Introduction: Klotho is a membrane protein predominantly expressed in the kidneys, and its discovery was serendipitously made through gene-targeting experiments conducted on mice. Klotho has a favorable role in the regulation of multiple cellular processes, such as aging, oxidative stress, inflammation, and apoptosis. This regulation occurs through the targeting of diverse signaling molecules, cell membrane receptors, and ion channels, achieved by physical contacts or enzymatic activities of Klotho. This review examines the role of Klotho in the epigenetic regulation of molecules associated with diabetes.

Methods: Authors conducted a thorough literature search using the PubMed®, Web of Science™, and Scopus®. Relevant articles up to September 2023, published in the English language were considered. We reviewed research databases searching for studies that included keywords klotho, epigenetic, and diabetes.

Results: 14 related papers about epigenetic modification of proteins involved in diabetes pathogenesis were selected to be included in this narrative review. In the studies, the kidney was the most investigated organ regarding this correlation. Also, phosphorylation and methylation were the common epigenetic modifications of proteins by Klotho.

Conclusion: Klotho has a significant role in the maturation of adipocytes and the regulation of systemic glucose metabolism, exhibiting a strong association with the pathogenesis of diabetes. Both epigenetic alterations and the modulation of protein phosphorylation by Klotho play significant roles in the regulation of Klotho expression and the modulation of other molecules implicated in the etiology of diabetes.