BBT improves glucose homeostasis by ameliorating β-cell dysfunction in type 2 diabetic mice
BBT improves glucose homeostasis by ameliorating β-cell dysfunction in type 2 diabetic mice
复制标题
BBT 通过改善 2 型糖尿病小鼠的 β 细胞功能障碍来改善葡萄糖稳态。
DOI：
10.1530/joe-14-0721
复制
发表时间：
2015-03-01
影响因子：
4
通讯作者：
Shen, Xu
中科院分区：
文献类型：
--
作者：
Yao, Xin-gang;Xu, Xin;Shen, Xu
葡萄糖刺激的胰岛素分泌 (GSIS) 受损和 β 细胞死亡增加是注定会患 2 型糖尿病的个体胰腺 β 细胞的两种典型功能障碍，通过 GSIS 增强和/或抑制 β 细胞死亡来改善 β 细胞功能是一种有前景的抗糖尿病治疗策略。在这项研究中，我们发现小分子 N-(2-苯甲酰基苯基)-5-溴-2-噻吩甲酰胺 (BBT) 能够有效增强 GSIS 并保护 β 细胞免受细胞因子或链脲佐菌素 (STZ) 诱导的细胞死亡。进一步的研究结果表明，cAMP/PKA 和持久（L 型）电压依赖性 Ca2+ 通道/CaMK2 通路参与了 BBT 对 GSIS 的作用，并且 cAMP/PKA 通路对于 BBT 对 β 细胞的保护作用至关重要。使用高脂饮食联合 STZ (STZ/HFD) 诱导的 2 型糖尿病小鼠模型进行的一项测定表明，BBT 给药可有效恢复 β 细胞功能，血浆胰岛素水平增加，STZ/HFD 诱导的 β 细胞损失减少。此外，结果表明，BBT 治疗可降低空腹血糖和 HbA1c，并改善口服糖耐量，进一步凸显了 BBT 在抗高血糖研究中的潜力。
Impaired glucose-stimulated insulin secretion (GSIS) and increasing beta-cell death are two typical dysfunctions of pancreatic beta-cells in individuals that are destined to develop type 2 diabetes, and improvement of beta-cell function through GSIS enhancement and/or inhibition of beta-cell death is a promising strategy for anti-diabetic therapy. In this study, we discovered that the small molecule, N-(2-benzoylphenyl)-5-bromo-2-thiophenecarboxamide (BBT), was effective in both potentiating GSIS and protecting beta-cells from cytokine-or streptozotocin (STZ)-induced cell death. Results of further studies revealed that cAMP/PKA and long-lasting (L-type) voltage-dependent Ca2+ channel/CaMK2 pathways were involved in the action of BBT against GSIS, and that the cAMP/PKA pathway was essential for the protective action of BBT on beta-cells. An assay using the model of type 2 diabetic mice induced by high-fat diet combined with STZ (STZ/HFD) demonstrated that BBT administration efficiently restored beta-cell functions as indicated by the increased plasma insulin level and decrease in the beta-cell loss induced by STZ/HFD. Moreover, the results indicated that BBT treatment decreased fasting blood glucose and HbA1c and improved oral glucose tolerance further highlighting the potential of BBT in anti-hyperglycemia research.