bluuebunny/crossref_metadata_2025 huggingface dataset:
1588-P: Galectin-3 Inhibitor Protect ApoE Knockout Mice against Metabolic Dysfunction–Associated Steatohepatitis
Authors: ARAUJO LAYANNE , SUCUPIRA FELIPE , AMARAL ANDRESSA , PAULO CAMPOREZ JOAO
Published: June 2024

Metabolic-dysfunction associated steatohepatitis is characterized by steatosis, inflammatory infiltrate and hepatocellular ballooning, and it can present fibrosis. The aim of work was to evaluate the effect of modified citrus pectin (MCP), inhibitor of galectin-3, in ApoE KO mice fed a western diet (WD). ApoE KO mice were divided into 3 groups: standard diet-fed (SD) group, WD-fed group, and WD-fed + MCP-treated group (WD+MCP). MCP treatment inhibited the increase of glucose tolerance, glycemia, plasma insulin and HOMA-IR, when compared to WD group. MCP treatment was able to inhibit the increase of TAG in the tissue by 9%, plasma TAG and VLDL, however had no significant difference for cholesterol and fatty acids in relation to WD group. We analyzed the expression of genes involved in the lipogenesis pathway in the liver (SREBP1, ACC, SCD1 and FASn). Only ACC gene expression was increased by 10x and SREBP1 protein expression by 183% in the WD group compared to the SD group. And the MCP treatment inhibited the increase of both. We also analyzed the collagen deposition and expression of genes involved in the collagen production (TGF-Beta, Col1alpha, MMP2), and MCP treatment inhibited the increase in collagen deposition by 8.2% and only MMP2 gene expression. The inflammatory profile of the liver was also shown, MCP treatment inhibited the increase of expression of F4/80, gene expression of cytokines (TNFa, IL-1b) and pJNK protein activity. We concluded that galectin-3 inhibition by the treatment with MCP protects ApoE KO mice against the development of MASH and insulin resistance

Disclosure

L. Araujo: None. F. Sucupira: None. A. Amaral: None. J. Camporez: None.

Funding

Spo Paulo State Research Support Foundation (2020/09094-1 and 2018/04956-5)
1597-P: High Fat and Fructose Diet Dysregulates Postprandial Gut and Hepatic Metabolism in a Canine Model
Authors: KRAFT GUILLAUME , SCOTT MELANIE , FARMER BEN , YANKEY KALISHA , EDGERTON DALE S. , RAJAGOPALAN HARITH , COZZI EMILY , GIBSON-CORLEY KATHERINE , FLYNN CHARLES R. , CHERRINGTON ALAN D.
Published: June 2024

Diets high in fat and sugar are associated with the development of metabolic disease, but pathogenic changes in the gut and downstream metabolic organs are not well understood. In the dog, we sought to assess 9 weeks of chow (n=5) versus high-fat, high-fructose diet (HFFD) (n=5) on the gut response and the impact on liver, pancreas fat, and muscle following a mixed meal (26g protein, 67g carbohydrates, 22g lipids). To measure the 6-hour postprandial rate of nutrient absorption and secretion of pancreatic and gut hormones, dogs underwent surgical placement of catheters in the portal vein, hepatic vein, and femoral artery, and flow probes around the portal vein and hepatic artery. Duodenal morphology and L and K cell distribution were evaluated. The meal-induced glucose absorption occurred rapidly with HFFD (peak 13.5±1.1 mg/kg/min at 90 min post-meal v 10.9±1.3 mg/kg/min at 120 min), resulting in a greater rise in glucose (231±25 v. 162±7 mg/dL, p=0.03) compared to chow. Insulin secretion rates for HFFD and chow groups were similar at the 90 min peak (1.6±0.3 v. 1.9±0.6 µU/kg/min) and 6h AUC (237±46 v 243±67 mU/kg). Meal-induced GIP secretion was markedly increased (542±70 v 295±74 pg/kg/min, p=0.05) while GLP-1 was reduced (100±40 v 219±64 pg/kg/min, p=0.16) in HFFD compared to chow. These changes were associated with increased duodenal total mucosal height (1817±133 v 1500±159 µm, p=0.04) but no change in L or K cell distribution. HFFD-induced liver response was markedly altered with a failure to switch from net hepatic glucose output pre-meal to glucose uptake and storage post-meal (output of 1.7±0.2 to output of 3.0±1.4 mg/kg/min) compared to chow (output of 1.6±0.3 to uptake of 3.4±1.1). Given the lack of hepatic uptake, meal glucose was likely taken up by muscle.

In conclusion, HFFD-induced changes in duodenal morphology, gut function, and gut hormone secretion that were associated with abnormal hepatic and pancreatic responses, suggesting a role for the gut in metabolic pathogenesis.

Disclosure

G. Kraft: None. M. Scott: None. B. Farmer: None. K. Yankey: None. D.S. Edgerton: None. H. Rajagopalan: Board Member; Fractyl Health, Inc. Employee; Fractyl Health, Inc. Stock/Shareholder; Fractyl Health, Inc. E. Cozzi: Employee; Fractyl Health, Inc. Stock/Shareholder; Fractyl Health, Inc. K. Gibson-Corley: None. C.R. Flynn: None. A.D. Cherrington: Consultant; Abvance Therapeutics. Research Support; Abvance Therapeutics. Advisory Panel; AdipoPharma. Research Support; Cellular Longevity, Inc. dba Loyal. Advisory Panel; Fractyl Health, Inc. Consultant; Fractyl Health, Inc. Research Support; Fractyl Health, Inc. Consultant; Novo Nordisk. Research Support; Novo Nordisk. Consultant; Paratus, Portal Insulin. Advisory Panel; Sekkei Bio, Sensulin Labs, LLC. Consultant; Thetis Pharmaceuticals, LLC.

Funding

Fractyl Health
1602-P: Exercise Training Reverses Skeletal Muscle DRP1 Hyperactivation and Improves Respiratory Capacity in Patients with Type 2 Diabetes
Authors: HEINTZ ELIZABETH C. , DANTAS WAGNER S. , ZUNICA ELIZABETH R.M. , BELMONT KATHRYN , MEY JACOB T. , BEYL ROBBIE A. , HSIA DANIEL S. , PARRY HAILEY A. , GLANCY BRIAN , HOPPEL CHARLES L. , AXELROD CHRISTOPHER L. , KIRWAN JOHN P.
Published: June 2024

Introduction: Chronic activation of DRP1 promotes mitochondrial network fragmentation and restricts skeletal muscle glucose uptake in patients with type 2 diabetes (T2D). The purpose of this study was to determine if exercise reverses hyperactivation of skeletal muscle mitochondrial fission in patients with T2D.

Methods: 24 sedentary adults (49 ± 10 years) with obesity (BMI 36 ± 6 kg/m2) and T2D (HbA1C 7.3 ± 1.3%; 1.3 ± 1.2 glucose lowering medications) were randomized to 12 wks of exercise training (Ex; n=11) or standard care (Ctrl; n=13). Participants randomized to Ex performed supervised aerobic exercise 5 d/wk for 60 min/session at 80-85% HRMAX. Participants underwent a 3-day inpatient stay consisting of DXA, VO2peak, and 2-stage hyperinsulinemic-euglycemic clamp at baseline and post intervention. Skeletal muscle biopsies were obtained for Western blot, high-resolution respirometry, and ion beam scanning electron microscopy with machine learning segmentation. Relative changes from baseline were calculated, and comparisons were made with unpaired Student’s t-tests. The primary outcome was change in pDRP1Ser616 expression.

Results: Age, sex, body weight, and diabetes status were similar at baseline (p>0.05). Ex increased VO2peak, lean mass, and peripheral insulin sensitivity and reduced fat mass relative to Ctrl (all p<0.05). Skeletal muscle pDRP1Ser616 was reduced in Ex (p<0.05) independent of PGC-1α and AMPK. Ex increased maximal NADH-linked OXPHOS (p<0.05) and improved succinate- and complex III-linked OXPHOS (p<0.1). Mitochondria were elongated and had reduced sphericity after Ex (p<0.001).

Conclusions: Exercise training reversed hyperactivation of skeletal muscle mitochondrial fission and improved respiratory capacity independent of biogenesis. Collectively, these data indicate that exercise improves skeletal muscle insulin sensitivity in T2D, in part, by restoring mitochondrial dynamics and networking.

Disclosure

E.C. Heintz: None. W.S. Dantas: None. E.R.M. Zunica: None. K. Belmont: None. J.T. Mey: None. R.A. Beyl: None. D.S. Hsia: None. H.A. Parry: None. B. Glancy: None. C.L. Hoppel: Advisory Panel; Cytokinetics Inc. C.L. Axelrod: None. J.P. Kirwan: None.

Funding

National Institutes of Health (DK108089 and GM104940)
1603-P: The Cardiovascular Impact of Appropriately-Timed Prandial Insulin in Type 1 Diabetes—A Randomized Crossover Study
Authors: HORTON WILLIAM B. , LOVE KAITLIN , JAHN LINDA , HARTLINE LEE , AYLOR KEVIN W. , BARRETT EUGENE
Published: June 2024

Introduction & Objective: Appropriately-timed (i.e., ~15 minutes before meal intake) prandial insulin administration improves postprandial glycemic control, but the cardiovascular impact of this intervention is unknown. In this study, we tested whether appropriate prandial insulin timing improves insulin’s microvascular action in people with type 1 diabetes (T1D).

Methods: The primary outcome was change in myocardial microvascular perfusion (via contrast-enhanced ultrasound) and secondary outcome was change in skeletal muscle microvascular perfusion. Following overnight fast, participants underwent baseline measures of microvascular perfusion and then consumed a standardized liquid mixed meal (10 kcal/kg body weight). Vascular measurements were then repeated 120 minutes later. 18 participants with T1D completed two admissions with a randomized crossover design: (A) prandial insulin injected 15 minutes before meal intake and (B) prandial insulin injected 15 minutes after meal intake began. Plasma insulin and glucose were measured every 30 minutes. Repeated measures ANOVA compared changes in insulin and glucose while paired and unpaired t-tests compared changes in microvascular outcomes.

Results: Myocardial microvascular blood flow was similar at baseline between the two admissions. Change in plasma glucose was greater (p<0.01) and plasma insulin was higher (54.43 vs 41.42 µIU/mL; p<0.01) at the 120-minute mark in Admission B compared to Admission A. Myocardial microvascular blood flow increased (p=0.03) in Admission A while it modestly decreased (p=0.08) in Admission B. There were no changes in skeletal muscle microvascular perfusion during either admission.

Conclusion: Appropriately-timed prandial insulin administration improved glycemic control and myocardial microvascular perfusion two hours after meal intake. Future work could investigate whether such improvements, occurring repetitively, can improve cardiovascular health.

Disclosure

W.B. Horton: None. K. Love: None. L. Jahn: None. L. Hartline: None. K.W. Aylor: None. E. Barrett: None.

Funding

American Heart Association (941481); Juvenile Diabetes Research Foundation (3-SRA-2023-1236-M-B)
1612-P: AGE Breaker Ameliorates Diet-Induced Hyperglycemia and Muscle Atrophy through Modulating Metabolic Memory in Muscle
Authors: TING HSIAO WEI , LEE CHIEN-WEI , LEE YUK-WAI
Published: June 2024

Metabolic memory reflects lasting effects of pre-exposed stimulations which can be manifested in transcription, translation, etc. It is also associated with diabetes progression and complications but lacks effective prevention strategies. To determine the impact of metabolic memory on the early disease stage, skeletal muscle with insulin resistance happened at early stage was chosen as study model. Given that advanced glycation endproduct (AGE) signaling and AGE-induced ECM changes have been reported to play crucial role in diabetes development, this study aimed to determine whether oral ALT711 AGE breaker administration could enhance the recovery of high-fat diet (HFD) induced hyperglycemia, and muscle structural and functional perturbations through modulating metabolic memory in male mice. We used 12-week-old male C57BL/6J mice with chow or repeated HFD feeding and ALT711 (20mg/kg/day) administration. GA muscle bulk RNA sequencing (n=3) identified DEGs with metabolic memory profiles. Mice (n=6) were sacrificed at specified time points, and extensor digitorum longus (EDL) and gastrocnemius (GA) muscles were collected for functional and structural assessment. Statistical analysis was conducted using two-way ANOVA. The GA muscle bulk RNA sequencing results revealed HFD-induced DEGs with a metabolic memory profile, which was associated with ECM remodeling and AGE signaling, and was validated by histology and QPCR. HFD-induced changes in muscle contraction, relaxation properties, and stiffness also displayed metabolic memory profiles. The administration of ALT711 significantly prevented the onset of HFD-induced weight gain and hyperglycemia and demonstrated a reduced extent of metabolic memory phenotypes. Our findings indicate the potential of the AGE breaker for diabetes and weight management, improving muscle quality by reducing metabolic memory. This offers a new avenue for mitigating hyperglycemia onset and progression.

Disclosure

W. Hsiao: None. C. Lee: None. Y. Lee: None.

Funding

Area of Excellence (AoE/M-402/20); General Research Fund (14104620); Start-up grant from Chinese University of Hong Kong (4930991 and 4930992); National Science and Technology Council, Taiwan (111–2320-B-039–070-MY3); Center for Neuromusculoskeletal Restorative Medicine (CT1.1)
162-OR: Sustained TNF-a Transcription Triggered in Obesity through H3K9/K18 Acetylation Is Associated with Metabolic Impairments
Authors: AHMAD RASHEED , BAHMAN FATEMAH , KOCHUMON SHIHAB P. , JACOB TEXY K. , ALRASHED FATEMA , WILSON AJIT , AREFANIAN HOSSEIN , THOMAS REEBY S. , AKHTER NADEEM , AL-MANSOUR NOURAH , ALBELOUSHI SHAIMA , AL MADHOUN ASHRAF , SINDHU SARDAR T.A.K. , ALZAID FAWAZ , ALMULLA FAHD
Published: June 2024

Obesity-induced metabolic inflammation contributes to the development of various metabolic disorders and can be induced by the consumption of high-fat diets (HFD) rich in saturated fatty acids. The role of the TNF-α in metabolic dysfunction is now clear, although the pathways that promote and sustain the transcriptional regulatory process of the TNF-α gene under the setting of obesity remain incompletely understood. To identify the obesity-mediated transcriptional regulatory program of TNF-α, we used a murine model of diet-induced obesity (DIO). Male C57BL6/J mice were fed a palmitate oil-based HFD or a control diet (CD) for 16 weeks. Compared to CD, mice with DIO displayed elevated levels of TNF-α along with increased acetylation levels of epigenetic marks histone H3 lysine 9 and 18 acetylation (H3K9/K18) in adipose tissue and liver. Determination of permissive histone acetylation marks in the promoter region of TNF-α in both adipose tissue and liver was achieved through the Chromatin Immunoprecipitation (ChIP) assay. ChIP-qPCR analysis data show that obesity led to increased levels of the transcriptionally permissive acetylation marks H3K9/K18 in the TNF-α promoter in adipose tissue and liver compared to lean mice. Increased TNF-α expression in obese adipose tissue and fatty liver at the chromatin level corresponds to the changes in the level of histone acetylation marks H3K9/K18. Moreover, TNF-α and histone acetylation marks are positively associated with body weight gain, insulin resistance, and liver steatosis.

In conclusion, our findings support a model in which DIO creates a setting for sustained transcriptional regulation of the TNF-α gene via chromatin remodeling, enabling TNF-α to contribute to metabolic dysfunction. We also propose that acetylation of H3K9/H3K18 may be considered valuable prognostic factors for metabolic impairment and liver steatosis in obesity.

Disclosure

R. Ahmad: None. F. Bahman: None. S.P. Kochumon: None. T.K. Jacob: None. F. Alrashed: None. A. Wilson: None. H. Arefanian: None. R.S. Thomas: None. N. Akhter: None. N. Al-Mansour: None. S. AlBeloushi: None. A. Al Madhoun: None. S.T. Sindhu: None. F. Alzaid: None. F. Almulla: None.
1629-P: Seven-Month HFD Feeding Abolishes the Protective Effect of STING Disruption on Obesity-Associated Hepatic Steatosis, Inflammation, and Insulin Resistance
Authors: GUO XINLEI , LI HONGGUI , WU CHAODONG
Published: June 2024

Insulin resistance (IR) means the failure of cells to respond normally to insulin, commonly associated with obesity and causing various metabolic dysregulations in type 2 diabetes. As a mediator of innate immunity, stimulator of interferon genes (STING) in human subjects is positively correlated with excessive fat deposition and liver inflammation, which both trigger hepatic and systemic IR. Also, STING expression is increased in insulin-responsive tissues in mice fed a high-fat diet (HFD) for 3 months, coupled with the decreased sensitivity of systemic insulin signaling. However, it is unknown about the effect of STING on IR in mice upon prolonged HFD feeding, which reflects the long-term course of human obesity. In this study, wild-type (WT) and STING-disrupted (STgt) male mice were fed an HFD for 3 months and examined for obesity and IR. Some HFD-fed mice were examined for hepatic insulin signaling upon a bolus injection of insulin into the portal vein. Additional STgt and WT mice were fed an HFD for 7 months and examined for obesity and systemic insulin sensitivity. Compared to male 3-m-HFD-WT mice, male 3-m-HFD-STgt mice gained smaller body weights and decreased levels of hepatic steatosis and inflammation, along with increased response to insulin. Consistently, insulin-stimulated Akt phosphorylation in the liver, adipose tissue, and skeletal muscle from male 3-m-HFD-STgt mice were much greater than those in the respective tissues from male 3-m-HFD-WT mice. However, upon prolonged HFD feeding, STgt mice displayed notably increased severity of obesity, hepatic steatosis and inflammation, all of which cause hepatic and systemic IR, relative to WT or STgt mice upon 3-month HFD feeding. These results indicate HFD feeding for 7 months abolishes the protective effect of STING deletion on obesity-associated hepatic steatosis/inflammation, and IR. As such, diets approach is key in managing obesity-induced metabolic diseases.

Disclosure

X. Guo: None. H. Li: None. C. Wu: None.

Funding

National Institutes of Health (DK124854)
1638-P: Metformin Enhances Upper Small Intestinal Lipid Sensing to Regulate Food Intake Independent of GDF15 Release
Authors: KUAH RACHEL , BRUCE KYLA , ZHANG SONG-YANG , LI ROSA J.W. , BARROS DANIEL R. , LAM TONY K.
Published: June 2024

Metformin, a first-line therapy for obesity-associated diabetes, lowers feeding and weight by increasing plasma growth differentiation factor 15 (GDF15) levels, but whether GDF15-independent mechanisms are involved is unknown. The upper small intestine (USI) detects lipids and triggers a gut-brain axis to lower food intake in chow but not high fat (HF)-fed conditions, while metformin enhances USI glucose sensing to lower glucose levels in HF rats. Here, we assessed whether metformin enhances lipid sensing in the USI of HF rats to lower food intake. We performed refeeding studies and measured plasma GDF15 levels after infusing 10% Intralipid into the USI of male rats. Infusion of Intralipid vs. saline into the USI suppressed food intake (lipid: 31±1 vs. sal: 43±2 kcal; p<0.01; n=18, 15) and increased plasma GDF15 levels (lipid: 113±9 vs. sal: 70±6 pg/ml; p<0.01; n=4, 5) up to 6h after refeeding in chow rats. In HF rats, both the effects of USI Intralipid vs. saline on feeding (lipid: 42±3 vs. sal: 41±1 kcal; n=10, 11) and plasma GDF15 levels (lipid: 68±6 vs. sal: 73±5 pg/ml; n=5, 3) were consistently abolished. Interestingly, metformin (50 mg/kg) administered to the USI of HF rats 1d prior to the refeeding studies enhanced USI Intralipid vs. saline infusion to suppress food intake (met-lipid: 35±2 vs. met-sal: 45±3 kcal; p<0.01; n=24,17), but notably did not increase plasma GDF15 levels (met-lipid: 69±3 vs. met-sal: 76±13 pg/ml; p>0.05; n=6, 5). Thus, for the first time we found that metformin enhances lipid sensing in the USI to lower food intake independent of GDF15 release. We propose that metformin lowers feeding in GDF15-dependent and -independent pathways.

Disclosure

R. Kuah: None. K. Bruce: None. S. Zhang: None. R.J.W. Li: None. D.R. Barros: None. T.K. Lam: None.

Funding

Canadian Institutes of Health Research (PJT-183901)
1641-P: Effect of Specific Weight-Reducing Interventions on Metabolic and Immunological Outcomes in Mice
Authors: BOSCH ANGELA J.T. , KELLENBERGER WANJA T. , KELLER LENA , LOW ANDY J.Y. , CAVELTI-WEDER CLAUDIA
Published: June 2024

Introduction & Objective: Obesity leads to glucose intolerance and immune cell alterations in different organs. Nevertheless, it remains unknown whether these metabolic and immunological changes are reversible following weight loss and if they differ with specific weight-reducing interventions. This study aimed to address whether obesity-associated metabolic and immunological changes are reversed after weight loss, comparing the effects of caloric restriction versus switch to a healthier diet.

Methods: Male C57Bl/6j mice were fed high fat diet (HFD), and randomized after 8 weeks into the following groups: continued HFD, HFD combined with caloric restriction or switched back to standard diet (HFD/SD), while an additional group was on SD throughout the experiment. Metabolic parameters were assessed at distinct timepoints and immune cells characterized by flow cytometry at the end of the experiment.

Results: The body weights of mice on SD, HFD/caloric restriction and HFD/SD were comparable from two weeks after the intervention onwards, while HFD fed mice had higher body weights. Initially, both HFD/caloric restriction and HFD/SD mice showed similar improvements in glucose tolerance and insulin secretion compared to mice on SD. However, glucose tolerance deteriorated over time in mice on HFD/caloric restriction, while their insulin levels remained low. Weight loss correlated with a decrease in inflammatory adipose tissue macrophages (ATMs), an increase in anti-inflammatory ATMs and eosinophils in AT, colon and liver. Colon B-cells decreased only in HFD/SD mice, while liver neutrophils and regulatory T-cells in AT increased.

Conclusion: Independent of the weight loss strategy, weight loss is associated with a reversal of hyperinsulinemia and AT inflammation as well as increased eosinophils in various organs. In contrast, a switch from HFD to SD specifically leads to reduced B-cells in the colon and increased neutrophils in liver and regulatory T-cells in AT.

Disclosure

A.J.T. Bosch: None. W.T. Kellenberger: None. L. Keller: None. A.J.Y. Low: None. C. Cavelti-Weder: None.

Funding

The Swiss National Science Foundation (SNSF) (32003B_204937/2)
1646-P: Apolipoprotein A4 Improves Glucose Homeostasis through Activation of BAT Thermogenesis in Obese Mice
Authors: LARUSSA ZACHARY D. , KUO HSUANCHIH , BAUMGARTE JACE , SHI HAIFEI , LO CHUNMIN C.
Published: June 2024

Obesity is associated with impaired insulin sensitivity and the development of type 2 diabetes. Activation of brown adipose tissue (BAT) thermogenesis enhances triglyceride clearance and insulin sensitivity. Apolipoprotein A4 (ApoA4) induced by dietary lipids elevates BAT thermogenesis in lean mice. Chronic consumption of high-fat diet (HFD) attenuates APOA4 production in small intestine and BAT thermogenesis. The hypothesis of this study was that the continuous infusion of mouse ApoA4 protein would increase BAT thermogenesis and improve glucose homeostasis in HFD-induced obese mice. Male mice were maintained on an HFD (60% kcals fat) for 10 weeks, during the last 4 weeks, mice received a pump infusion of vehicle or ApoA4 at a physiological dose (1.2 mg ApoA4/kg body weight). Glucose tolerance test, BAT thermogenesis, lipid accumulation in liver, and body weight were measured in mice with ApoA4 or vehicle treatment. Serum glucose and plasma insulin in ApoA4-treated mice was lower than in saline-treated mice following a glucose challenge. BAT temperature and thermogenesis were elevated in ApoA4-treated mice compared to saline-treated mice. Further, ApoA4-treated mice had increased fatty acid oxidation, reduced lipid content, and attenuated steatosis in the liver and decreased body weight gain relative to the saline control mice.

In conclusion, maintenance of ApoA4 protein elevates BAT thermogenesis, reduces body weight gain and hepatic lipid accumulation, and improves glucose homeostasis in HFD-induced obesity.

Disclosure

Z.D. LaRussa: None. H. Kuo: None. J. Baumgarte: None. H. Shi: None. C.C. Lo: None.

Funding

National Institutes of Health (AG078768); National Institutes of Health (DK118611)
1651-P: Effect of New Antidiabetics on Steatosis in of Nerve Tissues and Nerve Conduction Velocity—Possible Role of NGF/Synaptophysin and Nrf2/HO-1 Pathways
Authors: HUSSEIN ABDELAZIZ , EID ELSAYED M. , YEHYA YOMNA M. , TAHA MEDHAT , MOSA AHMED A.H. , AMMAR OMAR A. , ABDEL-HALIM NEHAL H.
Published: June 2024

Objectives: The current study examined the effects of new antihyperglycemic drugs (GLP1 analogue, semaglutide) and SGLT2 inhibitor; dapagliflozin) on nerve functions and morphology in obese rats as well as their underlying mechanisms.

Methods: 40 male Sprague Dawley rats, aged 6-8 weeks and classified into 5 groups; normal group, high-fat diet (HFD): HFD for 12 weeks, Metformin group: HFD for 12 weeks + metformin in last 4 weeks, DAPA group: HFD for 12 weeks +dapagliflozin in last 4 weeks, semaglutide group: HFD for 12 weeks + semaglutide in last 4 weeks. At the end of the experiment, sciatic nerve was collected for nerve conduction study, oxidative stress marker (MDA), real time PCR study (for HO-1 and Nrf2), red o oil staining, electron microscopic examination and immunohistochemistry for NGF and synaptophysin.

Results: HFD group showed significant rise in blood glucose, serum lipids, HOMA index, lipid deposition in nerve tissues and lipid peroxidation (MDA) in nerve tissues with significant attenuation in NCV, the expression of Nrf2 and HO-1 genes and significant attenuation in area stained with NGF and synaptophysin. On the other hand, pretreatment with either DAPA or semaglutide led to considerable enhancement in the deteriorated serum and nerve tissue parameters and reverse the pathological changes.

Conclusion: New antidiabetic drugs like SGLT2 inhibitors (more powerful) and GLP1 analogue might have neuroprotective beneficial effects beside controlling the glycemic state in obese rats. This effect may result from reduced oxidative stress and increased Nrf2 levels., HO-1, synaptophysin and NGF in nerve tissues of obese rats.

Keywords: nerve conduction velocity, obese, Nrf2, HO-1, NGF, synaptophysin, DAPA, semaglutide.

Disclosure

A. Hussein: None. E.M. Eid: None. Y.M. Yehya: None. M. Taha: None. A.A.H. Mosa: None. O.A. Ammar: None. N.H. Abdel-Halim: None.
1663-P: The Impact of Time-Restricted Eating on Beta-Cell Function in Overweight Adults with Type 2 Diabetes—A Randomized Crossover trial
Authors: KRAMER CAROLINE K. , RETNAKARAN RAVI , ZINMAN BERNARD
Published: June 2024

Time-restricted eating (TRE) has been proposed as a non-pharmacological strategy with cardio-metabolic benefits in overweight individuals but little is known about its metabolic impact in type 2 diabetes (T2DM). Thus, we sought to evaluate whether TRE can improve beta-cell function and metabolic status in overweight individuals with early T2DM. In a cross-over randomized trial, 39 participants (25 women, age 56.3 yrs, BMI 32.4 kg/m2, T2DM duration 2.9 yrs, A1c 6.6%) were randomized to either 6-weeks of TRE (20h-fasting/4h-eating) or standard lifestyle, followed by 4-weeks washout before 6-weeks of the other approach to eating. The primary outcome of beta-cell function was assessed by Insulin Secretion-Sensitivity Index-2 (ISSI-2) derived from an oral glucose tolerance test. As compared to standard lifestyle, TRE induced a 14% increase in ISSI-2 (p=0.03) accompanied by 14% reduction of HOMA-IR (p=0.03) (Figure). Fasting glucose did not differ between interventions, but TRE yielded a significant reduction in A1c (-0.32%, p<0.001). These metabolic improvements were likely driven by its effects in reducing body weight by 3.86% (p<0.001) and waist circumference by 3.8 cm (p=0.003).

In conclusion, TRE improved beta-cell function and insulin resistance in overweight patients with early T2DM, likely through its beneficial effects on adiposity.

Disclosure

C.K. Kramer: Research Support; Boehringer-Ingelheim. R. Retnakaran: Research Support; Boehringer-Ingelheim. Consultant; Eli Lilly and Company, Novo Nordisk, Sanofi. B. Zinman: Advisory Panel; Abbott, Eli Lilly and Company, Novo Nordisk.

Funding

Canadian Institutes of Health Research (PJT166091)
1673-P: Metaboepigenetic Regulation of Gene Expression in Obesity and Insulin Resistance
Authors: DAS SWAPAN K. , COMEAU MARY , LANGEFELD CARL D.
Published: June 2024

Altered DNA methylation (DNAm) in adipose tissue is involved in the pathogenesis of obesity and insulin resistance. The activity of enzymes involved in altering DNAm levels is dependent on several metabolite cofactors. To understand the role of metabolites as mechanistic regulators of epigenetic marks, we tested the association between selected plasma metabolites and DNAm levels in the adipose tissue of African Americans. In the AAGMEx cohort, plasma levels of metabolites were measured by untargeted LC-MS (DiscoveryHD4 panel; Metabolon, N=256), adipose tissue DNAm and transcript levels were measured by RRBS (Diagenode), and HumanHT-12V4 ExpressionBeadChips (Illumina), respectively. Among the 21 one-carbon metabolism pathway metabolites evaluated, six were associated with gluco-metabolic traits (FDR <0.05, for BMI, SI, or Matsuda index) in AAGMEx. We tested the association of three of these metabolites with DNAm levels in adipose. Methylation levels of 196, 116, and 180 CpG-sites were associated (P<0.0001) with S-adenosylhomocysteine (SAH), cystine, and hypotaurine, respectively. The CpG sites chr22:31002992 (P = 2.96x10-8), chr11:89135566 (P = 4.92x10-7), and chr21:38120202 (P = 5.53x10-8) were most significantly associated with plasma SAH, cystine, and hypotaurine levels, respectively. Cis-expression quantitative trait methylation (cis eQTM) analyses suggested the role of these metabolite-level-associated CpG sites in regulating the expression of adipose tissue transcripts. Plasma SAH level-associated CpG sites chr19:3403712 and chr19:3403735 were also associated with the expression of G protein subunit alpha 15 (GNA15) in adipose. The expression of GNA15 was significantly correlated with BMI (β = 1.87, P = 1.9x10-16) and SI (β = -1.61, P = 2.49 x 10-5). In summary, our study suggests that a subset of metabolites locus-specifically modulates the CpG-site methylation levels and, in turn, regulates the expression of transcripts involved in obesity and insulin resistance.

Disclosure

S.K. Das: None. M. Comeau: None. C.D. Langefeld: None.

Funding

American Diabetes Association (1-18- ICTS-113); National Institutes of Health (R01 DK118243)
1674-P: Development of a Once-a-Month Formulation of Semaglutide from an Innovative Injectable and Biodegradable Hydrogel
Authors: MARECHAL AUDREY , BESNARD ROMAIN , HAKIM SANA , NAESSENS ULYSSE , SOULA OLIVIER , GAUDIER MARTIN , DAUTY EMMANUEL , MEGRET CLAIRE
Published: June 2024

Semaglutide is a GLP-RA currently authorized for treatment of type 2 diabetes patients with insufficient glycaemic control and long-term weight management. Current dosage forms are administered either by once-weekly subcutaneous injection or by daily oral pill. AdoGel® is a hydrogel platform consisting of cross-linked degradable polymers injectable with 25G needle that allows sustained release of soluble peptides over 1 to 3 months duration. The challenge is to tailor the hydrogel to entrap the peptides to limit initial burst and, at the same time, to allow smooth release by controlled degradation of the hydrogel without generating toxic molecules. An AdoGel-semaglutide formulation was tested in rats (N=6) following a subcutaneous injection. The pharmacokinetics analysis showed limited burst and a regular release over a one-month period. The product is well tolerated with no inflammatory reaction during the one-month period. The results showed that a regular release of semaglutide over one month is achievable and could be a real benefit for patient compliance by limiting the injection frequencies, reduction of side effects and improved efficacy.

Disclosure

A. Marechal: Employee; ADOCIA. Stock/Shareholder; ADOCIA. R. Besnard: Employee; ADOCIA. Stock/Shareholder; ADOCIA. S. Hakim: Employee; ADOCIA. Stock/Shareholder; ADOCIA. U. Naessens: Employee; ADOCIA. Stock/Shareholder; ADOCIA. O. Soula: Board Member; ADOCIA. Stock/Shareholder; ADOCIA. M. Gaudier: Employee; ADOCIA. Stock/Shareholder; ADOCIA. E. Dauty: Stock/Shareholder; ADOCIA. Employee; ADOCIA. C. Megret: Employee; ADOCIA. Stock/Shareholder; ADOCIA. Consultant; Avadel. Stock/Shareholder; Avadel, Sanofi.
1684-P: CONCRETE—Characterization of Patients Receiving Telemedicine and Branded Antiobesity Medication for Medical Weight Management—A Retrospective Analysis
Authors: SHUKLA ALPANA , LI DAVID , CASPER ANTHONY J. , ARONNE LOUIS , D'ANGELO DEBRA , SAUNDERS KATHERINE H. , IGEL LEON I. , LUCAS EUGENE , PALEPU KATHYA , ZACHERLE EMILY , TRAINA ANDREA , OLSSON KELLY
Published: June 2024

Introduction & Objective: Use of branded anti-obesity medications (bAOMs) has increased concurrently with the rise of telemedicine, a convenient, cost-effective modality for patient care. However, limited data exist regarding characteristics of telemedicine users in medical weight management. This study examines the profile and treatment course of patients prescribed bAOMs for overweight or obesity via telemedicine at an academic weight center in New York City.

Methods: This is a retrospective observational study of patients who started telemedicine treatment between May 1, 2020, and September 30, 2022, received a bAOM prescription (Contrave®, Qsymia®, Saxenda®, or Wegovy®), and had ≥6 (±2) months’ follow-up. Data were abstracted by electronic medical record query using relevant ICD/diagnosis codes and biomarker data to curate a dataset of eligible patients for analysis.

Results: Patients who met inclusion criteria (N=1286) had a mean age of 47.2 (SD=12.8) years, initial weight of 220.9 (50.6) lb (n=934), initial BMI of 35.2 (6.5) (n=930), and an average of 2.2 weight-related comorbidities (most commonly dyslipidemia [n=705], hypertension [n=355], and prediabetes [n=595]). Most patients identified as White (63.7%); 72.2% of patients were female. Patients had a mean (SD) of 9.5 (7.2) telemedicine visits with physicians, nurse practitioners, and registered dietitians over 17.7 (7.2) months; 36.2% used both telemedicine and in-person visits, and 63.8% used only telemedicine. The most frequently prescribed bAOM was Wegovy® (70.3% of patients), followed by Saxenda® (17.6%), Contrave® (13.6%), and Qsymia® (12.4%).

Conclusion: In this study, Wegovy® was the most commonly prescribed bAOM, and telemedicine facilitated frequent appointments (every 1.9 months on average). Future research is necessary to examine the impact of this treatment model on obesity and obesity-related comorbidities.

Disclosure

A. Shukla: Research Support; Eli Lilly and Company, Novo Nordisk. Consultant; Sun Pharmaceutical Industries Ltd. D. Li: None. A.J. Casper: None. L. Aronne: Advisory Panel; Novo Nordisk. Consultant; Novo Nordisk. Advisory Panel; Lilly Diabetes, Altimmune Inc. Consultant; Lilly Diabetes. Advisory Panel; Pfizer Inc. Consultant; UnitedHealth Group. Advisory Panel; Boehringer-Ingelheim. Board Member; AstraZeneca. Advisory Panel; Amgen Inc. D. D'Angelo: None. K.H. Saunders: Other Relationship; Intellihealth. L.I. Igel: Consultant; Novo Nordisk. Employee; Intellihealth. E. Lucas: Consultant; Intellihealth. K. Palepu: None. E. Zacherle: Employee; Novo Nordisk. A. Traina: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. K. Olsson: Employee; Novo Nordisk.
1693-P: Irisin Levels, Glycometabolic Characteristics, and Muscle Performance in Type 2 Diabetes Patients with Sarcopenic or Nonsarcopenic Obesity
Authors: ROSSI ERICA , DI GIOIA LUDOVICO , MARRANO NICOLA , PERRINI SEBASTIO , LAVIOLA LUIGI , NATALICCHIO ANNALISA , GIORGINO FRANCESCO
Published: June 2024

Introduction: Sarcopenic obesity (SO), characterized by concurrent excessive body fat and reduced muscle mass, amplifies the risk of metabolic abnormalities, especially insulin resistance (IR). Irisin, a myokine linked to energy homeostasis, has shown inconsistent associations with sarcopenia. This study investigated irisin levels in T2DM patients with SO or non-sarcopenic obesity (NSO).

Methods: Patients with T2DM and BMI >30 kg/m² underwent glycometabolic assessment and irisin measurements. Muscle efficiency was evaluated using Handgrip Strength (HGS) and 5-times Sit To Stand Test (5-STST). Patients were categorized into SO and NSO groups per the 2022 ESPEN/EASO Consensus.

Results: Of 67 patients affected by obesity and T2DM, 50 had NSO and 17 SO. SO patients were older (70 [6] vs 66 [7] years, p=0.028), with higher BMI (36.7 [4.3] vs 34.7 [4] kg/m², p=0.036), FM (41.9 [7.7] vs 37.6 [8.7] kg, p=0.049), alcohol use (47.1% vs 22%, p=0.048), 5-STST (13.3 [4.1] vs 10.8 [3.1] s, p=0.016), and lower HGS results (24 [7.9] vs 36.4 [10.2] kg, p<0.001). No difference in HOMA-IR, HbA1c or irisin levels was found between SO and NSO patients. Irisin correlated negatively with HbA1c (r=-0.288, p=0.018), HGS (r=-0.249, p=0.042), muscle mass (r=-0.26, p=0.033), and creatinine (r=-0.308, p=0.011), and positively with relative FM (r=-0.274, p=0.025). Increasing HGS results predicted lower irisin levels (beta=-316, p=0.032). Multivariate logistic regression analysis associated older age with higher SO risk (OR=1.16, p=0.02), with a trend relationship for insulinemia (OR=1.05, p=0.073) and 5-STST (OR=1.19, p=0.068) (p=0.039, area under the curve=0.804).

Conclusion: People with T2DM and SO exhibit poorer lifestyle, anthropometric profile and physical performance. Irisin levels are linked with better glycemic control, negatively correlating with muscle mass and strength, suggesting a compensatory role in this context.

Disclosure

E. Rossi: None. L. Di Gioia: Consultant; Roche Diabetes Care, Eli Lilly and Company, Novo Nordisk, Sanofi. N. Marrano: None. S. Perrini: None. L. Laviola: Speaker's Bureau; A. Menarini Diagnostics, Abbott, AlfaSigma. Advisory Panel; Boehringer-Ingelheim, Eli Lilly and Company, Medtronic, Novo Nordisk. Speaker's Bureau; AstraZeneca. Advisory Panel; Roche Diabetes Care, Sanofi. Speaker's Bureau; Terumo Corporation. A. Natalicchio: Speaker's Bureau; AstraZeneca, Novo Nordisk, Sanofi, Eli Lilly and Company. F. Giorgino: Consultant; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, LifeScan Diabetes Institute, Merck Sharp & Dohme Corp., Medtronic, Novo Nordisk, Roche Diabetes Care, Sanofi. Research Support; Eli Lilly and Company, Roche Diabetes Care.
1718-P: Retinol-Binding Protein 4, an Adipokine Provoking Pancreatic Beta-Cell Apoptosis in Type 2 Diabetes
Authors: QU SHEN , MAO WANGJIA , CHENG XIAOYUN
Published: June 2024

Pancreatic b-cell apoptosis plays a decisive role in the progression of type 2 diabetes. Retinol-binding protein 4 (RBP4) is a prominent adipokine in type 2 diabetes(T2D), has been confirmed to that it may be involved in the pathogenesis of insulin resistance and T2D, but the underlying mechanisms of RBP4 inducing islet b-cell apoptosis are unknown. The stimulated by retinoic acid6 (STRA6), RBP4’s only known specific membrane receptor, is expressed in b-cells and mediates the inhibitory effect of RBP4 on insulin synthesis. Here, we found that at the cellular level apo-RBP4 can induce apoptosis in pancreatic b-cells by binding to STRA6. Compared to holo-RBP4, apo-RBP4 has a stronger induction effect, and this induction effect is dose-dependent. We also found that elevated circulating RBP4 levels were inversely correlated with pancreatic b-cell apoptosis in T2D mice across different glycemic stages. Islets isolated from RBP4 overexpressing mice showed a significant decrease of GSIS while injecting shRBP4 AAV mice showed a recovery of GSIS. Moreover, decreasing circulating RBP4 level could effectively restore b-cell dysfunction and ameliorate hyperglycemia in T2D mice. These observations revealed a role of RBP4 in promoting apoptosis of pancreatic b cells, which provides new insight into the diabetogenic effect of RBP4.

Disclosure

S. Qu: None. W. Mao: None. X. Cheng: None.
1722-P: Suppression of Glucagon Signaling Promotes α-to-ß Reprogramming
Authors: TAGUCHI TOMOMI , SUZUKI AGENA , SHIMIZU NAOYA , FUJISHIMA REI , KIMURA KAORI , ITO SHIORI , SHIMOTATARA HIDEAKI , INOUE MITSUKO , MIYATSUKA TAKESHI
Published: June 2024

The generation of surrogate β cells has attracted a lot of attention for the cure of diabetes. Recently, we have revealed that glucagon antibody induces α-cell neogenesis in adult mice, suggesting that the suppression of glucagon signaling could play a role in cellular plasticity in α-cell lineage. Therefore, we hypothesized that inhibiting glucagon signaling may affect the efficiency of α-to-β reprogramming. We generated a transgenic mouse line (αPdx1) that exogenously and inducibly expresses Pdx1 specifically in α cells, and treated the mice with glucagon receptor antagonist. As FLAG-tagged sequence is attached to Pdx1, the exogenous expression of Pdx1 can be distinguished from the endogenous Pdx1 gene. The reprogramming efficiency was evaluated by counting FLAG-tag/insulin double-positive cells, that is, α-cell-derived insulin-producing cells. Immunohistological analysis demonstrated that the number of α-cell-derived insulin-producing cells was significantly increased in αPdx1 mice treated with glucagon receptor antagonist (GRA), compared with the mice treated with vehicle (26.0 ± 1.6 vs 13.5 ± 1.3%, p < 0.0001). In addition, GRA significantly increased α-to-β reprogramming ratio in αPdx1 mice after β-cell ablation (73.7 ± 3.3 vs 52.0 ± 1.8%, p = 0.0004). Furthermore, when the mice were induced hyperglycemia by alloxan, the administration of GRA significantly improved hyperglycemia during intraperitoneal glucose tolerance test (IPGTT), compared αPdx1 mice administered by vehicle (p = 0.012). Notably, the insulin levels during IPGTT were significantly higher in the mice treated with GRA (p = 0.034). Thus, the suppression of glucagon signaling promotes α-to-β reprogramming in mice, which could lead to establishing efficient methods for generating surrogate β cells.

Disclosure

T. Taguchi: None. A. Suzuki: None. N. Shimizu: None. R. Fujishima: None. K. Kimura: None. S. Ito: None. H. Shimotatara: None. M. Inoue: None. T. Miyatsuka: None.
1727-P: Low-Protein Diet during Pregnancy and Lactation May Impair Islet Function of the Female Offspring Mice Potentially Due to Islet Epigenetic Changes
Authors: PENG YUEYUE , CHEN YALAN , LIU ZHIGU , LIN BEISI , LING PING , LI YANLI , XU FEN , LIANG HUA , YAN JINHUA , XU WEN
Published: June 2024

Objective: This study aimed to investigate how the low-protein diet during pregnancy and lactation affects the islet function of the female offspring mice, and explore the potential mechanisms.

Methods: Female mice were treated with control diet (28% protein) or low protein diet (9% protein) throughout their pregnancy and lactation. Their female offspring were divided into the control diet group (CD) and the low-protein diet (LPD) group based on their maternal diet. After weaning, all offspring received a standard diet until week 18. Body weight and FBG of the female offspring were measured. At week 17, intraperitoneal glucose tolerance test, simultaneous serum insulin test and intraperitoneal insulin tolerance test were performed in all offspring. Thereafter, transcriptome sequencing of offspring's primary islets was conducted. The bioinformatics analysis applied between the targeted genes of differentially expressed LncRNAs and the differentially expressed mRNA. LncRNA Gm38850 knockdown Min6 cell model was used to study the relationship between Gm38850 and lactate dehydrogenase A (Ldha).

Results: The LPD group showed impaired glucose tolerance and reduced insulin release compared to the control group. However, no significant differences were seen in FBG and intraperitoneal insulin tolerance. Transcriptome sequencing found 55 differentially expressed mRNAs and four down-regulated LncRNAs in islet cells. Pathway enrichment analysis suggested that these differentially expressed RNAs were mainly involved in the biological functions of pyruvate metabolism, IL-17 signaling, glucagon pathway, AGE-RAGE signaling, and HIF-1 signaling. Up-regulated Ldha expression in islets and Min6 cells after Gm38850 knockdown were confirmed with immunofluorescence.

Conclusions: Low-protein diet during pregnancy and lactation may impair islet function of the offspring female mice, potentially due to islet epigenetic changes.

Disclosure

Y. Peng: None. Y. Chen: None. Z. Liu: None. B. Lin: None. P. Ling: None. Y. Li: None. F. Xu: None. H. Liang: None. J. Yan: None. W. Xu: None.

Funding

Guangdong Natural Science Foundation (2022A1515012364); Guangzhou Science and Technology Plan Project (202102010175); Guangzhou Science and Technology Plan Project (202201020550)
1746-P: Understanding the Pancreatic Islet Proteome in Response to Prolonged High-Glucose Exposure
Authors: KHOSRAVIFAR MINA , HAEMMERLE MATTHEW W. , SEN SABYASACHI , STOFFERS DORIS A.
Published: June 2024

Introduction & Objective: Acute hyperglycemia challenges augment the functional status of β cells, whereas chronic high glucose exposure paradoxically impairs the ability of β cells to respond to and secrete appropriate amounts of insulin. We have found that 72 hr exposure of mouse islets to high glucose markedly increases glucose, and IBMX stimulated insulin secretion, while basal insulin secretion was also moderately elevated. Here, we examine the impact of 72 hr of 16.7 mM vs 2.8 mM glucose on the whole pancreatic islet proteome.

Methods: Isolated C57BL/6N mouse islets were treated with low (2.8 mM) or high (16.7 mM) glucose for 24 hr or 72 hr (n=6 islet preparations/group). The whole islet proteome was obtained using mass spectrometry. Pathway analysis was conducted using Gene Set Enrichment Analysis (GSEA) in R software.

Results: After 72 hr high vs low glucose exposure, a total of 5847 proteins were identified, with 136 proteins significantly upregulated, including Ins2 (Log2FC ≥1, Adj. PV<0.05), and 55 proteins significantly downregulated, including Insr (Log2FC ≤ -1, Adj. PV<0.05). The application of Principal Component Analysis to our proteomic data revealed a tightly clustered pattern that segregated according to glucose exposure. Our analysis revealed distinct regulatory patterns in cellular pathways in response to 72 h sustained high glucose. Among the prominent upregulated pathways were protein N-linked glycosylation, the ubiquitin-dependent ERAD pathway, and protein biosynthetic processes. Conversely, downregulated pathways predominantly centered around metabolic regulation and mitochondrial processes, including various components of the oxidative stress response and mitochondrial electron transport chain.

Conclusion: Considering the importance of glucose adaptation of islet function to the preservation of glucose homeostasis, this study provides a glucose response proteomic signature that raises known and novel targets for further exploration.

Disclosure

M. Khosravifar: None. M.W. Haemmerle: None. S. Sen: None. D.A. Stoffers: Other Relationship; Eiger BioPharmaceuticals.

Funding

National Institutes of Health (R01-DK-122039)