Abstract
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
(
Steap2
fl/fl
) in mice and crossed this to the rat insulin promoter (Rip)-Cre transgene. Ablation of
Steap2
induced glucose intolerance, blunted glucose-stimulated Ca
2+
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 Ca
2+
mobilization and insulin secretion.