Glucagon-like peptide-1 receptor agonist, liraglutide, attenuated retinal thickening in spontaneously diabetic Torii fatty rats

Abstract

Background This study aims to investigate the effect of the glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) liraglutide on retinal pathological findings as compared with insulin and hydralazine using an animal model of type 2 diabetes with obesity, hypertension, and hyperlipidemia. Methods Male spontaneously diabetic Torii (SDT) fatty rats at 8 weeks of age were randomly assigned to three groups: the liraglutide group (SDT-lira, n = 6) received a subcutaneous injection of liraglutide from the age of 8 to 16 weeks, the SDT-ins-hyd group (n = 6) was provided both insulin against hyperglycemia and hydralazine against hypertension to match levels of both blood glucose and blood pressure to those of the liraglutide group, and the control group of SDT fatty rats (SDT-vehicle, n = 7) and a nondiabetic control group of Sprague–Dawley rats (SD, n = 7) were injected with vehicle only. Both eyeballs of all groups were collected at the age of 16 weeks. Results Retinal thickness, which was found in the SDT-vehicle group, was significantly prevented to similar levels in both the SDT-lira and SDT-ins-hyd groups. Immunohistological analysis revealed that GLP-1 receptor was not expressed in the retina of all rats. The ocular protein expression of monocyte chemoattractant protein-1, which causes a proinflammatory situation, was significantly upregulated in all SDT fatty rats as compared to SD rats, but the expression levels were similar between all SDT fatty rats. With regard to neovascularization in the eyes, there were no significant differences in protein expressions of vascular endothelial growth factor, CD31, or endothelial nitric oxide synthase in all rats. Conclusions The present study indicates that liraglutide prevents retinal thickening, dependent on blood glucose and blood pressure levels in SDT fatty rats without ocular neovascularization. However, the effects did not improve the ocular proinflammatory state.

Angiotensin II type 1a receptor deficiency alleviates muscle atrophy after denervation

“…Protein samples extracted from frozen gastrocnemius muscle (15 µg) were separated by sodium dodecyl sulfate–polyacrylamide gel electrophoresis using NuPAGE 4–12% Bis–Tris gels and the XCell SureLock Mini-Cell system (Thermo Fisher Scientific) as described previously 48 . After blocking, the membranes were cut around molecular weight of each targeted molecule and were incubated overnight at 4 °C with primary antibodies against FoxO1 (rabbit monoclonal; #9454; 1:1000; Cell Signaling Technology, Danvers, MA, USA), phospho-FoxO1(Ser256) (rabbit monoclonal; #9461; 1:1000; Cell Signaling Technology), NF-κB p65 (rabbit monoclonal; #8242; 1:1000; Cell Signaling Technology), and phospho-NF-κB p65 (Ser536) (rabbit monoclonal; #3033; 1:1000; Cell Signaling Technology).…”

An Update on Strategies to Deliver Protein and Peptide Drugs to the Eye

“…However, enhanced prosurvival signaling pathways and a decrease in extracellular glutamate levels are two major drawbacks of the therapy. Liraglutide was found to inhibit the upregulation of inflammatory cytokines in the retina in fatty rodents without provoking neovascularization of the eye and lowered retinal thickening of the inner nuclear layer of the retina when injected subcutaneously . GLP-1R agonists, such as dulaglutide, liraglutide, lixisenatide, exenatide, and semaglutide have shown a reduced risk of developing open-angle glaucoma .…”

“…Liraglutide was found to inhibit the upregulation of inflammatory cytokines in the retina in fatty rodents without provoking neovascularization of the eye and lowered retinal thickening of the inner nuclear layer of the retina when injected subcutaneously. 62 GLP-1R agonists, such as dulaglutide, liraglutide, lixisenatide, exenatide, and semaglutide have shown a reduced risk of developing open-angle glaucoma. 63 No increased risk of DR was observed in the AngioSafe 1 research NCT02671864, which aimed to clarify the relationship between exposure to GLP-1R agonists and DR through clinical and preclinical study methods.…”

Angiotensin II type 1a receptor deficiency alleviates muscle atrophy after denervation

“…Frozen sections sliced to a thickness of 10 μm were prepared using a cryostat (HM 550; Thermo Fisher Scienti c, Rockford, IL, USA). Double-color immuno uorescent staining was performed to evaluate the diameter of each type IIb and I ber as described previously 41 ; brie y, the dried sections were incubated with the following primary antibodies at 4°C overnight: anti-type IIb MyHC isoform immunoglobulin (Ig)G1 (MyHCIIb; 1 : 100; F18; Developmental Studies Hybridoma Bank (DSHB), the University of Iowa, Iowa City, IA, USA), anti-type I myosin heavy chain (MyHC) isoform IgG2b (MyHCI; 1 : 200; BA-F8; DSHB),) and anti-laminin IgG (H+L) (1 : 3000; NB300-144; Novus Biologicals, Centennial, CO, USA). After washing three times with phosphate-buffered saline, the sections were incubated with the following uorescent-labeled secondary antibodies at room temperature for 1 h: Alexa Flour 568-labeled goat anti-mouse IgG1 (1 : 500; Invitrogen Corporation, Carlsbad, CA, USA), Alexa Flour 488-labeled goat anti-mouse IgG2b (1 : 500; Invitrogen Corporation), and Alexa Flour 488-labeled goat anti-rabbit IgG (H+L) (1 : 500; Invitrogen Corporation).…”