Beta-klotho in type 2 diabetes mellitus: From pathophysiology to therapeutic strategies
Beta-klotho in type 2 diabetes mellitus: From pathophysiology to therapeutic strategies
复制标题
2 型糖尿病中的 Beta-klotho：从病理生理学到治疗策略
DOI：
10.1007/s11154-021-09661-1
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发表时间：
2021-06-13
影响因子：
8.2
通讯作者：
Ye, Dewei
中科院分区：
文献类型：
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作者：
Hua, Shuang;Liu, Qianying;Ye, Dewei
2型糖尿病（T2 DM）已成为一个全球性的健康问题，无法治愈。尽管有生活方式的改变和各种药物选择，但实现稳定和持久的血糖控制沿着有效预防T2 DM相关心血管并发症仍然是临床管理中具有挑战性的任务。由于其在代谢组织（脂肪组织、肝脏和胰腺）中的选择性高丰度，β-Klotho是成纤维细胞生长因子（FGF）受体复合物的重要组分。内分泌FGF 19和FGF 21的高亲和力结合对于引起积极参与葡萄糖代谢和能量消耗的稳态维持的信号级联是必不可少的。在这篇综述中，我们讨论了β-Klotho在糖代谢调节中的生物学功能，并提供了其参与T2 DM病理生理学的机制见解。我们回顾了我们目前对β-Klotho和FGF（FGF 19和FGF 21）组成的内分泌轴及其在生理和T2 DM条件下对葡萄糖代谢的调节作用的理解。我们还强调了靶向β-Klotho和/或β-Klotho-FGFR复合物用于治疗T2 DM的药理学化合物的开发和临床前验证方面的进展。鉴于这一领域的显著进展，我们还讨论了基于β-Klotho疗法的临床开发中的突出研究问题和许多挑战。
Type 2 diabetes mellitus (T2DM) has become a global health problem with no cure. Despite lifestyle modifications and various pharmaceutical options, the achievement of stable and durable glucose control along with effective prevention of T2DM-related cardiovascular complications remains a challenging task in clinical management. With its selective high abundance in metabolic tissues (adipose tissue, liver, and pancreas), β-Klotho is the essential component of fibroblast growth factor (FGF) receptor complexes. It is essential for high-affinity binding of endocrine FGF19 and FGF21 to evoke the signaling cascade actively involved in homeostatic maintenance of glucose metabolism and energy expenditure. In this Review, we discuss the biological function of β-Klotho in the regulation of glucose metabolism and offer mechanistic insights into its involvement in the pathophysiology of T2DM. We review our current understanding of the endocrine axis comprised of β-Klotho and FGFs (FGF19 and FGF21) and its regulatory effects on glucose metabolism under physiological and T2DM conditions. We also highlight advances in the development and preclinical validation of pharmacological compounds that target β-Klotho and/or the β-Klotho-FGFRs complex for the treatment of T2DM. Given the remarkable advances in this field, we also discuss outstanding research questions and the many challenges in the clinical development of β-Klotho-based therapies.