{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:05:29Z","timestamp":1790017529398,"version":"4.0.1"},"reference-count":47,"publisher":"American Diabetes Association","issue":"10","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"DOI":"10.13039\/100017618","name":"Division of Diabetes, Endocrinology, and Metabolic Diseases","doi-asserted-by":"publisher","award":["1R01DK131064-01"],"award-info":[{"award-number":["1R01DK131064-01"]}],"id":[{"id":"10.13039\/100017618","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017618","name":"Division of Diabetes, Endocrinology, and Metabolic Diseases","doi-asserted-by":"publisher","award":["R01 DK134316-01"],"award-info":[{"award-number":["R01 DK134316-01"]}],"id":[{"id":"10.13039\/100017618","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,10,1]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>Hyperglycemia is a hallmark of type 2 diabetes and a key pathogenic driver of diabetes complications. Cullin RING E3 ligases (CRLs) are multisubunit E3 ubiquitin ligases that mediate cellular protein turnover. The activity of CRLs requires cullin neddylation, a posttranslational modification that can be pharmacologically targeted with therapeutic potentials. By using hyperinsulinemic-euglycemic clamp analysis, we discover that pan-neddylation inhibitor exerts both an insulin sensitization effect in liver and muscle and an insulinotropic effect in pancreatic \u03b2-cells. This dual action is mediated by cullin 3 (Cul3), a member of the seven canonical cullin family proteins. DI-1859, a selective Cul3 neddylation inhibitor, effectively protects against hyperglycemia in obese mice. DI-1859 enhances insulin signaling by preventing Cul3-mediated insulin receptor substrate degradation in liver and muscle cells. DI-1859 increases insulin secretion in a glucagon-like peptide-1\u2013independent manner in mice and directly enhances insulin secretion in INS-1 832\/13 \u03b2-cells and human islets. Cul3 inhibition leads to Ras homolog family member A (RhoA) stabilization. RhoA regulation of cytoskeleton remodeling may play a role in mediating the insulinotropic effect of DI-1859 in \u03b2-cells. In conclusion, this study demonstrates that a single agent targeting Cul3 neddylation promotes peripheral insulin sensitization and \u03b2-cell insulin secretion to attenuate hyperglycemia in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>Pan-neddylation inhibitors exhibit potent hypoglycemic effect. The target organs and mechanisms underlying the hypoglycemia effect of pan-neddylation inhibitors are incompletely understood. We found that inhibition of cullin 3 leads to a dual insulin sensitization and insulinotropic effect. Selective inhibition of cullin 3 neddylation is a feasible approach to lower hyperglycemia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db26-0029","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T16:21:21Z","timestamp":1785514881000},"page":"1921-1933","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":0,"title":["A Selective Cullin 3 RING E3 Ligase Inhibitor Attenuates Hyperglycemia via Dual Insulin Sensitizing and Insulinotropic Action"],"prefix":"10.2337","volume":"75","author":[{"given":"Lijie","family":"Gu","sequence":"first","affiliation":[{"name":"Harold Hamm Diabetes Center, Department of Biochemistry and Physiology, University of Oklahoma Health Campus , Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Xiong","sequence":"additional","affiliation":[{"name":"Harold Hamm Diabetes Center, Department of Biochemistry and Physiology, University of Oklahoma Health Campus , Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Nazmul","family":"Hasan","sequence":"additional","affiliation":[{"name":"Harold Hamm Diabetes Center, Department of Biochemistry and Physiology, University of Oklahoma Health Campus , Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhong","family":"Du","sequence":"additional","affiliation":[{"name":"Harold Hamm Diabetes Center, Department of Biochemistry and Physiology, University of Oklahoma Health Campus , Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Wu","sequence":"additional","affiliation":[{"name":"Harold Hamm Diabetes Center, Department of Biochemistry and Physiology, University of Oklahoma Health Campus , Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8568-0129","authenticated-orcid":false,"given":"Tiangang","family":"Li","sequence":"additional","affiliation":[{"name":"Harold Hamm Diabetes Center, Department of Biochemistry and Physiology, University of Oklahoma Health Campus , Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"2026092114520036200_B1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrm1547","article-title":"Function and regulation of cullin-RING ubiquitin ligases","volume":"6","author":"Petroski","year":"2005","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2026092114520036200_B2","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1186\/gb-2011-12-4-220","article-title":"The cullin protein family","volume":"12","author":"Sarikas","year":"2011","journal-title":"Genome Biol"},{"key":"2026092114520036200_B3","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/nature07884","article-title":"An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer","volume":"458","author":"Soucy","year":"2009","journal-title":"Nature"},{"key":"2026092114520036200_B4","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/nrm3919","article-title":"Protein neddylation: beyond cullin-RING ligases","volume":"16","author":"Enchev","year":"2015","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2026092114520036200_B5","doi-asserted-by":"crossref","first-page":"3215","DOI":"10.2174\/13816128113199990300","article-title":"Cullin-RING ligases as attractive anti-cancer targets","volume":"19","author":"Zhao","year":"2013","journal-title":"Curr Pharm Des"},{"key":"2026092114520036200_B6","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1042\/BJ20141450","article-title":"Targeting Cullin-RING E3 ubiquitin ligases for drug discovery: structure, assembly and small-molecule modulation","volume":"467","author":"Bulatov","year":"2015","journal-title":"Biochem J"},{"key":"2026092114520036200_B7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.metabol.2010.09.010","article-title":"Management of type 2 diabetes: evolving strategies for the treatment of patients with type 2 diabetes","volume":"60","author":"Nyenwe","year":"2011","journal-title":"Metabolism"},{"key":"2026092114520036200_B8","doi-asserted-by":"crossref","first-page":"2753","DOI":"10.2337\/dci22-0034","article-title":"Management of hyperglycemia in type 2 diabetes, 2022. 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