Loss of ZnT8 function protects against diabetes by enhanced insulin secretion

Om Prakash Dwivedi; Mikko Lehtovirta; Benoit Hastoy; Vikash Chandra; Nicole A. J. Krentz; Sandra Kleiner; Deepak Jain; Ann-Marie Richard; Fernando Abaitua; Nicola L. Beer; Antje Grotz; Rashmi B. Prasad; Ola Hansson; Emma Ahlqvist; Ulrika Krus; Isabella Artner; Anu Suoranta; Daniel Gomez; Aris Baras; Benoite Champon; Anthony J. Payne; Daniela Moralli; Soren K. Thomsen; Philipp Kramer; Ioannis Spiliotis; Reshma Ramracheya; Pauline Chabosseau; Andria Theodoulou; Rebecca Cheung; Martijn Van De Bunt; Jason Flannick; Maddalena Trombetta; Enzo Bonora; Claes B. Wolheim; Leena Sarelin; Riccardo C. Bonadonna; Patrik Rorsman; Benjamin Davies; Julia Brosnan; Mark I. Mccarthy; Timo Otonkoski; Jens O. Lagerstedt; Guy A. Rutter; Jesper Gromada; Anna L. Gloyn; Tiinamaija Tuomi; Leif Groop

doi:10.1038/s41588-019-0513-9

Loss of ZnT8 function protects against diabetes by enhanced insulin secretion

Om Prakash Dwivedi, Mikko Lehtovirta, Benoit Hastoy, Vikash Chandra, Nicole A. J. Krentz, Sandra Kleiner, Deepak Jain, Ann-Marie Richard, Fernando Abaitua, Nicola L. Beer, Antje Grotz, Rashmi B. Prasad, Ola Hansson, Emma Ahlqvist, Ulrika Krus, Isabella Artner, Anu Suoranta, Daniel Gomez, Aris Baras, Benoite ChamponAnthony J. Payne, Daniela Moralli, Soren K. Thomsen, Philipp Kramer, Ioannis Spiliotis, Reshma Ramracheya, Pauline Chabosseau, Andria Theodoulou, Rebecca Cheung, Martijn Van De Bunt, Jason Flannick, Maddalena Trombetta, Enzo Bonora, Claes B. Wolheim, Leena Sarelin, Riccardo C. Bonadonna, Patrik Rorsman, Benjamin Davies, Julia Brosnan, Mark I. Mccarthy, Timo Otonkoski, Jens O. Lagerstedt, Guy A. Rutter, Jesper Gromada, Anna L. Gloyn, Tiinamaija Tuomi, Leif Groop

Forskningsoutput: Tidskriftsbidrag › Artikel i vetenskaplig tidskrift › Peer review

Sammanfattning

A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D.

Originalspråk	engelska
Sidor (från-till)	1-22
Tidskrift	Nature Genetics
DOI	https://doi.org/10.1038/s41588-019-0513-9
Status	Published - 2019 nov. 1

FN:s Globala mål

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SDG 3 – God hälsa och välbefinnande

Ämnesklassifikation (UKÄ)

Medicinsk genetik och genomik (Här ingår: Genterapi)
Endokrinologi och diabetes

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10.1038/s41588-019-0513-9

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Dwivedi, O. P., Lehtovirta, M., Hastoy, B., Chandra, V., Krentz, N. A. J., Kleiner, S., Jain, D., Richard, A.-M., Abaitua, F., Beer, N. L., Grotz, A., Prasad, R. B., Hansson, O., Ahlqvist, E., Krus, U., Artner, I., Suoranta, A., Gomez, D., Baras, A., ... Groop, L. (2019). Loss of ZnT8 function protects against diabetes by enhanced insulin secretion. Nature Genetics, 1-22. https://doi.org/10.1038/s41588-019-0513-9

@article{adea1fb6d7214e0fb08b85a37539134e,

title = "Loss of ZnT8 function protects against diabetes by enhanced insulin secretion",

abstract = "A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D.",

author = "Dwivedi, \{Om Prakash\} and Mikko Lehtovirta and Benoit Hastoy and Vikash Chandra and Krentz, \{Nicole A. J.\} and Sandra Kleiner and Deepak Jain and Ann-Marie Richard and Fernando Abaitua and Beer, \{Nicola L.\} and Antje Grotz and Prasad, \{Rashmi B.\} and Ola Hansson and Emma Ahlqvist and Ulrika Krus and Isabella Artner and Anu Suoranta and Daniel Gomez and Aris Baras and Benoite Champon and Payne, \{Anthony J.\} and Daniela Moralli and Thomsen, \{Soren K.\} and Philipp Kramer and Ioannis Spiliotis and Reshma Ramracheya and Pauline Chabosseau and Andria Theodoulou and Rebecca Cheung and \{Van De Bunt\}, Martijn and Jason Flannick and Maddalena Trombetta and Enzo Bonora and Wolheim, \{Claes B.\} and Leena Sarelin and Bonadonna, \{Riccardo C.\} and Patrik Rorsman and Benjamin Davies and Julia Brosnan and Mccarthy, \{Mark I.\} and Timo Otonkoski and Lagerstedt, \{Jens O.\} and Rutter, \{Guy A.\} and Jesper Gromada and Gloyn, \{Anna L.\} and Tiinamaija Tuomi and Leif Groop",

year = "2019",

month = nov,

day = "1",

doi = "10.1038/s41588-019-0513-9",

language = "English",

pages = "1--22",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

}

Dwivedi, OP, Lehtovirta, M, Hastoy, B, Chandra, V, Krentz, NAJ, Kleiner, S, Jain, D, Richard, A-M, Abaitua, F, Beer, NL, Grotz, A, Prasad, RB , Hansson, O , Ahlqvist, E, Krus, U, Artner, I, Suoranta, A, Gomez, D, Baras, A, Champon, B, Payne, AJ, Moralli, D, Thomsen, SK, Kramer, P, Spiliotis, I, Ramracheya, R, Chabosseau, P, Theodoulou, A, Cheung, R, Van De Bunt, M, Flannick, J, Trombetta, M, Bonora, E, Wolheim, CB, Sarelin, L, Bonadonna, RC, Rorsman, P, Davies, B, Brosnan, J, Mccarthy, MI, Otonkoski, T, Lagerstedt, JO, Rutter, GA, Gromada, J, Gloyn, AL, Tuomi, T & Groop, L 2019, 'Loss of ZnT8 function protects against diabetes by enhanced insulin secretion', Nature Genetics, s. 1-22. https://doi.org/10.1038/s41588-019-0513-9

TY - JOUR

T1 - Loss of ZnT8 function protects against diabetes by enhanced insulin secretion

AU - Dwivedi, Om Prakash

AU - Lehtovirta, Mikko

AU - Hastoy, Benoit

AU - Chandra, Vikash

AU - Krentz, Nicole A. J.

AU - Kleiner, Sandra

AU - Jain, Deepak

AU - Richard, Ann-Marie

AU - Abaitua, Fernando

AU - Beer, Nicola L.

AU - Grotz, Antje

AU - Prasad, Rashmi B.

AU - Hansson, Ola

AU - Ahlqvist, Emma

AU - Krus, Ulrika

AU - Artner, Isabella

AU - Suoranta, Anu

AU - Gomez, Daniel

AU - Baras, Aris

AU - Champon, Benoite

AU - Payne, Anthony J.

AU - Moralli, Daniela

AU - Thomsen, Soren K.

AU - Kramer, Philipp

AU - Spiliotis, Ioannis

AU - Ramracheya, Reshma

AU - Chabosseau, Pauline

AU - Theodoulou, Andria

AU - Cheung, Rebecca

AU - Van De Bunt, Martijn

AU - Flannick, Jason

AU - Trombetta, Maddalena

AU - Bonora, Enzo

AU - Wolheim, Claes B.

AU - Sarelin, Leena

AU - Bonadonna, Riccardo C.

AU - Rorsman, Patrik

AU - Davies, Benjamin

AU - Brosnan, Julia

AU - Mccarthy, Mark I.

AU - Otonkoski, Timo

AU - Lagerstedt, Jens O.

AU - Rutter, Guy A.

AU - Gromada, Jesper

AU - Gloyn, Anna L.

AU - Tuomi, Tiinamaija

AU - Groop, Leif

PY - 2019/11/1

Y1 - 2019/11/1

N2 - A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D.

AB - A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D.

UR - https://www.scopus.com/pages/publications/85074370563

U2 - 10.1038/s41588-019-0513-9

DO - 10.1038/s41588-019-0513-9

M3 - Article

C2 - 31676859

SN - 1061-4036

SP - 1

EP - 22

JO - Nature Genetics

JF - Nature Genetics

ER -

Loss of ZnT8 function protects against diabetes by enhanced insulin secretion

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