The Botnia Study / Loss of ZnT8 function protects against diabetes by enhanced insulin secretion.
The study identified a biological mechanism through which a genetic variant protects against type 2 diabetes: changes in a gene that makes a zinc transporter protein reduce the risk of type 2 diabetes by enhancing insulin secretion from the pancreas.
Type 2 diabetes is caused by a combination of lifestyle and genetic factors. One such genetic factor is a variation in a gene called SLC30A8, which encodes a protein that carries zinc. This protein is important, since zinc is essential in ensuring that insulin has the right shape in the beta-cells of the pancreas.
For almost ten years it has been known that changes in the SLC30A8 gene can reduce the risk of getting type 2 diabetes, but the mechanisms have remained unknown. In order to study these mechanisms, members from families with a rare mutation in the gene were recruited and their response to sugar in a meal was studied. The test group was compared to a control group with people who have a similar genetic background and lifestyle, but do not carry the same variant of mutation in the SLC30A8. This ensured that the effects studied would be because of the mutation, and not because of another genetic or life-style factor. The results showed that people with the mutation have higher insulin and lower blood sugar levels, reducing their risk of diabetes.
An international collaboration also studied pancreatic cells with and without the mutation in the lab, and carried out experiments in mice and human cellular material to explore exactly what was happening when the function of the SLC30A8 gene changed. In tandem, the human and model system data show enhanced glucose-stimulated insulin secretion combined with enhanced conversion of the pre-hormone proinsulin to insulin as the explanation for protection against type 2 diabetes. The results position this zinc transporter as an appealing and safe target for antidiabetic therapies.
Dwivedi OP, Lehtovirta M, Hastoy B, Chandra V, Kleiner S, Jain D, Richard A-M, Beer N, 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 MIM, Otonkoski T, Lagerstedt JO, Gromada J, Gloyn AL, Tuomi T, Groop LC. Loss of ZnT8 function protects against diabetes by enhanced insulin secretion. Nat Genet 51: 1596-1606, 2020 (doi: 10.1038/s41588-019-0513-9).