胰腺β细胞中的BRSK2促进高胰岛素血症耦合胰岛素抵抗,其基因变异与人类2型糖尿病有关。

IF 5.3 2区 生物学 Q2 CELL BIOLOGY
Rufeng Xu, Kaiyuan Wang, Zhengjian Yao, Yan Zhang, Li Jin, Jing Pang, Yuncai Zhou, Kai Wang, Dechen Liu, Yaqin Zhang, Peng Sun, Fuqiang Wang, Xiaoai Chang, Tengli Liu, Shusen Wang, Yalin Zhang, Shuyong Lin, Cheng Hu, Yunxia Zhu, Xiao Han
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引用次数: 0

摘要

脑特异性丝氨酸/苏氨酸蛋白激酶2(BRSK2)在胰岛素分泌和β细胞生物学中发挥着关键作用。然而,BRSK2 是否与人类 2 型糖尿病(T2DM)有关尚未确定。在此,我们报告了在中国人群中,BRSK2 基因变异与高胰岛素血症和胰岛素抵抗导致的糖代谢恶化密切相关。由于蛋白质稳定性增强,T2DM 患者和高脂饮食(HFD)喂养小鼠的β细胞中 BRSK2 蛋白水平明显升高。诱导性β细胞特异性Brsk2基因敲除(βKO)的小鼠表现出正常的新陈代谢,在进食条件下有很高的胰岛素分泌潜力。此外,βKO 小鼠对高氟日粮诱导的高胰岛素血症、肥胖、胰岛素抵抗和葡萄糖不耐受具有保护作用。相反,成熟β细胞中的BRSK2功能增益可逆地引发高血糖,原因是β细胞分泌过多导致胰岛素抵抗。从机理上讲,BRSK2 能感知脂质信号,并以激酶依赖的方式诱导基础胰岛素分泌。基础胰岛素分泌的增强推动了胰岛素抵抗和β细胞衰竭,从而导致以高密度脂蛋白饲料喂养或β细胞中BRSK2功能增益的小鼠发生T2DM。这些研究结果表明,在携带人类基因变异或营养过剩的人群中,BRSK2通过β细胞和胰岛素敏感组织之间的相互作用,将高胰岛素血症与系统性胰岛素抵抗联系起来。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
BRSK2 in pancreatic β cells promotes hyperinsulinemia-coupled insulin resistance and its genetic variants are associated with human type 2 diabetes.

Brain-specific serine/threonine-protein kinase 2 (BRSK2) plays critical roles in insulin secretion and β-cell biology. However, whether BRSK2 is associated with human type 2 diabetes mellitus (T2DM) has not been determined. Here, we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population. BRSK2 protein levels are significantly elevated in β cells from T2DM patients and high-fat diet (HFD)-fed mice due to enhanced protein stability. Mice with inducible β-cell-specific Brsk2 knockout (βKO) exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions. Moreover, βKO mice are protected from HFD-induced hyperinsulinemia, obesity, insulin resistance, and glucose intolerance. Conversely, gain-of-function BRSK2 in mature β cells reversibly triggers hyperglycemia due to β-cell hypersecretion-coupled insulin resistance. Mechanistically, BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner. The enhanced basal insulin secretion drives insulin resistance and β-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 in β cells. These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay between β cells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.

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来源期刊
CiteScore
9.60
自引率
1.80%
发文量
1383
期刊介绍: The Journal of Molecular Cell Biology ( JMCB ) is a full open access, peer-reviewed online journal interested in inter-disciplinary studies at the cross-sections between molecular and cell biology as well as other disciplines of life sciences. The broad scope of JMCB reflects the merging of these life science disciplines such as stem cell research, signaling, genetics, epigenetics, genomics, development, immunology, cancer biology, molecular pathogenesis, neuroscience, and systems biology. The journal will publish primary research papers with findings of unusual significance and broad scientific interest. Review articles, letters and commentary on timely issues are also welcome. JMCB features an outstanding Editorial Board, which will serve as scientific advisors to the journal and provide strategic guidance for the development of the journal. By selecting only the best papers for publication, JMCB will provide a first rate publishing forum for scientists all over the world.
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