Reactive aldehydes – second messengers of free radicals in diabetes mellitus

Abstract

Elevated levels of pro-oxidants and various markers of oxidative tissue damage were found in diabetic patients, indicating involvement of oxidative stress in the pathogenesis of diabetes mellitus (DM). On one side, physiological levels of reactive oxygen species (ROS) play an important role in redox signaling of various cells, while on the other, excessive ROS production can jeopardize the integrity and physiological functions of cellular macromolecules, in particular proteins, thus contributing to the pathogenesis of DM. Reactive aldehydes, especially 4-hydroxynonenal (HNE), are considered as second messengers of free radicals that act both as signaling molecules and as cytotoxic products of lipid peroxidation causing long-lasting biological consequences, in particular by covalent modification of macromolecules. Accordingly, the HNE and related reactive aldehydes may play important roles in the pathophysiology of DM, both in the development of the disease and in its progression and complications due to the following: (i) exposure of cells to supraphysiological levels of 4-hydroxyalkenals, (ii) persistent and sustained generation of 4-hydroxyalkenals that progressively affect vulnerable cells that lack an efficient bioactive aldehyde neutralization system, (iii) altered redox signaling influenced by reactive aldehydes, in particular by HNE, and (iv) induction of extracellular generation of similar aldehydes under secondary pathological conditions, such as low-grade inflammation.

Keywords::

• diabetes mellitus
• reactive oxygen species
• lipid peroxidation
• reactive aldehydes
• 4-hydroxynonenal
• 4-hydroxydodecadienal
• advanced lipoxidation end products
• advanced glycation end products
• reactive carbonyl compounds
• PPARδ

Declaration of interest

The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.

The study was supported by the Croatian Ministry of Science, Education and Sports and by the COST CM1001 Action of the European Union. Shlomo Sasson is the Adolf D. and Horty Storch Chair in Pharmaceutical Sciences, at the Faculty of Medicine, The Hebrew University of Jerusalem, Israel.