in hepatic hydroxyproline (HP) (450.5, 351.7 and 253.6 nmol/g liver for vehicle, OCA and HM15211) and fibrosis score (1.7, 1.8 and 1.0 for vehicle, OCA and HM15211) compared to OCA. Consistently, HM15211, but not OCA, treatment was associated with the reduction of serum surrogate markers of fibrosis including TGF-β (-61.4, 9.1% vs. vehicle for HM15211, OCA), TIMP-1 (-71.6, -13.9% vs. vehicle), and hyaluronic acid (-68.9, 25.0% vs. vehicle). To further clarify its benefits in fibrosis, BDL (double ligation) mice with an extended induction period (up to 2 weeks) was used. Notably, despite the progression to advanced liver fibrosis, HM15211 treatment still attenuated HP (571.5 and 334.3 nmol/g liver for vehicle and HM15211) and fibrosis score markedly. Considering the pathologic features of BDL mice (liver fibrosis without liver fat accumulation), these results demonstrate the direct anti-fibrotic effect of HM15211. Further studies are needed to assess the clinical relevance of these findings.

Disclosure

J. Kim: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. H. Kwon: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. D. Kim: Board Member; Self; Hanmi Pharmaceutical. S. Bae: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. I. Choi: Board Member; Self; Hanmi Pharmaceutical.
1805-P: Dietary Nitrate Prevents High-Fat Diet-Induced Glucose Intolerance and Liver-Specific Reactive Oxygen Species Emission
Authors: DESORMEAUX GENEVIEVE , PETRICK HEATHER L. , BRUNETTA HENVER , HOLLOWAY GRAHAM
Published: June 2020

Introduction: The liver is particularly susceptible to the detrimental effects of a high fat diet (HFD), and rapidly develops insulin resistance. While the underlying mechanisms associated with hepatic insulin resistance are not fully understood, mitochondria play a crucial role in regulating lipid metabolism and redox balance. Recently, dietary nitrate was shown to attenuate HFD-induced glucose intolerance, however the mechanism(s) remains unknown. Therefore, in the present study we examined the possibility that dietary nitrate increased mitochondrial lipid-supported respiration and/or attenuated reactive oxygen species (ROS) emission.

Methods: Male C57Bl/6J mice (n = 22) were randomly assigned to consume a control diet (10% fat), HFD (60% fat), or HFD with 4mM sodium nitrate in drinking water for 8 weeks. Whole body glucose tolerance and energy expenditure (indirect calorimetry) were determined, and mitochondrial respiration and reactive oxygen species (ROS) emission were assessed in liver samples.

Results: Compared to control animals, the consumption of HFD increased whole body fat oxidation and body mass, and induced glucose intolerance. The consumption of dietary nitrate did not affect HFD-mediated changes in energy expenditure, rates of fat oxidation or body mass, but nevertheless attenuated the induction of glucose intolerance. Within the liver, HFD-feeding in the presence or absence of dietary nitrate, did not alter pyruvate or lipid (palmitoyl-CoA) supported respiration, or the sensitivity to malonyl-CoA-mediated inhibition of lipid-supported respiration. In contrast, while HFD increased the endogenous ROS production, nitrate prevented this response.

Conclusion: These data demonstrate that nitrate supplementation attenuated the HFD-mediated induction of whole-body glucose intolerance in association with a reduction in ROS emission within the liver. Future research needs to determine causality between these observations.

Disclosure

G. DesOrmeaux: None. H.L. Petrick: None. H. Brunetta: None. G. Holloway: None.

Funding

Natural Sciences and Engineering Research Council of Canada (400362)
1806-P: Vitamin D Deficiency Impairs mTORC2/Akt Signaling through Downregulating SIRT1 and Results in Increased Hepatic Gluconeogenesis
Authors: YUAN QI , YANG JINGLEI , SUN MENGYUE , TANG SHAN , DONG MEIJUAN , MAO LI
Published: June 2020

1,25(OH)2D3 as an active form of vitamin D is involved in the development of many metabolic-related diseases including diabetes. While prospective epidemiological studies have shown that vitamin D deficiency is implicated in the regulation of glucose metabolism, the specific mechanism still remains unclear. Here, we generated 1α(OH)ase-null mice and discovered that these mice developed hepatic glucose overproduction and hepatic insulin resistance accompanied by decreased expression of Sirt1. ChIP and Luciferase assay confirmed that 1,25(OH)2D3 activating vitamin D receptor (VDR) directly interacts with one vitamin D response element located in Sirt1 promoter to up-regulate its transcription, triggering a cascade of phosphorylation of Akt at S473 and FOXO1 at S256 and resulting in decreased transcription of the gluconeogenic genes glucose-6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase (PCK1), eventually hepatic glucose overproduction. We have identified a signaling pathway involving VDR, Sirt1, Rictor (a component of mTOR complex 2 [mTorc2]), Akt, and FoxO1 that regulates gluconeogenesis, and identified Sirt1 and FoxO1 as key modulators of increased gluconeogenesis induced by vitamin D deficiency. Our work demonstrates a novel mechanism of 1,25(OH)2D3 deficiency-induced hyperglycemia mediated through Sirt1 downregulation.

Disclosure

Q. Yuan: None. J. Yang: None. M. Sun: None. S. Tang: None. M. Dong: None. L. Mao: None.

Funding

National Natural Science Foundation of China (81400789)
1808-P: Hepatocyte Traf Family Members Link Inflammation to Liver Steatosis and Insulin Resistance
Authors: ZHANG ZHIGUO , LIN HAIYAN , ZHONG XIAO , RUI LIANGYOU
Published: June 2020

Obesity is associated with chronic inflammation that exacerbates insulin resistance and metabolic disease. Inflammation drives the pathogenesis of nonalcoholic fatty liver disease (NAFLD), hepatic manifestations of obesity. Hepatic inflammatory microenvironments are believed to induce reprogramming of metabolic pathways; however, intracellular molecules coupling inflammation to metabolism remain poorly understood. Cytokines, damage-associated (DAMPs) and pathogen-associated molecular patterns (PAMPs) are known to activate Traf family members that in turn activate the NF-κB and other inflammatory pathways. We previously reported that hepatic Traf2 and Traf3 augment hepatic glucose production. Here, we demonstrate that hepatocyte Traf2, Traf3 and Traf6 act in concert to promote liver steatosis and insulin resistance. We ablated hepatocyte Traf2, Traf3, and Traf6 individually and in combination (Traf2,3,6Δhep) in adult Traf2flox/flox, Traf3flox/flox, Traf6flox/flox, and Traf2,3,6flox/flox mice, respectively, using AAV-TBG-Cre vectors. Metabolic abnormality was more severe in Traf2,3,6Δhep mice relative to Traf2Δhep, Traf3Δhep and Traf6Δhep mice. Remarkably, Traf2,3,6Δhep mice were resistant to high fat diet-induced liver steatosis, insulin resistance, and glucose intolerance. Hepatic PPARα, a master regulator of fatty acid β oxidation, was substantially elevated in Traf2,3,6Δhep mice. Conversely, in primary hepatocytes, overexpression of Traf3 markedly decreased PPARα stability and protein levels. Traf3 coimmunoprecipitated with PPARα and decreased PPARα transcriptional activity. In primary hepatocytes, ablation of Traf2, Traf3 and Traf6 significantly increased fatty acid β oxidation, and overexpression of Traf3 had the opposite effects. Together, our results unveil an unrecognized hepatocyte Traf/PPARα/fatty acid β oxidation pathway that couples inflammation to liver steatosis and insulin resistance in obesity.

Disclosure

Z. Zhang: None. H. Lin: None. X. Zhong: None. L. Rui: None.
181-OR: Effect of Sevelamer and a Synbiotic on Insulin Sensitivity in Obese Individuals
Authors: BAEUERLE ERIC , LIANG HANYU , GANAPATHY VINUTHA , FERNANDEZ ROMAN , SATHAVARODOM NATTAPOL , WANG CHEN-PIN , ESPINOZA SARA E. , MUSI NICOLAS
Published: June 2020

The human gut and its microbial content (microbiome) may contribute to the pathogenesis of obesity, insulin resistance and type 2 diabetes. Possible mechanisms include altered bacterial profile, increased intestinal permeability, and elevated bacterial lipopolysaccharide (LPS) leading to low-grade systemic inflammation termed metabolic endotoxemia. We hypothesized that two interventions with putative LPS-lowering effects, sevelamer and a synbiotic (combination pre- and probiotic), would improve peripheral insulin sensitivity in obese subjects. Based upon pre-clinical studies, sevelamer is reported to sequester LPS in the GI tract, whereas a synbiotic of Bifidobacterium longum plus oligofructose can improve intestinal barrier integrity. We randomized 22, normal glucose tolerant (NGT), lean (15F/7M, BMI=23.0, age=45.4yr, A1c=5.3%) and 28 NGT, obese subjects (20F/8M, BMI=32.7, age=51.9yr, A1c=5.5%) to receive oral sevelamer, synbiotic or placebo daily for 28 days. Insulin sensitivity (euglycemic clamp), cholesterol, endotoxemia (LPS, LBP, CD14), and intestinal permeability (lactulose/mannitol ratio, zonulin) were assessed before and after intervention. Obese subjects had reduced baseline insulin sensitivity compared to lean subjects (M value, -28.6%, p=0.0001 based on 2-sample t-test). Generalized estimating equation analysis showed that sevelamer increased insulin sensitivity (M value, +25.6%, p=0.022) and lowered plasma LDL (-16.4%, p=0.016) in obese subjects compared to placebo-treated obese subjects. Synbiotic did not significantly alter insulin sensitivity or lipids compared to placebo in obese subjects. Lean subjects saw no change in insulin sensitivity with either treatment. Neither treatment significantly altered plasma LPS or intestinal permeability in lean or obese subjects.

In conclusion, sevelamer improves insulin sensitivity and LDL in obese subjects, and this effect is mostly independent of parameters of endotoxemia and intestinal permeability.

Disclosure

E. Baeuerle: None. H. Liang: None. V. Ganapathy: None. R. Fernandez: None. N. Sathavarodom: None. C. Wang: None. S.E. Espinoza: None. N. Musi: None.

Funding

American Diabetes Association (7-13-GSK-01 to N.M.); National Institutes of Health (T32GM113896)
1810-P: Triple Combination Therapy of GLP-1 Receptor Agonist Semaglutide with an FXR Agonist and AC Inhibitor Reverses Nonalcoholic Steatohepatitis (NASH) in Diet-Induced and Biopsy-Confirmed Mice
Authors: NORLIN JENNY , MIRANDA DIEGO A. , BATES JAMIE G. , ZOIS NORA E. , VEIDAL SANNE , FEIGH MICHAEL , TREVASKIS JAMES L. , LATTA MARKUS
Published: June 2020

Semaglutide (SEMA), FXR agonists and ACC inhibitors are under active clinical investigation for the treatment of NASH. Here, we explored whether the effects of SEMA (0.12 mg/kg, s.c., q.d.) on NASH endpoints could be enhanced by addition of an FXR agonist (cilofexor, CILO; 30 mg/kg) and/or an acetyl-CoA carboxylase inhibitor (firsocostat analogue, ACCi; 5 mg/kg, both p.o., q.d.) in the AMLN diet-induced and biopsy-confirmed DIO-NASH mouse (n=15-16/group). After 12 weeks of treatment, SEMA and triple therapy reduced body weight 18%, being slightly enhanced in the double combination of SEMA+CILO (21%). Liver triglyceride concentration was reduced by SEMA (by 38% vs. vehicle, p<0.001). Addition of CILO or ACCi or both to SEMA further reduced liver lipid by 64%, 73% and 81%, respectively (all p<0.001 vs. SEMA). Histopathological pre-to-post NAFLD activity score (NAS) was reduced in 3/16 (19%) of vehicle controls and in all mice (100%) treated with SEMA or triple therapy. Further, the number of mice that exhibited a 3+ point improvement in NAS was improved with the triple combination (12/16; 75%) vs. SEMA alone (2/16, 13%). Likewise, the triple combination caused the greatest improvements in fibrosis stage pre-to-post (7/16, 44%, improved; 1/16 worsened), followed by the SEMA-treated group (6/16, 38% improved; 0/16 worsened) relative to vehicle (2/16, 13% improved; 7/16, 44% worsened). Collagen-1a and a-SMA immunoreactivity (% area) tended to be or were significantly improved with SEMA (4.2%; n.s., and 1.4%; p<0.001) and triple therapy (3.9%; p<0.045 and 0.9% p<0.001) vs. vehicle (6.3% and 4.6%). SEMA significantly improved NAS and fibrosis endpoints. While addition of either single agent improved liver fat reduction, triple therapy improved pre-to-post NAS and fibrosis stage relative to SEMA alone in DIO-NASH mice. These data support development of combination approaches for NASH.

Disclosure

J. Norlin: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. D.A. Miranda: None. J.G. Bates: Employee; Self; Gilead Sciences, Inc. N.E. Zois: Employee; Self; Gubra. S. Veidal: None. M. Feigh: None. J.L. Trevaskis: Employee; Self; Gilead Sciences, Inc. M. Latta: Employee; Self; Novo Nordisk A/S.
1817-P: Elafibranor and Glucagon-Like Peptide-1 Receptor Agonists Synergize to Attenuate Hepatic Inflammation and Fibrosis in a Rodent Model of Obesity, Insulin Resistance, and NASH
Authors: LEGRY VANESSA , DESCAMPS EMELINE , DEBAECKER SIMON , STANKOVIC-VALENTIN NICOLAS , PARROCHE PEGGY , DEGALLAIX NATHALIE , POULAIN PHILIPPE , STAELS BART , WALCZAK ROBERT
Published: June 2020

Elafibranor and GLP-1 receptor agonists synergize to attenuate hepatic inflammation and fibrosis in a rodent model of obesity, insulin resistance and NASH.

Liver steatosis contributes to the development of hepatic insulin resistance and is present in the majority of T2DM patients, who are 50 or older. Therefore, many NAFLD patients with diabetes are currently treated with the antidiabetics, including GLP-1 receptor agonists (GLP-1RA). Elafibranor (ELA), a phase 3 candidate for the treatment of NASH, ameliorates insulin sensitivity and lowers HbA1c in patients with NASH-associated T2DM.

The aim of our study was to evaluate the pharmacological benefit of combining GLP-1RA and ELA in the context of NASH-associated insulin resistance.

GLP-1RA administration induced body weight loss, reduced insulinemia, HOMA-IR and liver steatosis in obese mice with NASH and insulin resistance, but its action on liver fibrosis was negligible. ELA co-administration allowed for GLP-1RA dose reduction and resolved all NASH features. Food intake was also normalized at reduced GLP-1RA doses.

Plasma CRP concentration was reduced by 56% in mice that received the combination treatment. Transcriptomic analyses revealed that the synergism between ELA and GLP-1RA in the liver was limited to the modulation of the inflammatory pathways with no effect on metabolic genes. Since ELA and GLP-1RA also synergize in vitro to reduce TNFa secretion in LPS-activated THP1 macrophages, we postulate that both drugs have a direct action on inflammatory cells in the liver. Further analyses to characterize ELA and GLP-1RA effects on innate and adaptive immune responses will be presented.

Conclusion: ELA and GLP-1RA synergize to reduce hepatic inflammation and fibrosis in a model of NASH and obesity. These results suggest a potential therapeutic interest of combining ELA and GLP-1RA for the treatment of T2DM in NASH patients.

Disclosure

V. Legry: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT. E. Descamps: Employee; Self; GENFIT. Employee; Spouse/Partner; GENFIT. Stock/Shareholder; Spouse/Partner; GENFIT. Stock/Shareholder; Self; GENFIT. S. Debaecker: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT. N. Stankovic-Valentin: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT. P. Parroche: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT. N. Degallaix: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT. P. Poulain: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT. B. Staels: Consultant; Self; Genfit. R. Walczak: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT.
1819-P: Gut Microbiota and PNPLA3 RS738409 Associated with Nonalcoholic Fatty Liver Disease in Obese Youth
Authors: KRAVETZ AYESHA MONGA , TESTERMAN TODD , GALUPPO BRITTANY , GRAF JOERG , SIEBEL STEPHAN , FEINN RICHARD , SANTORO NICOLA
Published: June 2020

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease. Since gut microbiota has been associated with pediatric obesity, we explored the potential relationship between gut microbiota and NAFLD in obese youth, while considering the role of PNPLA3 rs738409, a genetic contributor to NAFLD. Seventy-three obese youth (BMI > 95th percentile) underwent an MRI to measure hepatic fat fraction (HFF), an oral glucose tolerance test, and fasting blood sample collection. PNPLA3 rs738409 was assessed by automatic sequencing. A stool sample from each subject was collected to analyze the V4 region of the 16S rRNA gene and characterize intestinal bacteria. Shannon-Wiener index values were calculated for all samples and were compared between participants without NAFLD (HFF < 5.5%; n= 29) and with NAFLD (HFF ≥ 5.5%; n= 44). We observed that subjects with NAFLD had decreased (p=0.013) bacterial diversity compared to those without NAFLD. When comparing the abundance of each bacterial phylum (n=8) and genus (n=51) between the two groups, we observed a higher Firmicutes to Bacteroidetes (F/B) ratio (p=0.019) and lower abundance of Bacteroidetes (p=0.010), Prevotella (p=0.019), Gemmiger (p=0.003), and Oscillospira (p=0.036) in those with NAFLD, compared to those without NAFLD. Multiple linear regression was conducted to determine if each phylum and genus that was different (p<0.05) in abundance between the two groups was found to be predictive of HFF, while controlling for PNPLA3 genotype, race, and BMI z-score. Regression results showed that F/B ratio, Bacteroidetes, Gemmiger, and Oscillospira were associated with HFF when controlling for group variations. We also observed an additive effect of PNPLA3 rs738409 and Gemmiger, and PNPLA3 rs738409 and Oscillospira on HFF. We demonstrate that obese youth with NAFLD have different gut microbiota composition than those without NAFLD and identified individual phyla and genera that are associated with intrahepatic fat content.

Disclosure

A. Monga Kravetz: None. T. Testerman: None. B. Galuppo: None. J. Graf: None. S. Siebel: None. R. Feinn: None. N. Santoro: None.

Funding

National Institutes of Health (R01DK114504)
1823-P: Bromocriptine (BC) Normalizes Elevated Expression of Liver Genes Involved in Fatty Acid Oxidation, Lipogenesis, Inflammation, and Endoplasmic Reticulum (ER) Stress and Glucose Intolerance of High-Fat/Sucrose Diet-Fed Rats
Authors: ZHANG YAHONG , EZROKHI MICHAEL , COMINOS NICHOLAS , CINCOTTA ANTHONY H.
Published: June 2020

Consumption of the “westernized diet” (WD) of high fat and sucrose promotes the development of hepatic insulin resistance and metabolic syndrome (MS). This diet is well known to reduce brain dopamine activity and stimulate chronic over-activation of the sympathetic nervous system that potentiate liver insulin resistance by as yet unknown mechanisms. This study evaluated the effect of circadian-timed bromocriptine, a sympatholytic dopamine agonist, to reverse the adverse effects of the WD on glucose tolerance and liver expression of several genes involved in hepatic aspects of insulin sensitivity including lipid balance, inflammation and ER stress. Female Sprague-Dawley rats were maintained on a WD of high fat (40% by kcal/g) and sucrose (29% by kcal/g) for 4 weeks and then administered BC (7.5 mg/kg) or vehicle (N =10/group) at the onset of daily waking for an additional 10 weeks while maintained on WD to study end when a GTT (3g/kg glucose) was performed and 5 days later when animals were sacrificed for analyses of hepatic genes (via PCR) involved in insulin sensitivity. A regular chow fed group (N=10) served as positive control. BC treatment reduced the GTT glucose AUC by 39% vs. controls (P<0.001) without change in the insulin AUC and reduced body fat level by 35% (P= 0.01) without change in feeding vs. controls. BC also reduced hepatic gene transcripts for fatty acid oxidation - PPARa and CPT1A by 35 and 48%, respectively (P<0.03), for lipid synthesis - DGAT2 by 20% (P<0.04), and for inflammation and ER stress - monocyte chemoattractant protein 1 and C/EBP homologous protein by 40 and 47% (P<0.05), respectively, vs. controls, all to levels observed in regular chow fed rats. This study demonstrated that bromocriptine can reverse the adverse effects of WD on hepatic lipid, inflammation, and ER stress gene expression pathways that promote hepatic insulin resistance and MS.

Disclosure

Y. Zhang: Employee; Self; VeroScience LLC. M. Ezrokhi: Employee; Self; VeroScience LLC. N. Cominos: Employee; Self; VeroScience LLC. A.H. Cincotta: Employee; Self; VeroScience LLC.
1824-P: Activation of Cardiac Mitochondrial Akt1 Improved Diabetic Cardiomyopathy through Inhibition of Melatonin Degradation and Remotely Improved Liver Metabolism
Authors: TA ALBERT , CHEN YU-HAN , CHEN YUMAY , LIN HUGO Y.H. , WANG PING H.
Published: June 2020

Insulin resistance impaired Akt1 translocation to mitochondria in myocardium and contributed to diabetic cardiomyopathy (DCM). It is unknown whether activation of mitochondrial Akt in cardiac muscle can protect against DCM. To this end, we generated an inducible heart-specific transgenic mice with a mitochondria-targeting constitutively active Akt (CAMCAKT). A high fat-high fructose (HFF) diet induced myocardial fibrosis and heart failure, but cardiomyopathy was reversed in the CAMCAKT mice, indicating a mechanistic role of mitochondrial Akt1 signaling in DCM. RNAseq analysis revealed myocardial transcriptome changes, including suppressed Col1a1 and Col3a1 expression (fibrosis markers) recapitulating the mechanism of fibrosis. Accompanying lowered GP6 expression suggested a reduction in collagen-induced platelet activation. Pathway analysis revealed significant inhibition in multiple steps of melatonin degradation. Enhancing melatonin signaling, an emerging myocardial protective factor that reduces oxidative stress/apoptosis, is a novel mechanism through which mitochondrial Akt1 could protect against DCM. Under the HFF diet, cardiac mitochondrial Akt1 signaling also caused whole body changes; CAMCAKT mice had 15% less body fat, 30% lower total cholesterol and 42% lower LDL (p<0.05), and showed higher energy expenditure during night cycles and an elevated RER, an indicator for increased carbohydrate metabolism. The diet-induced fatty liver in the CAMCAKT mice was significantly lowered, suggesting that cardiac mitochondrial Akt signaling could remotely modulate hepatic fat metabolism. Liver RNAseq revealed that cholesterol synthesis in the liver was modulated by cardiac mitochondria.

In summary, activating cardiac mitochondrial Akt1 protected against DCM by inhibiting melatonin degradation, and attenuated the development of fatty liver by regulating cholesterol synthesis.

Disclosure

A. Ta: None. Y. Chen: None. Y. Chen: None. H.Y.H. Lin: None. P.H. Wang: Board Member; Self; Dianavi.

Funding

National Institutes of Health (R01HL096987)
1834-P: Neuronal Nitric Oxide Synthase Activity and Hepatic Insulin Resistance
Authors: WANG CHEN , LI QIAN , ZHU YUNXIA
Published: June 2020

Objective: Neuronal nitric oxide synthase (nNOS) contains PZD domain through which NOS1AP was connected. We reported previously that NOS1AP regulated hepatic insulin sensitivity depending on its PZD binding domain suggesting an involvement of nNOS in NOS1AP effect. Thus, in the present study, we aimed to explore the role of nNOS on hepatic glucose and lipid metabolism, and the mechanism underlined.

Methods: Liver specific nNOS overexpression was achieved by tail-vein-injection of adenovirus-nNOS in C57BL/6 mice fed with a high-fat diet (HFD). nNOS specific inhibitor (L-NPA) was used to change the activity of nNOS. Western blot was used to evaluate the protein expression. Real-time PCR was used to detect the gene expression.

Results: nNOS expressed in livers from humans and mice, and its phosphorylation in Ser1417 increased in the livers of ob/ob and HFD-induced obese mice. Overexpression of nNOS in the livers of HFD-induced obese mice further impaired the glucose tolerance, increased the intrahepatic lipid accumulation, decreased the glycogen storage, and blunted insulin-induced phosphorylation of IRβ and AKT in livers (all P <0.05). Similarly, overexpression of nNOS increased the triglyceride production, decreased the glucose utilization, and insulin-induced phosphorylation of IRβ, AKT and GSK3β in HepG2 cells (all P <0.05). In contrast, inhibition of nNOS with L-NPA in ob/ob mice improved the glucose tolerance and increased insulin-induced phosphorylation of IRβ and AKT in livers (all P <0.05). Moreover, overexpression of nNOS in HepG2 cells increased phosphorylation of P38 MAPK, whereas, inhibition of P38 MAPK with SB203580 significantly reversed the defect in insulin signaling activation -induced by nNOS overexpression.

Conclusions: Hepatic nNOS inhibited insulin signaling pathway through the activation of P38 MAPK, suggesting a role of nNOS as a potential therapeutic target for the prevention and treatment of type 2 diabetes.

Disclosure

C. Wang: None. Q. Li: None. Y. Zhu: None.

Funding

National Natural Science Foundation of China (81670707)
1837-P: Female Hormone Estradiol Regulates Hepatic FGF21 Expression via Wnt Pathway Activation
Authors: SHAO WEIJUAN , BADAKHSHI YASAMAN , JIN TIANRU
Published: June 2020

β-cat/TCF, formed by β-cat and a TCF family member, serves as the effector of the developmental canonical Wnt signaling cascade. β-cat/TCFs can also function as effectors of metabolic hormones or growth factors during adulthood.

We have demonstrated recently that liver-specific expression of dominant-negative TCF7L2 (TCF7L2DN) led to impaired glucose disposal in both male and female mice. Increased hepatic lipogenesis, however, was observed in male but not in female mice. Our further investigations on such LTCFDN transgenic mouse model revealed the role of estradiol (E2) in stimulating β-cat/TCF activity. E2 reconstitution in WT mice with ovariectomy (OVX) restored the resistance of female mice to HFD induced body weight gain, insulin intolerance and elevation of hepatic lipogenic gene expression. Such beneficial effects of E2 reconstitution, however, were absent in LTCFDN female mice.

To identify downstream metabolic effector/s of Wnt signaling in regulating hepatic lipogenesis, we assessed metabolic hormone expression in LTCFDN and WT littermates. Curiously, hepatic but not adipose tissue FGF-21 level was reduced in male LTCFDN mice. We then directly assessed the effect of E2 on hepatic FGF-21 expression. In WT mice on LFD diet, OVX leads to reduced hepatic FGF-21 mRNA and protein levels, associated with reduced circulating FGF-21 hormone level. These reduction was associated with reduced hepatic β-cat S675 phosphorylation, TCF7 and TCF7L2 expression. In WT mice on HFD, OVX also reduced hepatic FGF-21 mRNA and circulating FGF-21 hormone levels. Such reduction was also restored with E2 reconstitution. Our study hence identified that FGF-21 is likely among the downstream effectors of E2-Wnt signaling cascade in hepatic lipid homeostasis.

Disclosure

W. Shao: None. Y. Badakhshi: None. T. Jin: None.

Funding

Canadian Institutes of Health Research (PJT159735)
1839-P: Glycemic Control Impacts Severity of Hepatic Fibrosis in NAFLD/NASH
Authors: ALEXOPOULOS ANASTASIA-STEFANIA , CROWLEY MATTHEW , WANG YING , GUY CYNTHIA D. , HENAO RICARDO , SEYMOUR KERI A. , SUDAN RANJAN , PORTENIER DANA , DIEHL ANNA MAE , ABDELMALEK MANAL F. , COVIELLO ANDREA D.
Published: June 2020

T2DM increases risk for advanced fibrosis in NAFLD, however little is known about the impact of glycemic control on fibrosis severity.

Objective: To assess whether glycemic control is associated with severity of fibrosis in NAFLD.

Methods: We utilized the Duke NAFLD Clinical Database to examine the association between HbA1c and fibrosis in patients with biopsy (Bx)-proven NAFLD (n=941). A generalized linear regression model was used (adjusted for age, gender, race, BMI, HLD, eGFR) to assess the association of mean HbA1c (1 year pre- to 90d post-Bx) and fibrosis severity (stage 3-4=advanced vs. 0-2=mild). Patients with ≥3 HbA1c values (n=335) were examined by group-based trajectory analysis using HbA1c over 5 yrs pre- to 90d post-Bx.

Results: Every 1% increase in mean HbA1c was associated with 20% higher odds of advanced fibrosis (OR 1.20, 95%CI 1.02, 1.39 p=0.02). Group-based trajectory analysis identified three glycemic patterns - good, moderate and poor (groups 1,2,3, respectively); proportion of advanced fibrosis increased with worse glycemic control. Group 2 had higher odds of advanced fibrosis than group 1 (OR 4.46, 95%CI 2.29,8.70, p<0.01). Group 3 estimates were limited by small sample size (OR vs. group 1: 2.55, 95% CI 0.87,7.44, p<0.01).

Conclusion: Glycemic control preceding Bx impacts severity of liver fibrosis. We are currently analyzing 65 patients with paired Bx to assess impact of HbA1c trends on change in fibrosis severity.

Disclosure

A. Alexopoulos: None. M. Crowley: None. Y. Wang: None. C.D. Guy: Consultant; Self; CymaBay, HistoIndex, Madrigal, NGM. R. Henao: None. K.A. Seymour: Other Relationship; Self; Gore, Medtronic. R. Sudan: None. D. Portenier: Consultant; Self; Medtronic. Speaker’s Bureau; Self; Novo Nordisk Inc. A. Diehl: None. M.F. Abdelmalek: None. A.D. Coviello: Consultant; Self; GI Dynamics Inc., Novo Nordisk Inc. Research Support; Self; Allergan plc., GENFIT, Orthus Health. Speaker’s Bureau; Self; Novo Nordisk Inc.

Funding

Endocrine Fellows Foundation