Liraglutide Exerts Antidiabetic Effect via PTP1B and PI3K/Akt2 Signaling Pathway in Skeletal Muscle of KKAy Mice

Abstract

Background. Liraglutide (a glucagon-like peptide 1 analog) was used for the treatment of type 2 diabetes (T2DM) which could produce glucose-dependent insulin secretion. Aim. The aim was to investigate whether liraglutide could improve myofibril and mitochondria injury in skeletal muscle and the mechanisms in diabetic KKAy mice. Method. We divided the male KKAy mice into 2 groups: liraglutide group (250 μg/kg/day liraglutide subcutaneous injection) and model group; meanwhile, the male C57BL/6J mice were considered as the control. After 6 weeks, the ultrastructure of skeletal muscle was observed by electron microscope. The gene expressions of protein tyrosine phosphatase 1B (PTP1B), phosphatidylinositol 3-kinase (PI3K), and glucose transporter type 4 (GLUT4) were determined by real-time PCR. The protein levels of the above molecules and phospho-Akt2 (p-Akt2) were measured by Western blot. Results. Liraglutide significantly ameliorated the injury of mitochondria by increasing the number (+441%) and the area (+113%) of mitochondria and mitochondrial area/100 µm2 (+396%) in skeletal muscle of KKAy mice. The results of real-time PCR and Western blot showed that liraglutide downregulated PTP1B while it upregulated PI3K and GLUT4 (P < 0.01). The protein level of p-Akt2/Akt2 was also increased (P < 0.01). Conclusion. These results revealed that liraglutide could improve myofibril and mitochondria injury in skeletal muscle against T2DM via PTP1B and PI3K/Akt2 signaling pathway.

Roux-en-Y Gastric Bypass Improves Hepatic Glucose Metabolism Involving Down-Regulation of Protein Tyrosine Phosphatase 1B in Obese Rats

“…Glucose homeostasis has been shown to be tightly regulated by GLP-1, and continuous infusion with a potent GLP-1 receptor antagonist was shown to disrupt glucose tolerance [39]. Liraglutide, a long-acting GLP-1 analogue, has been shown to attenuate myofibril and mitochondria injury in skeletal muscle of patients with T2DM through PTP1B and the PI3K/Akt signaling pathway [40]. Moreover, Kanoski et al [41] reported that liraglutide reduces the expression of PTP1B, which could explain the effects of this compound on the enhancement of STAT3 phosphorylation after liraglutide-leptin co-administration.…”

Efek kandungan serat beras analog terhadap ekspresi GLUT4 otot rangka tikus diabetes

“…Studi lain membuktikan pemberian asam asetat, asam butirat, dan asam propionat dapat menstimulasi reseptor FFAR2 dan FFAR3 sel L di kolon yang dapat menstimulasi sekresi GLP-1 (33). Lebih lanjut, pemberian liraglutide yang merupakan analog GLP-1 berpengaruh dalam meningkatkan aktivasi phosphoinositide kinase 3 kinase (PI3K) dan AKT yang akan meningkatkan translokasi GLUT4 (34).…”

Design and synthesis of tricyclic terpenoid derivatives as novel PTP1B inhibitors with improved pharmacological property and in vivo antihyperglycaemic efficacy

“…1-Hydroxymethyl-abietane-p-methylbenzenesulfonate (10 4.1.8. General procedure 6: Zn/NaI-mediated reduction The solution of 1 equiv.…”

“…Though many anti-T2D drugs have emerged in the past decade 5,6 , traditional anti-T2D agents such as repaglinide, metformin, dipeptidyl peptidase-IV inhibitors, a-glucosidase inhibitors and glucagon-like peptide-1 agonists, and thiazolidinediones are still the most efficacious oral drugs in the first-line monotherapy of T2D 7 . It is undoubted that new insulin sensitisers will meet great needs of T2D patients 8,9 . Protein tyrosine phosphatase 1B (PTP1B) dephosphosphorylates the tyrosine-phosphorylated insulin receptor (IR) and the downstream insulin receptor substrate (IRS) to down regulate insulin transduction [10][11][12][13][14][15] . PTP1B inhibitors could potentially improve insulin sensitivity and normalise glucose levels and therefore could be a promising therapeutic strategy in the T2D patients.…”