Biochemistry Department, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia.
Eur Cytokine Netw. 2020 Dec 1;31(4):168-179. doi: 10.1684/ecn.2020.0454.
Type 2 diabetes (T2D) causes profound psychological and physical distress to patients and burdens the health-care system. Although several antidiabetic drugs have been approved, none of them are adequately effective in the long-term management of T2D. Therefore, novel treatment options are needed for disease prevention or delaying disease progression. Bruton's tyrosine kinase (BTK) is a cytoplasmic enzyme that plays a role in B-cell differentiation and proliferation, and therapeutic targeting of BTK offers protection against chronic diseases. In this study, we analyzed BTK expression and its correlation with inflammatory mediators in patients with diabetes and obesity. The levels of BTK were significantly high in visceral adipose tissues of patients (p < 0.01) with diabetes and obesity compared with healthy controls. Additionally, a positive correlation was noted between the expression of BTK and the inflammatory cytokine genes TNF-α, INF-γ, IL-6, and IL-1 (p < 0.01) in adipose tissue. In insulin-resistant HepG2 cells (IR-HepG2), ibrutinib inhibited BTK expression in parallel with inflammatory genes, and increased insulin signaling and activity compared with untreated IR-HepG2 cells. Additionally, ibrutinib-treated IR-HepG2 cells showed increased glucose uptake compared with untreated IR-HepG2 cells. These results provide evidence that BTK inhibition may serve as a novel therapeutic strategy for the treatment of T2D. These findings also uncover the novel role of BTK in diabetes and insulin resistance; however, further in vivo studies are required prior to translating the findings into clinical settings.
2 型糖尿病（T2D）给患者带来了深刻的心理和身体困扰，并给医疗保健系统带来了负担。尽管已经批准了几种抗糖尿病药物，但没有一种药物在 T2D 的长期管理中足够有效。因此，需要新的治疗选择来预防疾病或延缓疾病进展。布鲁顿酪氨酸激酶（BTK）是一种细胞质酶，在 B 细胞分化和增殖中发挥作用，BTK 的治疗靶向提供了对慢性疾病的保护。在这项研究中，我们分析了 BTK 表达及其与糖尿病和肥胖患者炎症介质的相关性。与健康对照组相比，患有糖尿病和肥胖症的患者（p < 0.01）的内脏脂肪组织中 BTK 水平显着升高。此外，BTK 的表达与脂肪组织中炎症细胞因子基因 TNF-α、INF-γ、IL-6 和 IL-1 之间呈正相关（p < 0.01）。在胰岛素抵抗 HepG2 细胞（IR-HepG2）中，与未处理的 IR-HepG2 细胞相比，依鲁替尼抑制 BTK 表达的同时也抑制炎症基因，并且增加了胰岛素信号和活性。此外，与未处理的 IR-HepG2 细胞相比，用依鲁替尼处理的 IR-HepG2 细胞显示出增加的葡萄糖摄取。这些结果提供了 BTK 抑制可能作为治疗 T2D 的新治疗策略的证据。这些发现还揭示了 BTK 在糖尿病和胰岛素抵抗中的新作用；然而，在将这些发现转化为临床环境之前，需要进行进一步的体内研究。
