A comprehensive review on zinc(II) complexes as anti-diabetic agents: The advances, scientific gaps and prospects

Zinc has gained notable attention in the development of potent anti-diabetic agents, due to its role in insulin storage and secretion, as well as its reported insulin mimetic properties. Consequently, zinc(II) has been complexed with numerous organic ligands as an adjuvant to develop anti-diabetic agents with improved and/or broader scope of pharmacological properties. This review focuses on the research advances thus far to identify the major scientific gaps and prospects. Peer-reviewed published data on the anti-diabetic effects of zinc(II) complexes were sourced from different scientific search engines, including, but not limited to "PubMed", "Google Scholar", "Scopus" and ScienceDirect to identify potent anti-diabetic zinc(II) complexes. The complexes were subcategorized according to their precursor ligands. A critical analysis of the outcomes from published studies shows promising leads, with Zn(II) complexes having a "tri-facet" mode of exerting pharmacological effects. However, the promising leads have been flawed by some major scientific gaps. While zinc(II) complexes of synthetic ligands with little or no anti-diabetic pharmacological history remain the most studied (about 72 %), their toxicity profile was not reported, which raises safety concerns for clinical relevance. The zinc(II) complexes of plant polyphenols; natural ligands, such as maltol and hinokitiol; and supplements, such as ascorbic acid (a natural antioxidant), l-threonine and l-carnitine, showed promising insulin mimetic and glycemic control properties but remain understudied and lack clinical validation, in spite of their minimal safety concerns and health benefits. A paradigm shift toward probing (including clinical studies) supplements, plant polyphenol and natural ligands as anti-diabetic zinc(II) complex is, therefore, recommended. Also, promising anti-diabetic Zn(II) complexes of synthetic ligands should undergo critical toxicity evaluation to address possible safety concerns.