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

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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.

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Abbreviations

T1DM:

Type 1 diabetes mellitus

T2DM:

Type 2 diabetes mellitus

GWAS:

Genome-wide association studies

ZiP:

Zinc importers

ZnTs:

Zinc transporters

MT:

Metallothioneins

Zn2+ :

Zinc ions

KATP :

Potassium channels activated by ATP

ATP:

Adenosine triphosphate

ADP:

Adenosine diphosphate

CDF:

Cationic diffusion facilitators

Ca2+ :

Calcium ions

K+ :

Potassium ions

SNP:

Single nucleotide polymorphism

IAPP:

Islet amyloid polypeptide

GABA:

Gamma aminobutyric acid

iPSCs:

Induced pluripotent stem cells

CRISPR:

Clustered regularly interspaced short palindromic repeats

siRNA:

Small interfering RNA

G6PC2:

Glucose-6-phosphatase catalytic subunit 2

PDX1:

Pancreatic and duodenal homeobox 1

MAPK:

Mitogen-activated kinase pathway

Glut2:

Glucose transporter 2

KO:

Knock down

ZnT8A:

ZnT8 autoantibodies

GADA:

GAD65 autoantibodies

IA-2A:

Islet antigen-2 autoantibodies

IAA:

Insulin autoantibodies

HLA:

Human leukocyte antigen

LADA:

Latent autoimmune diabetes in adults

HFD:

High-fat diet

5-HT:

5-Hydroxytryptamine

MCH:

Mean corpuscular hemoglobin

GESTALT:

Genome editing of synthetic target arrays for lineage tracing

LINNAEUS:

LINeage tracing by Nuclease-Activated Editing of Ubiquitous Sequences

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Acknowledgements

The authors would like to thank Gabriela Sagastegui and Michele Brennan for their advice in the academic writing.

Funding

The authors acknowledge support by Grants from the Research by funds from CONACyT (300638) and COECYTJAL (8084-2019; 7597).

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Authors and Affiliations

  1. Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Guadalajara, Mexico

    Carla P. Barragán-Álvarez, Eduardo Padilla-Camberos, Agustín Cota-Coronado & Nestor E. Díaz-Martínez

  2. Departamento de Fisiología y Desarrollo Celular, Instituto Nacional de Perinatología, Mexico City, Mexico

    Nestor F. Díaz

  3. Departamento de Cirugía Experimental, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico

    Claudia Hernández-Jiménez

  4. Departamento de Cirugía Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

    Carlos C. Bravo-Reyna

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  1. Carla P. Barragán-Álvarez
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All authors have seen and approved the manuscript and have contributed significantly to the paper. The idea for article, draft preparation, literature searching, and data analysis [CPBÁ]; draft preparation and critical revision [EPC]; draft preparation and critical revision [NFD]; draft preparation and literature searching [AC-C]; literature searching and data analysis [CHJ]; literature searching and data analysis [CCBR]; supervision, critical revision, approval of the version to be published, and submission [EDM].

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Barragán-Álvarez, C.P., Padilla-Camberos, E., Díaz, N.F. et al. Loss of Znt8 function in diabetes mellitus: risk or benefit?. Mol Cell Biochem 476, 2703–2718 (2021). https://doi.org/10.1007/s11010-021-04114-4

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