Abstract
<jats:p><p dir="ltr">Hyperglycemia is a hallmark of type-2 diabetes and a key pathogenic driver of diabetic complications. Cullin RING E3 ligases (CRLs) are multi-subunit E3 ubiquitin ligases that mediate cellular protein turnover. The activity of CRLs requires cullin neddylation, a post-translational modification that can be pharmacologically targeted with therapeutic potentials. By using hyperinsulinemic-euglycemic clamp analysis, we discover that pan neddylation inhibitor exerts both insulin sensitization effect in liver and muscle and insulinotropic effect in pancreatic b cells. This dual action is mediated by Cullin 3 (Cul3), a member of the 7 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-independent manner in mice and directly enhances insulin secretion in INS-1 832/13 b cells and human islets. Cul3 inhibition leads to RhoA stabilization. RhoA regulation of cytoskeleton remodeling may play a role in mediating the insulinotropic effect of DI-1859 in b cells. In conclusion, this study demonstrates that a single agent targeting Cul3 neddylation promotes peripheral insulin sensitization and b cell insulin secretion to attenuate hyperglycemia in mice.</p></jats:p>