Complete loss of SLC30A8 in humans improves glucose metabolism and beta cell function
Lindsey B. Lamarche, Christopher Koch, Shareef Khalid, Maleeha Khan, Richard Zessis, Matthew E. Clement, Daniel P. Denning, Allison B. Goldfine, Igor Splawski, Ali Abbasi, Jennifer Harrow, Christina Underwood, Kazuhisa Tsunoyama, Makoto Asaumi, Ikuyo Kou, Juan L. Rodríguez-Flores, Alan R. Shuldiner, Asif Rasheed, Muhammad Jahanzaib, Muhammad Rehan Mian, Muhammad Bilal Liaqat, Usman Abdulsalam, Riffat Sultana, Anjum Jalal, Muhammad Hamid Saeed, Shahid Abbas, Fazal Rehman Memon, Mohammad Ishaq, Allan Gurtan, John Dominy, Danish Saleheen
Abstract
Abstract Aims/hypothesis Genetic association studies have demonstrated that partial loss of SLC30A8 Function protects against type 2 diabetes in humans. We investigated the impact of complete loss of SLC30A8 Function on type 2 diabetes risk and related phenotypes in humans. Methods The Pakistan Genome Resource (PGR), a biobank comprising whole-exome and whole-genome sequences of 145,037 participants, was analysed for phenotypic associations with SLC30A8 loss-of-function (LoF) variants. To follow up on the observations in the PGR, we conducted recall-by-genotype analyses of SLC30A8 LoF heterozygotes and homozygotes, as well as their participating family members, using OGTTs. Results We identified 18 SLC30A8 knockouts, including homozygotes for a variant enriched in South Asians (Gln174Ter), and 1024 heterozygotes for LoF variants. Type 2 diabetes risk was lower in SLC30A8 LoF heterozygotes and homozygotes relative to non-carriers, and the protective effect strengthens in a gene dose-dependent manner (OR additive =0.62; 95% CI 0.53, 0.72; p =1.1×10 –9 ; OR recessive =0.34; 95% CI 0.12, 0.93; p =0.04). OGTTs in recall-by-genotype studies showed a gene dose-dependent reduction in glucose levels, coupled with elevated insulin. Conclusions/interpretation The corrected insulin response, disposition index and insulin sensitivity index in LoF heterozygotes and homozygotes indicated higher glucose-stimulated insulin secretion with preserved beta cell function that was independent of BMI. These data suggest that therapeutic inhibition of SLC30A8 , up to and including complete knockout, may treat type 2 diabetes safely and effectively. Graphical Abstract