InVivoSIM GLP-1 Receptor Agonist (Semaglutide Biosimilar)

InVivoSIM GLP-1 Receptor Agonist (Semaglutide Biosimilar) (CLONE: N/A)

Huang R, Xia H, Meng T, Fan Y, Tang X, Li Y, Zhang T, Deng J, Yao B, Huang Y, Yang Y (2025). "Construction of human pluripotent stem cell-derived testicular organoids and their use as humanized testis models for evaluating the effects of semaglutide" Theranostics 15(6):2597-2623. PubMed

Background: The generation of human testicular organoids from human induced pluripotent stem cells (hiPSCs) presents exciting opportunities for gonadal developmental biology, and reproductive disease modeling. However, creating organoids that closely mimic the tissue structure of testes remains challenging. Methods: In this study, we established a method for generating testicular organoids (TOs) from hiPSCs using a stepwise differentiation approach and a combination of hanging drop and rotational culture systems. The capability of hiPSC-derived precursor testicular cells to self-assemble into organoids was confirmed by detection of morphology, single-cell RNA-sequencing, and protein profiles. The reliability of testicular organoids as a drug evaluation model was assessed by the measurements of transcriptome signatures and functional features, including hormone responsiveness and blood-testis barrier (BTB) formation, and drug sensitivity assessment by recording cell viability and BTB integrity in organoids exposed to reproductive toxicants. Finally, we applied testicular organoids to evaluate the effects of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), on testicular function, thereby underscoring their utility as a model for drug evaluation. Results: These organoids exhibited testicular cord-like structures and BTB function. RNA sequencing and functional assays confirmed that testicular organoids possess gene expression profiles and endocrine functions regulated by gonadotropins, closely resembling those of testicular tissue. Notably, these organoids displayed sensitivity to semaglutide. Treatment with semaglutide resulted in reduced testosterone levels and downregulation of INHBB expression, aligning with previous clinical observations. Conclusions: These findings introduced a method for generating testicular organoids from human pluripotent stem cells, highlighting their potential as valuable models for studying testicular function, drug toxicity, and the effects of compounds like semaglutide on testicular health.

Iwai S, Kaji K, Nishimura N, Kubo T, Tomooka F, Shibamoto A, Suzuki J, Tsuji Y, Fujinaga Y, Kitagawa K, Namisaki T, Akahane T, Yoshiji H (2023). "Glucagon-like peptide-1 receptor agonist, semaglutide attenuates chronic liver disease-induced skeletal muscle atrophy in diabetic mice" Biochim Biophys Acta Mol Basis Dis 1869(7):166770. PubMed

A glucagon-like peptide-1 receptor agonist (GLP-1RA) has recently been established as a pharmacological option for the treatment of type 2 diabetes. Recent studies have demonstrated the molecular role of GLP-1R in skeletal muscle homeostasis; however, the therapeutic efficacy of semaglutide, a GLP-1RA, on skeletal muscle atrophy in chronic liver disease (CLD) under diabetic conditions remains unclear. In the present study, semaglutide effectively inhibited psoas muscle atrophy and suppressed declines in grip strength in a diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet-fed diabetic KK-A^y mouse model. Moreover, semaglutide inhibited ubiquitin-proteosome-mediated skeletal muscle proteolysis and promoted myogenesis in palmitic acid (PA)-stimulated C2C12 murine myocytes. Mechanistically, this effect of semaglutide on skeletal muscle atrophy was mediated by multiple functional pathways. First, semaglutide protected against hepatic injury in mice accompanied by increased production of insulin-like growth factor 1 and reduced accumulation of reactive oxygen species (ROS). These effects were associated with decreased proinflammatory cytokines and ROS accumulation, leading to the suppression of ubiquitin-proteosome muscle degradation. Moreover, semaglutide inhibited the amino acid starvation-related stress signaling that was activated under chronic liver injury, resulting in the recovery of the mammalian target of rapamycin activity in the skeletal muscle of DDC-diet fed KK-A^y mice. Second, semaglutide improved skeletal muscle atrophy by directly stimulating GLP-1R in myocytes. Semaglutide induced cAMP-mediated activation of PKA and AKT, enhanced mitochondrial biogenesis, and reduced ROS accumulation, thereby resulting in inhibition of NF-κB/myostatin-mediated ubiquitin-proteosome degradation and the augmentation of heat-shock factor-1-mediated myogenesis. Collectively, semaglutide may have potential as a new therapeutic strategy for CLD-related skeletal muscle wasting.

Cardoso LEM, Marinho TS, Martins FF, Aguila MB, Mandarim-de-Lacerda CA (2023). "Treatment with semaglutide, a GLP-1 receptor agonist, improves extracellular matrix remodeling in the pancreatic islet of diet-induced obese mice" Life Sci . PubMed

Aims: The extracellular matrix (ECM) is fundamental for the normal endocrine functions of pancreatic islet cells and plays key roles in the pathophysiology of type 2 diabetes. Here we investigated the turnover of islet ECM components, including islet amyloid polypeptide (IAPP), in an obese mouse model treated with semaglutide, a glucagon-like peptide type 1 receptor agonist. Main methods: Male one-month-old C57BL/6 mice were fed a control diet (C) or a high-fat diet (HF) for 16 weeks, then treated with semaglutide (subcutaneous 40 μg/kg every three days) for an additional four weeks (HFS). The islets were immunostained and gene expressions were assessed. Key findings: Comparisons refer to HFS vs HF. Thus, IAPP immunolabeling and beta-cell-enriched beta-amyloid precursor protein cleaving enzyme (Bace2, -40 %) and heparanase immunolabeling and gene (Hpse, -40 %) were mitigated by semaglutide. In contrast, perlecan (Hspg2, +900 %) and vascular endothelial growth factor A (Vegfa, +420 %) were enhanced by semaglutide. Also, semaglutide lessened syndecan 4 (Sdc4, -65 %) and hyaluronan synthases (Has1, -45 %; Has2, -65 %) as well as chondroitin sulfate immunolabeling, and collagen type 1 (Col1a1, -60 %) and type 6 (Col6a3, -15 %), lysyl oxidase (Lox, -30 %) and metalloproteinases (Mmp2, -45 %; Mmp9, -60 %). Significance: Semaglutide improved the turnover of islet heparan sulfate proteoglycans, hyaluronan, chondroitin sulfate proteoglycans, and collagens in the islet ECM. Such changes should contribute to restoring a healthy islet functional milieu and should reduce the formation of cell-damaging amyloid deposits. Our findings also provide additional evidence for the involvement of islet proteoglycans in the pathophysiology of type 2 diabetes.

Voetmann LM, Underwood CR, Rolin B, Hansen AK, Kirk RK, Pyke C, Knudsen LB, Frederiksen KS (2022). "In vitro cell cultures of Brunner's glands from male mouse to study GLP-1 receptor function" Am J Physiol Cell Physiol 322(6):C1260-C1269. PubMed

Exocrine glands in the submucosa of the proximal duodenum secrete alkaline fluid containing mucus to protect the intestinal mucosa from acidic stomach contents. These glands, known as Brunner's glands, express high glucagon-like peptide 1 receptor (GLP-1R) levels. Previous studies have suggested that activation of the GLP-1R induces expression of barrier protective genes in Brunner's glands. Still, the lack of a viable in vitro culture of Brunner's glands has hampered additional studies of the functional consequences of GLP-1R activation. In this study, we established a procedure to isolate and culture cells derived from murine Brunner's glands. The isolated glandular cells retained functional GLP-1R expression in culture, making this in vitro system suitable for the study of GLP-1R activation. We found that cells derived from the Brunner's glands of mice pretreated with semaglutide contained significantly more mucus compared with Brunner's glands from vehicle-treated mice. Our data suggest a protective intestinal response upon semaglutide treatment, but further studies are required to leverage the full potential of cultured Brunner's gland cells.

Jones B, Burade V, Akalestou E, Manchanda Y, Ramchunder Z, Carrat G, Nguyen-Tu MS, Marchetti P, Piemonti L, Leclerc I, Thennati R, Vilsboll T, Thorens B, Tomas A, Rutter GA (2022). "In vivo and in vitro characterization of GL0034, a novel long-acting glucagon-like peptide-1 receptor agonist" Diabetes Obes Metab 24(11):2090-2101. PubMed

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

Li R, Ye Z, She D, Fang P, Zong G, Hu K, Kong D, Xu W, Li L, Zhou Y, Zhang K, Xue Y (2022). "Semaglutide May Alleviate Hepatic Steatosis in T2DM Combined with NFALD Mice via miR-5120/ABHD6" Drug Des Devel Ther . PubMed

Objective: Although the pathogenesis of non-alcoholic fatty liver disease (NAFLD) has been extensively studied, the role of its underlying pathogenesis remains unclear, and there is currently no approved therapeutic strategy for NAFLD. The purpose of this study was to observe the beneficial effects of Semaglutide on NAFLD in vivo and in vitro, as well as its potential molecular mechanisms. Methods: Semaglutide was used to treat type 2 diabetes mellitus (T2DM) combined with NAFLD mice for 12 weeks. Hepatic function and structure were evaluated by liver function, blood lipids, liver lipids, H&E staining, oil red staining and Sirius staining. The expression of α/β hydrolase domain-6 (ABHD6) was measured by qPCR and Western blotting in vivo and in vitro. Then, dual-luciferase reporter assay was performed to verify the regulation of the upstream miR-5120 on ABHD6. Results: Our data revealed that Semaglutide administration significantly improved liver function and hepatic steatosis in T2DM combined with NAFLD mice. Furthermore, compared with controls, up-regulation of ABHD6 and down-regulation of miR-5120 were found in the liver of T2DM+NAFLD mice and HG+FFA-stimulated Hepa 1-6 hepatocytes. Interestingly, after Semaglutide intervention, ABHD6 expression was significantly decreased in the liver of T2DM+NAFLD mice and in HG+FFA-stimulated Hepa 1-6 hepatocytes, while miR-5120 expression was increased. We also found that miR-5120 could regulate the expression of ABHD6 in hepatocytes, while Semaglutide could modulate the expression of ABHD6 through miR-5120. In addition, GLP-1R was widely expressed in mouse liver tissues and Hepa 1-6 cells. Semaglutide could regulate miR-5120/ABHD6 expression through GLP-1R. Conclusion: Our data revealed the underlying mechanism by which Semaglutide improves hepatic steatosis in T2DM+NAFLD, and might shed new light on the pathological role of miR-5120/ABHD6 in the pathogenesis of T2DM+NAFLD.