A New Concept in Antidiabetic Therapeutics: A Concerted Removal of Labile Iron and Intracellular Deposition of Zinc

Author:

Vinokur VladimirORCID,Berenshtein Eduard,Chevion Mordechai,Chevion DrorORCID

Abstract

Background: The inflammatory process is known to be an integral part of the pathophysiology of type 2 diabetes mellitus (T2DM). The “labile,” redox-active iron, serving as a catalyst in Fenton reaction, producing the deleterious reactive oxygen species, triggering and maintaining inflammation, is hypothesized to play a causative role in this process. Concenter Biopharma continued the development of a new platform of iron chelators (Zygosids), first initiated at the Hebrew University of Jerusalem, Israel (HUJI), acting via the novel mechanism, based on a sequestration of the labile redox-active iron and its substitution by zinc or gallium. The mode of action of Zygosids is based on the higher affinity of the metal-binding moiety of the complex to Fe<sup>3+</sup> in comparison to already bound ion, leading to rapid release of the ion of another metal and chelation of Fe<sup>3+</sup>. Concomitantly, zinc ion, released by the complex, is known for its antidiabetic and anti-inflammatory role.Methods: The therapeutic effect of zinc-desferrioxamine (Zygosid-50) and gallium-desferrioxamine, was tested on fat sand rat (<i>Psammomys obesus</i>) model of diet-induced T2DM and on Lepr<sup>db</sup> transgenic diabetic mice.Results: Zygosids demonstrated an ability to noticeably reduce blood glucose and insulin levels and improve the lipid profile. Moreover, an ability to mitigate insulin resistance by >90% was shown on the sand rat model. In addition, a potent anti-inflammatory effect, expressed as a diminishment of the proinflammatory cytokines in tissue levels, was demonstrated.Conclusion: Zygosids demonstrated robust therapeutic efficacy in treatment of T2DM. Importantly, no adverse effects were detected, in all the experiments, indicating high safety profile.

Publisher

Korean Diabetes Association

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