{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T13:05:30Z","timestamp":1791378330942,"version":"4.3.2"},"posted":{"date-parts":[[2026,10,2]]},"group-title":"Genetics","reference-count":62,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["U01DK123594"],"award-info":[{"award-number":["U01DK123594"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  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\n                  <jats:italic>STEAP2<\/jats:italic>\n                  locus, encoding \u2018Six-transmembrane epithelial antigen of the prostate-2\u2019, are highly associated with altered glycemic traits and type 2 diabetes risk. To elucidate its function in pancreatic \u03b2-cells, we utilized Crisp-Cas9 assisted homologous recombination to derive a conditional null allele for\n                  <jats:italic>Steap2<\/jats:italic>\n                  (\n                  <jats:italic>\n                    Steap2\n                    <jats:sup>fl\/fl<\/jats:sup>\n                  <\/jats:italic>\n                  ) in mice and crossed this to the rat insulin promoter (Rip)-Cre transgene. Ablation of\n                  <jats:italic>Steap2<\/jats:italic>\n                  induced glucose intolerance, blunted glucose-stimulated Ca\n                  <jats:sup>2+<\/jats:sup>\n                  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\n                  <jats:italic>Steap2<\/jats:italic>\n                  variants is likely due to its function in maintaining optimal mitochondrial respiration in pancreatic \u03b2-cells.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Article Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>\n                        Common variants in the\n                        <jats:italic>STEAP2<\/jats:italic>\n                        gene are strongly associated with altered glycemic traits and type 2 diabetes.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Loss of\n                        <jats:italic>Steap2<\/jats:italic>\n                        in \u03b2-cells impairs mitochondrial respiration, resulting in attenuated glucose-stimulated Ca\n                        <jats:sup>2+<\/jats:sup>\n                        mobilization and insulin secretion.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.26.754731","type":"posted-content","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T14:00:12Z","timestamp":1790949612000},"source":"Crossref","is-referenced-by-count":0,"title":["The ortholog of the Human T2D Risk Gene\n                  <i>STEAP2<\/i>\n                  is Required for Glucose Stimulated Insulin Secretion in Mice"],"prefix":"10.64898","author":[{"given":"Avery","family":"Hawthorne","sequence":"first","affiliation":[{"name":"Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, The University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, USA 19104"},{"name":"Department of Genetics, Perelman School of Medicine, The University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, USA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Kelly","sequence":"additional","affiliation":[{"name":"Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, The University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, USA 19104"},{"name":"Department of Genetics, Perelman School of Medicine, The University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, USA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Tigue","sequence":"additional","affiliation":[{"name":"Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, The University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, USA 19104"},{"name":"Department of Genetics, Perelman School of Medicine, The University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, USA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilana","family":"El-Mekkoussi","sequence":"additional","affiliation":[{"name":"Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, The University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, USA 19104"},{"name":"Department of Genetics, Perelman School of Medicine, The University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, USA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Waite","sequence":"additional","affiliation":[{"name":"Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, The University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, USA 19104"},{"name":"Department of Genetics, Perelman School of Medicine, The University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, USA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yelda","family":"Erhan","sequence":"additional","affiliation":[{"name":"Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, The University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, USA 19104"},{"name":"Department of Biology, The School of Arts and Sciences, The University of Pennsylvania, 433 S University Ave, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Manduchi","sequence":"additional","affiliation":[{"name":"Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, The University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, USA 19104"},{"name":"Department of Genetics, Perelman School of Medicine, The University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, USA 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