Loss of ZnT8 function protects against diabetes by enhanced insulin secretion
By
Om Prakash Dwivedi,
Mikko Lehtovirta,
Benoit Hastoy,
Vikash Chandra,
Sandra Kleiner,
Deepak Jain,
Ann-Marie Richard,
Nicola L. Beer,
Nicole A J Krentz,
Rashmi B Prasad,
Ola Hansson,
Emma Ahlqvist,
Ulrika Krus,
Isabella Artner,
Daniel Gomez,
Aris Baras,
Fernando Abaitua,
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,
Guy A Rutter,
Benjamin Davies,
Julia Brosnan,
Mark I McCarthy,
Timo Otonkoski,
Jens O. Lagerstedt,
Jesper Gromada,
Anna L Gloyn,
Tiinamaija Tuomi,
Leif Groop
Posted 22 Oct 2018
bioRxiv DOI: 10.1101/436030
(published DOI: 10.1038/s41588-019-0513-9)
A rare loss-of-function variant p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8) 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, especially compared with individuals matched for the genotype of a common T2D risk variant in SLC30A8, p.Arg325. In genome-edited human IPS-derived β-like cells, we establish that the p.Arg138* variant 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, which was also seen in isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aiming at maintaining insulin secretion capacity in T2D.
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