Introduction: High Mobility Group Box-1 (HMGB1) is strongly associated with Type 2 Diabetes (T2D) and hepatocyte function. HMGB1 can regulate mitochondrial function under high glucose conditions. Our group has shown that knockdown of HMGB1 reduces hyperglycemia with decrease insulin activity. We want to further understand the role of HMGB1 in hepatocyte mitochondrial function and the insulin/AKT signaling, a vital pathway in glucose hemostasis. We hypothesize that by decreasing HMGB1, hepatocytes increase glucose uptake by regulating mitochondrial function with more effective Insulin/AKT signaling.

Methods: Primary hepatocytes and liver lysates were isolated from inducible HMGB1 KO (iHMGB1 KO) and HMGB1 Flox (wildtype) mice after Tamoxifen and Streptozotocin IP injections for HMGB1 knockout and T2D-10-weeks development. HMGB1 knockdown and insulin/AKT signaling were assessed by RT-PCR and immunoblot. Flow cytometry was performed on primary hepatocyte cell suspension for mitochondrial function/mass (TMRE, Mitotracker) and glucose uptake (NDBG) cellular markers.

Results: Liver lysates showed significant decreased expression/activity of HMGB1, Insulin Receptor-B, phosphorylated AKT, PDK and SIRT3 in iHMGB1 KO T2D mice. A counter regulator of metabolic and glucose activity, phosphorylated PDH, was found increased in iHMGB1 KO mice. Flow cytometry of isolated hepatocytes showed that iHMGB1 KO T2D animals had significantly less mitochondrial mass and functioning mitochondria, however showed increased glucose uptake.

Conclusion: We found a potential mechanism by which HMGB1 regulates glucose uptake by regulating mitochondrial function and mass potentially by regulating the effectiveness of the Insulin/Akt signaling in T2D. Future studies will be directed to test glucose transport/metabolism in HMGB1 KO hepatocytes guided by more effective Insulin activity in the mediation of mitochondria function at the different stages of T2D progression.

Disclosure

Z.Liu: None. C.Kaltenmeier: None. R.I.Mota alvidrez: None.

Funding

This work was funded by department of surgery support for RIMA

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