|Target Name||Glucagon-like peptide 1 |
|Type of Target||Clinical trial target |
|Drug Potency against Target||Albiglutide||EC50 = 1.5 nM|||
|Action against Disease Model||AVE0010||Lixisenatide protected Ins-1 cells (a rat-derived beta-cell line) from both lipid- and cytokine-induced apoptosis. More importantly, Lixisenatide also prevented lipotoxicity-induced insulin depletion in h uMan islets and preserved insulin production, storage and pancreatic beta-cell function in vitro. In animal models of diabetes, Lixisenatide improved basal blood glucose and HbA(1c) with a rapid onset and sustained duration of action, and prevented the deterioration of pancreatic responsiveness and glucose homeostasis. Lixisenatide also delayed gastric emptying and reduced food intake.|||
|The Effect of Target Knockout, Knockdown or Genetic Variations||Previous studies have shown that the incretin glucagon-like peptide 1 (GLP-1) helps to normalise insulin signalling in type 2 diabetes. GLP-1 also plays important roles in neuronal activity and brain functions. We tested the specific role of GLP-1 receptors in synaptic plasticity and cognitive processes in a GLP-1 receptor knockout (Glp1r(-/-)) mouse model. In an open field assessment, no general difference in exploratory and anxiety was found except for a small decrease in running speed was found (p<0.05). In an object recognition task, Glp1r(-/-) mice explored objects in a similar way to WT controls but did not learn to differentiate between novel and familiar objects (p<0.05) while in an object relocation task, no impairment was observed. In a water maze task, Glp1r(-/-) mice were impaired in the acquisition phase (p<0.001), and also in the probe recall task (p<0.05). LTP in area CA1 of the hippocampus was severely impaired in Glp1r(-/-) mice (p<0.0001). Paired-pulse facilitation was also impaired at 25ms interstimulus interval (p<0.05) but not at longer intervals. The results demonstrate that the murine GLP-1R plays an important role in the control of synaptic plasticity and in some forms of memory formation. The results shed light on the molecular processes that underlie the neuroprotective properties of GLP-1 analogues in animal models of Alzheimer's disease.|||
|Ref 1||ChemMedChem. 2010 Feb 1;5(2):179-85.Medicinal Chemistry of Incretin Mimetics and DPP-4 Inhibitors. To Reference|
|Ref 2||Cancer Res. 2011 Apr 1;71(7):2643-53. Epub 2011 Feb 15.Protein kinase C inhibitor sotrastaurin selectively inhibits the growth of CD79 mutant diffuse large B-cell lymphomas. To Reference|
|Ref 3||Behav Brain Res. 2009 Dec 14;205(1):265-71. Epub 2009 Jun 30.Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice: Interaction between type 2 diabetes and Alzheimer's disease. To Reference|
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Deputy Director of Center
for Computational Science and Engineering
Professor in Department of Pharmacy
National University of Singapore, Singapore
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