Gingipain from Porphyromonas gingivalis causes insulin resistance by degrading insulin receptors through direct proteolytic effects.

IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE International Journal of Oral Science Pub Date : 2024-08-01 DOI:10.1038/s41368-024-00313-z
Fen Liu, Bofeng Zhu, Ying An, Zhifei Zhou, Peiying Xiong, Xuan Li, Yang Mi, Tongqiang He, Faming Chen, Buling Wu
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Abstract

Periodontitis is a critical risk factor for the occurrence and development of diabetes. Porphyromonas gingivalis may participate in insulin resistance (IR) caused by periodontal inflammation, but the functional role and specific mechanisms of P. gingivalis in IR remain unclear. In the present study, clinical samples were analysed to determine the statistical correlation between P. gingivalis and IR occurrence. Through culturing of hepatocytes, myocytes, and adipocytes, and feeding mice P. gingivalis orally, the functional correlation between P. gingivalis and IR occurrence was further studied both in vitro and in vivo. Clinical data suggested that the amount of P. gingivalis isolated was correlated with the Homeostatic Model Assessment for IR score. In vitro studies suggested that coculture with P. gingivalis decreased glucose uptake and insulin receptor (INSR) protein expression in hepatocytes, myocytes, and adipocytes. Mice fed P. gingivalis tended to undergo IR. P. gingivalis was detectable in the liver, skeletal muscle, and adipose tissue of experimental mice. The distribution sites of gingipain coincided with the downregulation of INSR. Gingipain proteolysed the functional insulin-binding region of INSR. Coculture with P. gingivalis significantly decreased the INSR-insulin binding ability. Knocking out gingipain from P. gingivalis alleviated the negative effects of P. gingivalis on IR in vivo. Taken together, these findings indicate that distantly migrated P. gingivalis may directly proteolytically degrade INSR through gingipain, thereby leading to IR. The results provide a new strategy for preventing diabetes by targeting periodontal pathogens and provide new ideas for exploring novel mechanisms by which periodontal inflammation affects the systemic metabolic state.

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牙龈卟啉单胞菌中的 Gingipain 通过直接蛋白水解作用降解胰岛素受体,从而导致胰岛素抵抗。
牙周炎是糖尿病发生和发展的一个重要风险因素。牙龈卟啉单胞菌可能参与牙周炎症引起的胰岛素抵抗(IR),但牙龈卟啉单胞菌在IR中的功能作用和具体机制仍不清楚。本研究对临床样本进行了分析,以确定牙龈卟啉菌与 IR 发生之间的统计学相关性。通过培养肝细胞、肌细胞和脂肪细胞,以及给小鼠口服牙龈脓毒性菌,进一步研究了牙龈脓毒性菌与 IR 发生之间在体外和体内的功能相关性。临床数据表明,分离出的牙龈脓胞的数量与 IR 的平衡模型评估得分相关。体外研究表明,与牙龈脓疱共培养可降低肝细胞、肌细胞和脂肪细胞的葡萄糖摄取量和胰岛素受体(INSR)蛋白表达。喂食了牙龈脓疱病菌的小鼠往往会出现 IR。在实验小鼠的肝脏、骨骼肌和脂肪组织中都能检测到牙龈脓疱噬菌体。Gingipain的分布位置与INSR的下调相吻合。Gingipain蛋白水解了INSR的胰岛素结合功能区。与牙龈脓胞共培养可显著降低 INSR 与胰岛素的结合能力。敲除牙龈脓胞中的gingipain可减轻牙龈脓胞对体内IR的负面影响。综上所述,这些研究结果表明,远距离迁移的牙龈脓胞可能通过gingipain直接蛋白水解INSR,从而导致IR。这些结果为通过靶向牙周病原体预防糖尿病提供了新策略,并为探索牙周炎症影响全身代谢状态的新机制提供了新思路。
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来源期刊
International Journal of Oral Science
International Journal of Oral Science DENTISTRY, ORAL SURGERY & MEDICINE-
CiteScore
31.80
自引率
1.30%
发文量
53
审稿时长
>12 weeks
期刊介绍: The International Journal of Oral Science covers various aspects of oral science and interdisciplinary fields, encompassing basic, applied, and clinical research. Topics include, but are not limited to: Oral microbiology Oral and maxillofacial oncology Cariology Oral inflammation and infection Dental stem cells and regenerative medicine Craniofacial surgery Dental material Oral biomechanics Oral, dental, and maxillofacial genetic and developmental diseases Craniofacial bone research Craniofacial-related biomaterials Temporomandibular joint disorder and osteoarthritis The journal publishes peer-reviewed Articles presenting new research results and Review Articles offering concise summaries of specific areas in oral science.
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