GIP und GLP-1-Rezeptoragonismus in der Therapie des Typ 2 Diabetes mit Fokus auf Tirzepatid

Zusammenfassung

Die Wirkung von Inkretinen trägt wesentlich zur Aufrechterhaltung einer normalen oralen Glukosetoleranz bei gesunden Personen bei. Diese wird größtenteils durch zwei Darmhormone vermittelt: das Glukose-abhängige insulinotrope Polypeptid (GIP) und das Glukagon-ähnliche Peptid 1 (Glucagon-like peptide-1, GLP-1). Dieser Mechanismus ist bei Patienten/Patientinnen mit Typ-2-Diabetes deutlich reduziert. Inkretin-basierte Therapien wie GLP-1-Rezeptoragonisten und Dipeptidylpeptidase-4 (DPP-4)-Inhibitoren sind heute etablierte Substanzklassen in der Therapie des Typ-2-Diabetes. Neue Forschungsergebnisse, insbesondere mit Agonisten, die sowohl an GIP- als auch GLP-1-Rezeptoren wirken, steigerten das Interesse an GIP in der Therapie des Typ-2-Diabetes. In der Bauchspeicheldrüse verstärken beide Inkretine die Glukose-abhängige Insulinsekretion. GLP-1 unterdrückt glukose-abhängig die Glukagon-Sekretion, während GIP die Glukagon-Sekretion besonders bei niedrigen Plasmaglukosekonzentrationen stimuliert. Im Fettgewebe fördert GIP die Durchblutung, erhöht die Glukoseaufnahme und Triglyzerid-Speicherung und kann bei hohen Glukosespiegeln und niedrigen Plasmainsulinspiegeln eine direkte lipolytische Wirkung haben. Tierexperimentelle Studien deuten darauf hin, dass GIP wie auch GLP-1 einen Effekt auf die Sättigungsregulation im Gehirn haben kann.

Tirzepatid wurde so entwickelt, dass es das physiologische Inkretin-Gleichgewicht nachahmt, indem es sowohl an GIP- als auch GLP-1-Rezeptoren wirkt. Jüngste Daten aus dem SURPASS-Programm klinischer Phase-3-Studien mit Tirzepatid weisen darauf hin, dass sich der neuartige Wirkstoff besonders stark auf die Blutzuckersenkung und die Körpergewichtsreduktion auswirkt. Die Effekte übertreffen bezüglich glykämischer Kontrolle, Insulinsekretion, Glukagon-Suppression, Insulinsensitivität und Körpergewichtsreduktion sowohl die Wirkung potenter GLP-1-Rezeptoragonisten als auch von Basalinsulinen, sodass der Einfluss von GIP neu bewertet werden muss. Der vorliegende Übersichtsartikel fasst die physiologischen Effekte von GIP und GLP-1 zusammen. Um den genauen Wirkmechanismus von Tirzepatid und anderen GIP- und GLP-1-Rezeptoragonisten vollständig zu verstehen, bedarf es weiterer Forschung.

Abstract

The incretin effect is a major contributor to maintaining normal oral glucose tolerance in healthy individuals. The incretin effect is largely mediated by two gut-derived hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). This mechanism is substantially reduced in patients with type 2 diabetes. Incretin-based therapies such as GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are now established in the therapy of type 2 diabetes. New research results, especially with agonists acting on both GIP and GLP-1 receptors, increased the interest in GIP in the therapy of type 2 diabetes. In the pancreas, both incretins enhance glucose-dependent insulin secretion. GLP-1 suppresses glucose-dependent glucagon secretion, while GIP stimulates glucagon secretion especially at low plasma glucose concentrations. In adipose tissue, GIP promotes blood flow, increases glucose uptake and triglyceride storage, and may have a direct lipolytic effect when glucose levels are high and plasma insulin levels are low. Animal studies suggest that GIP as well as GLP-1 has an effect on the satiation regulation in the brain.

Tirzepatide acts on both GIP and GLP-1 receptors. Recent data from the SURPASS series of Phase 3 clinical trials with tirzepatide indicate that this novel agent has especially strong effects on lowering of glycated haemoglobin and body weight reduction. The effects exceed those of potent GLP-1 receptor agonists in terms of glycaemic control, insulin secretion, glucagon suppression, insulin sensitivity and body weight reduction, as well as of basal insulin preparations, so that the influence of GIP has to be reassessed. The present review summarises the physiological effects of GIP and GLP-1. More research is necessary to fully understand the exact mechanism of action of tirzepatide and other agonists of both the GIP and GLP-1 receptor.

Schlüsselwörter

Glukagon-ähnliches Peptid 1 - Glukose-abhängiges insulinotropes Polypeptid - Inkretin - Tirzepatid - Typ 2 Diabetes

Keywords

Glucagon-like peptide-1 - glucose-dependent insulinotropic polypeptide - incretin - tirzepatide - type 2 diabetes

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