Binding Kinetics, Bias, Receptor Internalization and Effects on Insulin Secretionin vitroandin vivoof a Novel GLP-1R/GIPR Dual Agonist, HISHS-2001

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Abstract The use of incretin analogues has emerged in recent years as an effective approach to achieve both enhanced insulin secretion and weight loss type 2 diabetes (T2D) patients. Agonists which bind stimulate multiple receptors have shown particular promise. However, off target effects, including nausea diarrhoea, remain a complication using these agents, modified versions with optimized pharmacological profiles and/or biased signaling at the cognate are increasingly sought. Here, we describe synthesis properties molecule binds glucagon-like peptide-1 (GLP-1) glucose-dependent insulinotropic polypeptide (GIP) (GLP-1R GIPR) enhance secretion. HISHS-2001 shows increased affinity GLP-1R, well tendency towards reduced internalization recycling this receptor versus FDA-approved dual GLP-1R/GIPR agonist tirzepatide. also displayed significantly greater bias cAMP generation β-arrestin recruitment compared In contrast, G αs was lower tirzepatide but higher GIPR. Administered obese hyperglycaemic db/db mice, circulating whilst lowering body HbA1c similar efficacy substantially doses. Thus, represents novel improved profile.

Language: Английский

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In vivo and in vitro characterization of GL0034, a novel long‐acting glucagon‐like peptide‐1 receptor agonist

Diabetes Obesity and Metabolism, Journal Year: 2022, Volume and Issue: 24(11), P. 2090 - 2101

Published: June 9, 2022

Abstract Aims To describe the in vitro characteristics and antidiabetic vivo efficacy of novel glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) GL0034. Materials Methods Glucagon‐like (GLP‐1R) kinetic binding parameters, cyclic adenosine monophosphate (cAMP) signalling, endocytosis recycling were measured using HEK293 INS‐1832/3 cells expressing human GLP‐1R. Insulin secretion was cells, mouse islets islets. Chronic administration studies to evaluate weight loss glycaemic effects performed db/db diet‐induced obese mice. Results Compared leading GLP‐1RA semaglutide, GL0034 showed increased affinity potency‐driven bias favour cAMP over GLP‐1R β‐arrestin‐2 recruitment. secretory responses similar for both ligands. (6 nmol/kg) led at least as much lowering blood glucose did semaglutide a higher dose (14 nmol/kg). Conclusions is G protein‐biased that shows powerful mice, may serve promising new patients with type 2 diabetes.

Language: Английский

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RISING STARS: Targeting G protein-coupled receptors to regulate energy homeostasis

Journal of Molecular Endocrinology, Journal Year: 2023, Volume and Issue: 70(4)

Published: March 21, 2023

G protein-coupled receptors (GPCRs) have a critical role in energy homeostasis, contributing to food intake, expenditure and glycaemic control. Dysregulation of can lead metabolic syndrome (abdominal obesity, elevated plasma triglyceride, LDL cholesterol glucose, high blood pressure), which is associated with an increased risk developing diabetes mellitus, non-alcoholic fatty liver disease cardiovascular complications. As the prevalence these chronic diseases continues rise worldwide, there need understand molecular mechanisms by regulated facilitate development effective therapeutic strategies treat prevent conditions. In recent years, drugs targeting GPCRs been focus efforts improve treatments for type-2 GLP-1R agonists particular success. this review, we on nine roles homeostasis that are current emerging targets obesity diabetes. We discuss findings from pre-clinical models clinical trials challenges must be overcome before routinely used clinics. also describe new insights into how signal, including accessory proteins, biased signalling, complex spatial signalling could provide unique opportunities develop more efficacious therapies fewer side effects. Finally, combined therapies, multiple targeted, may outcomes reduce off-target

Language: Английский

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Development of a novel Fc fusion protein dual glucagon‐like peptide‐1 and gastric inhibitory polypeptide receptor agonists

Diabetes Obesity and Metabolism, Journal Year: 2023, Volume and Issue: 25(11), P. 3356 - 3365

Published: Aug. 14, 2023

Abstract Aim To develop and investigate an imbalanced dual gastric inhibitory polypeptide receptor (GIPR)/glucagon‐like peptide‐1 (GLP‐1 R) agonist with Fc fusion protein structure. Methods We designed constructed that is a (HEC‐CG115) empirically optimized potency ratio for GLP‐1R GIPR. The long‐term effects of HEC‐CG115 on body weight glycaemic control were evaluated in diet‐induced obese mice diabetic db/db mice. Repeat dose toxicity assays performed to the safety profile Sprague‐Dawley rats. Results displayed high GIPR relatively low GLP‐1R, we labelled it ‘imbalanced’. In animal models, (3 nmol/kg) led more loss than semaglutide at higher (10 model (one every 3 days) reduced fasting blood glucose glycated haemoglobin levels similar those after (once daily) same dose. 4‐week subcutaneous study conducted assess biosafety HEC‐CG115, no observed adverse effect level was determined be mg/kg. Conclusion novel agonism shows superior loss, metabolic improvement has optimal according repeat‐dose study. Therefore, use appears safe effective treatment obesity type 2 diabetes.

Language: Английский

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Sustained metabolic benefits of ΔTRTX‐Ac1, a tarantula venom‐derived peptide, when administered together with exenatide in high‐fat fed mice

Diabetes Obesity and Metabolism, Journal Year: 2023, Volume and Issue: 26(1), P. 329 - 338

Published: Oct. 11, 2023

Abstract Aim The aim of the present study was to assess long‐term therapeutic efficacy a recently discovered 28 amino acid peptide, Δ‐theraphotoxin‐Ac1 (Δ‐TRTX‐Ac1), originally isolated from venom Aphonopelma chalcodes tarantula. Δ‐TRTX‐Ac has previously been shown improve pancreatic beta‐cell function and suppress appetite. Materials Methods Δ‐TRTX‐Ac1 administered twice daily in high‐fat fed (HFF) mice with streptozotocin (STZ)‐induced insulin deficiency, namely HFF/STZ mice, for days both alone combination venom‐derived glucagon‐like peptide‐1 (GLP‐1) mimetic, exenatide. Results Initial pharmacokinetic profiling ΔTRTX‐Ac1 revealed plasma half‐life 2 h also evidenced pancreas 12 post‐injection. Accordingly, HFF‐STZ received twice‐daily injections Δ‐TRTX‐Ac1, exenatide or peptides days. As anticipated, presented hyperglycaemia, impaired glucose tolerance, decreased disturbed islet morphology. Administration reduced body weight, improved tolerance augmented content while decreasing glucagon content. Exenatide had similar benefits on weight hormone reducing circulating glucose. energy expenditure day whereas no impact. All treatment regimens restored area towards lean control levels, which linked significantly elevated proliferation rates. In terms combined over individual agents, there augmentation ambulatory activity therapy, these increased glucagon. Conclusion These data highlight promise diabetes, suggestion that could be enhanced through administration

Language: Английский

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Comparative Analysis of the Anti-Inflammatory Effects of Liraglutide and Dulaglutide

International Heart Journal, Journal Year: 2024, Volume and Issue: 65(3), P. 548 - 556

Published: May 14, 2024

Inflammation plays a pathophysiological role in atherosclerosis and its clinical consequences. In addition to glycemic control, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are of wide concern for cardioprotective effects. The structure, half-life, homology, efficacy GLP-1RAs exhibit remarkable disparity. Several studies have compared the disparities anti-inflammatory effects between daily weekly GLP-1RAs. This study aimed compare similarities differences liraglutide dulaglutide terms inhibiting atherosclerotic inflammation improving co-cultured endothelial cell function. expression markers was examined by immunofluorescence, Western blotting, real-time PCR. tube-forming ability cells tested on Matrigel. results verify that 10/50/100 nmol/L 100 markedly suppressed inflammatory factors LPS-induced after 24 72 hours, respectively. Moreover, they promoted polarization M1 macrophages toward M2 phenotype improved function cells. Both ameliorate development. difference two resided extended intervention duration required observe effect dulaglutide, demonstrated superior dose-dependent manner. We provide potential strategy understand dynamics drug action possible timing administration.

Language: Английский

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Metabolic State Determines Central and Peripheral Mechanisms of Liraglutide-Enhanced Insulin Secretion

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 25, 2024

While liraglutide effectively treats type 2 diabetes (T2D) and obesity, its mechanism of action across disease progression remains poorly understood. Liraglutide selectively enhances GSIS in islets from glucose-intolerant donors exposed to prediabetic conditions, but not normoglycemic or T2D islets. In healthy mice, liraglutide's insulinotropic effect requires tanycyte-mediated central transport, whereas glucose intolerance it acts directly on Additionally, reduces blood mice through insulin-independent mechanisms involving decreased gluconeogenesis enhanced peripheral uptake. These findings demonstrate that the therapeutic window for pancreatic effects may be optimal during prediabetes, while actions predominate other metabolic states.

Language: Английский

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