Glucagon-like peptide 1 receptor agonist ameliorates the insulin resistance function of islet β cells via the activation of PDX-1/JAK signaling transduction in C57/BL6 mice with high-fat diet-induced diabetes

Abstract

Long-term exposure to a high-fat diet (HFD) causes glucotoxicity and lipotoxicity in islet β cells and leads to the development of metabolic dysfunctions. Reductions in pancreatic and duodenal homeobox-1 (PDX-1) expression have been shown to induce type 2 diabetes mellitus by causing impairments to islet β cells. Glucagon-like peptide 1 (GLP-1) treatment reduces endogenous insulin resistance in HFD-induced type 2 diabetes mellitus. In the present study, the underlying mechanism by which GLP-1 exerts its function in type 2 diabetes mellitus was investigated. The effect of liraglutide (GLP-1 receptor agonist) administration on glucose tolerance, insulin release, and glucose-dependent insulinotropic polypeptide level was detected in a HFD-induced diabetes C57/BL6 mouse model. Moreover, the role of liraglutide administration on the activity of PDX-1 was quantified to demonstrate the association between the two indicators. The results showed that administration of liraglutide could ameliorate the impairments to β cells due to HFD consumption. Liraglutide restored the insulin capacity and stimulated glucose disposal by improving the function and increasing the number of islet β cells. Furthermore, the hyperplasia and redundant function of islet α cells were inhibited by liraglutide treatment as well. At the molecular level, administration of liraglutide induced the expression of PDX-1, MafA, p-JAK2 and p-Stat3 in HFD model to relatively normal levels. It was suggested that the effect of liraglutide-induced activation of GLP-1 was exerted via activation of PDX-1 rather than its function in decreasing body weight. The study demonstrated that GLP-1 played an essential role in type 2 diabetes mellitus.

Regulatory effect of chemerin and therapeutic efficacy of chemerin‑9 in pancreatogenic diabetes mellitus

“…The present study revealed that PdX1 mrna levels decreased during the development of PDM but significantly increased following the administration of chemerin-9, which alleviated ir. This is consistent with previously published studies reporting that PdX1 expression was decreased in patients with T2dM (30,31) and that the activation of the PdX1/JaK signal transduction cascade in c57Bl/6 mice ameliorates the ir of dM (32). Thus, this supports the notion that the impaired proliferation of pancreatic β-cells resulting from decreased PdX1 expression may be causally related to the pathogenesis of PdM, and that restoring PdX1 signaling using chemerin-9 may explain the protective role against ir in PdM.…”

Effect of liraglutide on the Janus kinase/signal transducer and transcription activator (JAK/STAT) pathway in diabetic kidney disease in db/db mice and in cultured endothelial cells

“…Very few studies have evaluated the effect of a GLP‐1 analog on the JAK/STAT pathway. Using a mouse model with diabetes induced by a high‐fat diet, Hao et al demonstrated that liraglutide reduced p‐JAK2 and p‐STAT3 expression. Also in mice, Tong et al found that a high‐fat diet resulted in severe non‐alcoholic fatty liver disease (NAFLD), whereas liraglutide reduced bodyweight and improved glucose tolerance and liver triglyceride composition.…”

Alzheimer's disease and metabolic syndrome: A link from oxidative stress and inflammation to neurodegeneration

“…The two main incretins are the gastric inhibitory polypeptide (GIP) and the glucagon‐like peptide type 1 (GLP‐1), which have been the subject of research to design new drugs that are useful in the treatment of T2DM. Incretins reduce blood glucose levels, through the stimulation of insulin release (Hao, Zhang, Li, & Tian, ). In animal models, it has been observed that the central nervous system decreases the inflammatory response mediated by reactive astrocytes (Iwai et al, ; Qin, Chong, Rodriguez, & Pugazhenthi, ).…”