bluuebunny/crossref_metadata_2025 huggingface dataset:
207-OR: ADA Presidents' Select Abstract: Apolipoprotein C-III Proteoforms and Their Relationships with Plasma Lipids and Cardiovascular Events in Multiethnic Study of Atherosclerosis (MESA)
Authors: KOSKA JURAJ , SINARI SHRIPAD , HU YUEMING , FURTADO JEREMY , BILLHEIMER DEAN , NEDELKOV DOBRIN , MCCLELLAND ROBYN , REAVEN PETER
Published: May 2022

Apolipoprotein C-III (apoC-III) exists in four major proteoforms - unglycosylated form (C-III0a) , and glycosylated forms with zero (C-III0b) , one (C-III1, most abundant) or two (C-III2) sialic acids - which modify lipoprotein metabolism. The relation of these proteoforms with plasma lipids and cardiovascular disease (CVD) risk in a general population is unknown. Total apoC-III concentrations and apoC-III proteoforms were measured in baseline plasma of 5,787 MESA participants. Plasma lipids and CVD risk were assessed over 15 years. Proteoform percentages correlated modestly with total apoC-III (r2<0.10) . ApoC-III0b decreased and C-III2 increased with age (by 11% per 5 yrs) . Compared to non-Hispanic whites, African Americans had lower (35%) total apoC-III and C-III0b and higher C-III2 (88%) , and Chinese Americans and Hispanics had higher C-III0a (88%; 40%) . Females had higher total apoC-III, C-III1 and C-III0b (23%; 31%; 30%) , and lower C-III0a and C-III2 (17%; 28%) . Total apoC-III, C-III0b, C-III1 and C-III2 were higher in diabetes. Prospectively, in models that included baseline characteristics, lipid-lowering medications and total apoC-III, higher C-III2 to C-III1 ratio (C-III2/III1) was associated with lower triglycerides (22%) and higher HDL (19%) . After adjustment for baseline characteristics (including lipids) and total apoC-III, higher C-III0b to C-III1 ratio was associated with reduced risk of CVD (n=629 events, HR= 0.89) and coronary heart disease (n=426, HR=0.86) . In contrast, despite links with better lipids, higher C-III2/III1 was associated with increased risk of CVD (HR=1.09) . No CVD events were related to total apoC-III. Our data indicate differences in clinical and demographic determinants of total apoC-III concentrations and apoC-III proteoforms and highlight the importance of apoC-III proteoform distribution in predicting future lipid concentrations and CVD risk.

Disclosure

J.Koska: None. S.Sinari: None. Y.Hu: None. J.Furtado: Research Support; Eli Lilly and Company, Pfizer Inc. D.Billheimer: None. D.Nedelkov: None. R.Mcclelland: None. P.Reaven: Research Support; AstraZeneca, Dexcom, Inc.

Funding

National Institutes of Health (R01-HL138969)
209-LB: Evidence Thathypothalamic Glucoregulatory Neurons Sense and Respond to Changes of Glycemia in Conscious, Free-Living Mice
Authors: DEEM JENNIFER D. , TINGLEY DAVID , BJERREGAARD ANNE-METTE , FABER CHELSEA L. , DOAN TAMMY P. , PHAN BAO ANH N. , NASIR ZAINAB , WU BRANDON , HWANG MATTHEW K. , KUMAR ASMIT , SCARLETT JARRAD M. , MORTON GREGORY J. , SCHWARTZ MICHAEL W.
Published: May 2022

The brain’s capacity to normalize the defended blood glucose level in diabetic animals is now well established. We hypothesized that for this to occur, the brain, like the pancreas, must detect and respond to changes in circulating glucose, but whether and how this occurs remains unknown. To identify specific neuronal subsets that are responsive to changes in glycemia in conscious, free-living mice, we combined continuous arterial glucose monitoring (CGM) with fiber photometry (FP) to measure the calcium activity of neurons located in the hypothalamic ventromedial nucleus that express the peptide, Pacap (VMHPacap neurons) . CGM and FP data from each of six mice were obtained during both a 1-h baseline monitoring period (without access to food) and over a 2-h intervention period in which the blood glucose (BG) level was elevated by either chow or a high-sucrose meal consumption, or by IP glucose injection. Cross-correlation analysis revealed that following a 60-80 s delay, interventions that raise the BG level are reliably associated with significantly reduced VMHPacap neuron activity (p < 0.01) . Interestingly, levels of BG and VMHPacapneuron calcium activity were also significantly correlated under baseline conditions (i.e., in the absence of any intervention) , but unlike what occurs following an intervention, these two variables were positively correlated with a ∼25 min offset, suggestive of an oscillatory pattern. We conclude that after a short delay, physiological stimuli that raise the BG level are coupled to reduced activity of VMHPacap neurons in vivo. In the basal state, levels of these two variables are positivity correlated in a delayed manner suggestive of an oscillatory control mechanism. These findings identify hypothalamic glucoregulatory neurons that are capable of sensing and responding to changes of glycemia in conscious, free-living mice.

Disclosure

J. D. Deem: None. A. Kumar: None. J. M. Scarlett: None. G. J. Morton: Research Support; Novo Nordisk A/S. M. W. Schwartz: None. D. Tingley: None. A. Bjerregaard: Employee; Novo Nordisk. C. L. Faber: None. T. P. Doan: None. B. N. Phan: None. Z. Nasir: None. B. Wu: None. M. K. Hwang: None.

Funding

NIDDK:P30 DK035816 K01 DK126793 R01 DK124238 R01 DK83042 NIDA:P30 DA048736; Novo Nordisk Research Agreement:CMS-431104
209-OR: Ceramide-Based Lipid Profiles and the Prevalence of Type 2 Diabetes Differ between Patients with Coronary Artery Disease and Those with Peripheral Artery Disease
Authors: LEIHERER ANDREAS , MUENDLEIN AXEL , BRANDTNER EVA MARIA , SAELY CHRISTOPH H. , VONBANK ALEXANDER , MADER ARTHUR , SPRENGER LUKAS , MAECHLER MAXIMILIAN , LARCHER BARBARA , JYLHA ANTTI , LAAPERI MITJA , LAAKSONEN REIJO , MAERZ WINFRIED , FRAUNBERGER PETER , KLEBER MARCUS , DREXEL HEINZ
Published: May 2022

Serum lipids and metabolic diseases, in particular type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD) , predict the atherosclerotic diseases coronary artery disease (CAD) and peripheral arterial disease (PAD) . However, it is not known in how far a more detailed characterization including serum lipids improves discrimination of PAD from CAD. A cohort of 274 statin-naïve patients with either PAD (n = 89) or stable CAD (n = 185) were referred to metabolic screening and were characterized using nuclear magnetic resonance- and liquid chromatography-tandem mass spectrometry based advanced lipid and lipoprotein analysis. Results were validated in an independent cohort of 1239 patients with PAD or CAD. We found a significant difference in T2D prevalence and in the ceramide-based lipid profile between PAD and CAD patients. However, neither cholesterol-based markers (including LDL-C, HDL-C) and detailed lipoprotein profiles nor the NAFLD status differed significantly between PAD and CAD patients (figure) . The difference between ceramide-based lipid profiles of CAD and PAD remained significant also after adjusting for body composition, smoking, inflammatory parameters, and T2D. We conclude that PAD and CAD differ in ceramide-based lipid profiles and T2D status, but not in other lipid characteristics or metabolic diseases.

Disclosure

A.Leiherer: None. A.Jylha: None. M.Laaperi: None. R.Laaksonen: None. W.Maerz: None. P.Fraunberger: None. M.Kleber: None. H.Drexel: None. A.Muendlein: None. E.Brandtner: None. C.H.Saely: None. A.Vonbank: None. A.Mader: None. L.Sprenger: None. M.Maechler: None. B.Larcher: None.
210-LB: Central Regulation of Peripheral Adiposity by Nos1PVHNeurons
Authors: FAULKNER LATRICE D. , LEWIS KENNETH , MEEK THOMAS H. , MERCER AARON J. , MACDOUGALD ORMOND A. , OLSON DAVID
Published: May 2022

Within the CNS, the paraventricular nucleus of the hypothalamus (PVH) is critical for energy homeostasis, as developmental or mechanical lesions targeting the PVH lead to massive obesity. The PVH is composed of multiple cell types expressing an assortment of neuropeptides, receptors, and enzymes, including a subset of neurons expressing nitric oxide synthase-1 (Nos1PVH) . Nos1PVH neurons project to the nucleus of the solitary tract and the intermediolateral column of the spinal cord suggesting a neural substrate through which Nos1PVH neurons might directly modulate sympathetic output and energy balance [1]. To understand the necessity of Nos1PVH neurons in basal energy balance regulation, we bilaterally injected the PVH of Nos1-iCre mice with an AAV expressing a Cre-dependent tetanus toxin (Nos1TT) . Chronic silencing of the Nos1PVH resulted in acute onset of subcutaneous and visceral obesity without changes in food intake. Surprisingly, metabolic analyses indicated no significant changes in energy expenditure, although Nos1TT treated animals preferred to utilize fat as the predominant fuel source. Pair feeding experiments also confirmed that the obesity observed in Nos1TT animals was not secondary to increased caloric intake. Adipose tissues receive input from CNS cell groups that are part of the general SNS outflow from the brain [2, 3]. Analysis of subcutaneous white adipose tissue of Nos1TT animals revealed a significant decrease in tyrosine hydroxylase (TH) immunoactivity within WAT suggesting decreased capacity for sympathetic activation of lipolysis. These data indicate that Nos1PVH neurons regulate energy homeostasis possibly through changes in peripheral aspects of energy balance without the influence of energy consumption. Therefore, the main goal of this project is to clarify the physiological roles of Nos1PVH neurons in the regulation of peripheral adiposity, which may lead to the development of more refined anti-obesity therapies. 1. PMID: 25392498 2. PMID: 9688991 3. PMID: 15142857

Disclosure

L. D. Faulkner: n/a. K. Lewis: None. T. H. Meek: Employee; Novo Nordisk. A. J. Mercer: Employee; Novo Nordisk. O. A. Macdougald: None. D. Olson: Research Support; AstraZeneca, Novo Nordisk A/S.

Funding

American Diabetes Association (7-21-PMF-020) ; Novo Nordisk A/S; National Institutes of Health (5R01DK104999-05)
211-LB: The Islet Tester Mouse, a Stable and Reproducible In Vivo Model to Study Human Islet Function
Authors: WAITE ERIC , MAY CATHERINE L. , PANCREAS ANALYSIS PROGRAM (HPAP) HUMAN , KAESTNER KLAUS H.
Published: May 2022

The current gold standard for assessing the function of human islet in vivo, is to engraft islets under the kidney capsule of hyperglycemic, immunodeficient mice. Current models, such as Streptozotocin (STZ) treatment or NSG-Akita mice, are limited due to instable hyperglycemia and/or morbidity of the mouse strain. The glycemia in STZ treated mice is variable and can even result in death or spontaneous recovery of normoglycemia, making it difficult to discern small differences in human islet function. The NSG-Akita mouse is difficult to breed and maintain, and thus has reduced practicality. To address these limitations, we developed a stable, highly reproducible immunodeficient Islet Tester mouse via CRISPR-Cas9 mediated gene editing of glucokinase (GCK) directly in NSG zygotes. Islet Tester mice are heterozygous for the Arg345->stop variant and present with stable hyperglycemia (∼250mg/dl) , without the severe age-dependent morbidity of the NSG-Akita mice. This mouse will allow us to study human islet biology over time and under different physiological conditions and could provide a useful preclinical platform to investigate drugs targeting islet cells.

Disclosure

E. Waite: None. C. L. May: None. Human pancreas analysis program (hpap) : n/a. K. H. Kaestner: None.
212-OR: Five-Year Follow-Up of Lipid, Inflammatory, Hepatic, and Renal Markers in People with T2 Diabetes on a Very-Low-Carbohydrate Intervention Including Nutritional Ketosis (VLCI) via Continuous Remote Care (CRC)
Authors: ROBERTS CAROLINE G.P. , ATHINARAYANAN SHAMINIE J. , VANTIEGHEM MICHELLE , MCKENZIE AMY L. , VOLK BRITTANIE M. , ADAMS REBECCA N. , FELL BRANDON , RATNER ROBERT E. , VOLEK JEFF , PHINNEY STEPHEN , HALLBERG SARAH
Published: May 2022

Objective: To address the long-term effectiveness of VLCI for T2D, we report changes in lipids, inflammatory, hepatic, and renal markers at 5y.

Research Design and Methods: Of the 200 subjects with T2D reaching 2-years in a non-randomized, controlled trial of CRC emphasizing VLCI, 169 (84.5%) consented to 3-year extension and 122 (61%) completed 5y. Metabolic changes from baseline (BL) to 5y were assessed with linear mixed effect models as an intent-to-treat analysis (n=169) . Holm-Bonferroni adjusted p-values are <0.05 unless otherwise noted.

Results: At 5y, there were significant changes in HDLc from 43.0 mg/dl to 50.6 mg/dl (+17.7%) , apoA-I from 146.9 mg/dl to 153.5 mg/dl (+4.5%) , and no changes in Total Cholesterol, LDLc, apoB. There were marginal improvements in non-HDLc from 139.2 mg/dl to 128.9 mg/dl (-7.4%, unadjusted p-value <0.01) , and triglycerides from 202.3 mg/dl to 165.1 mg/dl (-18.4%, unadjusted p-value <0.01) . Inflammatory markers significantly improved: hs-CRP from 7.8 nmol/L to 4.4 nmol/L (-43.6%) , white blood cell count from 7.2 k/mm3 to 6.4 k/mm3 (-11.1%) . At all time points, liver markers have been in the normal range. There were no changes in renal biomarkers. eGFR was stable at CKD2. Subcohort completers’ analysis of those with eGFR<60 ml/min/1.73m2 (n=10) showed an increase from 47.8 to 57.1 ml/min/1.73m2 (p=0.01). Six of the subjects (60%) with BL CKD3 who completed 5y rose to CKD2. Of the 107 subjects with BL CKD2, 7 (6.5%) progressed to CKD3.

Conclusions: People with T2D following VLCI for 5y show improvements in diabetic dyslipidemia and inflammation. Notably, there is no change in LDLc. There is no significant deterioration in liver and renal labs, although regression from CKD3 to 2 is possible with a VLCI and warrants further investigation.

Disclosure

C.G.Roberts: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. S.Phinney: Employee; Virta Health Corp. S.Hallberg: Advisory Panel; Atkins Nutritionals Inc., Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. S.J.Athinarayanan: Employee; Virta Health Corp. M.Vantieghem: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. B.M.Volk: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.N.Adams: Employee; Virta Health Corp. B.Fell: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.E.Ratner: Employee; Virta Health Corp. J.Volek: Advisory Panel; Abbott Diagnostics, Simply Good Foods, Stock/Shareholder; Virta Health Corp.
213-OR: Antidiabetic Potential of Novel, Long-Acting Amylin Analogue ZP8396 in ZDF Rats
Authors: SKARBALIENE JOLANTA , BAADER-PAGLER TAMARA , ERIKSSON PER-OLOF
Published: May 2022

Amylin improves glucose homeostasis through at least three distinct mechanisms of action, including prevention of the postprandial rise in plasma glucagon, slowing of gastric emptying, and increased satiety, leading to decreased caloric intake and potential weight loss. Clinical efficacy has been demonstrated with short-acting amylin analogue pramlintide. ZP8396, currently in phase 1 clinical testing, is a long-acting, amylin analogue designed to improve solubility, stability and allow for co-formulation with other relevant peptides. We previously reported that ZP8396 provides body weight reduction in DIO rats alone and in combination with semaglutide, a once-weekly GLP-1 agonist (Skarbaliene et al, Obesity Week 2021) . Here we investigated the antidiabetes potential of ZP8396 in Zucker Diabetic Fatty (ZDF) rats. The antidiabetes potential after a single subcutaneous (s.c.) injection of ZP8396 (nmol/kg) or vehicle was measured in ZDF rats (aged 12-13 weeks, n=10) , an animal model of type 2 diabetes, and continuously monitored for 168 h after dosing.ZP8396 induced a significant body weight loss in ZDF rats vs. vehicle group. A significant decrease in body weight was observed in rats treated with ZP8396 from initiation of the dosing and up to 96 h post-dose. In addition, single s.c. injection of ZP8396 showed a significant reduction in blood glucose levels at 24 h post-dose, reaching a 20 % difference in blood glucose levels vs. vehicle group (14,97±0,39 and 18,60±1,18 mmol/L, respectively; p <0.05) . Also, ZP8396 significantly reduced plasma glucagon levels, reaching a 55% difference in ZP8396-treated diabetic rats vs. vehicle group at 24 h post-dose (p <0.05) .

In conclusion, in diabetic rat ZP8396 improved glycaemic status, supporting that long-acting amylin analogues may provide future valuable therapeutic options to manage diabetes. Further preclinical characterization of the antidiabetes effects of long-term treatment with ZP8396 is ongoing.

Disclosure

J.Skarbaliene: Employee; Zealand Pharma A/S, Stock/Shareholder; Zealand Pharma A/S. T.Baader-pagler: Employee; Boehringer Ingelheim International GmbH. P.Eriksson: Employee; Zealand Pharma A/S.
215-LB: Silencing of Fructose 1,6-Bisphosphatase (FBP1) in Liver Improves Glucose Homeostasis in Insulin-Resistant Rodent and Human Models
Authors: FLEDELIUS CHRISTIAN , IVERSEN HELLE , INGVORSEN RIKKE S. , ERIKSEN LISBETH B. , BLOIS ANNA , MONTAUBAN YVENET , RIJNBRAND RENE , HAN WEN , JEPPESEN JACOB F. , DEMOZAY DAMIEN
Published: May 2022

Insulin resistant individuals display elevated fasting and post-prandial glucose levels which are mainly driven by inadequate inhibition of gluconeogenesis (GNG) and are rarely normalized. The aim of this study was to investigate whether direct inhibition of GNG could be a new therapeutical approach to improve glucose homeostasis using in vitro and in vivo models of insulin resistance. Fructose 1,6-bisphosphatase (FBP1) is key in controlling GNG in liver and kidney and loss of function patients display hypoglycaemia episodes and lactate acidosis. Systemic FBP1 inhibition using small molecules has shown to improve glucose homeostasis. To assess the clinical efficacy and safety potential of silencing FBP1 selectively in the liver we dosed insulin resistant DIO rats with a hepatocyte specific GalXC-FBP1 siRNA entity. GalXC-FBP1 siRNA markedly reduced FBP1 mRNA level in the liver by over 90%. This was associated with a complete lack of glucose excursion following a pyruvate challenge indicating inhibition of GNG. Blood glucose level decreased similarly in rats treated with GalXC-FBP1 siRNA or vehicle during an insulin challenge or a prolonged fast suggesting that hepatic FBP1 silencing is not inducing hypoglycaemia. Insulin sensitivity and hyperinsulinemia were improved. Plasma lactate and liver enzymes were not elevated, but a significant 2-fold increase in liver triglycerides was observed in the GalXC-FBP1 siRNA group. Using human hepatocytes in a Liver-on-Chip in vitro model FBP1 silencing reduced glucose production by 30% supporting the relevance of this approach in humans. Collectively these data suggest that liver specific FBP1 silencing has the potential to improve insulin sensitivity in DIO rats without inducing hypoglycaemia but may be associated with a risk of liver steatosis overtime. This concept highlights the difficulty of blocking liver GNG without re-directing the metabolic intermediates fluxes toward triglycerides accumulation in liver.

Disclosure

C. Fledelius: Employee; Novo Nordisk A/S. D. Demozay: Employee; Novo Nordisk A/S. H. Iversen: None. R. S. Ingvorsen: None. L. B. Eriksen: None. A. Blois: Employee; Novo Nordisk. Y. Montauban: None. R. Rijnbrand: Employee; Novo Nordisk. W. Han: None. J. F. Jeppesen: Employee; Novo Nordisk A/S.
216-OR: Hypoglycemia Frequency and Physiological Response to Double or Triple Doses of Once-Weekly Insulin Icodec vs. Once-Daily Insulin Glargine in T2D
Authors: SVEHLIKOVA EVA , ARFELT KRISTINE NISS , CAILLETEAU ROMAN , DELLER SIGRID , THOMSEN KAREN MARGRETE , HART MARLIES , MURSIC INES , PIEBER THOMAS , HAAHR HANNE
Published: May 2022

Insulin icodec is a basal insulin in development for once-weekly (OW) dosing. The aim of this study was to compare the hypoglycemia frequency and response after icodec vs. insulin glargine U100 (IGlar) overdosing. In a randomized, open-label, two-period crossover trial, 43 individuals with T2D on basal insulin±metformin (mean±SD age 56±9 yrs, HbA1c 7.2±0.7%) received OW icodec for 6 weeks and once-daily IGlar for 12 days at equimolar total weekly doses based on the individual daily run-in IGlar dose (mean 30±14 U) titrated to a fasting SMPG target of 80-130 mg/dL. Once at steady state, double (DD) and triple (TD) doses of icodec and IGlar were followed by hypoglycemia induction 44 h (icodec) or 7 h (IGlar) post-dose (expected time of maximum glucose-lowering effect) : First, euglycemia was maintained at 100 mg/dL by variable i.v. glucose. Then, PG was allowed to decrease to a nadir of no less than 45 mg/dL maintained for 15 min. Euglycemia was restored by constant i.v. glucose. Hypoglycemic symptom score (HSS) and counterregulatory hormones were assessed at PG 100 mg/dL and at predefined PG levels until nadir PG. For DD, clinically significant hypoglycemia (PG<54 mg/dL) occurred in 40 vs. 36% of subjects for icodec vs. IGlar (odds ratio 1.28; p=0.63) . For TD, clinically significant hypoglycemia occurred in 53 vs. 70% of subjects (odds ratio 0.48; p=0.14) , mean nadir PG was 56 vs. 52 mg/dL (treatment ratio 1.07; p<0.001) , change in HSS at nadir PG was comparable for icodec vs. IGlar (treatment difference 0.46; p=0.77) , responses in adrenaline, noradrenaline and cortisol during hypoglycemia development were greater for icodec vs. IGlar, while glucagon and growth hormone levels increased similarly.

In conclusion, a DD or TD of once-weekly insulin icodec does not lead to increased risk of hypoglycemia compared to once-daily IGlar. During hypoglycemia, a comparable symptomatic response and a moderately greater endocrine response were seen for icodec vs. IGlar.

Disclosure

E.Svehlikova: n/a. K.Niss arfelt: Employee; Novo Nordisk. R.Cailleteau: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. S.Deller: None. K.Thomsen: Employee; Novo Nordisk. M.Hart: None. I.Mursic: None. T.Pieber: Advisory Panel; Arecor, Novo Nordisk A/S, Research Support; AstraZeneca, European Union, JDRF, Novo Nordisk Foundation, Sanofi, Speaker's Bureau; Novo Nordisk A/S, Roche Diagnostics. H.Haahr: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S.

Funding

Novo Nordisk
217-OR: A Randomized Controlled Trial Comparing the Safety and Efficacy of IDegLira vs. Basal Bolus in Patients with Poorly Controlled Type 2 Diabetes and Very High HbA1c (>9%–15%) : IDegLira HIGH Trial
Authors: GALINDO RODOLFO J. , MOAZZAMI BOBAK , SCIOSCIA MARIA F. , VELLANKI PRIYATHAMA , DAVIS GEORGIA M. , PASQUEL FRANCISCO J. , FAYFMAN MAYA , MIGDAL ALEXANDRA L. , SALING JARROD , UMPIERREZ GUILLERMO E.
Published: May 2022

IDegLira-HIGH trial was a non-inferiority, prospective, randomized clinical trial, comparing the efficacy and safety of insulin degludec/liraglutide combination (IDegLira) and a regimen of multiple daily injections (MDI) with basal-bolus insulin (BB) in adults (>18-80 years of age) , with type 2 diabetes (T2D) , and very high HbA1c (>9%-15%) , previously treated with basal insulin or multiple oral agents. Primary endpoint was change in HbA1c from baseline to week 26. Secondary endpoints included incidence of hypoglycemia, changes on weight and glycemic variability (% coefficient of variation [%CV]) . Treatment with IDegLira and BB insulin resulted in similar improvement in glycemic control: 7.7±1.7% and 7.7±1.5%, (p=0.76) , with a reduction from baseline of -3.2±2.3% and -3.0±1.8%, (p=0.39) at 26-weeks. IDegLira resulted in lower rates of hypoglycemia <70 mg/dl (22% vs. 36%, p=0.05) , similar glycemic variability (CGM %CV 30.4±9.1% vs. 33.2±7.3%, p=0.08) , and greater weight loss (-3.7±4.1 kg vs. +8.4±5.4 kg, p<0.01) compared to BB. IDegLira was associated with higher rates of nausea (Table 1) . Conclusions: In patients with T2D and very high HbA1c (≥9%-15%) , a regimen of daily IDegLira injection is non-inferior to MDI with BB insulin on HbA1c reduction and was associated with weight loss and less hypoglycemia.

Disclosure

R.J.Galindo: Advisory Panel; Sanofi, WW International, Inc., Research Support; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk. G.E.Umpierrez: Research Support; AstraZeneca, Dexcom, Inc., Novo Nordisk. B.Moazzami: None. M.F.Scioscia: None. P.Vellanki: n/a. G.M.Davis: Consultant; Medscape, Research Support; Insulet Corporation. F.J.Pasquel: Consultant; AI Health LLC, Boehringer Ingelheim International GmbH, Dexcom, Inc., Research Support; Dexcom, Inc., Insulet Corporation, Merck & Co., Inc. M.Fayfman: None. A.L.Migdal: None. J.Saling: None.

Funding

Investigator-initiated study to Emory University (PI. Dr. Rodolfo J. Galindo) from Novo Nordisk.
218-OR: The Effect of Insulin Degludec vs. Insulin Glargine U100 on Continuous Glucose Monitoring (CGM) Recorded Glycemic Metrics in People with Type 1 Diabetes and Recurrent Nocturnal Severe Hypoglycemia
Authors: BRØSEN JULIE M. , AGESEN RIKKE , ALIBEGOVIC AMRA CIRIC , ANDERSEN HENRIK U. , GUSTENHOFF PETER , HANSEN TROELS K. , HEDETOFT CHRISTOFFER , STOLBERG CHARLOTTE R. , JUHL CLAUS B. , LERCHE SUSANNE , NØRGAARD KIRSTEN , TARNOW LISE , THORSTEINSSON BIRGER , PEDERSEN-BJERGAARD ULRIK
Published: May 2022

Background and Aims: Insulin Degludec (IDeg) , in comparison with Insulin Glargine U100 (IGla) , reduces the risk of hypoglycemic events in people with type 1 diabetes (T1D) . The impact on CGM assessed glycemic metrics: the coefficient of variation (CV) , time in range (TIR) , time below range (TBR) , and time-above range (TAR) is less known. We present CGM results from the HypoDeg trial comparing treatment with IDeg and IGla in people with T1D and recurrent nocturnal severe hypoglycemia.

Materials and Methods: This is a pre-defined optional substudy of the HypoDeg trial: a 2-year investigator-initiated, randomized, cross-over trial comparing treatment with IDeg or IGla in 149 participants with T1D and at least one nocturnal severe hypoglycemic event within the last two years. Participants underwent 2 x 6 days of blinded CGM (Medtronic iPro) in each treatment arm after 6 and 12 months of treatment. Seventy-four participants completed at least one CGM period in each treatment arm. The endpoints were CV, TIR (3.9 - 10.0 mmol/L) , TBR at level 2 (< 3.0 mmol/L) and TAR (>10.0mmol/L, >13.9mmol/L) . Time spent in, below, or above range provided as percentage of readings.

Results: We collected 261 CGM traces with a mean (SD) observation period of 5.9 (0.7) days. The all-day CV was lower with IDeg than IGla, with a mean (SE) CV of 40.5% (0.9) and 42.5% (0.9) , respectively (p=0.009) . A difference in CV during the night (23:00h to 07:00h) drove this, with a mean CV of 35.7% (1.1) for IDeg versus 39.6% (1.1) for IGla (p=0.001) . The all-day level 2 TBR was lower with IDeg than IGla, with a mean TBR of 1.8% (0.4) and 3.1% (0.4) , respectively (p=0.001) . The percentages of TIR and TAR were not different between treatments.

Conclusion: In people with T1D prone to nocturnal severe hypoglycemia, treatment with IDeg results in a lower mean CV, reaching the definition of stable glucose levels during the night and a lower all-day TBR than IGla.

Disclosure

J.M.Brøsen: None. S.Lerche: None. K.Nørgaard: Advisory Panel; Medtronic, Novo Nordisk A/S, Consultant; Novo Nordisk A/S, Research Support; Dexcom, Inc., Medtronic, Novo Nordisk A/S, Zealand Pharma A/S, Speaker's Bureau; Medtronic, Stock/Shareholder; Novo Nordisk A/S. L.Tarnow: None. B.Thorsteinsson: None. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. R.Agesen: Employee; Novo Nordisk A/S. A.Alibegovic: Employee; Novo Nordisk A/S, Novo Nordisk A/S. H.U.Andersen: Advisory Panel; Abbott Diabetes, Stock/Shareholder; Novo Nordisk A/S. P.Gustenhoff: Advisory Panel; Abbott Diagnostics. T.K.Hansen: None. C.Hedetoft: None. C.R.Stolberg: None. C.B.Juhl: None.

Funding

Novo Nordisk
219-LB: The Mitochondrial Calcium Uniporter Regulates Hepatic Lipid Accumulation and Mitochondrial Oxidation
Authors: LAMOIA TRACI E. , HUBBARD BRANDON T. , GUERRA MATEUS , GOODMAN RUSSELL , NATHANSON MICHAEL H. , MOOTHA VAMSI , SHULMAN GERALD I.
Published: May 2022

The mitochondrial calcium uniporter (MCU) facilitates mitochondrial calcium influx, and several enzymes that catalyze key steps of the tricarboxylic acid (TCA) cycle require calcium for their activation. As such, it is generally accepted that rates of mitochondrial oxidation correlate with mitochondrial calcium activity. Decreased rates of hepatic mitochondrial oxidation are associated with metabolic dysfunction and ectopic lipid accumulation as seen with type 2 diabetes and nonalcoholic fatty liver disease. Despite this, a role for MCU and mitochondrial calcium in regulating hepatic mitochondrial oxidation is still unclear. To address this question, we generated a liver-specific MCU knockout (MCU KO) mouse model which displayed significantly reduced mitochondrial calcium ([Ca2+]mt, p<0.05) and increased cytosolic calcium ([Ca2+]cyt, p<0.01) in isolated hepatocytes. Despite decreased [Ca2+]mt, we found that deletion of hepatic MCU resulted in increased rates of isocitrate dehydrogenase flux (VIDH, p<0.01) , α-ketoglutarate dehydrogenase flux (VOGDH, p<0.01) , and succinate dehydrogenase flux (VSDH, p<0.05) , using a novel in vivo [13C5]glutamine tracer technique. Further, we report that rates of [14C16]palmitate oxidation (p<0.01) and intrahepatic lipolysis (p<0.05) were significantly increased in precision-cut liver slices collected from MCU KO mice compared to WT, consistent with [Ca2+]cyt activation of CAMKII (p<0.01) and ATGL (p<0.001) in MCU KO mice, and were associated with reductions in hepatic triacylglycerol content in vivo (p<0.01) . Taken together, these data demonstrate that hepatic mitochondrial activity can be dissociated from mitochondrial calcium concentrations and reveal a key role for cytosolic calcium and mitochondrial anaplerosis in the regulation of hepatic mitochondrial fat oxidation.

Disclosure

T. E. Lamoia: n/a. B. T. Hubbard: None. M. Guerra: None. R. Goodman: None. M. H. Nathanson: None. V. Mootha: Advisory Panel; 5AM Ventures, LLC, Janssen Research & Development, LLC. G. I. Shulman: Advisory Panel; 89bio, Inc., AstraZeneca, Equator Therapeutics, Inc., Janssen Research & Development, LLC, Merck & Co., Inc., Consultant; DiCerna Pharmaceuticals, Inc. , Novo Nordisk, Other Relationship; Generian Pharmaceuticals, iMetabolic Biopharma Corporation, Maze Therapeutics, The Liver Company, Stock/Shareholder; Levels Health, Inc. .

Funding

F31 DK126362/DK/NIDDK NIH HHST32 GM007324/GM/NIGMS NIH HHS
222-LB: Switching Palmitoyl and Oleoyl Position in Sn-2 and Sn-3 of a Triacylglycerol Led to Differential Body Weight Gain Rates and Hepatic Gene Expressions in Mice Fed a High-Fat Diet
Authors: HU XINGE , WANG TIANNAN , CHEN GUOXUN
Published: May 2022

Alterations of fatty acid metabolism have been associated with diabetes. Triacylglycerol (TAG) can be obtained from dietary sources and synthesized de novo. The composition and location of the fatty acyl groups in a TAG can affect its physicochemical features such as melting temperature, and physiological characteristics such as digestion, absorption, and lipid metabolism. We hypothesize that the TAG fatty acyl position affects the body weight gain and lipid metabolism of mice in a high-fat diet (HFD) setting. Twenty-seven 6-week-old male C57/BL6J mice were randomly assigned to 3 dietary treatment groups, 1,2-dipalmitoyl-3-oleoylglycerol (PPO, 36 % w/w diet) , 1,3-dipalmitoyl-2-oleoylglycerol (POP, 36% w/w diet) , and the chow diet control groups. Mice in each group were fed their respective diet for 6 weeks, and food intake and body weight were measured daily. Mice fed the PPO diet had significantly higher food intake, calories intake and body wight gain rate, and lower liver to body weight ratio than those fed the POP diet. Mice fed the chow diet had significantly higher total grams of food intake, but lower calories intake, liver and epididymal fat weight, and body weight gain rate than those fed the PPO, but not the POP, diet. Mice in the PPO group had significantly higher serum glucose than that in other two groups, whereas mice fed the chow diet had significantly lower plasma cholesterol level than those HFD groups. The plasma TAG levels were not different among them. The hepatic levels of insulin receptor substrate 1, and fatty acid synthase, and phosphorylated acetyl CoA carboxylase in mice fed the chow diet are significantly higher than those fed the PPO or POP diet, whereas the hepatic expression level of stearoyl CoA desaturase 1 in mice fed the POP diet was lower than those fed the PPO or chow diet. We conclude that feeding a HFD affects the expression levels of hepatic proteins for lipid metabolism in mice. In addition, the position of fatty acyl group in a TAG affects the food intake, the body weight gain rate and lipid homeostasis in mice.

Disclosure

X. Hu: None. T. Wang: None. G. Chen: None.
224-LB: Mitochondrial Capacity of Skeletal Muscle in Older Adults with Diabetes
Authors: RAMOS SOFHIA V. , DISTEFANO GIOVANNA , CAWTHON PEGGY , MARSHALL STEPHANIE M. , KRAMER PHILIP , MOLINA ANTHONY , JURCZAK MICHAEL J. , TOLEDO FREDERICO , GOODPASTER BRET H. , COEN PAUL M.
Published: May 2022

Skeletal muscle mitochondrial capacity is reduced in both aging and diabetes. Whether diabetes further impairs mitochondrial capacity in older adults and how this relates to cardiorespiratory fitness (VO2peak) and glycemic control (HbA1c) remains uncertain. We examined muscle mitochondrial capacity of those with diabetes (self-reported, including Type 1 and 2) and without diabetes in the Study of Muscle Mobility and Aging (SOMMA) (273 men, 194 women; mean±SD age: 76.8±5.3 years) . Mitochondrial capacity was assessed by 31P magnetic resonance spectroscopy (ATPmax) and respirometry of vastus lateralis biopsy specimens. ATPmax (diabetes; 0.48 ± 0.1, nondiabetes; 0.54 ± 0.1 mM/sec, p=0.07) and fatty acid oxidation (FAO) supported OXPHOS (FAO: diabetes; 11.5 ± 4.5, nondiabetes; 12.5 ± 4.4 pmol/min/mg, p=0.01) were lower in those with diabetes compared to those without. VO2peak, assessed by a graded exercise test, was lower in those with diabetes (diabetes; 1478.8± 399.9, nondiabetes; 1495.5 ± 431.3 mL/min, p=0.01) . In all participants, ATPmax (r2=0.07, p=<0.01) and FAO (r2=0.04, p=0.14) explained a small proportion of variance in HbA1c. VO2peak significantly related to mitochondrial capacity (ATPmax: r2=0.66, p=<0.01, FAO: r2=0.64, p<0.01) , but the relationships do not vary by diabetes status.

In summary, older adults with diabetes have marginally lower fitness and mitochondrial capacity. Mitochondrial capacity is related to both glycemic control and cardiorespiratory fitness regardless of diabetes status.

Disclosure

S. V. Ramos: None. P. M. Coen: None. G. Distefano: None. P. Cawthon: None. S. M. Marshall: None. P. Kramer: None. A. Molina: None. M. J. Jurczak: None. F. Toledo: None. B. H. Goodpaster: None.

Funding

Study of Muscle, Mobility and Aging (SOMMA) RO1 AG059416
225-OR: 5-Methoxytryptamine Improves Obesity-Related Inflammation and Insulin Resistance by Regulating M1/M2 Macrophage Polarization
Authors: LIAO XIAOYU , LIU BINGYAO , ZHENG HONGTING
Published: May 2022

In our previous study, we demonstrated that hypoglycemic agent DPP-4i changed the gut microbiota composition in diabetic patients and mice, and the DPP-4i-altered microbiome improved glucose tolerance in colonized mice. However, the mediators and their mechanisms remain to be elucidated. Comparing the intestinal metabolite profiles of HFD mice treated with or without sitagliptin (Sit) , we identified tryptophan derivative 5-methoxytryptomine (5-MT) was obviously increased after Sit treatment. In HFD and db/db mice, 5-MT treatment significantly reduced the body weight, improved glucose tolerance and insulin resistance, and ameliorated hepatic steatosis and inflammation. Drug affinity responsive target stability (DARTS) assay demonstrated the interaction between 5-MT and Aryl hydrocarbon receptor (AhR) . Specific inhibition of AhR attenuated the effects of 5-MT on improving insulin resistance. Furthermore, molecular mechanism exploration revealed that 5-MT promoted the expression and secretion of chemokine Cxcl14, which promoted macrophages maturation into alternative activation (M2-like) , subsequently inhibiting the production of inflammatory factors. These data demonstrate novel beneficial roles of 5-MT in improving obesity-related inflammation, insulin resistance and hepatic steatosis.

Funding

National Science Fund for Distinguished Young Scholars of China (No.81925007) , National Natural Science Foundation of China (No.81700757)
228-OR: Differential Expression of miRNA in Human Subcutaneous and Visceral Adipose Tissue Is Related to Insulin Resistance
Authors: SAINI NATESH , DENG ALICIA , CHEN HENRY , XU YUE , TSAO PHILIP S. , MCLAUGHLIN TRACEY
Published: May 2022

Introduction: Obesity is related to insulin resistance (IR) but not all obese individuals are IR. Differences in regional fat distribution and function contribute to the metabolic heterogeneity of obesity. miRNA is known to regulate mRNA and may play a role in mediating IR by modifying adipose tissue function. We tested the hypothesis that miRNA in human visceral (VAT) and subcutaneous (SAT) fat would be differentially expressed in individuals who were classified as insulin sensitive (IS) or IR.

Methods: 12 participants, classified as IR or IS (top 40 percentile) via steady-state plasma glucose (SSPG) test, were recruited from the Stanford Bariatric Surgery Clinic. Tissue samples (SAT and VAT) were harvested from the greater momentum during bariatric surgery. Total RNA was extracted with QIAGEN RNeasy® Lipid Tissue Mini Kit. The miRNA experiment used QuantStudio™ 12K Flex OpenArray® microRNA Starter Kit with modifications by adding Ath-miR-159a spike-in, and use of SuperScript VILO cDNA Synthesis Kit. Data analysis done via Applied Biosystems™ Relative Quantitation Analysis. miRNA comparisons with fold-change <0.5 or >2 and p<0.were considered statistically significant. Known target genes of significant miRNA were quantified via RT-PCR from tissue samples.

Results: Differential expression in VAT vs. SAT showed one upregulated (miR-885-5p) and 12 downregulated miRNAs. In SAT, for IR vs. IS individuals showed 12 upregulated miRNA, while in VAT, IR vs. IS included one upregulated (miR-30c) and downregulated miRNA.

Conclusion: In VAT relative to SAT, miR-885-5p was a significant predictor of fatty liver and majority of downregulated miRNA (miR-335, 196b, 497, 22, 106b, 340) reduced lipogenesis and increased insulin signaling. In IR vs. IS of SAT, majority of miRNA reduced insulin sensitivity (miR-146b, 29c, 502-3p) . For IR vs. IS of VAT, miR-30c promoted adipocyte differentiation and majority of downregulated miRNA increased insulin sensitivity (miR-106b, 24, 143, 340) .

Disclosure

N.Saini: None. A.Deng: None. H.Chen: None. Y.Xu: None. P.S.Tsao: None. T.Mclaughlin: Board Member; January, Inc., Research Support; Merck & Co., Inc., Novo Nordisk, Stock/Shareholder; Eiger BioPharmaceuticals.
231-OR: Antecedent Hypoglycemia Increases Damage Due to a Subsequent Myocardial Infarction in Rats
Authors: CHRISTENSEN CAMILLE G. , FISHER SIMON , RENO CANDACE M.
Published: May 2022

Several clinical trials have noted an association between hypoglycemia and major cardiovascular events; however, a direct link between antecedent hypoglycemia and worse cardiac outcomes has not been established. We hypothesized that antecedent recurrent hypoglycemia predisposes the heart to increased damage following a subsequent myocardial infarction. To test this hypothesis, adult Sprague Dawley rats were subjected to 3 days of recurrent insulin-induced hypoglycemia (25-30 mg/dl, 90 minutes each day; n = 6) or saline (control, n = 6) . On the following day, all rats underwent a myocardial infarction (MI) induced by occlusion of the left anterior descending artery for 30 minutes followed by reperfusion for 60 minutes. Electrocardiograms indicated ST elevation during the MI, which returned to normal sinus rhythm upon reperfusion. Hearts were removed immediately and analyzed for damage. MI induced ventricular damage from rats that underwent antecedent recurrent hypoglycemia (39 ± 5%) was significantly higher than control rats (16 ± 4%; p<0.001, Figure) . Additionally, plasma norepinephrine levels were elevated 14-fold in rats that underwent recurrent hypoglycemia. These studies indicate that antecedent hypoglycemia directly contributes to worse outcomes following an MI and that increased norepinephrine is associated with this damage.

Disclosure

C.G.Christensen: None. S.Fisher: None. C.M.Reno: None.

Funding

University of Utah’s Driving Out Diabetes, a Larry H. Miller Family Wellness InitiativeNational Institutes of Health (P30 DK020579) Juvenile Diabetes Research Foundation (1-FAC-2020-984-A-N)
232-LB: Housing Temperature Can Profoundly Influence Pharmacologically Induced Weight Loss Efficacy and Mode of Action in Diet-Induced Mice—A Cautionary Consideration for Human Translation
Authors: PETERSEN NATALIA , TORZ LOLA , GERSTENBERG MARINA K. , PEDERSEN KENT , MADSEN SUZI H. , ØSTERGAARD SØREN , WULFF BIRGITTE S. , JØRGENSEN SEBASTIAN B. , ANDERSEN BIRGITTE S. , CHRISTOFFERSEN BERIT Ø. , JOHN LINU M. , KUHRE RUNE E.
Published: May 2022

Objectives: Pre-clinical evaluation of drug efficacy on weight loss is usually done in diet-induced obese (DIO) mice housed at room temperature (∼22°C) , where the mice display adaptive thermogenic responses through brown adipose tissue (BAT) activation to increase energy expenditure (EE) and maintain core-temperature. These adaptive responses may influence drug-induced weight loss and ultimately likelihood for translatability to humans, who does not have thermogenic responses at room-temperature. We tested whether the efficacy of diverse weight-reducing pharmaco-therapies with distinct mode of action is impacted by housing temperature.

Methods: Male DIO mice were studied with indirect calorimetry (Sable Systems International) at 22°C or 30°C (thermoneutrality) . Mice were treated daily for 10-21 days with analogues of weight-modulating compounds that have been in clinical development: glucagon-like peptide-1 (GLP-1) , melanocortin-4-receptor (MC4R) agonist, growth differentiation factor 15 (GDF15) , peptide YY (PYY) , and fibroblast growth factor 21 (FGF21) aiming for a weight loss (WL) of 10-25%.

Results: Energy expenditure was ∼30% higher 22°C compared to 30°C. Housing temperature did not affect GLP-1 (∼20%) and MC4R (∼10%) mediated WL. However, FGF21 and PYY-mediated WL was higher at 30°C (∼20% vs. ∼17% for FGF21 and ∼9% vs. ∼1% for PYY) . In contrast, GDF15-mediated WL was higher at 22°C (∼14% vs. ∼8%) . The relative contribution of inhibition of food intake vs. increase in EE differed for FGF21 but not for the other compounds. In this case, increased EE, by BAT, drove more of the weight loss in the 22°C group.

Conclusion: Ambient temperature may affect both efficacy and mode of action of weight-reducing pharmaco-therapies in DIO mice. This may affect human translatability, and we, therefore, suggest that studies at thermoneutrality should be included at an early stage in drug-development programs.

Disclosure

N. Petersen: Employee; Novo Nordisk A/S. B. Ø. Christoffersen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. L. M. John: None. R. E. Kuhre: Employee; Novo Nordisk. L. Torz: Other Relationship; Novo Nordisk A/S. M. K. Gerstenberg: Employee; Novo Nordisk. K. Pedersen: Employee; Novo Nordisk A/S. S. H. Madsen: None. S. Østergaard: Employee; Novo Nordisk A/S. B. S. Wulff: Employee; Novo Nordisk A/S. S. B. Jørgensen: Employee; Novo Nordisk A/S. B. S. Andersen: Employee; Novo Nordisk A/S.

Funding

Novo Nordisk A/S
234-LB: Role of P311 in Adipocyte Plasticity and Metabolic Regulation
Authors: BADRI KAMESWARA R.
Published: May 2022

The prevalence of obesity in the United States and worldwide has increased dramatically over the past 20 years. Currently it is affecting about 40% of adults and more alarmingly about 20% of children in the US. Obesity is a major risk factor and comorbid condition for chronic metabolic conditions like insulin resistance, Type 2 diabetes and dyslipidemia etcetera. Hence, the increase in the incidence of obesity and the metabolic dysregulation-associated morbidity and mortality and rising costs of treatments warrants a deeper understanding of all aspects of adipocyte biology to develop novel therapeutics to thwart this pandemic. Recent research developments identified three different types of adipose tissues, white adipose tissue (WAT) , beige adipose tissue and brown adipose tissue, increasing the complexity of adipose biology and adipocyte plasticity in metabolic regulation. P311 is a small intrinsically unstructured protein that shows adipogenic properties. We show for the first time that P311 is expressed in white, beige and brown adipose tissue and young P311 knockout mice show increased WAT and/or decreased beige AT implicating that P311 plays a key role in adipocyte plasticity and regulating quality and quantity of the AT. Further, aged P311 KOs are significantly obese with hyperglycemia and deranged glucose tolerance. Our findings are the first to show the role of P311 in adipose biology, adipocyte plasticity and metabolic regulation.

Disclosure

K. R. Badri: None.

Funding

National Institute of Health (U54MD007602, S21MD000101)
237-LB: Weight-Independent Effects of Roux-en-Y Gastric Bypass Surgery on Remission of Nonalcoholic Fatty Liver Disease in Mice
Authors: AXELROD CHRISTOPHER L. , LANGOHR INGEBORG M. , DANTAS WAGNER S. , LEIGH TOWNSEND R. , ALBAUGH VANCE L. , KIRWAN JOHN P. , BERTHOUD HANS-RUDOLF
Published: May 2022

Introduction: Obesity is the primary determinant of nonalcoholic fatty liver disease (NAFLD) . Interventions that decrease body weight, such as bariatric surgery and/or calorie restriction (CR) , may serve as effective therapies for NAFLD. The purpose of this study was to compare the effects of Roux-en-Y gastric bypass surgery (RYGB) to CR on hepatic function in mice with obesity and NAFLD.

Methods: 6-week-old male C57BL/6J mice were fed a two-choice chow/high-fat diet (HFD) to promote diet-induced obesity. At 16 weeks of age, mice were randomized to (1) sham surgery (Sham) , (2) RYGB, or (3) sham + weight-matched calorie restriction to RYGB (WM) . Mice were euthanized at 36 weeks for determination of NAFLD/NASH and hepatic function. Body weight/composition and food intake were measured weekly during the treatment period. ANCOVA-adjusted energy expenditure (EE) was determined 3 and 17 weeks after treatment. Hepatic lipid content and NAFLD scores were determined from H&E-stained tissue sections. Hepatic enzymes and glycogen content were determined by ELISA.

Results: RYGB & WM achieved a similar reduction in body weight relative to baseline. RYGB decreased adiposity to a greater extent than WM relative to baseline and Sham (-4.4±0.6 vs. -1.3±0.6 Δg, P<0.001) . Decreased body weight was attributable to lower food intake in WM compared to RYGB and Sham (P<0.0001) . WM decreased EE relative to RYGB and Sham (WM:8.6±0.4 vs. RYGB:10.4±0.4 vs. Sham:10.5±0.6 kcals/day, P<0.001) . RYGB decreased hepatic lipid content to a greater extent than WM (92.6 vs. 76.5 % reduction, P=0.02) . RYGB and WM similarly decreased AST and ALT activity relative to Sham. RYGB increased hepatic glycogen relative to both Sham and WM (P<0.001) .

Conclusions: RYGB and WM improve hepatic function and decrease the severity of NAFLD through shared and discrete mechanisms of action. RYGB decreases hepatic lipid content to a greater extent than WM independent of food intake, indicating that evading the expected metabolic adaptation in EE after weight loss likely accounts for the additive hepatic benefit of RYGB.

Disclosure

C. L. Axelrod: None. I. M. Langohr: None. W. S. Dantas: None. R. Townsend: None. V. L. Albaugh: None. J. P. Kirwan: None. H. Berthoud: None.

Funding

National Institutes of Health (U54GM104940)