@article{Dwivedi:2019:10.1038/s41588-019-0513-9,
author = {Dwivedi, OP and Lehtovirta, M and Hastoy, B and Chandra, V and Krentz, NAJ and Kleiner, S and Jain, D and Richard, A-M and Abaitua, F and Beer, NL and Grotz, A and Prasad, RB and Hansson, O and Ahlqvist, E and Krus, U and Artner, I and Suoranta, A and Gomez, D and Baras, A and Champon, B and Payne, AJ and Moralli, D and Thomsen, SK and Kramer, P and Spiliotis, I and Ramracheya, R and Chabosseau, P and Theodoulou, A and Cheung, R and van, de Bunt M and Flannick, J and Trombetta, M and Bonora, E and Wolheim, CB and Sarelin, L and Bonadonna, RC and Rorsman, P and Davies, B and Brosnan, J and McCarthy, MI and Otonkoski, T and Lagerstedt, JO and Rutter, GA and Gromada, J and Gloyn, AL and Tuomi, T and Groop, L},
doi = {10.1038/s41588-019-0513-9},
journal = {Nature Genetics},
pages = {1596--1606},
title = {Loss of ZnT8 function protects against diabetes by enhanced insulin secretion.},
url = {http://dx.doi.org/10.1038/s41588-019-0513-9},
volume = {51},
year = {2019}
}

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TY  - JOUR
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.
AU  - Dwivedi,OP
AU  - Lehtovirta,M
AU  - Hastoy,B
AU  - Chandra,V
AU  - Krentz,NAJ
AU  - Kleiner,S
AU  - Jain,D
AU  - Richard,A-M
AU  - Abaitua,F
AU  - Beer,NL
AU  - Grotz,A
AU  - Prasad,RB
AU  - Hansson,O
AU  - Ahlqvist,E
AU  - Krus,U
AU  - Artner,I
AU  - Suoranta,A
AU  - Gomez,D
AU  - Baras,A
AU  - Champon,B
AU  - Payne,AJ
AU  - Moralli,D
AU  - Thomsen,SK
AU  - Kramer,P
AU  - Spiliotis,I
AU  - Ramracheya,R
AU  - Chabosseau,P
AU  - Theodoulou,A
AU  - Cheung,R
AU  - van,de Bunt M
AU  - Flannick,J
AU  - Trombetta,M
AU  - Bonora,E
AU  - Wolheim,CB
AU  - Sarelin,L
AU  - Bonadonna,RC
AU  - Rorsman,P
AU  - Davies,B
AU  - Brosnan,J
AU  - McCarthy,MI
AU  - Otonkoski,T
AU  - Lagerstedt,JO
AU  - Rutter,GA
AU  - Gromada,J
AU  - Gloyn,AL
AU  - Tuomi,T
AU  - Groop,L
DO  - 10.1038/s41588-019-0513-9
EP  - 1606
PY  - 2019///
SN  - 1061-4036
SP  - 1596
TI  - Loss of ZnT8 function protects against diabetes by enhanced insulin secretion.
T2  - Nature Genetics
UR  - http://dx.doi.org/10.1038/s41588-019-0513-9
UR  - https://www.ncbi.nlm.nih.gov/pubmed/31676859
UR  - https://www.nature.com/articles/s41588-019-0513-9
UR  - http://hdl.handle.net/10044/1/74608
VL  - 51
ER  - 

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