Reactome | DPP4 binds DPP4 inhibitors

DPP4 binds DPP4 inhibitors

Stable Identifier

R-HSA-9709179

Type

Reaction [binding]

Species

Homo sapiens

Compartment

extracellular region

ReviewStatus

5/5

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Dipeptidyl peptidase-4 (DPP4) is a serine exopeptidase that cleaves X-proline or X-alanine dipeptides from the N-terminus of polypeptides. It is expressed on the surface of most cells but also in a soluble form in blood plasma. DPP4 can cleave a broad range of substrates including growth factors, chemokines, neuropeptides, and vasoactive peptides, with the cleaved products usually losing their biological activity. DPP4 plays a major role in glucose metabolism where it is responsible for the degradation of incretins such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP, formerly called gastric inhibitory peptide). Incretins decrease blood sugar by increasing consumption of sugar by the body, mainly through stimulating insulin production in the pancreas, and by reducing the release of sugar from glucagon by the liver (Drucker 2006). Incretins secreted into the bloodstream are subject to rapid inactivation by DPP4 (Mentlein et al. 1993) thus inhibitors of this enzyme are therapeutic agents used to control type 2 diabetes mellitus (T2DM aka NIDDM). The inhibition of DPP4 increases levels of GLP-1, which inhibits glucagon production from pancreatic alpha cells and increases production of insulin from pancreatic beta cells.

DPP4 inhibitors ("gliptins") are a class of oral hypoglycemic agents used to treat T2DM (Deacon 2019). Their mechanism of action is to increase incretin levels which inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels (Ahrén et al. 2002, Ahrén et al. 2004). The first gliptin, sitagliptin, was FDA-approved in 2006.

Literature References

PubMed ID	Title	Journal	Year
11978683	Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes Simonsson, E, Båvenholm, P, Ahrén, B, Sandqvist, M, Larsson, H, Holmes, D, Dickinson, S, Efendic, S, Jansson, PA, Torgeirsson, H, Eriksson, JW, Landin-Olsson, M	Diabetes Care	2002
30828317	Physiology and Pharmacology of DPP-4 in Glucose Homeostasis and the Treatment of Type 2 Diabetes Deacon, CF	Front Endocrinol (Lausanne)	2019
15126524	Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes Ahrén, B, Svensson, M, Holmes, D, Jansson, PA, Schweizer, A, Landin-Olsson, M	J Clin Endocrinol Metab	2004