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 (OR_additive=0.63 [0.53-0.78, p=7.5E-07], OR_recessive=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.