Loss of ZnT8 function protects against diabetes by enhanced insulin secretion
Dwivedi OP., Lehtovirta M., Hastoy B., Chandra V., Kleiner S., Jain D., Richard A-M., Beer NL., Krentz NAJ., Prasad RB., Hansson O., Ahlqvist E., Krus U., Artner I., Gomez D., Baras A., Abaitua F., 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., Rutter GA., Davies B., Brosnan J., McCarthy MI., Otonkoski T., Lagerstedt JO., Gromada J., Gloyn AL., Tuomi T., Groop L.
<jats:title>Abstract</jats:title><jats:p>A rare loss-of-function variant p.Arg138* in <jats:italic>SLC30A8</jats:italic> 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 <jats:italic>SLC30A8</jats:italic>, p.Arg325. In genome-edited human IPS-derived β-like cells, we establish that the p.Arg138* variant results in reduced <jats:italic>SLC30A8</jats:italic> expression due to haploinsufficiency. In human β-cells loss of <jats:italic>SLC30A8</jats:italic> leads to increased glucose responsiveness and reduced K<jats:sub>ATP</jats:sub> 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.</jats:p>