bluuebunny/crossref_metadata_2025 huggingface dataset:
1726-P: Male Mice Lacking Estrogen Receptor Beta Develop Obesity but Are Protected from Diet-Induced Insulin Resistance in Skeletal Muscle
Authors: FRIEDLINE RANDALL H. , NOH HYE LIM , SUK SUJIN , GORAL CEREN , DUNPHY KAREN A. , ROBERTS AMY L. , TRAN DUY A. , TAUER LAUREN A. , HU XIAODI , KIM LAUREN H. , KIM ALLISON M. , JERRY D. JOSEPH , KIM JASON K.
Published: June 2020

Estrogen has an important role in regulating female metabolism. Whereas the role of estrogen receptor (ER) α on female reproductive system is well defined, the role of ERβ (encoded by Esr2) remains unclear. Here we examined the metabolic effects of high-fat diet (HFD) in male Esr2-/- mice on BALB/c background (n=8∼9). After 6 weeks of HFD, Esr2-/- mice became more obese than wild type (WT) mice (Figure 1; *P<0.05). Surprisingly, metabolic cage study showed significantly increased energy expenditure in Esr2-/- mice, likely resulting from skeletal muscle as lean mass tended to be higher in these mice (Figure 2). We performed a hyperinsulinemic-euglycemic clamp to measure insulin sensitivity in awake mice. Despite being more obese, HFD-fed Esr2-/- mice tended to show increased insulin sensitivity with 20% increases in whole body glucose turnover and glycolysis (Figure 3). This was mostly due to a significant increase (52%) in skeletal muscle glucose uptake in HFD-fed Esr2-/- mice (Figure 4). Interestingly, glucose uptake into brown fat tended to be reduced by 50% in HFD-fed Esr2-/- mice.

In conclusion, these results indicate that deletion of Esr2 in male mice increases diet-induced obesity, but selectively prevents muscle insulin resistance. Our findings implicate a potential therapeutic role of estrogen signaling to treat insulin resistance.

Disclosure

R.H. Friedline: None. H. Noh: None. S. Suk: None. C. Goral: None. K.A. Dunphy: None. A.L. Roberts: None. D.A. Tran: None. L.A. Tauer: None. X. Hu: None. L.H. Kim: None. A.M. Kim: None. D. Jerry: None. J.K. Kim: None.

Funding

National Institutes of Health (5U2CDK093000)
1754-P: Prebiotic Early Intervention Improves Blood Glucose in Pup Mice
Authors: ZHANG QIAN , XIAO XINHUA , LI MING
Published: June 2020

Maternal high fat (HF) during pregnancy is known to have numerous adverse effects on offspring, including increased adiposity and impaired glucose tolerance later in life. The aim of this study was to determine if prebiotic early intervention could mitigate some of the negative effects of maternal HF. C57BL mice were fed a HF diet, normal diet or a HF diet with prebiotic supplementation during pregnancy and lactation. At 3 weeks of age, glucose tolerance were measured in the offspring. And offspring livers were obtained. Hepatic DNA methylation and gene expression was assayed. Maternal HF diet led offspring glucose intolerance and insulin resistance. Prebiotic early intervention moderated glucose metabolism and insulin resistance in male pup mice. Maternal HF diet reduced phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alph (Pik3c2a), phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 beta (Pik3c2b), and phosphoinositide-3-kinase regulatory subunit 2 (Pik3r2) gene expression in male pup mice (P<0.01). Prebiotic early intervention increased these gene expression in pup livers (P<0.01). Moreover, maternal HF diet led these three gene hypermethylated (P<0.01). These three genes were hypomethylated in prebiotic early intervention group (P<0.01). Prebiotic early intervention improved glucose intolerance by changing DNA methylation and gene expression of Pi3k in mice exposed to a maternal HF diet.

Disclosure

Q. Zhang: None. X. Xiao: None. M. Li: None.

Funding

National Natural Science Foundation of China (81870545, 81870579); Beijing Natural Science Foundation (7202163, 7172169)
1764-P: Specific Viral Targeting of Peripheral Pancreatic Innervation
Authors: GONZALEZ MARIA JIMENEZ , LI ROSEMARY , POMERANZ LISA E. , SCHWARTZ GARY J. , STANLEY SARAH
Published: June 2020

The brain and peripheral organs communicate through the peripheral nervous system (PNS) comprised of autonomic (sympathetic and parasympathetic) and sensory nerves. Pancreas is densely innervated by the PNS and their cell bodies reside in several ganglia, including nodose (NG), coeliac (CG) dorsal root ganglia (DRG) and intrapancreatic ganglia. Pancreatic innervation is altered in diabetes. Until now, we have lacked the ability to identify and specifically target pancreatic nerves and modulate their function to determine the physiological roles of pancreatic nerves. Here, we delivered retrograde tracers into the pancreas and quantified pancreas-projecting neurons in NG/DRG/CG with 3D visualization and tissue clearing. Next, we assessed the efficiency of different adeno-associated virus (AAV) serotypes, delivery routes and promoters to target construct expression in defined pancreatic nerves. Specific AAV serotypes selectively target pancreas-projecting efferent CG neurons or afferent NG neurons. We utilized Cre-dependent AAV to deliver activating chemogenetic constructs into pancreatic parasympathetic nerves. Targeted activation of the pancreatic parasympathetic neurons improved glucose tolerance and increased insulin secretion. Our studies demonstrate that specific AAV serotypes can target defined pancreatic innervation. Targeted modulation of pancreatic parasympathetic nerves can clarify crucial roles of peripheral nerves in pancreatic function and pathophysiology.

Disclosure

M. Jimenez Gonzalez: None. R. Li: None. L.E. Pomeranz: None. G.J. Schwartz: None. S. Stanley: None.

Funding

American Diabetes Association (1-17-ACE-31 to S.S.); National Institutes of Health (1R01NS097184, OT2OD024912); Alexander and Alexandrine Sinsheimer Scholar Award
1771-P: Hypothalamic Perineuronal Net Assembly Is Required for Sustained Diabetes Remission Induced by FGF1
Authors: ALONGE KIMBERLY M. , MIRZADEH ZAMAN , SCARLETT JARRAD , LOGSDON ARIC , BROWN JENNY M. , CABRALES ELAINE , CHAN CHRISTINA K. , KAIYALA KARL , BENTSEN MARIE A. , BANKS WILLIAM A. , GUTTMAN MIKLOS , WIGHT THOMAS N. , MORTON GREGORY J. , SCHWARTZ MICHAEL W.
Published: June 2020

Defective glucoregulatory neurocircuit activity within the hypothalamic arcuate nucleus (ARC) is implicated in the pathogenesis of type 2 diabetes (T2D). In the ARC of T2D-Zucker Diabetic Fatty (ZDF) rats, we have identified significant changes in the composition and abundance of extracellular perineuronal nets (PNNs) that enmesh glucoregulatory neurocircuits. Imaging of ARC PNNs, which are comprised of the chondroitin sulfate (CS) proteoglycan aggrecan and attached CS glycosaminoglycans (GAGs), show that T2D-ZDF rats exhibit a 66.4% and 77.3% decrease in aggrecan in the medial and lateral ARC areas, respectively, compared to normoglycemic controls. Distinctive sulfation of the attached CS-GAG isomers (0S-, 4S-, 6S-, 4S6S-, 2S6S-CS) differentially influence the function of PNNs. Using LC-MS/MS, we provide the first description of hypothalamic CS-GAG sulfation patterns and show that in T2D-ZDF rats, levels of the ∆4S- isomer is increased, whereas ∆6S- and ∆2S6S-CS isomers are decreased, differences predicted to disrupt protein-GAG interactions involved in neurite outgrowth and favor tissue stiffening. To determine if ARC PNNs are targets for the antidiabetic effect of fibroblast growth factor 1 (FGF1), we performed intracerebroventricular (icv) injection of FGF1 in ZDF rats and report that both the hypothalamic CS-GAG sulfation patterns and content of ARC PNNs are normalized 24 d after treatment. Western blot analysis shows that the latter effect entails a 1.7-fold increase in aggrecan protein abundance. To assess the functional significance of ARC PNN restoration by FGF1, ZDF rats received an icv FGF1 injection followed by bilateral microinjection of either ChABC, a PNN digesting enzyme, or its vehicle control into the ARC. Our finding that the duration of sustained FGF1-induced blood glucose lowering was shortened following ARC PNN digestion (p<0.05) identifies PNNs as novel participants in the central control of glucose homeostasis and diabetes remission by FGF1.

Disclosure

K.M. Alonge: Research Support; Self; Novo Nordisk Inc. Z. Mirzadeh: None. J. Scarlett: None. A. Logsdon: None. J.M. Brown: None. E. Cabrales: None. C.K. Chan: None. K. Kaiyala: None. M.A. Bentsen: None. W.A. Banks: None. M. Guttman: None. T.N. Wight: None. G.J. Morton: Research Support; Self; Novo Nordisk A/S. M.W. Schwartz: Research Support; Self; Novo Nordisk A/S.

Funding

National Institutes of Health (P30DK017047, F32DK122662, R01DK101997, R01DK089056, R01DK083042, K08DK114474, R01GM127579, K12NS080223, P30DK035816); Barrow Neurological Foundation (1800253005); University of Washington; Novo Nordisk (CMS431104); Novo Nordisk Foundation (NNF170C0024328, NNF10CC1016515)
1779-P: Liraglutide + Metformin Delays Worsening of Glycemia in Adults with Impaired Glucose Tolerance (IGT) or Type 2 Diabetes (T2D)
Authors: SAM SUSAN , EDELSTEIN SHARON , UTZSCHNEIDER KRISTINA , HANNON TAMARA S. , BARENGOLTS ELENA , XIANG ANNY , EHRMANN DAVID A. , MATHER KIEREN J. , KAHN STEVEN E. ,   THE RISE CONSORTIUM
Published: June 2020

The Restoring Insulin Secretion (RISE) Study examined the effect of medications to preserve β-cell function in 267 adults with IGT or drug-naïve, recently diagnosed T2D. Participants were randomized to receive 12 months of blinded metformin (MET) or placebo, 12 months of liraglutide (LIRA)+MET, or 3 months of glargine followed by 9 months of MET, all followed by 9 months off treatment. We examined glycemic worsening, defined as progression from IGT to diabetes by fasting or 2-h glucose on an OGTT at baseline, 6, 12, 15 and 21 months or a rise in quarterly HbA1c to ≥7%s. Time-to-worsening was evaluated across treatment groups using a modified product-limit life-table distribution with a log-rank test. Compared to the other treatments, LIRA+MET had less glycemic worsening at 12 months (on treatment) and 21 months (9 months off treatment); each p<0.01. After stopping treatment, group differences persisted but all groups showed similar rates of glycemic progression (Figure). Using logistic regression, independent predictors of worsening glycemia by months 12 and 21 were treatment with LIRA+MET (p=0.01; p=0.03) and baseline 2-h glucose (p=0.02; p=0.03). Overall, despite similar rates of glycemic worsening after discontinuation of therapy, the sustained on-treatment interval of normoglycemia resulted in less glycemic worsening in LIRA+MET compared with the other RISE interventions.

Disclosure

S. Sam: None. S. Edelstein: None. K. Utzschneider: Other Relationship; Self; Medtronic. T.S. Hannon: None. E. Barengolts: None. A. Xiang: None. D.A. Ehrmann: None. K.J. Mather: Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc. T. Consortium: None.

Funding

American Diabetes Association (1-14-RISE-01 to S.E.K.); National Institute of Diabetes and Digestive and Kidney Diseases
1780-P: Differential Effects of Medications and Gastric Banding on OGTT-Modeled Measures of ß-Cell Function in Adults with IGT or Recent-Onset Type 2 Diabetes (T2D)
Authors: UTZSCHNEIDER KRISTINA , GHORMLI LAURE EL , SAM SUSAN , EHRMANN DAVID A. , MATHER KIEREN J. , BARENGOLTS ELENA , HANNON TAMARA S. , TRIPPUTI MARK , EDELSTEIN SHARON , MARI ANDREA ,   THE RISE CONSORTIUM
Published: June 2020

We compared 3-hr OGTT model-derived measures of insulin sensitivity and β-cell function after 12 mo treatment with placebo (PLAC), metformin (MET), liraglutide plus MET (L+M), 3 mo glargine followed by 9 mo MET (G/M) and gastric banding (GB) in adults with IGT or T2D in the Restoring Insulin Secretion (RISE) Study. Modeling parameters included insulin sensitivity (OGIS), insulin secretion rate (ISR) at reference glucose 6.5 mM (ISR@6.5), total integrated ISR (tISR), glucose sensitivity (GS: slope ISR vs. glucose concentration) and rate sensitivity (RS: ISR relative to glucose rate of change). Adjusted linear mixed models compared model parameters over time within and between each study arm.

Results: Baseline model parameters did not differ by treatment arm. OGIS increased in all groups except PLAC. ISRs and GS increased in L+M but decreased or were unchanged in the other treatment arms. RS only increased in the G/M and GB arms. Treatment effects differed by arm. For L+M, GS and ISRs were increased vs. all other arms. For GB, RS was increased and tISR decreased vs. PLAC and GS was increased vs. MET.

In summary, L+M augments insulin secretion and increases GS, while GB increases RS. Clinically, both L+M and GB appear to improve β-cell function at 12 mo and may benefit adults with IGT or recent-onset T2D while on treatment.

Disclosure

K. Utzschneider: Other Relationship; Self; Medtronic. L. El Ghormli: None. S. Sam: None. D.A. Ehrmann: None. K.J. Mather: Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. E. Barengolts: None. T.S. Hannon: None. M. Tripputi: None. S. Edelstein: None. A. Mari: Consultant; Self; Lilly Diabetes. Research Support; Self; Boehringer Ingelheim International GmbH. T. Consortium: None.

Funding

American Diabetes Association (1-14-RISE-01); National Institute of Diabetes and Digestive and Kidney Diseases
1787-P: Insulin Pulse Characteristics Do Not Alter Hepatic Glucose Metabolism and Insulin Action
Authors: LAURENTI MARCELLO C. , MAN CHIARA DALLA , VARGHESE RON T. , JONES JOHN , BAROSA CRISTINA , RIZZA ROBERT A. , MATVEYENKO ALEKSEY , NICOLAO GIUSEPPE DE , COBELLI CLAUDIO , VELLA ADRIAN
Published: June 2020

Insulin is secreted into the portal vein in a pulsatile manner. Portal vein insulin concentrations directly and rapidly alter endogenous glucose production (EGP). Pulse frequency has been inversely correlated with hepatic insulin action in some, but not all, human studies. Indeed, increased pulse disorderliness, decreased secretory burst mass and decreased pulse frequency have been observed in type 2 diabetes, in aging and in obesity. In dogs, disruption of pulsatile insulin secretion is associated with defects in hepatic insulin action. As part of a series of experiments examining the mechanisms underlying prediabetes, we studied 29 nondiabetic subjects (BMI 28 ± 1 Kg/m2) on 2 occasions. On one occasion, EGP was measured using [3-3H]glucose after an overnight fast (14.2 ± 0.5μmol/kg/min) and during a euglycemic clamp (6.8 ± 1.1μmol/kg/min). The deuterated water method was used to estimate the contribution of gluconeogenesis to EGP. On a separate study day we utilized nonparametric stochastic deconvolution of frequently sampled peripheral C-peptide concentrations during fasting to reconstruct portal insulin secretion. In addition to measuring basal and pulsatile insulin secretion, we used Approximate Entropy (ApEn) to measure orderliness and a Fourier transform to measure the average and the dispersion of insulin pulse frequency. The gradient of Loge EGP vs. Loge insulin in each individual (-1.2 ± 0.5) was used as a measure of hepatic insulin action. Basal secretion (126 ± 8 pmol/min, R2=0.04), pulse amplitude (41 ± 38 pmol/min, R2=0.02), ApEn (1.14 ± 0.03, R2=0.01), pulse interval (5.7 ± 0.4 min, R2<0.01) and frequency dispersion (0.47 ± 0.01, R2<0.01) did not correlate (all p > 0.10) with hepatic insulin action. Suppression of gluconeogenesis by insulin also did not correlate with fasting insulin pulse characteristics. Overall, our data demonstrate that insulin pulse characteristics do not directly alter the sensitivity of EGP and gluconeogenesis to insulin in humans.

Disclosure

M.C. Laurenti: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. R.T. Varghese: None. J. Jones: None. C. Barosa: None. R.A. Rizza: None. A. Matveyenko: None. G. De Nicolao: 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

National Institutes of Health (DK78646, DK116231)
179-LB: Characteristics of Children with Medication-Induced Diabetes (MID): A Canadian Pediatric Surveillance Program (CPSP) Study
Authors: PATEL TRISHA J. , AYUB AYSHA , IRVINE MICHAEL A. , HADJIYANNAKIS STASIA , HENDERSON MÉLANIE , NOUR MUNIER A. , PINTO TERESA , WICKLOW BRANDY , HAMILTON JILL , SELLERS ELIZABETH , AMED SHAZHAN
Published: June 2020

Objectives: There is limited data on MID in children. This study aimed to compare the demographic and clinical characteristics of 1) a historical MID cohort to a new cohort and 2) children with MID based on overweight/obese BMI (O-BMI) and normal weight BMI (N-BMI).

Methods: National surveillance was conducted via the CPSP. Pediatric clinicians reported new cases (children <18 years old) of non-type 1 diabetes for 24-months (cohort 1: 2006-08, cohort 2: 2017-19). MID cases were classified by the presence of diabetes as defined by Diabetes Canada and exposure to a diabetogenic medication. Comparisons were made between the two cohorts and between MID patients with O-BMI (BMI ≥85th percentile for age and sex) and N-BMI (BMI <85th percentile for age and sex). Descriptive statistics and Fisher exact, chi-squared and t-tests were used where applicable.

Results: There were 55 cases of MID in cohort 1 and 51 cases in cohort 2, with no significant differences between cohorts. Mean age (+/- SD) at presentation was 13.1 +/- 3.6 years and 13.3 +/- 3.5 years in cohort 1 and 2, respectively. Glucocorticoid therapy was documented in >95% of cases in both cohorts. In the combined cohorts there were 50 cases with N-BMI and 43 cases with O-BMI. There were no statistically significant differences in age, sex or ethnicity across BMI groups. Mean hemoglobin A1c (+/- SD) (n = 40) was 6.45% +/- 1.11% in the N-BMI group and 7.26% +/- 2.51% in the O-BMI group (p = 0.184). The O-BMI group were more likely to have a parent with type 2 diabetes (T2D) (p = 0.042) and acanthosis nigricans (p = 0.007) compared to the N-BMI group.

Conclusions: The demographic and clinical features of children with MID have not changed over a 10-year period. The presence of acanthosis nigricans and/or a parent with T2D may be used to identify children who require more intensive glycemic monitoring when on a diabetogenic medication. Further studies are needed to better understand the evolution of MID and the risk it confers to developing T2D.

Disclosure

T.J. Patel: None. A. Ayub: None. M.A. Irvine: None. S. Hadjiyannakis: None. M. Henderson: None. M.A. Nour: None. T. Pinto: None. B. Wicklow: None. J. Hamilton: None. E. Sellers: None. S. Amed: None.

Funding

Diabetes Canada; Manitoba Institute for Child Health and Sick Kids Hospital; Public Health Agency of Canada (F18-02353)
1796-P: A-ß+ Ketosis-Prone Diabetes (KPD) Patients Augment Insulin Response to Arginine but Not to Glucose after Sustained Hyperglycemia
Authors: HSU JEAN W. , CARDENAS ADRIANA J. , GABA RUCHI , TOSUR MUSTAFA , RAM NALINI , GUTIERREZ ABSALON D. , BOHREN KURT M. , CADUCOY EUNICE I. , JAHOOR FAROOK , BALASUBRAMANYAM ASHOK
Published: June 2020

We previously showed that patients with A-β+ KPD (“obese ketosis-prone type 2 diabetes”) have diminished intracellular arginine availability that may impair their ability to generate an adequate beta cell response in the face of hyperglycemia, and thus make them vulnerable to develop ketoacidosis (Mulukutla et al, J Nutr 2018). To investigate further their β cell responsiveness to exogenous arginine, we studied 9 recently diagnosed, stable, near-normoglycemic A-β+ KPD patients and 10 age-, sex- and BMI-matched nondiabetic controls with dynamic measures of insulin and C-peptide responses to glucose or arginine bolus under two conditions: in the euglycemic, fasting (basal) state and after a 5h hyperglycemic clamp. In the basal state, total and first phase insulin areas under the curve (AUC) in response to glucose were significantly greater in controls than KPD (total AUC 1756 ± 298 vs. 857 ± 126 min·µU/mL; P = 0.05); after hyperglycemia, AUC insulin response to glucose remained significantly greater in controls (total AUC 2470 ± 296 vs. 1512 ± 316 min·µU/mL; P = 0.04), and KPD patients mounted only a non-significant increase in total AUC insulin compared to the basal state (P = 0.12). In contrast, total and first phase AUC insulin in response to arginine in the basal state was similar in controls and KPD (total AUC 544 ± 85 vs. 337 ± 50 min·µU/mL; P = 0.75). After hyperglycemia, although AUC insulin response to arginine was greater in controls (total AUC 1854 ± 2227 vs. 1149 ± 207 min·µU/mL; P = 0.002), the KPD patients mounted a significant 70% increase in total AUC insulin compared to the basal state (P = 0.002). C-peptide responses mirrored those of insulin under all conditions. Thus, KPD patients exhibit a robust β cell response to arginine but not to glucose, both during fasting euglycemia and after sustained hyperglycemia. Exogenous arginine could augment insulin secretion during hyperglycemia and prevent the episodes of ketoacidosis that characterize A-β+ KPD.

Disclosure

J.W. Hsu: None. A.J. Cardenas: None. R. Gaba: None. M. Tosur: None. N. Ram: None. A.D. Gutierrez: Speaker’s Bureau; Self; AstraZeneca. K.M. Bohren: None. E.I. Caducoy: None. F. Jahoor: None. A. Balasubramanyam: None.

Funding

National Institutes of Health (R01DK101411)
1799-P: Insulin Secretion during a Graded Glucose Infusion Correlates with GPS2 mRNA Expression in Adipocytes
Authors: VELHO GILBERTO , DRARENI KARIMA , NGUEWA JEAN-LOUIS , ROUSSEL RONAN , RIVELINE JEAN-PIERRE , VENTECLEF NICOLAS , GAUTIER JEAN-FRANÇOIS
Published: June 2020

The transcriptional corepressor GPS2 plays a key role in human adipose tissue homeostasis. Decreased expression of GPS2 in adipocytes was associated with increased expression of inflammatory genes and with a pro-diabetic status. Here we assessed associations of GPS2 expression in adipocytes with insulin secretion in human volunteers. Dose response relationships between glucose and insulin secretion rates (ISR) were studied in 22 people (7 with normal glucose tolerance and 15 with type 2 diabetes; aged 48±12 years; men 68%) following a stepped intravenous glucose infusion at 2, 4, 6, 8 and 10 mg/kg/min. ISR was derived by deconvolution of plasma C-peptide level. GPS2 mRNA was quantified in adipose tissue biopsies by RT-qPCR. Participants were stratified by GPS2 mRNA expression into low (Lexp) or high expression (Hexp), defined by values below or above the median. Basal glucose level and ISR were higher in Lexp than in Hexp participants: 8.0±0.5 vs. 5.6±0.3 mmol/l, mean±SEM, p=0.0008, and 3.04±0.19 vs. 2.12±0.17 pmol/kg/min, p=0.002, respectively. Following glucose infusion, glucose level increased by 178±17% and 174±23% (p=0.88) in Lexp and Hexp participants, with average values of 14.9±0.6 and 11.4±0.78 mmol/l (p=0.002), respectively. Concomitant ISR increased by 236±40% and 487±75% (p=0.006) in Lexp and Hexp participants. Average ISR following glucose infusion (10-200 min) was 5.40±0.67 vs. 8.49±0.75 pmol/kg/min, p=0.01, respectively. Average ISR correlated positively with GPS2 expression: r2=0.34, p=0.004. Analysis of the glucose/ISR response curve demonstrated significantly higher ISR in Hexp than in Lexp participants at all glucose levels (p=0.005, adjusted for sex, age, BMI, and glycemic status). It was ∼52%, ∼60% and ∼45% higher at 7, 10 and 15 mmol/l glucose, respectively. Our results suggest a potential role for GPS2 in adipocyte-pancreatic beta cells cross-talk regulation of insulin secretion response to glucose, in line with previous experimental findings.

Disclosure

G. Velho: None. K. Drareni: None. J. Nguewa: None. R. Roussel: Advisory Panel; Self; Abbott, AstraZeneca, Diabnext, Eli Lilly and Company, Merck & Co., Inc., Mundipharma International, Novo Nordisk A/S, Sanofi-Aventis. J. Riveline: None. N. Venteclef: None. J. Gautier: None.
180-LB: Standardizing the Hemoglobin Glycation Index (HGI)
Authors: HSIA DANIEL S. , YANG SHENGPING , LIU SHUQIAN , HEMPE JAMES M.
Published: June 2020

HGI measures how far a person’s HbA1c lies above or below average compared to other people with similar blood glucose concentrations. Multiple studies confirm that high HGI is associated with greater risk for iatrogenic hypoglycemia in diabetes patients and chronic vascular disease in diabetic and nondiabetic populations. However, significant differences in how blood glucose is assessed and in the demographic composition of different study populations have resulted in marked interstudy differences in the slopes and intercepts of regression equations used to calculate HGI. The purpose of the present study was to develop a standard linear regression equation that could be widely used to calculate HGI in diverse human populations. To accomplish this, we used data from the demographically diverse 1999-2016 National Health and Nutrition Examination Survey (NHANES) to identify 18,675 participants age ≥20 y without self-reported diabetes. The regression equation developed from this treatment naïve adult reference population was HbA1c = 0.024 FPG + 3.1. HGI was calculated for reference population participants who were then subdivided into 1) low, moderate, and high subgroups, and 2) normal, prediabetic and diabetic subgroups based on OGTT results. Novel observations include lack of association between HGI and hemoglobin concentration, plasma insulin or HOMA-IR. Consistent with previous reports, high HGI was associated with 1) black race regardless of diabetes status, 2) older age and higher BMI in nondiabetic but not diabetic participants, and 3) no difference in 2 h OGTT results in normal, prediabetic or treatment naïve diabetic participants. Standardizing how HGI is calculated across studies will facilitate clinical and basic research to better understand 1) why some people have lower or higher than average HbA1c levels independent of blood glucose concentration, 2) why high HGI is associated with greater risk for chronic vascular disease in diabetic and nondiabetic people, and 3) what can be done to reduce risk in high HGI people.

Disclosure

D.S. Hsia: None. S. Yang: None. S. Liu: None. J.M. Hempe: None.

Funding

National Institute of General Medical Sciences (U54GM104940)
1800-P: Cotadutide, a GLP-1/GCG Receptor Co-Agonist, Improves Insulin Sensitivity and Restores Normal Insulin Secretory Capacity in DIO Mice
Authors: LAKER RHIANNA C. , LANTIER LOUISE , MCGUINNESS OWEN , WILL SARAH , KUSZPIT KYLE , ALFARO ALEX R. , JERMUTUS LUTZ , RHODES CHRISTOPHER J.
Published: June 2020

Cotadutide (MEDI0382) is a peptide with targeted GLP-1/glucagon (Gcg) receptor activity that has beneficial effects on T2D and obesity in humans and mice, and shows marked improvements in NAFLD/NASH in mice. We performed hyperinsulinemic clamps in diet induced obese (DIO) mice to better understand whether improved insulin sensitivity and β-cell function are responsible for the improved glycemia in our clinical studies. Following 28 days of daily dosing with Cotadutide (10 nmol/kg), Liraglutide (5 nmol/kg; GLP-1 agonist) or g1437 (5 nmol/kg; Gcg analog) mice underwent continuous infusion of 4mU/kg/min insulin and [3H]-glucose to assess glucose turnover. Tissue-specific glucose uptake was assessed using 14C-2-deoxyglucose. We observed lower body weight in all groups compared with vehicle control, with g1437 eliciting the largest response and Liraglutide the least. Fasting glucose was significantly higher in g1437 treated mice. Fasting insulin was dramatically lower in Cotadutide and g1437 groups compared with vehicle. Despite an equal rate of human insulin infusion between groups, the total insulin levels during the clamp remained lower in Cotadutide and g1437 treated mice. The glucose infusion rate, to maintain euglycemia ∼130 mg/dL, was significantly higher in Cotadutide treated mice in line with increased glucose disposal rate. Hepatic glucose production was suppressed in all groups, despite significantly lower levels of insulin in Cotadutide and g1437 treated mice. Finally, glucose uptake was elevated in brown adipose tissue in Cotadutide treated mice, which was confirmed in a separate study of [18F]FDG uptake by PET imaging. These experiments demonstrate that Cotadutide improved insulin sensitivity in concert with dramatic reductions for insulin demand, which may result in recovery of endogenous β-cell function in T2D.

Disclosure

R.C. Laker: Employee; Self; AstraZeneca. L. Lantier: None. O. McGuinness: None. S. Will: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. K. Kuszpit: None. A.R. Alfaro: None. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. C.J. Rhodes: Employee; Self; AstraZeneca.
1804-P: HM15211, a Novel Long-Acting GLP-1/GIP/Glucagon Triple Agonist, Exhibits Anti-inflammatory and Fibrotic Effects in AMLN/TAA–Induced Liver Inflammation and Fibrosis Mice
Authors: KIM JUNG KUK , LEE JONG SUK , PARK EUNJIN , LEE JONGSOO , BAE SUNGMIN , KIM DAEJIN , CHOI IN YOUNG
Published: June 2020

Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, is characterized by hepatic steatosis, inflammation, and fibrosis. Despite increased prevalence and related mortality, no approved medication is available, leading to a significant burden for public health. Although advances in targeting hepatic steatosis demonstrate meaningful benefits, their overall impact in inflammation and fibrosis remains elusive. Hence, recent approaches directly modulating inflammation and fibrosis still showed marginal efficacy. Thus, to provide novel option for NASH treatment, HM15211, a novel long-acting GLP-1/GIP/Glucagon triple agonist, is developed. Because of the benefits of GLP-1, GIP, and Glucagon in liver inflammation and fibrosis in addition to steatosis, HM15211 might confer more effective treatment in NASH. Previously, HM1521 treatment led to potent liver fat reduction along with weight loss in DIO mice. Here, we investigated the potential effect of HM15211 in animal model of liver inflammation and fibrosis. To induce liver inflammation and fibrosis, mice fed with AMLN diet were concomitantly treated with thioacetamide (AMLN/TAA mice) for 16 weeks, and HM15211 was administered during last 8 weeks. Of note, HM15211 treatment reduced the hepatic marker expression for inflammation (-92.8, -34.7 and -34.9% vs. vehicle (Veh) for F4/80, MCP-1 and IL-6) and fibrosis (-53.9, -41.4 and -51.9 % vs. Veh for α-SMA, TIMP-1 and collagen1a1). Similar reduction in blood level of TIMP-1, PIIINP and hyaluronic acid (-49.3, -48.0 and -49.1% vs. Veh) was observed. Strikingly, HM15211 significantly reduced both hepatic hydroxyproline (-53.1 % vs. Veh) and sirius red positive area (-70.6% vs. Veh). Therefore, in addition to steatosis improvement, HM15211 may provide anti-inflammatory and -fibrotic effect. Human studies are ongoing to assess the clinical relevance of these findings.

Disclosure

J. Kim: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. E. Park: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Bae: Employee; Self; Hanmi Pharmaceutical. D. Kim: Board Member; Self; Hanmi Pharmaceutical. I. Choi: Board Member; Self; Hanmi Pharmaceutical.
1813-P: Coadministration of a GLP-1/Glucagon Receptor Agonist with an FXR Agonist and ACC Inhibitor Reverses Nonalcoholic Steatohepatitis (NASH) in Diet-Induced and Biopsy-Confirmed Mice
Authors: TREVASKIS JAMES L. , NORLIN JENNY , MIRANDA DIEGO A. , BATES JAMIE G. , ZOIS NORA E. , VEIDAL SANNE , FEIGH MICHAEL , LATTA MARKUS
Published: June 2020

Combination approaches for the treatment of NASH are being actively pursued. We examined the effects of administration of a dual GLP-1 and glucagon receptor agonist (GLP-1:GCG, 0.015 mg/kg, s.c., q.d.) alone and combined with an FXR agonist (cilofexor, CILO; 30 mg/kg) and/or an acetyl-CoA carboxylase inhibitor (firsocostat analog, ACCi; 5 mg/kg, both p.o., q.d) on NASH endpoints in the AMLN diet-induced and biopsy-confirmed DIO-NASH mouse (n=15-16/group). After 12 weeks of treatment, GLP-1:GCG reduced body weight 15%, being slightly greater in the GLP-1:GCG + CILO group (22%). Liver triglyceride was reduced by GLP-1:GCG (by 76% vs. vehicle, p<0.001). Addition of CILO, ACCi or both to GLP-1:GCG further reduced liver lipid (by 82%, 88% and 91%, respectively). Histopathological pre-to-post NAFLD activity score (NAS) was reduced in 7/16 (44%) of vehicle controls and in all mice (100%) in the GLP-1:GCG-containing groups. In vehicle controls, 0/16 mice had a final NAS of 0-1 whereas this increased to 5/15 mice (33%) with GLP-1:GCG, and was not significantly improved by addition of CILO (7/15, 47%) or ACCi (6/16, 38%). Triple therapy increased number of mice with NAS of 0-1 to 11/16 (69%). GLP-1:GCG was associated with 1/15 mice (7%) improving pre-to-post fibrosis stage which was not altered by addition of CILO or ACCi, but increased to 7/16 (44%) with triple therapy. Collagen-1a and α-SMA immunoreactivity (% area) revealed no significant effect of GLP-1:GCG for collagen (5.7%), but reduction in α-SMA (1.4%, p<0.001) vs. vehicle (6.8% and 4.9%, respectively). Triple therapy reduced both collagen and α-SMA area (3.8% and 1.5%, respectively, both p<0.001 vs. vehicle).

In conclusion, GLP-1:GCG effectively reduced hepatic lipid and the addition of an FXR agonist and ACC inhibitor further improved pre-to-post NAS and fibrosis stage in DIO-NASH mice, supporting development of combination approaches for NASH.

Disclosure

J.L. Trevaskis: Employee; Self; Gilead Sciences, Inc. 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. M. Latta: Employee; Self; Novo Nordisk A/S.
1814-P: JAZF1 Knockout Mice Are Protected against Diet-Induced Metabolic Syndrome
Authors: SRIVASTAVA CHITRANGDA , DORR KERRY , GRIMM SARA , DEGRAFF LAURA M. , GRUZDEV ARTIOM , JETTEN ANTON M.
Published: June 2020

JAZF1/TIP27 is a 27kD transcriptional co-regulator. GWAS studies have indicated that single nucleotide polymorphisms in the JAZF1 gene are associated with increased risk of typeII diabetes (T2D) and several autoimmune diseases. Diet induced obesity is a major risk factor for different metabolic disorders, including T2D and nonalcoholic fatty liver disease (NAFLD). To obtain greater insights into the physiological functions of JAZF1, we generated Jazf1 null mice (Jazf1-/-) and fed them a high fat diet (HFD) for 8 to 15 weeks. We demonstrated that Jazf1-/- mice fed-HFD exhibit lower body-weight and fat-mass compared to obese WT mice. HFD-fed Jazf1-/- mice maintained normal blood glucose levels and were more insulin sensitive and glucose tolerant than obese WT-littermates. Histological examination showed that Jazf1-/- mice were less susceptible to HFD-induced hepatic steatosis than WT littermates as indicated by the greatly reduced hepatic lipid droplets (LD) in Jazf1-/- liver. Furthermore, HFD-fed Jazf1-/- mice also showed reduced levels of serum aspartate aminotransferase, alkaline phosphatase, and sorbitol dehydrogenase, enzymes indicative of hepatocytoxicity. HFD-fed Jazf1-/- mice exhibited a dramatic decrease in the level of liver triglycerides. HFD-fed WT mice showed induction of Jazf1 expression in liver as compared to WT mice with normal diet. RNA-seq and qPCR analysis of liver demonstrated that LD-formation genes (e.g., Plin2/Plin3/Plin4/Cd36/Cidec/Cidea) were greatly suppressed in Jazf1-/- compared to WT mice. Go-term and IPA analysis revealed that inflammatory (e.g., Ccl7/Lcn2/Cd14) and hepatic fibrosis (Col1a1/Egr2/Timp1) were among top pathways down-regulated in HFD-fed Jazf1-/- liver. Our results indicate that JAZF1 functions as a critical regulator of LD formation and inflammation in NAFLD and loss of JAZF1 function protects against metabolic syndrome. Our study may provide new insights into the development of progression of metabolic syndrome and its complications.

Disclosure

C. Srivastava: None. K. Dorr: None. S. Grimm: None. L.M. DeGraff: None. A. Gruzdev: None. A.M. Jetten: None.

Funding

National Institutes of Health
1818-P: High-Sucrose Diet Causes Increased Hepatic Histone Acetylation Due to Increased Bacterial Acetate Production and Reduced Lipogenesis in ChREPB-Deficient Mice
Authors: IIZUKA KATSUMI , TAKAO KEN , LIU YANYAN , NONOMURA KENTA , KATO TAKEHIRO , MIZUNO MASAMI , HORIKAWA YUKIO , YABE DAISUKE
Published: June 2020

ChREBP is known to play a critical role in the development of obesity and diabetes by regulating hepatic lipogenesis. High-sucrose diet (HSD) feeding is known to cause irritable bowel syndrome-like phenotype in ChREBP knockout mice (KO) with some alterations in gut microbiota. However, effects of the gut microbiota alteration on whole-body metabolism in KO remains unknown. Twelve-week old wild type mice (WT) and KO, both fed on HSD for 7 days, were analyzed. KO had 3-fold higher cecum contents compared to WT (WT, 71±24.4; and KO, 205.7±46.0 g). KO had a remarkable increase in acetate-producing bacteria (e.g., Bifidobacterium and Bacteroides) in the cecum. Consistently, KO showed 2-fold higher acetate levels in the cecum (WT, 27.5±6.0; and KO, 55.6±22.3 μmoles/g stool). Interestingly, KO also showed higher hepatic acetate contents (WT, 0.81±0.18; and 1.08±0.14 μmoles/g liver). Since acetate is converted into acetyl-CoA; and used for lipogenesis, ketogenesis and protein acetylation, we investigated hepatic triglyceride contents, plasma 3OHBA levels and histone acetylation. While hepatic acetyl-CoA contents and plasma 3-OHBA levels did not differ between the two groups, hepatic triglyceride contents were much lower in KO (WT, 11.45±5.47; and KO, 4,11±0.44 mg/g liver), consistent with reduced expression of hepatic lipogenic genes. In contrast, histone acetylation on selected genes (e.g., Fasn, Chrebp and Pklr) was significantly enhanced in KO. These results together indicated that increased supply of acetyl-CoA in the liver, possibly due to enhanced acetate-production in the gut and reduced hepatic lipogenesis, leads to enhancement of histone acetylation in KO, while physiological relevance awaits further investigation.

Disclosure

K. Iizuka: Speaker’s Bureau; Self; Kowa Company, Ltd., Novo Nordisk Inc. K. Takao: None. Y. Liu: None. K. Nonomura: None. T. Kato: None. M. Mizuno: None. Y. Horikawa: None. D. Yabe: Research Support; Self; ARKRAY, Astellas Pharma Inc., AstraZeneca K.K., Eli Lilly Japan K.K., Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science, Kowa Company, Ltd., Nippon Boehringer Ingelheim Co. Ltd., Sanofi K.K., Sanwa Kagaku Kenkyusho, Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; Abbott, ARKRAY, Astellas Pharma Inc., AstraZeneca K.K., Bayer Yakuhin, Ltd., Daiichi Sankyo, Eli Lilly Japan K.K., Fukuda Denshi, Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., LifeScan, Inc., Medtronic, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Novo Nordisk Inc., Sanofi K.K., Sanwa Kagaku Kenkyusho, Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Other Relationship; Self; Japan Diabetes Society.

Funding

Grant-in-Aid for Scientific Research (17K00850)
183-LB: Prediction of Osteoporosis in Patients with Newly Diagnosed Type 2 Diabetes Based on Their Impaired Bone Turnover: A Retrospective Study in Chinese Population
Authors: SONG LIGE , LI HUIJUAN , WEN YUHUA , ZHANG XIAOYA , LIU PEIPEI
Published: June 2020

The patients with type 2 diabetes (T2DM) have higher fracture risk, and this study is conducted to identify the contributors of the abnormal bone turnover in newly diagnosed T2DM patients and to set a prediction model for osteoporosis in this population. This retrospective study includes 244 newly diagnosed patients with T2DM and 218 individuals without diabetes. Demographic characteristics, clinical history, biochemical indexes, bone turnover markers were detected. BMD was measured by DEXA. SPSS 20.0 software is hired for statistical analysis. Comparing to the patients without diabetes, the patients with T2DM have lower levels of P1NP, CTX, OC, PTH, 25(OH)D and higher level of BALP. The patients with T2DM have higher BMD in lumbar, femur neck and total hip comparing to the controls. In T2DM group, HbA1c level is negatively related to P1NP and OC, and total cholesterol is positively related to BALP, independently. In the patients without diabetes, HbA1c level is negatively related to the level of OC and positively related to 25(OH)D, and HDL is positively related to P1NP, independently. The level of PTH is negatively related to HbA1c in all the participants. After adjusted with age, BMI and menopausal status, BALP and OC were positively correlated with the risk of osteoporosis in all the participants, moreover in the patients with T2DM, HbA1c, TRAP5b and P1NP were also positively correlated with the onset of osteoporosis. The prediction model including age, BMI, menopausal status, TRAP-5b and OC for osteoporosis in T2DM patients had the area under the ROC curve as 0.817 with the sensitivity and specificity at 70% and 82% respectively. The above data indicate that increased glucose level contributes to impaired maturation of osteoblasts, and the prediction model including age, BMI, menopausal status and bone turnover markers may find out the T2DM patients with high fracture risk. However, this result needs to be proven with fracture data.

Disclosure

L. Song: None. H. Li: None. Y. Wen: None. X. Zhang: None. P. Liu: None.

Funding

Shanghai Municipal Health Commission (201840217 to L.S.); Clinical Science and Technology Innovation Program of Hospital Development Center (SHDC12018X10 to L.S.); Tongji Hospital (ITJ(ZD)1904 to L.S.); Fundamental Research Funds for the Central Universities of Tongji University (22120180355 to L.S.); Shanghai Science and Technology Foundation (19ZR1448600 to L.S.)
1836-P: Nonalcoholic Steatohepatitis (NASH) Significantly Contribute to ß-Cell Function Impairment Independently of Glucose Tolerance Status
Authors: VONGHIA LUISA , DIRINCK EVELINE , CARLI FABRIZIA , VERRIJKEN AN , WEYLER JONAS , MICHIELSEN PETER , VANWOLLEGHEM THOMAS , DRIESSEN ANN , GAAL LUC VAN , FRANCQUE SVEN , DE BLOCK CHRISTOPHE , GASTALDELLI AMALIA
Published: June 2020

ß-cell dysfunction is a strong risk factor for type 2 diabetes (T2D). The liver plays a central role since insulin clearance (ClearIns) is up to 80% of the insulin secretion rate (ISR). ClearIns is reduced with insulin resistance (IR) and in patients with nonalcoholic fatty liver disease (NAFLD) . Our aim was to evaluate if ISR and ß-cell function were decreased in NASH vs. NAFL thus increasing their risk of T2D and the impact of ClearIns and IR. We measured glucose, insulin and c-peptide during a 3h oral glucose tolerance test in 341 subjects with liver biopsy and evaluated ISR (from deconvolution of c-peptide), ClearIns, Matsuda insulin sensitivity index (ISI) and disposition index (DI=ISI∙ΔAUC-I/ΔAUC-G); a low DI indicates a risk to develop T2D. Subjects were grouped according to glucose tolerance, normal (NGT), impaired (IGT) or T2D, and liver histology (noNAFL, NAFL, NASH-Fibrosis F0-F1 and F2-F4). The groups had similar BMI (∼34kg/m2). Severity of NAFLD was associated with increased IR, fasting and postprandial ISR and decreased ClearIns, after adjusting for age and BMI. DI was significantly lower in NASH-F24 in each glucose tolerance group (Figure).

Conclusion: Disposition index is reduced in relation to presence and severity of NASH independent of glucose tolerance status supporting an independent role of NASH in the development of T2D.

Disclosure

L. Vonghia: None. E. Dirinck: None. F. Carli: None. A. Verrijken: None. J. Weyler: None. P. Michielsen: None. T. Vanwolleghem: None. A. Driessen: None. L. Van Gaal: None. S. Francque: None. C. De Block: Advisory Panel; Self; A. Menarini Diagnostics, Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD, Novartis AG, Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S. A. Gastaldelli: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Inventiva Pharma, Novo Nordisk Inc.

Funding

Horizon2020 (634413)
1848-P: Insulin Sensitivity and Metabolic Profile of Subjects with Type 2 Diabetes and Nonalcoholic Steatohepatitis after Exposure to Cenicriviroc: A Subanalysis of the CENTAUR Study
Authors: COVIELLO ANDREA D. , RODRIGUEZ GERARDO , MARTINS EDUARDO B. , ALKHOURI NAIM , ABDELMALEK MANAL F.
Published: June 2020

Introduction: In mice, C-C motif chemokine receptor (CCR)5 deletion protects against insulin resistance, hepatic steatosis, and glucose intolerance. We aimed to characterize the metabolic effects of cenicriviroc (CVC), a potent CCR2/5 inhibitor, in type 2 diabetes mellitus (T2DM) patients with nonalcoholic steatohepatitis (NASH) fibrosis from the Phase 2b CENTAUR study.

Methods: Subjects from CENTAUR with T2DM, biopsy-proven NASH, and fibrosis Stages F1-3 were included. CVC-exposed subjects for 1 year (Arm A) and placebo (PBO) [Arms B and C] were analyzed. Liver, metabolic, and inflammatory biomarkers were analyzed. Homeostatic model assessments (HOMA-IR and -b) were calculated. Change (from baseline to Year 1) was compared between groups using a general parametric linear model analysis of covariance (2-sided ANCOVA) based on the mITT population.

Results: Of the 289 subjects in CENTAUR, 134 (46%) had T2DM and were included in this analysis. Baseline characteristics were similar for CVC (n=76) and PBO (n=58) groups (mean ±SD): age 57.5 ±7.75 years vs. 55.41 ±8.65 years, HbA1c 7.30 ±1.29 vs. 7.20 ±1.21 %, BMI 33.02 ±5.25 vs. 35.16 ±7.67 kg/m2, NAS 5.25 ±1.06 vs. 5.52 ±1.13, and fibrosis scores of F1 (31.6%), F2 (21%), and F3 (47.4%) vs. F1 (24.2%), F2 (22.4%), and F3 (53.4%), respectively. At 1 year, there was a significant decrease in HOMA-IR and interleukin (IL)-6 in the CVC group. The least squares mean changes (SE) in HOMA-IR (p=0.0159) and IL-6 (p=0.0094), respectively, were −2.75 (1.27) and −1.9 (0.35) for CVC and 1.94 (1.45) and −0.5 (0.39) for PBO. After 1-year exposure to CVC or PBO, no significant differences vs. baseline in HOMA-b, HDL cholesterol, LDL cholesterol, ALT, and AST were noted.

Conclusion: CVC may improve HOMA-IR and pro-inflammatory cytokine IL-6, suggesting that CVC could potentially improve insulin resistance in NASH patients. These findings warrant further investigation.

Disclosure

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. G. Rodriguez: Employee; Self; Allergan plc. E.B. Martins: Employee; Self; Allergan plc. Stock/Shareholder; Self; Allergan plc. N. Alkhouri: Research Support; Self; Allergan plc. M.F. Abdelmalek: None.

Funding

Allergan plc