Exendin-4, a glucagon-like peptide receptor agonist, facilitates osteoblast differentiation via connexin43

Chen, Jin Hong; Shen, Chen; Oh, Haram; Park, Ji Hyun

doi:10.1007/s12020-021-02664-7

Cited by 2 publications

(2 citation statements)

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“…12 A synthetic form of exendin-4 (Ex-4), exenatide, was the first GLP-1 RA approved for the treatment of T2DM. 13 Ex-4 was extracted from the saliva of a venomous lizard (Heloderma suspectum); 53% of the amino acid sequence of Ex-4 is homologous to mammalian GLP-1, and Ex-4 is able to bind and activate GLP-1 receptors. 14 Byetta ® , an Ex-4 developed by Lilly and Amylin Pharmaceuticals, was first approved by the US Food and Drug Administration (US FDA) to treat T2DM in 2005.…”

Section: Introductionmentioning

confidence: 99%

“…Several research groups have focused on the development of GLP‐1 analogues with various structural modifications aimed at increasing stability 12 . A synthetic form of exendin‐4 (Ex‐4), exenatide, was the first GLP‐1 RA approved for the treatment of T2DM 13 . Ex‐4 was extracted from the saliva of a venomous lizard ( Heloderma suspectum ); 53% of the amino acid sequence of Ex‐4 is homologous to mammalian GLP‐1, and Ex‐4 is able to bind and activate GLP‐1 receptors 14 .…”

Section: Introductionmentioning

confidence: 99%

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Safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of Exendin‐4‐IgG4‐Fc in healthy subjects: A phase 1, single‐centre, randomized, double‐blind, dose escalation study

Chen,

Liu,

Gao

et al. 2024

Diabetes Obesity Metabolism

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AimNovel long‐acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin‐4‐IgG4‐Fc (E4F4) is a long‐acting glucagon‐like peptide‐1 receptor agonist. This first‐in‐human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects.MethodsThis single‐centre, randomized, double‐blind, placebo‐controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level.ResultsE4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose‐dependent relationship between frequency, severity or causality of treatment‐emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45‐14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose‐dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose‐response relationship in the 1.8‐10.35 mg dose range, with an increased response at the higher doses.ConclusionE4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5‐10.35 mg once every 2 weeks.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of Exendin‐4‐IgG4‐Fc in healthy subjects: A phase 1, single‐centre, randomized, double‐blind, dose escalation study

Chen,

Liu,

Gao

et al. 2024

Diabetes Obesity Metabolism

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The GLP-1R Agonist Exenatide Improves Sheep Sperm Motility by Regulating Cellular Metabolic Levels

Wang,

Zhu,

Liu

et al. 2024

Preprint

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Glucagon-like peptide-1 (GLP-1) is a peptide hormone involved in regulating insulin secretion and energy metabolism. It typically needs to bind to Glucagon-like peptide-1 Receptor (GLP-1R) in the body to exert its regulatory effects. Exenatide-4 (EX-4) is a synthetic GLP-1 analogue that is widely used as a weight loss and blood sugar-lowering medication due to its high stability and slow degradation rate. Since there is no current research on whether GLP-1 affects energy metabolism and sperm motility, it is necessary thatthe effects of GLP-1 analogues on sperm motility and energy metabolism will be investigated by treating sheep sperm with EX-4. Our results showed that GLP-1R was present in sheep sperm, and expressed in the head of the sperm. After concentration screening, it was found that 300 pM EX-4 was most effective for improving sheep sperm motility. Incubating sperm with EX-4 resulted in a significant increase in LDH, G6PDH, lipase activity, and ATP content (P < 0.05), while triglyceride content significantly decreased (P < 0.05). Additionally, EX-4 significantly promoted insulin secretion in sheep sperm (P < 0.05). When EX-4 was used in combination with GLP-1R inhibitor (GLP-1R AB), the levels of LDH, G6PDH, lipase activity, ATP content, and insulin concentration significantly decreased (P < 0.05), while triglyceride content significantly increased (P < 0.05). The further results showed that EX-4 effectively promoted cholesterol efflux in sheep sperm (P < 0.05), which is beneficial for sperm energy acquisition and maturation. Both insulin receptor inhibitors (IR AB) and GLP-1R AB reduced the promoting effect of EX-4 on cholesterol efflux in sheep sperm (P < 0.05). Our other results revealed that EX-4 regulates sperm metabolism through the GLP-1R/PI3K/Akt pathway, enhancing energy levels in sheep sperm. Generally, sperm motility is closely related to metabolic levels, and it is believed that EX-4 enhances the activity of some metabolic enzymes in sheep sperm by activating this signaling pathway, thereby promoting energy acquisition, maturation, and significantly improving sperm motility.

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Exendin-4, a glucagon-like peptide receptor agonist, facilitates osteoblast differentiation via connexin43

Cited by 2 publications

References 20 publications

Safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of Exendin‐4‐IgG4‐Fc in healthy subjects: A phase 1, single‐centre, randomized, double‐blind, dose escalation study

Safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of Exendin‐4‐IgG4‐Fc in healthy subjects: A phase 1, single‐centre, randomized, double‐blind, dose escalation study

The GLP-1R Agonist Exenatide Improves Sheep Sperm Motility by Regulating Cellular Metabolic Levels

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