Introduction: Type-2 diabetes (T2D) characterizes by chronic hyperglycemia and insulin resistance. Hyperglycemia causes tissue damage and serious complications. High Mobility Group Box-1 (HMGB1) mediates the onset and progression of T2D, but the exact mechanism of HMGB1 glucose regulation in T2D is poorly understood. Global knockout of HMGB1 is fatal in neonatal mice primarily due to hypoglycemia. Therefore, using an inducible HMGB1 Knockout (iHMGB1 KO) model we evaluated the role of HMGB1 in adult mice progression of T2D (3) . We hypothesize that iHMGB1 KO mice will have decreased longitudinal hyperglycemia with decreased insulin resistance in a Streptozotocin (STZ) induced model of T2D.
Methods: Male 8-week adult iHMGB1 KO mice were injected with Tamoxifen IP for days (1mg/kg) to induce HMGB1 knockdown. HMGB1 Flox (wildtype) were used as control. Then, mice were injected with STZ IP for 5 days (25mg/kg) , diabetic phenotype developed for weeks. HMGB1 knockdown was characterized via immunoblot and RT-PCR. Mice were placed on normal or high fat diet to evaluate T2D progression via metabolic cage analysis (MCA) . Glucose and insulin tolerance tests (GTT and ITT) were performed.
Results: HMGB1 was significantly knocked down in iHMGB1 KO mice. MCA showed that STZ + normal diet had the appropriate respiratory quotient for translational T2D. GTT and ITT demonstrated higher glucose sensitivity and insulin tolerance in iHMGB1 KO T2D mice. Longitudinal glycemia measurement showed that iHMGB1 KO T2D mice have a progressively lower glycemia.
Conclusion: With an effective knockdown of HMGB1, we evidenced increased glucose sensitivity, decreased hyperglycemia and insulin resistance in STZ induced T2D mice. Findings show that decreasing HMGB1 allows T2D adult mice to regulate glucose metabolism and insulin sensitivity better. Further studies will be directed to investigate the mechanisms that govern the role of HMGB1 in T2D.
Z.Liu: None. R.I.Mota alvidrez: None.
This work was funded by department of surgery support for RIMA