Neue Aspekte zur Betazelle und mögliche Therapieansätze

Zusammenfassung

In diesem Beitrag soll am Beispiel der metabolischen Stimulus-Sekretionskopplung der pankreatischen b-Zelle gezeigt werden, wie aus der Grundlagenforschung heraus neue Strategien zur Therapie des Typ-2-Diabetes-mellitus entwickelt werden können. Die metabolische Stimulus-Sekretionskopplung setzt die Verstoffwechselung von Stimuli der Insulinsekretion voraus, die Nährstoffcharakter besitzen. Die Änderung der ATP/ADP-Ratio in der b-Zelle löst dann die Exozytose der Insulingranula aus. Das glukosephosphorylierende Enzym Glukokinase fungiert als metabolischer Glukosesensor, der Änderungen der physiologischen Glukosekonzentrationen in den b-Zellen des Pankreas und auch der Leber an den Intermediärstoffwechsel, d.h. Glykolyse, Citratzyklus und Atmungskettenphosphorylierung, koppelt und hierdurch die Insulinsekretion und den Leberstoffwechsel positiv beeinflusst. Verschiedene Pharmaunternehmen (Roche, Merck, Astra-Zeneca, Lilly) haben inzwischen erste Glukokinase-aktivierende Substanzen entwickelt und ihre Wirksamkeit in der Behandlung von Tiermodellen des Typ-2-Diabetes belegt. Diese Glukokinase-Aktivatoren verhindern, dass die Glukokinase eine katalytisch inaktive strukturelle Konformation einnimmt. Sie erhöhen die Glukose-Affinität des Enzyms und stabilisieren eine katalytisch aktive Form des Glukokinaseproteins. Hierdurch steigern Glukokinase-Aktivatoren die glukoseinduzierte Insulinsekretion und hemmen die hepatische Glukoneogenese. Glukokinaseaktivatoren stellen eine interessante Innovation für die künftige Behandlung des Typ-2-Diabetes dar, da ihre Wirkung an der b-Zelle und der Leber von Änderungen der Blutglukosekonzentrationen abhängt.

Summary

Using the metabolic stimulus-secretion coupling of pancreatic beta cells as an example, this review illustrates how new strategies in the treatment of type 2 diabetes mellitus can be developed from the results of basic research. Metabolic stimulus-secretion coupling presupposes the metabolizing of those stimuli of insulin secretion that have the properties of nutritional substances. Changes in the ATP/ADP ratio within the beta cells will then trigger the release of insulin granules from them. Glucokinase, a glucose phosphorylating enzyme, functions as a metabolic glucose sensor, which couples changes in physiological glucose concentration in the pancreatic beta cells and in the liver to the intermediary metabolism, i.e. glycolysis, the citrate cycle and respiratory-chain phosphorylation. In this way insulin secretion and hepatic metabolism are positively influenced. Several pharmaceutical companies (Roche, Merck, Astra-Zeneca, Lilly) have recently developed first examples of glucokinase-activating compounds and demonstrated in animal models their efficacy in the treatment of type 2 diabetes mellitus. These glucokinase activators prevent glucokinase from changing into a catalytically inactive structure. They also increase glucose affinity of the enzyme and stabilize a catalytically active form of glucokinase proteins. In this way glucokinase activators increase glucose-induced insulin secretion and inhibit hepatic glucogenesis. Glucokinase activators are an interesting innovation in the future treatment of type 2 diabetes, because their action on beta cells and the liver is caused by changes in blood glucose concentration.

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