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

The zinc transporter 8 (ZnT8) plays an essential role in zinc homeostasis inside pancreatic beta 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.

Automated summary

ZnT8 plays a crucial role in zinc homeostasis inside pancreatic beta cells and is linked to the stabilization of insulin hexameric form. Studies have shown dual and controversial effects of ZnT8 variants on the risk of developing type 2 diabetes mellitus.