bluuebunny/crossref_metadata_2025 huggingface dataset:
1773-P: Postprandial Hyperglycemia after a High–Glycemic Index Meal Activates Brain Areas Associated with Food Cravings and Overeating in T1D
Authors: LENNERZ BELINDA S. , MUNSCH FANNY , ALSOP DAVID C. , STEIL GARRY M. , SIMONSON DONALD C. , LUDWIG DAVID S.
Published: June 2020

High vs. low glycemic index (GI) foods elicit late postprandial activation of mesolimbic brain areas, which may contribute to the associated increases in hunger, food intake and cravings. It is unknown whether changes in blood glucose or higher insulin levels mediate this activation and its potential adverse downstream effects. Fifteen men with T1D, mean (SD) BMI 21 (1.4) kg/m2, aged 21 (1.6) yr underwent three conditions in random order: C1 - high GI (GI=84) meal with IV insulin to maintain euglycemia; C2 - macronutrient matched low GI (37) meal with IV insulin to maintain euglycemia; C3 - high GI meal with IV insulin to match C2. Insulin was algorithmically adjusted for 4.5 hr with blood glucose checks every 5 min. Brain imaging (arterial spin labeling) was obtained at baseline, in the early (1 hr) and late (4 hr) postprandial period. This design allowed us to compare high vs. low GI meals with similar glucose response (incremental area under the curve 192 [22] vs. 41 [12], p=0.6) but different insulin doses (25 [2] vs. 17 [1] units, p=0.003; C1 vs. C2) or similar insulin doses (17 [1] units each, p=0.5) with different glucose response (1257 [37] vs. 41 [12] mg/dl*h, p<0.001, C3 vs. C2). As expected, a high GI meal elicits increased hunger and late postprandial activation of brain areas linked to food cravings. This activation was mediated by postprandial hyperglycemia rather than insulin level. Thus, a high GI meal may promote overeating with insulin dose deviations in either direction: 1) via mesolimbic signaling if hyperglycemia results from inadequate insulin coverage, or 2) via compensatory carbohydrate intake if excessive coverage causes hypoglycemia.

Disclosure

B.S. Lennerz: None. F. Munsch: None. D.C. Alsop: Other Relationship; Self; General Electric, Hitachi America, Ltd., Philips Healthcare, Siemens Corporation. G.M. Steil: Consultant; Self; Eli Lilly and Company. D.C. Simonson: Stock/Shareholder; Self; GI Windows. Stock/Shareholder; Spouse/Partner; Phase V Technologies, Inc. D.S. Ludwig: None.
1776-P: ROCK1 Deletion in Sim1-Expressing Neurons of the Hypothalamus Leads to Obesity Despite Hypophagia
Authors: LEE HYON , HAN JUNG SUK , UNER AYKUT G. , CHOI SOO J. , PEREIRA RODRIGO M. , SUN XIAOFANG , KIM HYUN JEONG , KIM YOUNG-BUM
Published: June 2020

The paraventricular nucleus of the hypothalamus (PVN) is a key site in the brain for regulating energy balance. ROCK1 has also been shown to be a major regulator of energy balance and metabolism in the hypothalamus, but its role in the PVN is still unclear. To explore this role, mice selectively lacking ROCK1 in single-minded homolog 1 gene (Sim1) neurons (Sim1-ROCK1-/-), which are densely expressed in the PVN and in parts of the amygdala, were studied. ROCK1 deficiency in Sim1 expressing neurons leads to obesity on regular chow in male and female mice after 11-12 weeks. This effect is due to increased fat mass as assessed by EchoMRI and direct dissection of fat depots. Serum levels of insulin, leptin and free fatty acid in Sim1-ROCK1-/- mice were markedly increased compared to control mice. Surprisingly, daily food intake in Sim1-ROCK1-/- mice were significantly decreased compared with control mice. Moreover, the ability of melanocortin to decrease food intake was impaired when ROCK1 was deleted from Sim1-expressing neurons. No differences in O2 consumption and CO2 production measured by the Comprehensive Lab Animal Monitoring System (CLAMS) were found between obese and lean mice with or without ROCK1 deletion. These data identify ROCK1 as an important mediator of energy balance in the PVN, which leads to a paradoxical obese/hypophagic phenotype. The underlying mechanisms for the divergence in obesity, energy expenditure and caloric intake are being further explored in our lab.

Disclosure

H. Lee: None. J. Han: None. A.G. Uner: None. S.J. Choi: None. R.M. Pereira: None. X. Sun: None. H. Kim: None. Y. Kim: None.
178-LB: Insights from the University of Chicago Monogenic Diabetes Registry on Diagnosis and Management of Monogenic Diabetes
Authors: HARRIS ANASTASIA , NAYLOR ROCHELLE N. , SANYOURA MAY , GREELEY SIRI ATMA W. , KANDASAMY BALAMURUGAN , PHILIPSON LOUIS H. , LETOURNEAU-FREIBERG LISA R.
Published: June 2020

Monogenic diabetes (MDM), caused by a single gene or chromosomal abnormality, affects ~2% of people diagnosed with diabetes under 35 years of age, but is frequently misdiagnosed and mistreated. The Monogenic Diabetes Registry began in 2008, and has served to diagnose and longitudinally follow individuals with congenital diabetes and MODY. Research-based genetic testing and pragmatic cohort studies have clarified genotype-phenotype correlations and barriers to diagnosis and appropriate management. Interested participants complete a secure web-based registration form. They are screened and consented by phone or in-person. Participants provide medical and family history information at baseline and annually thereafter via REDCap, as well as DNA samples that are stored in laboratory databases. The Registry has grown exponentially from 430 total participants enrolled by 2009 to over 3,600 participants, from 1,900 families, with an average yearly increase of 38.5%. Fifty-seven percent were referred to the Registry through their diabetes provider. To date, 1,050 participants have a confirmed genetic diagnosis. The majority of testing has been completed through our lab (73%), followed by commercial labs (22%) and other research labs (5%). The average time for an MDM diagnosis is 10 years. The most common cause of MODY in the Registry is GCK-MODY (60%) while the most common cause of congenital diabetes is mutations in KCNJ11 (38%). Of those with baseline survey data on insulin use, 81% were found to have a genetic cause of MDM typically amenable to oral therapies or no treatment. The Registry provides a robust network of MDM resources and support to participants and providers throughout the United States. However, research-based diagnosis has constraints not faced by commercial labs. The long delay in diagnosis and high proportion of research-based testing suggests that broader access to clinical testing via insurance coverage is critically needed.

Disclosure

A. Harris: None. R.N. Naylor: None. M. Sanyoura: None. S.W. Greeley: None. B. Kandasamy: None. L.H. Philipson: None. L.R. Letourneau-Freiberg: None.

Funding

National Institutes of Health (R01DK104942, P30DK020595, K23DK094866, UL1TR000430)
1781-P: Remission of Type 2 Diabetes over 2 Years Normalizes Morphology of the Whole Pancreas
Authors: TAYLOR ROY , ZHYZHNEUSKAYA SVIATLANA V. , PETERS CARL , BARNES ALISON C. , HOLLINGSWORTH KIEREN G. , SATTAR NAVEED , LEAN MICHAEL E. , AL-MRABEH AHMAD
Published: June 2020

In type 2 diabetes, the pancreas is 30% smaller with irregular borders. The lack of rapid postprandial rise in insulin may explain the loss of exocrine tissues mass was postulated to be reversible on remission of diabetes. 90 people (38/52 F/M, 52.8±7.9 years, initial weight 100.2±16.3kg, and BMI 34.7±4.3 kg/m2) were randomized (Diabetes Remission Clinical Trial) to low calorie diet or to continue with routine diabetes management. A group of nondiabetic controls (n=25) matched to the post-diet weight was studied in one occasion. MR techniques were used for anatomical and fat fraction images of the pancreas (3T Philips, Netherlands). Specifically developed methods were used to quantify intrapancreatic fat, change in pancreas volume and irregularity of the border. At baseline, pancreas volume was lower in diabetes (63.8±1.8 vs. 79.8±2.9cm3, p<0.0001). It was unchanged after 5 months, increased at 12 months, and at 24 months had increased further by 12.6±1.5cm3 in responders compared with 4.5±1.3cm3 in non-responders (p<0.0001). Over 24 months, pancreas fat content decreased only in responders (p<0.0001) and responders lost 1.56±0.3% vs. 0.51±0.4% (p<0.05). At 12 months, there were negative correlations between decrease in pancreas fat and increase of insulin secretion (r=-0.55, p<0.0001), and increase in pancreas volume and the decrease of pancreas fat within the whole study (r=-0.35, p=0.02). Reflecting irregularity, Fractal Dimension (FD) of the pancreas borders was higher in the diabetic group (1.116±0.013 vs. 1.097±0.005, p<0.0001) and decreased to 24 months only in those who achieved remission (1.097±0.008, p=0.0003). The low pancreas volume of type 2 diabetes is likely to be related to deficiency of acute insulin secretion over many years of disease progression. Fat removal from the pancreas can restore β cells function and may lead to restoration of exocrine tissues mass via trophic effects of insulin. Pancreas morphology appears to reflect the pathophysiology of type 2 diabetes.

Disclosure

R. Taylor: Speaker’s Bureau; Self; Novo Nordisk Foundation. S.V. Zhyzhneuskaya: None. C. Peters: Speaker’s Bureau; Self; Sanofi-Aventis. A.C. Barnes: None. K.G. Hollingsworth: None. N. Sattar: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Sanofi. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. M.E. Lean: None. A. Al-Mrabeh: None.

Funding

Diabetes UK
1782-P: Impact of Treatment with Medication vs. Laparoscopic Gastric Banding (GB) on ß-Cell Function in Adults with Impaired Glucose Tolerance (IGT) or Type 2 Diabetes (T2D) in the Restoring Insulin Secretion (RISE) Study
Authors: EHRMANN DAVID A. , EDELSTEIN SHARON , XIANG ANNY , BUCHANAN THOMAS A. , ARSLANIAN SILVA A. , CAPRIO SONIA , MATHER KIEREN J. , NADEAU KRISTEN J. , KAHN STEVEN E. ,   THE RISE CONSORTIUM
Published: June 2020

The RISE Consortium conducted a study in adults with IGT or recently diagnosed T2D to determine if β-cell function can be conserved or improved. Participants were randomized to GB, metformin, liraglutide + metformin (L+M), or placebo. β-cell function was assessed at baseline (BAS) and at 12 mo (12M) on therapy. Hyperglycemic clamp measures of β-cell function were: acute C-peptide (CP) response to glucose (ACPRg), steady-state CP (SSCP) at a plasma glucose of 11.1 mmol/L and maximal CP response to arginine, a non-glucose secretogogue, at a plasma glucose >25 mmol/L (ACPRmax). At BAS, BMI, ACPRg, SSCP, and ACPRmax were similar across groups. BMI was lower at 12M in all treatment groups and unchanged in those on placebo (Table). Analyses were adjusted for age, sex, and race. Participants randomized to L+M had significant increases in ACPRg and SSCP. There was also a modest but significant attenuation in ACPRmax in the L+M group. In contrast, participants who received GB or metformin alone had no change in β-cell function. Liraglutide appears to result in increased acute and steady-state responses, but greater β-cell “exhaustion” evidenced by a relative reduction in the CP response to arginine. Mechanisms responsible for this finding and its long-term implications are needed.

Disclosure

D.A. Ehrmann: None. S. Edelstein: None. A. Xiang: None. T.A. Buchanan: None. S.A. Arslanian: Research Support; Self; National Institutes of Health. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. S. Caprio: None. K.J. Mather: Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. K.J. Nadeau: None. 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
18-LB: Increased Acidosis and Free-Radical Production Causes Recurrent Hypoglycemia–Induced Increase in Post-ischemic ER Stress in Treated Diabetic Rats
Authors: REHNI ASHISH K. , CHO SUNJOO , DAVE KUNJAN R.
Published: June 2020

Cerebral ischemia is a serious complication of diabetes. Treatment of diabetes causes recurrent hypoglycemia (RH). Prior RH exposure increases ischemic brain damage in insulin-treated diabetic (ITD) rats. However, the mechanism of this injury is not well understood. We showed that ischemic acidosis increases reactive oxygen species (ROS) production in RH-exposed ITD (ITD + RH) rats. As enhanced acidosis and ROS production in normal subjects activate PERK, we hypothesized that increased ischemic acidosis and ROS production in RH-exposed ITD rats activate PERK. Therefore, we determined if the administration of tris-(hydroxymethyl)-aminomethane (THAM; an alkalizing agent) and N-acetylcysteine (NAC; an antioxidant) decrease RH-induced post-ischemic PERK activation in ITD + RH rats. Wistar rats were treated with insulin 2-3 weeks after streptozotocin induced diabetes. After 2 weeks, hyperinsulinemic hypoglycemia was induced for 3 hours for 5 days. Following groups were employed: (I) ITD + vehicle (Veh) (n = 6); (II) ITD + RH + Veh (n = 7); (III) ITD + RH + THAM (0.3 M, 3 ml/kg/hr, i.v.) (n = 6); and (IV) ITD + RH + NAC (150 mg/kg, i.v.) (n = 6). Transient global cerebral ischemia was induced by bilateral carotid artery occlusion with hypotension a day after RH. THAM/Veh was infused from 15 min before to 88 minutes after ischemia. NAC/Veh was administered 5 min before and 12 h after ischemia. Based on Western blot analysis, pPERK to total PERK ratio in the ITD + RH + THAM and ITD + RH + NAC groups were significantly lower by 32% and 26%, respectively, when compared with ITD + RH + Veh group. CHOP levels in the ITD + RH + THAM and ITD + RH + NAC group were lower by 38% and 63%, respectively, when compared with ITD + RH + Veh group. Therefore, ischemic acidosis and ROS production may mediate RH-induced ischemic activation of PERK. Understanding the ischemic damage in RH-exposed ITD rats may help identify new treatments for diabetes induced increase in ischemic injury.

Disclosure

A.K. Rehni: None. S. Cho: None. K.R. Dave: None.

Funding

National Institutes of Health (NS073779); American Heart Association (18POST34070061)
18-OR: Joslin Home: An Innovative Integrated Digital-Health Model of Diabetes Care in the Technology Era
Authors: HAMDY OSAMA , MITRI JOANNA , BARRETT ALANA , GABBAY ROBERT A.
Published: June 2020

Despite major advances in diabetes care and technology, the current clinic-based model is costly and at times inefficient with limited scalability. Joslin Home model (JH) includes 5 new pillars of diabetes interactions: short visits of 5-15 min conducted by telehealth, more frequent visits with a multidisciplinary team (MD, NP, RD, CDE, exercise physiologist (EP), and behavioral therapist (BT)), direct 2-way electronic scheduling, brief documentations and easy one-step billing.

In this 6-month pilot study, we tested the feasibility of JH among 17 patients with critically high A1C (average 9.5±1.6%), age 62±14 yrs, weight 225±35 lbs and 70.6% treated with insulin. Cellular glucose meter, body-weight scale and BP kit were delivered to subjects’ homes for self-reporting. Patients were instructed to self-schedule/cancel appointments using an electronic calendar. Five precise questions were asked before each encounter. Providers were asked to briefly document encounters.

Results: Virtual visits were completed in an average of 16 min, MDs and NPs concluded them in <15 min (∼11 min), but BT needed the longest time (20-30 min). Patients had an average of one encounter/week. Higher visit frequency was only seen in <25% of patients. Around 76% of scheduled encounters were completed (range 56-100%). Visit cancellation was the lowest with RD and EP (10-18%) and highest with BT and CDE (29-31%). A1C dropped significantly by 1.2% (to 8.2±1.5%, p<0.001). Patients’ satisfaction was high and they were willing to pay out-of-pocket of $50-200/encounter. We conclude that JH model is potentially acceptable alternative to clinic-based model and that is potentially scalable for remote and underserved areas where multidisciplinary approach is lacking. Frequent and short encounters of <20 min resulted in significant A1C improvement. JH may be ideal for high-risk patients who require frequent encounters with a diabetes team. Larger adoption in a randomized clinical study warrants consideration.

Disclosure

O. Hamdy: Consultant; Self; Abbott, AstraZeneca, Merck & Co., Inc., Sanofi-Aventis. Research Support; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Healthimation, LLC. J. Mitri: Consultant; Spouse/Partner; Janssen Pharmaceuticals, Inc., kymera. Consultant; Self; national dairy council/local dairy council. Research Support; Spouse/Partner; AbbVie Inc., beigene, Janssen Pharmaceuticals, Inc. Research Support; Self; Kowa Pharmaceuticals America, Inc., national dairy council. Research Support; Spouse/Partner; pharma cyclic, TG therapeutics. A. Barrett: None. R.A. Gabbay: Advisory Panel; Self; FormHealth, Health Reveal, Lark, Onduo, Vida Health.

Funding

Joslin Diabetes Center
1815-P: Dipeptidyl Peptidase-4 Inhibitor Improves Steatohepatitis by Targeting Trail Receptor-Mediated Apoptosis Under Modulation of Dipeptidyl Peptidase-4 Expression
Authors: LEE SEJEONG , LEE MINYOUNG , SHIN EUGENE , KIM YOUNG-EUN , KANG EUN SEOK , CHA BONG-SOO
Published: June 2020

Dipeptidyl peptidase-4 inhibitors (DPP-4i) are useful antidiabetic medications that prevent cleavage of incretin hormones by dipeptidyl peptidase-4 (DPP-4). As DPP-4 targets diverse substrates besides incretin, DPP-4i may exert nonglycemic pleiotropic effects. Recent studies have reported that hepatic DPP-4 expression is upregulated under nonalcoholic steatohepatitis (NASH) condition in animals and humans. We investigated whether DPP-4i could ameliorate the pathological phenotype of NASH and evaluated the underlying mechanisms in a mouse model. Mice were randomly assigned to one of three groups: Group 1, chow-fed mice with vehicle treatment for 20 weeks; group 2, high-fat, high-fructose, and high-cholesterol AMLN diet-fed mice with vehicle treatment for 20 weeks; group 3, AMLN diet-fed mice with vehicle treatment for 10 weeks followed by DPP-4i (teneligliptin 20 mg/kg/day by oral gavage) treatment for 10 weeks. Serum and liver tissues were analyzed. Administration of DPP-4i significantly reduced the body weight, liver to body weight ratio, and serum liver enzyme levels in AMLN diet-induced NASH model. DPP-4i-treated AMMN diet-fed mice revealed a marked alleviation in liver steatosis and fibrosis compared with vehicle-treated AMLN-fed mice. NASH alleviation in vivo significantly correlated with the suppression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis and decreased DPP-4 expression in the liver. In vitro assay of palmitate-treated hepatocytes, treatment with DPP-4i significantly attenuated the hallmarks of TRAIL receptor-mediated lipoapoptosis, suppressing DPP-4 expression. DPP-4i may efficiently attenuate the pathogenesis of AMLN diet-induced NASH in mice by suppressing lipotoxicity-induced apoptosis, possibly through the modulation of hepatic DPP-4 expression.

Disclosure

S. Lee: None. M. Lee: None. E. Shin: None. Y. Kim: None. E. Kang: None. B. Cha: None.

Funding

Handok Inc. (2017-31-0006)
1816-P: Hepatic Mitochondrial Alterations in a Murine Model of Combined Diabetes and Fatty Liver Disease
Authors: DEWIDAR BEDAIR , ENGLISCH CORNELIA , PESTA DOMINIK , ROHBECK ELISABETH , RESS CLAUDIA , ESPOSITO IRENE , RODEN MICHAEL
Published: June 2020

Nonalcoholic fatty liver disease (NAFLD) is tightly associated with obesity and type 2 diabetes. There is evidence that mitochondrial function is altered in both diseases. Here, we examined hepatic mitochondria during different stages of NAFLD in mice with experimental diabetes.

Two-days old male C57BL/6j mice received 200 µg streptozotocin (STAM) or vehicle (CTRL). From 4 weeks on, they were on high-fat diet for either 4 w or 8 w to induce steatosis or nonalcoholic steatohepatitis (NASH). Liver histology was performed to quantify steatosis, inflammation and fibrosis. Mitochondrial respiration was assessed in liver tissues using high-resolution respirometry with different substrate protocols. Citrate synthase activity (CSA) served as a surrogate marker for mitochondrial content. Immunoblotting was used to quantify mitochondrial complexes.

Compared to CTRL, STAM mice showed 140% and 54% higher blood glucose and liver/body weight. Hepatic steatosis increased from 2% to 15% at 4 w and decreased to 5% at 8 w. NAFLD activity score was 0.25 in CTRL and increased to 2.5 at 4 w and 8 w in STAM. STAM mice had lower CSA, indicating lower mitochondrial content at both time points, whereas complex III protein content was decreased only at 8 w. Of note, maximal uncoupled β-oxidation-associated respiration, normalized to CSA, was 1.7- and 2.7-fold higher in livers of STAM mice after 4 w and 8 w, respectively, as compared to CTRL.

In conclusion, combined diabetes and NASH decreased mitochondrial content but resulted in greater maximal oxidative capacity per mitochondrion, possibly reflecting an adaptation of mitochondrial function during NAFLD progression in adult mice.

Disclosure

B. Dewidar: None. C. Englisch: None. D. Pesta: None. E. Rohbeck: None. C. Ress: None. I. Esposito: None. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S.

Funding

German Federal Ministry of Health and Ministry of Culture and Science of the State North Rhine-Westphalia; German Federal Ministry of Education and Research by the European Regional Development Fund (KomIT, EFRE-0400191); German Research Foundation (DFG; SFB 1116/2)
182-OR: A Novel Dual-Acting Glucokinase Activator (GKA) Dorzagliatin (HMS5552) Achieved Primary Efficacy Endpoint with Good Safety Profiles in T2DM Patients after 24 Weeks of Treatment in a Phase III Monotherapy Trial
Authors: ZHU DALONG , ZHANG YI , CHEN LI
Published: June 2020

GK acts as a ’glucose sensor’ to regulate glucose homeostasis. Dorzagliatin is a novel dual-acting allosteric GKA targeting both pancreatic and liver GK. The study aimed to confirm the efficacy and safety of dorzagliatin as a monotherapy in Chinese T2D patients. It is the first successful Phase III trial for a GKA. It was a multicenter, randomized, double-blind, placebo-controlled trial. 463 drug-naïve adult subjects were randomized to 75 mg dorzagliatin or placebo (2:1) BID for 24 wks. The primary endpoint was the change in HbA1c from baseline to wk 24. Secondary endpoints included 2h PPG and other glycemic variables. Safety assessment included AE, hypoglycemia, laboratory tests, ECG, etc. The MMRM results suggested the LS mean change in HbA1c from baseline at wk 24 was -1.07% in dorzagliatin group, significantly lower than the placebo group (P<0.0001). The homeostatic control rate (HbA1c <7% without hypoglycemia), was 45.0% in dorzagliatin group compared to 21.5% in placebo group (P<0.0001). At wk 24, the mean change of 2h PPG (mM) from baseline was -3.05 and -0.78 for the dorzagliatin and placebo groups (P<0.0001). The mean change of FPG (mM) from baseline at wk 24 was -0.70 in dorzagliatin group and -0.34 in placebo group with no significant difference. The change of HbA1c from baseline at each study visit was significantly lower (P<0.001) in dorzagliatin group compared with the placebo group. Dorzagliatin was well-tolerated during the 24 wks and had a good safety profile. Fewer than 1% of patients experienced incident of hypoglycemia over 24 wks. There were no death, drug-related SAEs, and severe hypoglycemia in subjects treated with dorzagliatin. Overall, dorzagliatin had a favorable effect on glycemic control and a good safety profile over 24 wks in Chinese T2D patients. It brings the reality a step further in developing a novel T2D drug with GKA mechanism of action.

Disclosure

D. Zhu: None. Y. Zhang: None. L. Chen: None.
1826-P: Dietary Models of Nonalcoholic Fatty Liver Disease in Normal and Diabetic Nonhuman Primates
Authors: GAO JIAJUN , WANG DAVEY , JI YANQIN , ZHANG XIAOYU , YANG CHEN , ZHANG JIAPING , YE WEIWEI , SHI FENG , JIANG MENGNAN , JIN QIAN , ZHANG DUNWEI , WANG XIAOLI , SONG WEIHUA , CHNG KEEFE , JIANG HAISHAN , WANG YIXIN , XIAO YONG-FU
Published: June 2020

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome as an arising health issue globally. Obesity and diabetes seem coherent with high NAFLD occurrence. Currently, its underlying mechanism of cause and progression remains to be elicited and effective therapy is unavailable. Huge investment on studying its pathogenesis and innovative therapy is underway. As mechanistic studies are more difficult or unethical to be performed in humans, animal model that recapitulates the human disease is urgently needed. Nonhuman primates (NHPs) with NAFLD can highly mimic the human disease. This study aimed to induce NAFLD by various diets (Table 1) in normoglycemic and diabetic NHPs with biomarker and histopathology assays to quantify NAFLD occurrence. Our data show that diabetic monkeys with high-fat-high-fructose (HFHF) diet developed NAFLD which could assemble to the human disease and be highly valuable for NAFLD research. However, low choline (LC), LC+10% fructose, LC+low methionine (LCM)+10% fructose diets for 31 weeks had no significant effects on liver function, except significant decrease in body weight and food intake in LCM+10%F group and some increase in liver histological scores in LC+10%F group (Table 1).

In summary, normal diet with LC or LCM ± high fructose is hardly to induce NAFLD in normoglycemic NHPs, at least in 31 weeks. HFHF could induce or enhance NAFLD in diabetic NHPs.

Disclosure

J. Gao: Employee; Self; Crown Bioscience. D. Wang: Employee; Self; Crown Bioscience. Y. Ji: Employee; Self; Crown Bioscience. X. Zhang: Employee; Self; Crown Bioscience. C. Yang: None. J. Zhang: Employee; Self; Crown Bioscience. W. Ye: Employee; Self; Crown Bioscience. F. Shi: Employee; Self; Crown Bioscience. M. Jiang: Employee; Self; Crown Bioscience. Q. Jin: Employee; Self; Crown Bioscience. D. Zhang: None. X. Wang: None. W. Song: Employee; Self; Crown Bioscience. K. Chng: None. H. Jiang: Employee; Self; SYSE Bio-tec Co., Ltd. Y. Wang: None. Y. Xiao: Employee; Self; Crown Bioscience.
1829-P: Aggravating Liver Lipid Accumulation and Fibrosis in Nonalcoholic Steatohepatitis Model of MS-NASH Mice by a Modified Amylin Diet
Authors: ZHANG GUODONG , CHNG KEEFE , WANG YIXIN
Published: June 2020

MS-NASH mouse is a leptin pathway intact model of spontaneous metabolic diseases. Our previous work developed a nonalcoholic steatohepatitis (NASH) model in MS-NASH mice fed with western diet and fructose drinking water (WDF). This study showed aggravated liver cholesterol content and fibrosis score by using a modified Amylin diet (GAN). Liver Cholesterol was increased from 10.11±1.58 mg/g to 14.07±0.81 mg/g and fibrosis score increased from 1.5±0.3 to 2.1±0.2 when comparing GAN with WDF and with C57Bl/6 mice. Administration of 30 mg/kg Obeticholic Acid (OCA, QD, PO) or 30 mg/kg Elafibranor (GFT-505, QD, PO) for 8 weeks significantly reduced serum liver enzymes, liver lipids and fibrosis scores.

Conclusion: The GAN diet fed MS-NASH mice can be a better NASH model for novel compound efficacy.

Disclosure

G. Zhang: None. K. Chng: None. Y. Wang: None.
183-OR: Allogenic Adipose-Derived Mesenchymal Stem Cells (ASCs) and Vitamin D Supplementation in Patients with Recent-Onset Type 1 Diabetes Mellitus: A 6-Month Follow-Up Pilot Study
Authors: DANTAS JOANA R. , ARAUJO DEBORA B. , BAPTISTA LEANDRA S. , SOUTO DEBORA L. , PEREIRA KARINA , PEREIRA MARIA F. , CLAUDIO-DA-SILVA CESAR S. , MANTUANO MATHEUS S. , DAGA DEBORA R. , SENEGAGLIA ALEXANDRA C. , REBELATTO CARMEN K. , COURI CARLOS EDUARDO B. , OLIVEIRA JOSE E. , ZAJDENVERG LENITA , RODACKI MELANIE
Published: June 2020

Objective: To evaluate safety and efficacy of ASCs infusion from healthy donors and daily cholecalciferol (VitD) supplementation in patients with recent-onset T1D, after a 6-month follow-up.

Methods: This is a phase II, prospective, one center, open trial, in which patients with recent onset T1D received one infusion of ASCs (1x106 cells/kg) and VitD 2000UI/day for 6 months. They were compared to controls with standard insulin therapy. C-peptide (CP) after mixed meal, insulin dose(UI/kg), HbA1c and CD45+CD3+CD4+FoxP3+T-cells frequencies (flow cytometry) were measured at baseline (T0) and after 3 (T3) and 6 months (T6).

Results: Eleven patients were included. Mean age and disease duration were 24.2 ± 5.2 years and 3.11 ± 0.88 months, respectively. Group 1 (n=7) received ASCs+VitD and group 2 (n=4) standard insulin therapy. Age, insulin dose, HbA1c and area under the curve (AUC) of CP were similar at T0 between groups (p=0.23, 0.23, 0.98 and 0.73, respectively). After intervention, group 1 had lower insulin requirement than group 2 at T3 (0.24±0.18 vs. 0.53±0.23IU/Kg, p=0.04) and T6 (0.24±0.15 vs. 0.66±0.33 UI/kg, p=0.04). Two patients in group 1 became transiently insulin free. HbA1C was lower in group 1 at T6 (6.77±0.79 vs. 8.75±0.95%; p=0.01). CP AUC was higher in group 1 at T3 (211.20 ± 100.42 vs. 106.05±47.25 ng/ml.min;p=0.04) and T6 (220.58 ± 97.06 vs. 63.37±37.96ng/ml.min, p=0.006). At T6, 6 patients in group 1 (85.7%) were in honeymoon phase (insulin dose ≤ 0.5IU/kg and HbA1c <7.5%) vs. none in group 2 (p=0.01). At T6 there was an inverse correlation between serum VitD and HbA1C (p=0.03; r=-0.66) and a positive correlation between VitD and CP AUC (p=0.02, r=0.67). CD45+CD3+CD4+FoxP3+ T-cells increased at T1 in group 1 (p=0.04), without differences at T3 and T6.

Conclusion: Allogenic ASCs infusion + VitD without immunosuppression was safe and may be an effective approach for the treatment of patients with recent onset T1D.

Disclosure

J.R. Dantas: None. D.B. Araujo: None. L.S. Baptista: None. D.L. Souto: None. K. Pereira: None. M.F. Pereira: None. C.S. Claudio-da-Silva: None. M.S. Mantuano: None. D.R. Daga: None. A.C. Senegaglia: None. C.K. Rebelatto: None. C.B. Couri: None. J.E. Oliveira: None. L. Zajdenverg: None. M. Rodacki: None.

Funding

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior; Fundação de Amparo a Pesquisa do Rio de Janeiro
1842-P: Modeling Nonalcoholic Steatohepatitis in Aged C57BL/6J Mice
Authors: SERRANO JASON , FRENCH RICHARD D. , LEIGHTON KRYSTAL , SANMIGUEL ADAM , ELLIS MICHAEL , IMAI DENISE , SCHILE ANDY
Published: June 2020

Nonalcoholic steatohepatitis (NASH) is usually diagnosed in 40-60 year old patients with metabolic syndrome, but many common mouse models involve dietary or chemical interventions that begin at young ages. We established 3 NASH models using year-old C57BL/6J (B6J) males with approximate human age equivalence of 40 years. In one model, aged mice ate Gubra Amylin NASH (GAN) diet (40 kcal% fat with 18 kcal% palm oil; 20% fructose; 2% cholesterol; N=12) or chow diet (6% fat by weight; N=10) for 5 months. Aged mice fed GAN had rapid signs of liver damage: by 1 month, serum alanine aminotransferase (ALT) rose from 53 ± 20 to 309 ± 188 IU/L (Repeated measures ANOVA; P < 0.0001) and aspartate aminotransferase (AST) increased from 77 ± 33 to 399 ± 420 IU/L (P < 0.0001); values were stable in aged B6J fed chow. In contrast, liver damage progressed more slowly when B6J were started on GAN as young adults (6 weeks old; N=11); ALT increased from 27 ± 5 to 231 ± 96 IU/L and AST from 53 ± 18 to 177 ± 88 IU/L after 5 months. After 1 month, GAN-fed aged B6J serum cholesterol rose from 166 ± 24 to 290 ± 65 mg/dL (P < 0.0001) but not in aged B6J fed chow or young B6J fed GAN. Triglycerides and glucose did not change after 5 months in any group, while ALT, AST and cholesterol remained high in aged GAN mice throughout. Histopathology of aged B6J fed GAN for 5 months showed severe submassive to diffuse steatosis; perivascular, bridging, and perisinusoidal fibrosis; necrosis and hepatocyte degeneration. A second model was created by treating year-old B6J mice with 3 daily doses of 50 mg/kg streptozotocin (STZ) and 60 kcal% high fat diet (STZ-HFD). Serum glucose, ALT, AST and cholesterol rose in STZ-HFD mice. Steatosis and fibrosis were less severe in STZ-HFD mice compared to aged mice fed GAN. In a third model, young and aged B6J responded similarly to a choline-deficient, reduced-methionine diet with elevated ALT and AST; reduced glucose, cholesterol and body weight; and comparable histopathology scores. The results show the value of studying mice at a life stage that more closely resembles age of clinical diagnosis.

Disclosure

J. Serrano: None. R.D. French: None. K. Leighton: None. A. SanMiguel: None. M. Ellis: None. D. Imai: None. A. Schile: None.
1846-P: Low-Dose Dihydrotestosterone Increased Lipogenic Proteins Resulting in Increased NAFLD via Regulation of SREBP1c in Liver Tissue of Normal Weight Female Mice
Authors: ANDRISSE STANLEY
Published: June 2020

Hyperandrogenemia (HA) and insulin resistance are hallmarks of polycystic ovary syndrome (PCOS). These hallmarks are also integral elements of nonalcoholic liver disease (NALFD). Administering low dose dihydrotestosterone (DHT) induced a lean female mouse model with a PCOS-like phenotype. The molecular mechanism of HA-induced NAFLD has not been determined. We hypothesized that low dose DHT would interrupt hepatic lipid metabolism leading to NAFLD. We extracted white adipose tissue (WAT), liver, and skeletal muscle from control and low dose DHT female mice; and performed Western blot and real-time quantitative PCR (qRT-PCR) analysis of lipogenic intermediates. Low-dose DHT lowered the active form of cytosolic SREBP1 in the liver and WAT compared to controls. Additionally, low dose DHT increased inactive SREBP1 in the liver. However, DHT did not alter the levels of the active and inactive forms of SREBP2 in the liver and WAT. DHT increased SCAP protein expression and SCAP-SREBP1 binding, which helps activate SREBP. Regarding lipogenic enzymes, FAS mRNA and protein expression was increased in liver of DHT mice. p-ACC levels were unaltered in liver but decreased in WAT. Other lipid metabolism pathways were examined in liver and WAT but no changes were observed. Taken together, our findings support the hypothesis that cytosolic SREBP1 decreased due to its translocation to the nucleus, where it upregulated lipogenic mRNA expression. We showed that low-dose DHT increased SCAP-SREBP-1 association promoting the activation and translocation of SREBP1 from the cytosol to the nucleus to influence lipogenic gene expression leading to increased lipogenesis contributing to NAFLD.

Disclosure

S. Andrisse: None.

Funding

Robert Wood Johnson Foundation (74250); Eunice Kennedy Shriver National Institute of Child Health and Human Development (K23HD095075)
1849-P: Fructose Induces Hepatic Steatosis via ME1-Mediated Cytosolic Redox Status
Authors: JIANG HAOWEN , LI JIA
Published: June 2020

Increased consumption of fructose-rich beverages has emerged as an important risk factor for development of hepatic steatosis, type 2 diabetes and metabolic syndrome. As is well-known, fructose robustly stimulates de novo lipogenesis in vivo; but how this occurs is less clarified and may involve multiple mechanisms. To determine the mechanism of fructose-induced hepatic steatosis and associated metabolic disease, we fed mice with chow diet and 30% fructose in drinking water. Fasting blood glucose level was elevated and insulin sensitivity was impaired in fructose fed group. Also, mice fed with fructose showed exaggerative lipid accumulation in the liver. To find out how fructose induced hepatic steatosis, we performed liver proteomic analysis following fructose fed. Compared with chow fed, Fructose fed significantly increased malic enzyme 1 (ME1), which is NADP-dependent and responsible for NADPH generation. Consistently, the ratio of NADPH/NADP+ in liver was increased by fructose fed, suggesting that fructose increased hepatic redox status. NADPH performed as a hydrogen donor for the synthesis of fatty acids, nucleic acids, etc. We also found that the multiple metabolites depending on NADPH production was dramatically enriched in our metabolome analysis. Then, we use selective ME1 inhibitor to decrease NAPDH production and redox status. The accumulation of triglyceride (TG) in primary hepatocytes by fructose was dose-dependently reduced by ME1 inhibitor. Similarly, the increasing of intracellular TG accumulation and NADPH/NADP+ ratio by fructose was inhibited upon ME1 knockdown by the application of siRNA. Taken together, our preliminary results suggested that ME1 mediated cytosolic redox status might play an important role in fructose induced hepatic steatosis and associated metabolic disease.

Disclosure

H. Jiang: None. J. Li: None.
185-LB: Does Having Coexisting Diabetes Mellitus Improve Outcomes of Hospitalizations for Rheumatoid Arthritis?
Authors: EDIGIN EHIZOGIE , YAP SARA ELIZABETH T. , SHAKA HAFEEZ , XU JING , PADILLA SORTO MARIA ELENA
Published: June 2020

Background: Diabetes mellitus (DM) is a common metabolic disorder, which has negative outcomes on various medical conditions.

Objectives: This study aims to determine if DM has an impact on the outcomes of patients primarily admitted for rheumatoid arthritis (RA). The primary outcome is inpatient mortality, and secondary outcomes are hospital length of stay (LOS) and total hospital charge.

Methods: Data were extracted from the Nationwide Inpatient Sample (NIS) Database for 2016 and 2017. This database contains the largest collection of inpatient hospitalization data in the USA. NIS was searched for hospitalizations for RA as the principal diagnosis, with and without DM as a secondary diagnosis, using ICD-10 codes. Hospitalizations for adults from the above groups were included. Multivariate logistic and linear regression analysis was used to adjust for possible confounders for the primary and secondary outcomes respectively.

Results: Over 71 million hospitalizations were included in the combined 2016 and 2017 NIS database. There were 18,905 hospitalizations for those 18 years or older, who had RA as the principal diagnosis. Of these, 14,822 (78.4%) had no secondary diagnosis of DM and 4,083 (21.6%) had co-existing DM. RA hospitalizations had 175 inpatient deaths (0.93%), of which, 25 occurred in hospitalizations with DM (0.61%). The adjusted odds ratio (AOR) of inpatient mortality for RA with DM compared to without DM was 0.342 (95% CI: 0.137 - 0.85, P=0.021). In hospitalizations for RA with DM, there was a decreased mean adjusted LOS of 0.76 days (95% CI -1.26 - {-0.26}, P=0.003) compared to without DM. The adjusted mean total hospital charge for hospitalizations for RA with DM was lower by $6243 compared to without DM (95% CI -12250 - {-236}, P=0.042).

Conclusions: Hospitalizations for RA with co-existing DM had less inpatient mortality, LOS and total hospital charge compared to without DM. More studies are needed to determine if indeed DM is protective in hospitalizations for RA.

Disclosure

E. Edigin: None. S.T. Yap: None. H. Shaka: None. J. Xu: None. M. Padilla Sorto: None.
1853-P: Neutrophils Play a Pivotal Role in Obesogenic Diet-Induced Nonalcoholic Steatohepatitis
Authors: ZHOU QIONG L. , KHAN SHOAIB , RIGOR MICHAEL , BEERAM INDEEVAR , JIANG ZHEN Y.
Published: June 2020

Lipid deposition, inflammatory damage, and fibrotic remodel are the hallmarks of nonalcoholic steatohepatitis (NASH). However, the molecular and cellular mechanisms by which obesogenic diet-induced progression from steatosis to NASH remains elusive. Here, we report that neutrophils play a significant role in mediating NASH in the liver. Remarkably, high-fat high-fructose diet (HFHFD) feeding increased expression of chemokines in the liver leading to a dramatic upsurge of neutrophil infiltration into the liver with a concomitant increase of macrophages and Th17 cell accumulation and collagen deposition in the liver. In contrast, inhibition or deletion of neutrophil elastase (NE) significantly reduced lipid deposition, metabolic stress, and inflammation in the liver in mice fed obesogenic diets. Inhibition of NE dramatically reduced the expression of chemokines, accumulation of neutrophils, macrophages, and Th17 cells, and progress of fibrosis in the liver. Together, our data suggest that NE contributes to NASH progression through regulating metabolic signaling and inflammatory damage in the liver.

Disclosure

Q.L. Zhou: None. S. Khan: None. M. Rigor: None. I. Beeram: None. Z.Y. Jiang: None.

Funding

National Institutes of Health (1R56DK121142)
1865-P: SGLT2 Inhibition Compared with Iso-energetic/Low-Carbohydrate Diet Reprograms Systemic Substrate Oxidation in Type 2 Diabetes
Authors: IGARASHI HIROYUKI , UCHINO HIROSHI , FURUTA MASASHI , MIYAGI MASAHIKO , KUMASHIRO NAOKI , HIROSE TAKAHISA
Published: June 2020

Introduction: Pharmacologic inhibition of the renal sodium/glucose cotransporter-2 (SGLT2i) facilitates lipid oxidation. Iso-energetic/low-carbohydrate diet (i-Carbo) eliminates the same amount of glucose as SGLT2 inhibition (∼ 50 g/day of glucose). We examined whether i-Carbo and SGLT2i may have any impact, on 1) fasting and postprandial energy expenditure (EE) and substrate oxidation, 2) the basal-bolus dose of insulin that achieve euglycemia.

Method: Twenty four T2D (M/F = 15/9, age 53.6 ± 14.2, BMI 26.9 ± 4.8 kg/m2, HbA1c 12.5 ± 1.6 %) were enrolled to this 12 weeks, randomized, 3 arms open-label, prospective study with basal-bolus insulin titration algorithm, control diet (CON) or adding canagliflozin 100 mg/day to CON (SGLT2i) and the i-Carbo. We measured indirect calorimetry to provide EE and respiratory quotient (RQ) during fasting and postprandial before and after the intervention.

Results: In spite of similar carbohydrate amount in the i-Carbo, compared to the SGLT2i, the total daily dose of insulin was significantly higher (p=0.02). Compared to the CON, fasting EE were similar on both SGLT2i and i-Carbo, however, postprandial EE were elevated, respectively (p=0.03, 0.04). Fasting RQ was marginally higher in SGLT2i compared to the CON (p=0.049). Postprandial RQ was elevated by means of increased carbohydrate substrate utilization on both SGLT2i (p=0.04) and i-Carbo (p=0.03) groups compared to the CON.

Conclusion: Iso-energetic/low-carbohydrate in i-Carbo, which matches urinary carbohydrate loss in SGLT2i, had similar fasting and postprandial energy expenditure and substrate oxidation rate. Increased insulin requirement in i-Carbo indicates that relative high lipid and protein ratio, compared to SGLT2i, may have any effect to insulin requirement.

Disclosure

H. Igarashi: None. H. Uchino: None. M. Furuta: None. M. Miyagi: None. N. Kumashiro: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker’s Bureau; Self; Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. T. Hirose: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; AstraZeneca, Lilly Diabetes, Novo Nordisk Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd.
1872-P: Metabolomic Profiling during Diabetic Ketoacidosis (DKA) Demonstrates Unique Defects Underlying the Pathophysiology of Ketosis-Prone Diabetes
Authors: HSU JEAN W. , MEHTA PARAS , KEENE KELLY R. , MULUKUTLA SURYA N. , CADUCOY EUNICE I. , PEACOCK WILLIAM , BALASUBRAMANYAM ASHOK , JAHOOR FAROOK
Published: June 2020

Obese patients with ketosis-prone type 2 diabetes (“A-β+ KPD”) have increased catabolism of the ketogenic amino acids leucine/isoleucine (Leu/Ile) and impaired ketone oxidation when stable and normoglycemic (Patel et al, Diabetes 2013). We performed comparative serum metabolomics on patients at presentation with hyperglycemic crisis without (N = 29) or with (N = 73) DKA compared to healthy controls (N = 17). The diabetic groups included normal weight and overweight/obese subgroups. DKA patients had higher plasma cortisol and catecholamines and lower C-peptide than the other groups. Three metabolite patterns distinguished the DKA patients from the other groups: 1) Elevated levels of Leu/Ile and of their respective ketoacids, no difference in isovaleryl carnitine (C5) but markedly lower ratio of C5 to C2 (acetyl carnitine) - implying accelerated shunting of Leu/Ile into their catabolic pathways but impaired oxidation because defective TCA cycle activity restrains acetyl CoA entry and metabolism. These changes were most pronounced in obese DKA patients, recapitulating the pattern of A-β+ KPD patients when stable; 2) Markedly decreased levels of glutamate, ammonia and many non-essential amino acids including citrulline, in the presence of increased glutamine, suggesting a defect in glutaminase activity; 3) Low levels of 3-methyl histidine, suggesting a surprising decrease in muscle protein breakdown. The pattern of amino acids and their metabolites among the DKA (especially obese) patients indicate that both increased ketone production from Leu/Ile and their blunted oxidation contribute to the proclivity to develop DKA; elevated leucine and low citrulline could contribute to beta cell dysfunction via mTOR hyperactivity and diminished intracellular arginine availability. Thus serum metabolomic profiling during an acute DKA episode helps define a unique pathophysiology underlying the phenotype of obese ketosis-prone T2D.

Disclosure

J.W. Hsu: None. P. Mehta: None. K.R. Keene: None. S.N. Mulukutla: None. E.I. Caducoy: None. W. Peacock: None. A. Balasubramanyam: None. F. Jahoor: None.

Funding

National Institutes of Health (R01DK101411)
1882-P: The Comparative Effects of Atorvastatin, a Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor (PCSK9i), and Estrogen on Oxidative Muscle Mitochondria in a Rat Model of Obesity with Menopause
Authors: THONUSIN CHANISA , ARUNSAK BUSARIN , AMPUT PATCHAREEYA , PALEE SIRIPONG , PRATCHAYASAKUL WASANA , CHATTIPAKORN NIPON , CHATTIPAKORN SIRIPORN C.
Published: June 2020

The aim of this study was to compare the effects of atorvastatin, a PCSK9i, and estrogen on oxidative muscle mitochondria in a rat model of obesity and menopause. Female Wistar rats consumed either a normal diet (ND: n = 12) or a high-fat diet (HFD: n = 60). At week 13, ND-fed rats received a sham-operation, while HFD-fed rats were undergone either a sham-operation (n = 12) or an ovariectomy (n = 48). At week 19, all sham-operated rats were treated with vehicle, while ovariectomized HFD-fed rats were separated into 4 groups (n = 12/group) to receive either vehicle, 40 mg/kg/day of atorvastatin, 4 mg/kg/day of PCSK9i (SBC-115076), or 50 µg/kg/day of estrogen for 3 weeks. Metabolic panel and soleus muscle were investigated at the end of week 21. Sham-operated and ovariectomized HFD-fed rats developed obesity, insulin resistance, and hyperlipidemia. Increased MDA level, OXPHOS proteins, ratio of p-Drp1/total Drp1 protein, mitochondrial ROS, and mitochondrial membrane depolarization in soleus muscle were observed in both groups of HFD-fed rats. Both drugs and estrogen equally decreased insulin resistance, MDA level, OXPHOS proteins, and ratio of p-Drp1/total Drp1 protein. However, only atorvastatin and PCSK9i attenuated hypertriglyceridemia. Estrogen showed greater efficacy in weight loss than both drugs. In addition, estrogen decreased mitochondrial ROS and mitochondrial membrane depolarization in soleus muscle of ovariectomized HFD-fed rats. Interestingly, only atorvastatin increased cytochrome C protein and ratio of active caspase 3,8/caspase 3,8 proteins in soleus muscle. Our findings suggested that atorvastatin and PCSK9i are superior to estrogen in the reduction of hypertriglyceridemia. However, estrogen is more effective than both drugs in weight loss and exhibits the least harmful impact on oxidative muscle. PCSK9i displays less skeletal muscle toxicity than atorvastatin.

Disclosure

C. Thonusin: None. B. Arunsak: None. P. Amput: None. S. Palee: None. W. Pratchayasakul: None. N. Chattipakorn: None. S.C. Chattipakorn: None.