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Loss of ZnT8 function protects against diabetes by enhanced insulin secretion

Dwivedi, Om Prakash ; Lehtovirta, Mikko ; Hastoy, Benoit ; Chandra, Vikash ; Krentz, Nicole A. J. ; Kleiner, Sandra ; Jain, Deepak LU ; Richard, Ann-Marie ; Abaitua, Fernando and Beer, Nicola L. , et al. (2019) In Nature Genetics p.1-22
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... (More)
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. (Less)
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Nature Genetics
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1 - 22
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Nature Publishing Group
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1061-4036
DOI
10.1038/s41588-019-0513-9
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English
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adea1fb6-d721-4e0f-b08b-85a37539134e
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2019-11-03 17:30:27
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2019-11-05 02:17:45
@article{adea1fb6-d721-4e0f-b08b-85a37539134e,
  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 Lehtovirta, Mikko and Hastoy, Benoit and Chandra, Vikash and Krentz, Nicole A. J. and Kleiner, Sandra and Jain, Deepak and Richard, Ann-Marie and Abaitua, Fernando and Beer, Nicola L. and Grotz, Antje and Prasad, Rashmi B. and Hansson, Ola and Ahlqvist, Emma and Krus, Ulrika and Artner, Isabella and Suoranta, Anu and Gomez, Daniel and Baras, Aris and Champon, Benoite and Payne, Anthony J. and Moralli, Daniela and Thomsen, Soren K. and Kramer, Philipp and Spiliotis, Ioannis and Ramracheya, Reshma and Chabosseau, Pauline and Theodoulou, Andria and Cheung, Rebecca and Van De Bunt, Martijn and Flannick, Jason and Trombetta, Maddalena and Bonora, Enzo and Wolheim, Claes B. and Sarelin, Leena and Bonadonna, Riccardo C. and Rorsman, Patrik and Davies, Benjamin and Brosnan, Julia and Mccarthy, Mark I. and Otonkoski, Timo and Lagerstedt, Jens O. and Rutter, Guy A. and Gromada, Jesper and Gloyn, Anna L. and Tuomi, Tiinamaija and Groop, Leif},
  issn         = {1061-4036},
  language     = {eng},
  month        = {11},
  pages        = {1--22},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Loss of ZnT8 function protects against diabetes by enhanced insulin secretion},
  url          = {http://dx.doi.org/10.1038/s41588-019-0513-9},
  doi          = {10.1038/s41588-019-0513-9},
  year         = {2019},
}