Lamarche, Lindsey, Khalid, Shareef, Koch, Christopher, Zaman, Maleeha, Denning, Daniel, Rasheed, Asif, Saleheen, Kashif, Clement, Matthew, Zessis, Richard, Goldfine, Allison, Gurtan, Allan, Dominy, John and Saleheen, Danish (2025) Complete loss of SLC30A8 in humans improves glucose metabolism and beta cell function. Diabetologia. ISSN 1432-0428

Abstract

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.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.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 (ORadditive=0.62; 95% CI 0.53, 0.72; p=1.1×10-9; ORrecessive=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.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.

Item Type:	Article
Date Deposited:	11 Oct 2025 00:45
Last Modified:	11 Oct 2025 00:45
URI:	https://oak.novartis.com/id/eprint/51611