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Hamostaseologie 2001; 21(04): 159-166
DOI: 10.1055/s-0037-1619519
Original article
Schattauer GmbH

Typ-2-Diabetes, Insulinresistenz und endotheliale Dysfunktion

Type 2 diabetes, insulin resistance and endothelial dysfunction
B. M. Balletshofer
1   Medizinische Klinik, Universität Tübingen, Abteilung Endokrinologie, Stoffwechsel und vaskuläre Medizin (Ärztlicher Direktor: Prof. Dr. H. U. Häring)
,
H. U. Häring
1   Medizinische Klinik, Universität Tübingen, Abteilung Endokrinologie, Stoffwechsel und vaskuläre Medizin (Ärztlicher Direktor: Prof. Dr. H. U. Häring)
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Publication Date:
27 December 2017 (online)

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Zusammenfassung

Endotheliale Funktionsstörungen zeigen eine hohe Korrelation sowohl zu atherosklerotischen Gefäßerkrankungen als auch zu isoliert vorliegenden kardiovaskulären Risikofaktoren. Bei Patienten mit Diabetes mellitus, gestörter Glukosetoleranz und bereits bei normoglykämischen insulinresistenten Nachkommen von Typ-2-Diabetikern findet sich eine erhöhte Prävalenz endothelabhängiger Funktionsstörungen. Im Sinne antiatherosklerotischer Schutzmechanismen der Gefäßwand scheint vor allem der endothelabhängigen Stickoxid-(NO-)Produktion eine wesentliche Rolle zuzukommen. NO ist involviert in Schlüsselereignisse in der Pathogenese der Atherosklerose, wie z.B. Störungen der Vasotonusregulation, der Thrombozyten-Gefäßwand-Interaktion, der Monozytenadhäsion und der Proliferationshemmung der glatten Gefäßmuskulatur. Deshalb könnte die nachweisbare Reduktion der endothelialen NO-Bioverfügbarkeit bei Patienten mit Insulinresistenz zum beschleunigten Ablauf atherosklerotischer Gefäßveränderungen beitragen. Der Mangel an NO stellt am ehesten einen Summationseffekt aus metabolisch induzierter Hemmung der NO-Synthase-Aktivität (z.B. durch nicht veresterte Fettsäuren) und parallel beschleunigtem NO-Abbau durch oxidativen Stress dar. Die vermehrte Bildung reaktiver Sauerstoffverbindungen resultiert u.a. aus einer gesteigerten NAD(P)H-Oxidase-Aktivität, Interaktionen sog. »advanced glycosylated end products« (AGE) und einer Erhöhung der Aldose-Reduktaseaktivität bei Hyperglykämie mit einer Verarmung an NAD(P)H, einem Kosubstrat der NO-Synthese aus L-Arginin. Auf der anderen Seite lassen sich bei Diabetikern Störungen antioxidativer Abwehrsysteme nachweisen, wie z.B. im Sinne einer verminderten Superoxid-Dismutase-Aktivität. Somit entsteht bereits in der Phase des Prädiabetes ein Circulus vitiosus mit relevant pro-atherosklerotischem Potenzial. Interventionsstudien belegen eine potenzielle Reversibilität dieser funktionellen Gefäßschäden.

Summary

Endothelial dysfunction is highly correlated with vascular disease as well as with a cluster of cardiovascular risk factors. Patients with diabetes, pathological glucose tolerance and even insulin resistant normoglycemic first-degree relatives of patients with type 2 diabetes present a high prevalence of disturbed endothelial dependent functions. There is substantial evidence, that endothelium-derived nitric oxide (NO) plays here a major role regarding the antiatherosclerotic property of the vascular wall. NO is involved in key events in the pathogenesis of atherosclerotic disease, such as the regulation of the vascular tone, platelet-vessel wall interaction, monocyte adhesion and the inhibition of smooth muscle cell proliferation. Therefore reduced bioavailability of endothelium derived NO in patients with insulin resistance may contribute to the accelerated process of arteriosclerosis. The lack of NO seems to result from a combination of metabolically induced decrease of NO-synthase activity (e.g. by elevated levels of non-esterified free fatty acids) and over an inactivation of NO by oxidative stress. The enhanced generation of oxygen-derived free radicals is in part due to an increase in NAD(P)H-oxidase activity, interactions of advanced glycosylation end products (AGE) and a hyperglycemia induced increase in aldose reductase activity, leading to a further depletion of NAD(P)H, which is required for generation of NO from L-arginine. On the other side diabetes is associated with disturbed antioxidative defense mechanisms, such as reduced activity of superoxide dismutase. Thus already in the stage of “prediabetes” a vicious circle develops with a relevant proatherosclerotic impact. Recent intervention studies prove the potential reversibility of endothelial dysfunction.

Schlüsselwörter

Insulinresistenz - endotheliale Dysfunktion - endothelabhängige Vasodilatation - NO-Synthase - Diabetes mellitus - pathologische Glukosetoleranz

Keywords

Insulin resistance - endothelial dysfunction - endothelial dependent vasodilation - NO-synthase - diabetes mellitus - impaired glucose tolerance
 

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