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Review
. 2021 Jul;476(7):2703-2718.
doi: 10.1007/s11010-021-04114-4. Epub 2021 Mar 5.

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

Carla P Barragán-Álvarez  1 , Eduardo Padilla-Camberos  1 , Nestor F Díaz  2 , Agustín Cota-Coronado  1 , Claudia Hernández-Jiménez  3 , Carlos C Bravo-Reyna  4 , Nestor E Díaz-Martínez  5
Affiliations
Review

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

Carla P Barragán-Álvarez et al. Mol Cell Biochem. 2021 Jul.

Abstract

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.

Keywords: Insulin; Low-frequency variants; Type-2 diabetes mellitus; Zinc; Zinc transporters; ZnT8.

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