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Pathway Description
Sitagliptin Action Pathway
Homo sapiens
Drug Action Pathway
Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor used for the management of type 2 diabetes mellitus. Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor used in conjunction with diet and exercise to improve glycemic control in patients. Inhibition of DPP-4 by sitagliptin slows DPP-4 mediated inactivation of incretins like GLP-1. GLP-1 is then able to go on to stimulate insulin secretion in beta cells. GLP-1 activates GLP-1 receptors on beta cells, triggering the Gs signaling cascade by activating adenylate cyclase to produce cAMP. cAMP activates protein kinase A (PKA) and Rap guanine nucleotide exchange factor 4 (EPAC2). PKA inhibits the ATP-sensitive potassium channel, preventing K+ efflux, leading to an accumulation of K+ ions in the cell causing depolarization of the cell. This depolarization activates the voltage gated L-type calcium channel, causing calcium influx. PKA may also directly activate the voltage gated L-type calcium channel. EPAC2 activates the ryanodine receptor on the endoplasmic reticulum, causing calcium to move from the endoplasmic reticulum and into the cytosol. The high concentration of calcium ions in the cytosol triggers insulin release via exocytosis, lowering blood glucose levels. Sitagliptin may also increase insulin biosynthesis, increase beta cell proliferation, decrease beta cell apoptosis and decrease glucagon secretion since these are also effects mediated by GLP-1.
References
Sitagliptin Pathway References
National Center for Biotechnology Information (2021). PubChem Compound Summary for CID 16133831, Glucagon-like peptide-I(7-36) amide. Retrieved August 27, 2021 from https://pubchem.ncbi.nlm.nih.gov/compound/Glucagon-like-peptide-I_7-36_-amide.
Knudsen LB, Pridal L: Glucagon-like peptide-1-(9-36) amide is a major metabolite of glucagon-like peptide-1-(7-36) amide after in vivo administration to dogs, and it acts as an antagonist on the pancreatic receptor. Eur J Pharmacol. 1996 Dec 30;318(2-3):429-35. doi: 10.1016/s0014-2999(96)00795-9.
Pubmed: 9016935
Rolin B, Deacon CF, Carr RD, Ahren B: The major glucagon-like peptide-1 metabolite, GLP-1-(9-36)-amide, does not affect glucose or insulin levels in mice. Eur J Pharmacol. 2004 Jun 28;494(2-3):283-8. doi: 10.1016/j.ejphar.2004.05.013.
Pubmed: 15212985
Müller, T. D., Finan, B., Bloom, S. R., D'Alessio, D., Drucker, D. J., Flatt, P. R., Fritsche, A., Gribble, F., Grill, H. J., Habener, J. F., Holst, J. J., Langhans, W., Meier, J. J., Nauck, M. A., Perez-Tilve, D., Pocai, A., Reimann, F., Sandoval, D. A., Schwartz, T. W., Seeley, R. J., … Tschöp, M. H. (2019). Glucagon-like peptide 1 (GLP-1). Molecular metabolism, 30, 72–130. https://doi.org/10.1016/j.molmet.2019.09.010
Wishart, D., Knox, C., Guo, A., Shrivastava, S., Hassanali, M., Stothard, P., . . . Woolsey, J. (2005, June). Sitagliptin. Retrieved August 29, 2021, from https://go.drugbank.com/drugs/DB01261
Islam, M. S. (2002). The Ryanodine receptor calcium channel OF -Cells: MOLECULAR regulation and Physiological significance. Diabetes, 51(5), 1299–1309. https://doi.org/10.2337/diabetes.51.5.1299
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