SLC30A8 gene is famous for its connections to prevention of type 2 diabetes. In it, scientists discovered multiple variants influencing predisposition to diabetes – from common alleles increasing the risk to rare mutations with prevention-like effects. 70% of people carry a variant at 325th position (at least in France, Sladek 2007), which increases the prevalence of diabetes by 14% (Rutter 2015). At the same time, we know about extremely rare mutations in Icelandic and Finnish populations, which lower the risk by up to 83% (Flannick 2014), essentially preventing the onset of type 2 diabetes.

Those protective mutations – resulting in the loss of function of SLC30A8 – were recently investigated in a comprehensive approach, involving epidemiological evidence (n = 14,375), induced pluripotent stem cells modified with CRISPR, as well as in vivo experiments in mice, serving as models of genetic diabetes.

A definite strength of our study is that 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 life-style. Tiinamaija Tuomi

Scientists focused on a variant present in 0.2% of the Finnish population: change at 138th position to arginine. Moreover, they checked the effects of reversing the common 325th position allele to tryptophan.

Mutations lead to the loss of enzyme translated from SLC30A8:

This enzyme, ZnT8, was found in the study to interfere with insulin secretion. Cells and humans with impaired ZnT8 respond faster to glucose and are able to more efficiently convert prehormone proinsulin to insulin. After 30 minutes of the oral glucose tolerance test, individuals with protective mutations had ~1.4 higher insulin level in comparison to the control group, which corresponds to general mechanisms of type 2 diabetes.

The role of zinc in the observed mechanism was not clear. Researchers measured inner-cell levels of zinc and found lower concentrations in SLC30A8-deficient cells. Although ions of zinc are essential for insulin crystallization, it remains unknown why a lack of ZnT8 results in enhanced insulin secretion. However, this evidence adds even more weight to the notion that diabetes is heavily influenced by genetics.

Gene therapy for diabetes?

The results and developed models could pave the way to the clinical application. Scientists suggested targeting directly ZnT8:

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. Leif Groop on possibility of gene therapy for diabetes type2

Publication: Dwivedi, O. P., Lehtovirta, M., Hastoy, B., Chandra, V., Krentz, N. A. J., Kleiner, S., … Groop, L. (2019). Loss of ZnT8 function protects against diabetes by enhanced insulin secretion. Nature Genetics. DOI:10.1038/s41588-019-0513-9.

Cover photo: Hanif Omar.

Content photo: Diapedia.org.