Diabetes, Insulin, Insulinanaloga und Karzinome

Zusammenfassung

Zahlreiche epidemiologische Studien haben einen Zusammenhang zwischen einem erhöhten Krebsrisiko und Typ-2-Diabetes ebenso wie Adipositas gezeigt. Auch wenn die genauen zugrunde liegenden Mechanismen noch unklar sind, scheint eine Hyperinsulinämie in Gegenwart einer Insulinresistenz ein wichtiger Faktor zu sein. Die Hyperinsulinämie begünstigt möglicherweise die Tumorgenese, da Insulin nicht nur metabolische Wirkung besitzt, sondern in hoher Konzentration auch mitogen ist. Zudem könnte die Suszeptibilität von Tumorzellen gegenüber Insulin durch Änderung des Insulinrezeptorbesatzes erhöht sein. Eine Diabetestherapie mit Insulin oder Sulfonylharnstoffen, die zu erhöhten exogenen oder endogenen Insulinspiegeln führt, scheint mit einem erhöhten Krebsrisiko vergesellschaftet zu sein, während die Gabe von Metformin oder Thiazolidinedionen, die mit einem Abfall der Insulinkonzentration einhergeht, zu einer Risikoreduktion führt. Allerdings ist angesichts zahlreicher epidemiologischer Studien, die auf einen Zusammenhang zwischen einem erhöhten Krebsrisiko und einer verminderten körperlichen Bewegung hindeuten, nicht ausgeschlossen, dass die Hyperinsulinämie in Gegenwart einer Insulinresistenz möglicherweise nur ein Surrogatparameter für eine reduzierte physische Aktivität ist. In den vergangenen Jahren sind eine Reihe von Analoginsulinen entwickelt worden, die aufgrund der veränderten Struktur möglicherweise eine andere mitogene Wirkung als Humaninsulin haben. Für das langwirksame Analoginsulin Glargin ergaben die, wenn auch widersprüchlichen, In-vitro-Daten einen Hinweis auf eine gesteigerte Mitogenität, die sich im Tierversuch jedoch nicht bestätigte. In diesem Jahr sind sechs klinische Studien erschienen, die sich mit dem Zusammenhang zwischen der Gabe des lang wirksamen Analoginsulins Glargin (Lantus®) und der Entstehung von Krebs beschäftigten. Die aktuellen klinischen Daten erlauben nicht den Rückschluss auf einen Zusammenhang zwischen einer Behandlung mit Insulin Glargin und einem erhöhten Krebsrisiko. Andererseits liegen keine prospektiven Studien vor, die in Risikopopulationen eine Beeinflussung des Krebsrisiko ausschließen. In zukünftigen Studien sollte untersucht werden, ob eine Subpopulation, die durch eine langsamere Metabolisierung von Insulin Glargin in vivo charakterisiert ist, möglicherweise ein erhöhtes Krebsrisiko aufweist.

In der vorliegenden Arbeit geben wir einen Überblick über den Zusammenhang zwischen Diabetes mellitus, seiner Behandlung mit Analoginsulinen und Krebs.

Abstract

Numerous epidemiological studies have demonstrated an association between increased risk of cancer development and progression and type 2 diabetes mellitus as well as obesity. The underlying mechanisms remain elusive, but hyperinsulinaemia in the presence of insulin resistance appears to be an important factor. Hyperinsulinaemia may favour tumorigenesis, as insulin has not only metabolic actions, but is also mitogenic at high concentrations. Besides, susceptibility of tumour cells against insulin may be increased due to changes in the insulin receptor profile. A diabetes therapy with insulin or sulfonylureas, which leads to elevated exogenous or endogenous insulin levels, appears to be related with an increased cancer risk, whereas administration of metformin or thiazolidinediones, which is associated with a decrease of insulin concentrations, results in risk reduction. However, in light of the numerous epidemiological studies showing an association between increased cancer risk and reduced physical activity one cannot exclude that hyperinsulinaemia in the presence of insulin resistance is only a surrogate parameter of reduced physical activity. In the past years, several insulin analogues have been developed which may have altered mitogenic actions compared to human insulin due to their structural changes. For the long-acting analogue insulin glargine, in vitro data, though controversial, pointed to an increased mitogenicity that was, however, not confirmed by in vivo studies. Recently, six clinical studies have been published that analysed the association between the application of insulin glargine (Lantus®) and cancer development. The current clinical data do not allow the conclusion that treatment with insulin glargine is associated with increased cancer risk. On the other hand, prospective studies that exclude an impact on cancer risk in risk populations are currently not available. Future studies are required to investigate whether a subpopulation characterised by a less rapid metabolization of insulin glargine in vivo may be at increased cancer risk.

In the present article, we give an overview on the association between diabetes mellitus, its treatment with insulin analogues, and cancer.

Schlüsselwörter

Krebs - Brustkrebs - Mitogenität - Insulin Glargin

Keywords

cancer - breast cancer - mitogenecity - insulin glargine

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