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.
The pathogenesis of nonalcoholic fatty liver disease non-alcoholic steatohepatitis (naSH) has not been fully elucidated, and there are currently no effective treatments for naSH. The aim of the present study was to explore the therapeutic effects of the glucagon-like peptide-1 (GlP-1) receptor agonist liraglutide (lrG) on naSH and the underlying mechanisms. c57Bl6J mice were fed a high-fat diet (HFd) for 8 weeks to induce hepatic steatosis, and then lrG was injected subcutaneously for 4 weeks. The expression of sterol regulatory element-binding protein 1 (SreBP1) and adenosine monophosphate-activated protein kinase (aMPK) as well as the phosphorylation of mechanistic target of rapamycin (mTor) and p70 ribosomal S6 kinase (p70S6K) were determined by western blot analysis. The intracellular distribution of SREBP1 was assessed by immunofluorescence staining. The results revealed that lrG treatment ameliorated HFd-induced hepatic lipid accumulation and inhibited body weight gain. in addition, LRG treatment significantly suppressed the expression of hepatic SreBP1 as well as the phosphorylation of mTor and p70S6K; it also increased the phosphorylation of aMPK and acetyl coenzyme a carboxylase. Furthermore, lrG treatment inhibited the hepatic nuclear translocation of SreBP1. it was suggested that the GlP-1 receptor agonist lrG may have ameliorated hepatic steatosis by activating the aMPK/mTor/SreBP1 signaling pathway as opposed to inhibiting body weight gain.
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