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 beta-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 beta-cells.

Exosome secretion is required for Sonic Hedgehog dispersal and signal gradient formation in the embryonic limb bud mesenchyme
Sean Corcoran, Joshua Fisher, Timothy A. Sanders +1
Cell Reports1 Nov 2026Peer-reviewedCC BY-NC-ND 4.0General biologyCrossref
Serotonin signals through ciliary 5-HT6 to control insulin secretion
S. E. Townsend, J. H. Jo, M. Opp +3
bioRxiv30 Oct 2026PreprintAll rights reservedFull textCell biologybioRxiv
Secretion of small extracellular vesicles is required for commissural axon guidance at a choice point
A. Dumoulin, J. M. R. Wyss, E. T. Stoeckli
bioRxiv9 Sep 2026PreprintCC BY-NC-NDFull textNeurosciencebioRxiv
An INSR-BECN1-KIAA0825 complex prevents hepatocytic insulin receptor secretion via extracellular vesicles against monogenic diabetes
K. Kuramoto, M. Chen, C. He
bioRxiv13 Sep 2026PreprintCC BYFull textCell biologybioRxiv
Unveiling a missing component of the atypical type IV secretion system required for natural transformation of Helicobacter pylori
J. Francisco Villa, Sumedha Kondekar, Yoann Fauconnet +7
PLoS Pathogens14 Jul 2026Peer-reviewedCC BY 4.0Full textProteomics & metabolomics Genetics & genomicsHAL

Cite

BibTeX RIS

BibTeX

@misc{hawthorne2026ortholog,
  title = {{The ortholog of the Human T2D Risk Gene STEAP2 is Required for Glucose Stimulated Insulin Secretion in Mice}},
  author = {A. Hawthorne and K. Kelly and M. Tigue and H. El-Mekkoussi and E. Waite and Y. Erhan and E. Manduchi and S. Dashti and A. Rozzo and J. Roman and N. Doliba and D. Stoffers and K. H. Kaestner},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.26.754731},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.26.754731v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - The ortholog of the Human T2D Risk Gene STEAP2 is Required for Glucose Stimulated Insulin Secretion in Mice
AU  - A. Hawthorne
AU  - K. Kelly
AU  - M. Tigue
AU  - H. El-Mekkoussi
AU  - E. Waite
AU  - Y. Erhan
AU  - E. Manduchi
AU  - S. Dashti
AU  - A. Rozzo
AU  - J. Roman
AU  - N. Doliba
AU  - D. Stoffers
AU  - K. H. Kaestner
PY  - 2026
DA  - 2026/09/26
PB  - bioRxiv
DO  - 10.64898/2026.09.26.754731
UR  - https://www.biorxiv.org/content/10.64898/2026.09.26.754731v1
AB  - 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 beta-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 beta-cells.
ER  -

Abstract

Related

Cite