Researchers have known for almost ten years that changes in the SLC30A8 gene can reduce the risk of getting type 2 diabetes, but not how this happened. What was known is that SLC30A8 encodes a protein that carries zinc, which is essential for ensuring that insulin, has the right shape in the beta-cells of the pancreas.
Now the scientists have recruited new members from families with a rare mutation in the SLC30A8 gene to study how they responded to sugar in a meal.
“A definite strength of our study is we could study families. We could compare people with the mutation with their relatives who do not have the mutation, but who have similar genetic background and lifestyle,” said departmental chief doctor Tiinamaija Tuomi, MD, PhD, from Helsinki University Hospital, who co-led the study (“Loss of ZnT8 function protects against diabetes by enhanced insulin secretion”) that appears in Nature Genetics. “This way, we could make sure that the effects we were seeing were definitely because of this gene, and not because of another genetic or lifestyle factor.”
The results showed that people with the mutation have higher insulin and lower blood sugar levels, reducing their risk for diabetes. “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,” the investigators wrote.
“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.”
A large 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 understand exactly what was happening when the function of the SLC30A8 gene changed.
“The work is a collaborative effort bringing pharma and academia together and researchers from multiple European Countries. It is a tour de force, since we were able to measure the impact of the mutation in many different systems, including human beta-cells,” said Anna Gloyn, DPhil, who co-led the study, a professor of molecular genetics & metabolism at the Wellcome Centre for Human Genetics, University of Oxford.
“We found that this mutation had collateral consequences on key functions of pancreatic beta cells and during their development. Importantly, this study exposes the extraordinary molecular complexity behind a specific gene variation conferring risk or protection from type 2 diabetes,” added Benoit Hastoy, PhD, postdoctoral fellow and co-first author from the Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford.
“Taken together, the human and model system data show enhanced glucose-stimulated insulin secretion combined with enhanced conversion of the prehormone proinsulin to insulin as the most likely explanation for protection against type 2 diabetes,” said Om Prakash Dwidedi, PhD, postdoctoral researcher and the co-first author of the study from the Institute for Molecular Medicine Finland (FIMM), University of Helsinki.
Better understanding of the genetic and pathological mechanism behind diabetes can open up new ways of preventing or treating type 2 diabetes.
“Our results position this zinc transporter as an appealing and safe target for antidiabetic therapies. If a drug can be developed that mimics the protective effect of this mutation, beta-cell function could be preserved and the insulin secretion capacity in diabetic patients maintained,” said Leif Groop, MD, PhD, a senior professor from the University of Helsinki and Lund University, who directed the study.
Dwivedi OP, Lehtovirta M, Hastoy B, Chandra V, Kleiner S, Jain D, Richard A, 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. Loss of ZnT8 function protects against diabetes by enhanced insulin secretion. Nature Genetics | VOL 51 | NOVEMBER 2019 | 1596–1606.Go To Nature Genetics