A Selective Cullin 3 RING E3 Ligase Inhibitor Attenuates Hyperglycemia via Dual Insulin Sensitizing and Insulinotropic Action

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 β-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–independent manner in mice and directly enhances insulin secretion in INS-1 832/13 β-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 β-cells. In conclusion, this study demonstrates that a single agent targeting Cul3 neddylation promotes peripheral insulin sensitization and β-cell insulin secretion to attenuate hyperglycemia in mice. Article Highlights 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.