Glucagon-like peptide-1 receptor agonists as a novel therapy in Type II Diabetes Mellitus
Introduction: Type II diabetes mellitus (T2DM) is a chronic metabolic disease in which pancreatic β-cells do not produce sufficient insulin and peripheral cells become insulin resistant.1 Insulin resistant cells have a reduced intake of glucose which leads to the hyperglycemic condition characteristic of T2DM. Glucagon-like peptide-1 receptor (GLP-1R) agonists are a relatively new T2DM therapy that function by stimulating insulin production and inhibiting glucagon secretion.2 Due to the rapidly rising rate of T2DM and increasing usage of GLP-1R agonists, many researchers have focused on determining the mechanism of action of the drug class. Studies have suggested that GLP-1R agonists exert their effects by increasing β cell proliferation and decreasing β-cell apoptosis by targeting the protein kinase B (Akt) pathway.3 GLP-1R agonists are also used for weight loss in obese T2DM patients and studies have shown that they do so by promoting satiety and targeting metabolic pathways.4–6 Methods: A diabetic mouse model was utilized and the TUNEL assay was conducted to quantify β cell apoptosis.6 βTC-6 cells were grown in a well plate, treated with 1nmol/L Liraglutide for 3-30 minutes and lysed before performing western blot to identify any changes in phosphorylation of proteins involved in the Akt pathway. Human adipose-derived stromal cells (hADSCs) were isolated from omental adipose tissue samples from non-diabetic patients.5 Cells were exposed to 0, 1, 10, 100 and 1000 nM concentrations of Exedrin-4 for 10 days and assessed for viability. Using western blot, samples were evaluated for alterations in phosphorylation of critical proteins in MAPK, P13K and PKA signaling pathways. Results: Liraglutide, a GLP-1R agonist, decreased B cell apoptosis in diabetic mice and elicited time dependent phosphorylation of Akt, FoxO1/FoxO3a and BAD proteins. There was significant hyperplasia in hADSCs exposed to Exedrin-4, a GLP-1R agonist. Exedrin-4 increased the amount of phosphorylated MEK1/2, Erk1/2, Akt, GSK-3B, PKA and CREB in a concentration dependent manner. Conclusions: Liraglutide exerts its anti-apoptotic effects by stimulating the Akt pathway, which results in downstream phosphorylation and thus, inactivation of the apoptotic proteins BAD and FoxO. Exedrin-4 elicits hyperplasia in hADSCs by increasing the expression of phosphorylated proteins in the MAPK, P13K and PKA pathways. These are just two mechanisms by which GLP-1R agonists affect the body. There is still a great need to gain a better understanding of GLP-1R agonists’ mechanism of action throughout the body as well as their potential side effects.
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- He X, Guan H, Liang W, et al. Exendin-4 modifies adipogenesis of human adipose-derived stromal cells isolated from omentum through multiple mechanisms. International Journal of Obesity. February 2018:1. doi:10.1038/s41366-018-0024-2
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