Gliptine

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Sitagliptin, lead substance of the new (as of July 2007) antidiabetic class of dipeptidyl-peptidase-4 inhibitors

Gliptins , dipeptidyl peptidase-4 inhibitors , dipeptidyl peptidase 4 inhibitors , also known as DPP4 inhibitors , DPP-4 inhibitors or incretin enhancers , are substances that reduce the breakdown of the hormone glucagon-like peptide 1 (GLP-1) by the Inhibit the enzyme dipeptidyl peptidase 4 (DPP-4). They represent a class of active substances among the antidiabetics .

Metabolic effect of glucagon-like peptide 1 (GLP-1)

The hormone GLP-1 is one of the incretin hormones. In addition to the islet cells of the pancreas, it is formed in the upper small intestine, the distal ileum, and the colon. When eating food, its level rises in a glucose-dependent manner ( incretin effect ) and leads to a reduction in blood glucose by increasing insulin secretion by beta cells and reducing glucagon secretion by alpha cells of the pancreas. Furthermore, extra-pancreatic effects lead to a slower gastric emptying and a stimulation of the feeling of satiety. The activity of GLP-1 is limited by the breakdown of GLP-1 by dipeptidyl peptidase 4 into an inactive metabolite .

Pharmacology of the gliptins

Dipeptidyl peptidase 4 inhibitors prevent the degradation of glucagon-like peptide 1 (GLP-1) by inhibiting the degrading enzyme. As a result, the release of insulin only increases after ingestion of food, since only then do increased blood levels of GLP-1 exist. This active principle prevents hypoglycaemia from occurring . Medicinal products that contain these active ingredients can be taken orally and are well tolerated.

Inhibition Mechanisms

Transition State Inhibitors

Transition state inhibitors are currently of no therapeutic value. They interrupt the process of splitting GLP-1 in the active part of the splitting enzyme DPP-4. While the first step, the formation of the intermediate (a brief intermediate state), is still being carried out, the spatial structure of these inhibitors hinders the further progress of the cleavage of the substrate .

Inclusion inhibitors

The active center of the DPP 4 contains a hydrophobic pocket. This is an area of ​​the enzyme in which non-polar , non-ionic amino acids predominate. The inclusion inhibitors have a hydrophobic part of the molecule that has a similar non-polar nature, which means that they can be located in this hydrophobic region of the active center. The inclusion inhibitor contains one or more positively charged chemical groups elsewhere on the molecule, which facilitates penetration into the negatively charged environment of the active center. The presence of the inhibitor in the active site prevents the cleavage of GLP-1 by taking the place of GLP-1. This process is called competitive inhibition . Inclusion inhibitors currently represent the therapeutically relevant group.

Medicinal substances

literature

  • Richard Daikeler, Götz Use, Sylke Waibel: Diabetes. Evidence-based diagnosis and therapy. 10th edition. Kitteltaschenbuch, Sinsheim 2015, ISBN 978-3-00-050903-2 , pp. 158-160.

Individual evidence

  1. ^ W. Siegenthaler, HE Blum (Ed.): Clinical Pathophysiology. Thieme, Stuttgart 2006, ISBN 3-134-49609-7 , p. 77. Restricted preview in the Google book search.