InVivoSIM GLP-1 Receptor Agonist (Dulaglutide Biosimilar)

Glucagon-like peptide-1 receptor agonists are promising therapies in treating various obesity-associated diseases; however, the mechanisms are convoluted with the benefits of weight loss. Dulaglutide has weight-independent therapeutic effects on the liver, reducing hepatic steatosis and improving liver function. Dulaglutide reduces de novo lipogenesis, lipid droplet stability, inflammation, and oxidative stress in the liver and lipolysis in adipose tissue. Weight loss may play an important role in glucagon-like peptide-1 receptor agonists' effect on decreasing coronary vascular disease risk.

Background: Type 2 diabetes mellitus increases the risk of sarcopenia, which is characterized by decreased muscle mass, strength, and function. However, there are no effective drugs to treat diabetic sarcopenia, and its underlying mechanism remains unknown. Here, we aimed to determine whether the GLP-1 receptor agonist (GLP-1RA) dulaglutide (Dul) affects the progression of diabetic sarcopenia. Methods: db/db mice were injected intraperitoneally with 0.6 mg/kg dulaglutide for 10 weeks. Mouse muscle tissues were then pathologically evaluated and stained with F4/80 or MPO to detect macrophages and neutrophils, respectively. In addition, inflammatory factors and FNDC5 in the muscle tissues were detected using qRT-PCR. Moreover, C2C12 cells were induced to enable their differentiation into skeletal muscle cells, and muscle factor levels were then detected. Furthermore, changes in muscle factor levels were detected at various glucose concentrations (11 mM, 22 mM, and 44 mM). Results: In vivo, dulaglutide alleviated muscle tissue injury; reduced levels of the inflammatory factors, IL-1β, IL-6, CCL2, and CXCL1; and reversed the level of FNDC5 in the muscle tissues of db/db mice. In vitro, a C2C12 cell differentiation model was established through the observation of cell morphology and determination of myokine levels. Upon stimulation with high glucose, the differentiation of C2C12 cells was inhibited. Dulaglutide improved this inhibitory state by upregulating the levels of both FNDC5 mRNA and protein. Conclusions: Treatment with the GLP-1RA dulaglutide protects db/db mice against skeletal muscle injury by inhibiting inflammation and regulating the differentiation of myoblasts. High glucose inhibited the differentiation of C2C12 cells and decreased the mRNA and protein levels of myokines. Dulaglutide could reverse the differentiation state induced in C2C12 cells by high glucose.

Diabetic nephropathy is one of the most important chronic microvascular complications of diabetes, and its main feature is diabetic glomerulosclerosis. Endothelial sirtuin 1 (SIRT1) expression is related to aging, and reducing SIRT1 expression promotes endothelial cell aging. Plasminogen activator inhibitor-1 (PAI-1) can be synthesized in a variety of cells, such as endothelial cells. Dulaglutide is a glucagon-like peptide-1 (GLP-1) drug, and it can activate the GLP-1 receptor and promote the conversion of intracellular adenosine triphosphate to adenylate cyclase, thereby activating phosphokinase A, and regulating blood glucose levels effectively in the body. We analyzed the effects of Dulaglutide on inhibiting cell senescence by studying the effects of its different concentrations on telomerase activity and senescence-related gene expression. Our results suggest that Dulaglutide can alleviate high-glucose-induced oxidative stress in human retinal endothelial cells by restoring the expressions of SIRT1 and endothelial nitric oxide synthase (eNOS), thereby inhibiting the expression of PAI-1, and restoring telomerase activity. This suggests that the activity of retinal endothelial cells can be controlled by regulating the expression of SIRT1, so as to achieve the effect of treating diabetic retinopathy.

Dulaglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effects on muscle wasting due to aging are poorly understood. In the current study, we investigated the therapeutic potential and underlying mechanism of dulaglutide in muscle wasting in aged mice. Dulaglutide improved muscle mass and strength in aged mice. Histological analysis revealed that the cross-sectional area of the tibialis anterior (TA) in the dulaglutide-treated group was thicker than that in the vehicle group. Moreover, dulaglutide increased the shift toward middle and large-sized fibers in both young and aged mice compared to the vehicle. Dulaglutide increased myofiber type I and type IIa in young (18.5% and 8.2%) and aged (1.8% and 19.7%) mice, respectively, compared to the vehicle group. Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, decreased but increased by dulaglutide in aged mice. The expression of atrophic factors such as myostatin, atrogin-1, and muscle RING-finger protein-1 was decreased in aged mice, whereas that of the myogenic factor, MyoD, was increased in both young and aged mice following dulaglutide treatment. In aged mice, optic atrophy-1 (OPA-1) protein was decreased, whereas Toll-like receptor-9 (TLR-9) and its targeting inflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor-α [TNF-α]) were elevated in the TA and quadriceps (QD) muscles. In contrast, dulaglutide administration reversed this expression pattern, thereby significantly attenuating the expression of inflammatory cytokines in aged mice. These data suggest that dulaglutide may exert beneficial effects in the treatment of muscle wasting due to aging.