Depletion of TBC1D4 improves the metabolic exercise response by overcoming genetically induced peripheral insulin resistance

IF 6.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes Pub Date : 2024-04-12 DOI:10.2337/db23-0463

Christian Springer, Christian Binsch, Deborah Weide, Laura Toska, Anna Lena Cremer, Heiko Backes, Anna K. Scheel, Lena Espelage, Jörg Kotzka, Sebastian Sill, Anette Kurowski, Daebin Kim, Sandra Karpinski, Theresia M. Schnurr, Torben Hansen, Sonja Hartwig, Stefan Lehr, Sandra Cames, Jens Brüning, Matthias Lienhard, Ralf Herwig, Stefan Börno, Bernd Timmermann, Hadi Al-Hasani, Alexandra Chadt

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Abstract

The RabGTPase-activating protein (RabGAP) TBC1D4 (=AS160) represents a key component in the regulation of glucose transport into skeletal muscle and white adipose tissue (WAT) and is therefore crucial during the development of insulin resistance and type-2 diabetes. Increased daily activity has been shown to be associated with improved postprandial hyperglycemia in allele carriers of a loss-of-function variant in the human TBC1D4 gene. Using conventional Tbc1d4-deficient mice (D4KO) fed a high-fat diet (HFD), we show that already a moderate endurance exercise training leads to substantially improved glucose and insulin tolerance and enhanced expression levels of markers for mitochondrial activity and browning in WAT from D4KO animals. Importantly, in vivo and ex vivo analyses of glucose uptake revealed increased glucose clearance in interscapular brown adipose tissue (iBAT) and WAT from trained D4KO mice. Thus, chronic exercise is able to overcome the genetically induced insulin resistance caused by the Tbc1d4-depletion. Gene variants in TBC1D4 may be relevant in future precision medicine as determinants of exercise response.

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通过克服基因诱导的外周胰岛素抵抗，消耗 TBC1D4 改善代谢运动反应

RabGTP酶激活蛋白（RabGAP）TBC1D4（=AS160）是调节葡萄糖向骨骼肌和白脂肪组织（WAT）转运的关键成分，因此在胰岛素抵抗和2型糖尿病的发展过程中至关重要。研究表明，在人类 TBC1D4 基因功能缺失变异等位基因携带者中，增加日常活动与改善餐后高血糖有关。我们使用传统的 Tbc1d4 基因缺失小鼠（D4KO）喂养高脂饮食（HFD），结果表明中等强度的耐力运动训练就能大幅改善葡萄糖和胰岛素耐受性，并提高 D4KO 动物脂肪中线粒体活性和棕色化标记物的表达水平。重要的是，体内和体外葡萄糖摄取分析表明，训练过的 D4KO 小鼠肩胛间棕色脂肪组织（iBAT）和脂肪组织的葡萄糖清除率提高了。因此，慢性运动能够克服基因诱导的 Tbc1d4 缺失引起的胰岛素抵抗。TBC1D4的基因变异作为运动反应的决定因素，可能与未来的精准医疗相关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.

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