The ortholog of the Human T2D Risk Gene STEAP2 is Required for Glucose Stimulated Insulin Secretion in Mice

Abstract

Type 2 diabetes is a complex metabolic disease with a strong genetic component, yet this genetic risk is driven by common variants in up to 600 loci with small effect sizes. Variants in the STEAP2 locus, encoding ‘Six-transmembrane epithelial antigen of the prostate-2’, are highly associated with altered glycemic traits and type 2 diabetes risk. To elucidate its function in pancreatic β-cells, we utilized Crisp-Cas9 assisted homologous recombination to derive a conditional null allele for Steap2 (Steap2fl/fl) in mice and crossed this to the rat insulin promoter (Rip)-Cre transgene. Ablation of Steap2 induced glucose intolerance, blunted glucose-stimulated Ca2+ mobilization and stunted first phase glucose-simulated insulin secretion. In contrast, the incretin effect and second phase insulin secretion were not affected. Islet respirometry and transmission electron microscopy (TEM) identified disrupted cristate morphology and impaired glucose-stimulated oxygen consumption as causally responsible for the observed, impaired triggering pathway of insulin secretion. These findings suggest that at least part of the genetic risk for T2D conferred by Steap2 variants is likely due to its function in maintaining optimal mitochondrial respiration in pancreatic β-cells. Article Highlights Common variants in the STEAP2 gene are strongly associated with altered glycemic traits and type 2 diabetes. Loss of Steap2 in β-cells impairs mitochondrial respiration, resulting in attenuated glucose-stimulated Ca2+ mobilization and insulin secretion.