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. Disclosure Z.Liu: None. R.I.Mota alvidrez: None. Funding This work was funded by department of surgery support for RIMA

中文翻译：

---

1513-PUB：HMGB1 敲低可增加 2 型糖尿病患者的葡萄糖敏感性、降低高血糖和胰岛素抵抗

简介： 2 型糖尿病 (T2D) 以慢性高血糖和胰岛素抵抗为特征。高血糖会导致组织损伤和严重的并发症。High Mobility Group Box-1 (HMGB1) 介导 T2D 的发病和进展，但 HMGB1 在 T2D 中调节葡萄糖的确切机制知之甚少。HMGB1 的全局敲除在新生小鼠中是致命的，主要是由于低血糖。因此，使用诱导型 HMGB1 敲除 (iHMGB1 KO) 模型，我们评估了 HMGB1 在成年小鼠 T2D 进展中的作用 (3)。我们假设在链脲佐菌素 (STZ) 诱导的 T2D 模型中，iHMGB1 KO 小鼠的纵向高血糖症会随着胰岛素抵抗的降低而降低。方法：雄性 8 周成年 iHMGB1 KO 小鼠注射他莫昔芬 IP 数天（1mg/kg）以诱导 HMGB1 敲低。HMGB1 Flox（野生型）用作对照。然后，给小鼠注射 STZ IP 5 天（25mg/kg），糖尿病表型发展了数周。通过免疫印迹和 RT-PCR 表征 HMGB1 敲低。将小鼠置于正常或高脂肪饮食以通过代谢笼分析 (MCA) 评估 T2D 进展。进行了葡萄糖和胰岛素耐量试验（GTT 和 ITT）。结果： HMGB1 在 iHMGB1 KO 小鼠中被显着敲低。MCA 显示 STZ + 正常饮食对平移 T2D 具有适当的呼吸商。GTT 和 ITT 在 iHMGB1 KO T2D 小鼠中表现出更高的葡萄糖敏感性和胰岛素耐受性。纵向血糖测量显示 iHMGB1 KO T2D 小鼠的血糖逐渐降低。结论：通过有效敲低 HMGB1，我们证明了葡萄糖敏感性增加，STZ 诱导的 T2D 小鼠的高血糖和胰岛素抵抗降低。研究结果表明，降低 HMGB1 可使 T2D 成年小鼠更好地调节葡萄糖代谢和胰岛素敏感性。进一步的研究将直接研究控制 HMGB1 在 T2D 中的作用的机制。披露 Z.Liu：没有。RIMota alvidrez：没有。资金 这项工作由 RIMA 手术支持部门资助