Loss of Znt8 function in diabetes mellitus: risk or benefit?

Carla P Barragán-Álvarez, Eduardo Padilla-Camberos, Nestor F Díaz, Agustín Cota-Coronado, Claudia Hernández-Jiménez, Carlos C Bravo-Reyna, Nestor E Díaz-Martínez

Molecular and cellular biochemistry 2021 Jul

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The zinc transporter 8 (ZnT8) plays an essential role in zinc homeostasis inside pancreatic β cells, its function is related to the stabilization of insulin hexameric form. Genome-wide association studies (GWAS) have established a positive and negative relationship of ZnT8 variants with type 2 diabetes mellitus (T2DM), exposing a dual and controversial role. The first hypotheses about its role in T2DM indicated a higher risk of developing T2DM for loss of function; nevertheless, recent GWAS of ZnT8 loss-of-function mutations in humans have shown protection against T2DM. With regard to the ZnT8 role in T2DM, most studies have focused on rodent models and common high-risk variants; however, considerable differences between human and rodent models have been found and the new approaches have included lower-frequency variants as a tool to clarify gene functions, allowing a better understanding of the disease and offering possible therapeutic targets. Therefore, this review will discuss the physiological effects of the ZnT8 variants associated with a major and lower risk of T2DM, emphasizing the low- and rare-frequency variants.

Citation

Carla P Barragán-Álvarez, Eduardo Padilla-Camberos, Nestor F Díaz, Agustín Cota-Coronado, Claudia Hernández-Jiménez, Carlos C Bravo-Reyna, Nestor E Díaz-Martínez. Loss of Znt8 function in diabetes mellitus: risk or benefit? Molecular and cellular biochemistry. 2021 Jul;476(7):2703-2718