Loss of ZnT8 function protects against diabetes by enhanced insulin secretion.,Nature Genetics

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Loss of ZnT8 function protects against diabetes by enhanced insulin secretion.
Nature Genetics ( IF 31.7 ) Pub Date : 2019-11-01 , DOI: 10.1038/s41588-019-0513-9
Om Prakash Dwivedi ₁ , Mikko Lehtovirta ₁ , Benoit Hastoy ₂ , Vikash Chandra ₃ , Nicole A J Krentz ₄ , Sandra Kleiner ₅ , Deepak Jain ₆ , Ann-Marie Richard ₇ , Fernando Abaitua ₄ , Nicola L Beer ₂ , Antje Grotz ₂ , Rashmi B Prasad ₈ , Ola Hansson _{1,

8} , Emma Ahlqvist ₈ , Ulrika Krus ₈ , Isabella Artner ₈ , Anu Suoranta ₁ , Daniel Gomez ₅ , Aris Baras ₅ , Benoite Champon ₄ , Anthony J Payne ₄ , Daniela Moralli ₄ , Soren K Thomsen ₂ , Philipp Kramer ₄ , Ioannis Spiliotis ₂ , Reshma Ramracheya ₂ , Pauline Chabosseau ₉ , Andria Theodoulou ₉ , Rebecca Cheung ₉ , Martijn van de Bunt _{2,

4} , Jason Flannick _{10,

11} , Maddalena Trombetta ₁₂ , Enzo Bonora ₁₂ , Claes B Wolheim ₈ , Leena Sarelin ₁₃ , Riccardo C Bonadonna ₁₄ , Patrik Rorsman ₂ , Benjamin Davies ₄ , Julia Brosnan ₇ , Mark I McCarthy _{2,

4,

15} , Timo Otonkoski ₃ , Jens O Lagerstedt ₆ , Guy A Rutter ₉ , Jesper Gromada ₅ , Anna L Gloyn _{2,

4,

15} , Tiinamaija Tuomi _{1,

13,

16} , Leif Groop _{1,

8}

Affiliation

Institute for Molecular Medicine Finland, Helsinki University, Helsinki, Finland.
Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
Stem Cells and Metabolism Research Program and Biomedicum Stem Cell Centre, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
Regeneron Pharmaceuticals, Tarrytown, NY, USA.
Department of Experimental Medical Science, Lund University, Lund, Sweden.
Pfizer Inc., Cambridge, MA, USA.
Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
Section of Cell Biology, Department of Medicine, Imperial College London, Imperial Centre for Translational and Experimental Medicine, Hammersmith, Hospital, London, UK.
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy.
Folkhälsan Research Center, Helsinki, Finland.
Department of Medicine and Surgery, University of Parma School of Medicine and Azienda Ospedaliera Universitaria of Parma, Parma, Italy.
Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.
Abdominal Center, Endocrinology, Helsinki University Central Hospital, Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland.

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.

中文翻译：

ZnT8 功能的丧失可通过增强胰岛素分泌来预防糖尿病。

SLC30A8 中编码锌转运蛋白 8 (ZnT8) 的罕见功能丧失等位基因 p.Arg138* 在芬兰西部富集，可预防 2 型糖尿病 (T2D)。我们招募了已识别携带者的亲属，结果表明，由于葡萄糖反应性和胰岛素原转化增强，保护与更好的胰岛素分泌相关，特别是与与 SLC30A8（p.Arg325）常见 T2D 风险等位基因基因型匹配的个体相比时。在基因组编辑的人类诱导多能干细胞 (iPSC) 衍生的 β 样细胞中，我们确定 p.Arg138* 等位基因由于单倍体不足而导致 SLC30A8 表达减少。在人 β 细胞中，SLC30A8 的缺失会导致葡萄糖反应性增加和 KATP 通道功能降低，类似于从 T2D 保护性等位基因 p.Trp325 携带者中分离出的胰岛。这些数据使 ZnT8 成为维持 T2D 胰岛素分泌能力的有吸引力的治疗靶点。

更新日期：2019-11-01

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