Complete loss of SLC30A8 in humans improves glucose metabolism and beta cell function

Genetic association studies have demonstrated that partial loss of SLC30A8 function protects against type 2 diabetes (T2D) in humans, but the impact of complete loss of SLC30A8 function remains unknown. From whole-exome and genome sequencing of 100,814 participants in the Pakistan Genome Resource, we identified fifteen SLC30A8 knockouts, including homozygotes for a variant enriched in South Asians (Gln174Ter) and 615 heterozygotes for loss-of-function (LoF) variants. T2D risk was lower in SLC30A8 LoF hetero- and homozygotes, and the protective effect strengthens in a gene dose-dependent manner (ORadditive=0.63 [0.53-0.78, p=7.5E-07], ORrecessive=0.27 [0.09-0.80, p=0.018]). Recall-by-genotype of SLC30A8 LoF hetero- and homozygotes and their family members with oral glucose tolerance tests showed a gene dose-dependent reduction in glucose levels coupled with elevated insulin. Corrected Insulin Response, Disposition Index, and Insulin Sensitivity Index in LoF hetero- and homozygotes indicated higher glucose-stimulated insulin secretion with preserved beta cell function. These data suggest that therapeutic knockdown of SLC30A8 , up to and including complete knockout, may treat T2D safely and effectively. ### Competing Interest Statement D.S. has received funding from Regeneron Pharmaceuticals, Eli Lilly & Company, Novartis, Merck, Astra Zeneca, NGM Biopharmaceuticals Inc., GSK, Astellas Pharma Inc., and Novo Nordisk. Sequencing for 37,804 exomes was performed at the Regeneron Genetics Center, Tarrytown, New York. C.K., L.B.L., R.Z., M.E.C., D.P.D., A.B.G., A.M.G., and J.E.D. are employees of Novartis. A.A., J.L.H., and C.U. are employees of AstraZeneca. K.T., M.A., and I.K. are employees of Astellas Pharma. A.R.S. and J.L.R. are employees of the Regeneron Genetics Center. ### Funding Statement Part of this work has been funded by the National Institutes of Health (NIH). Industry-affiliated authors were funded by their respective employers, as listed in the "Competing Interests" statement. The Center for Non-Communicable Diseases (CNCD) received funding from the Regeneron Genetics Center, AstraZeneca, Astellas, and Novartis for work reported in this study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board (IRB) at the Center for Non-Communicable Diseases (IRB: 00007048, IORG0005843, FWAS00014490) gave ethical approval for this work. The National Bioethics Committee for Research Pakistan (Reference number: NBC-756) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All academic requests to access relevant data should be sent to ks76{at}cncdpk.com. CNCD will ask relevant investigators to sign a data confidentiality agreement which would limit any investigator not to de-identify any of the study participants.