Jonas M. Kristensen, Rasmus Kjøbsted, Trine J. Larsen, Christian S. Carl, Janne R. Hingst, Johan Onslev, Jesper B. Birk, Anette Thorup, Dorte E. Steenberg, Jonas R. Knudsen, Nicolai S. Henriksen, Elise J. Needham, Jens F. Halling, Anders Gudiksen, Carsten F. Rundsten, Kristian E. Hanghøj, Sara E. Stinson, Birgitte Hoier, Camilla C. Hansen, Thomas E. Jensen, Ylva Hellsten, Henriette Pilegaard, Niels Grarup, Jesper Olesen, Sean J. Humphrey, David E. James, Michael L. Pedersen, Erik A. Richter, Torben Hansen, Marit E. Jørgensen, Jørgen F. P. Wojtaszewski
{"title":"Skeletal muscle from TBC1D4 p.Arg684Ter variant carriers is severely insulin resistant but exhibits normal metabolic responses during exercise","authors":"Jonas M. Kristensen, Rasmus Kjøbsted, Trine J. Larsen, Christian S. Carl, Janne R. Hingst, Johan Onslev, Jesper B. Birk, Anette Thorup, Dorte E. Steenberg, Jonas R. Knudsen, Nicolai S. Henriksen, Elise J. Needham, Jens F. Halling, Anders Gudiksen, Carsten F. Rundsten, Kristian E. Hanghøj, Sara E. Stinson, Birgitte Hoier, Camilla C. Hansen, Thomas E. Jensen, Ylva Hellsten, Henriette Pilegaard, Niels Grarup, Jesper Olesen, Sean J. Humphrey, David E. James, Michael L. Pedersen, Erik A. Richter, Torben Hansen, Marit E. Jørgensen, Jørgen F. P. Wojtaszewski","doi":"10.1038/s42255-024-01153-1","DOIUrl":null,"url":null,"abstract":"In the Greenlandic Inuit population, 4% are homozygous carriers of a genetic nonsense TBC1D4 p.Arg684Ter variant leading to loss of the muscle-specific isoform of TBC1D4 and an approximately tenfold increased risk of type 2 diabetes1. Here we show the metabolic consequences of this variant in four female and four male homozygous carriers and matched controls. An extended glucose tolerance test reveals prolonged hyperglycaemia followed by reactive hypoglycaemia in the carriers. Whole-body glucose disposal is impaired during euglycaemic-hyperinsulinaemic clamp conditions and associates with severe insulin resistance in skeletal muscle only. Notably, a marked reduction in muscle glucose transporter GLUT4 and associated proteins is observed. While metabolic regulation during exercise remains normal, the insulin-sensitizing effect of a single exercise bout is compromised. Thus, loss of the muscle-specific isoform of TBC1D4 causes severe skeletal muscle insulin resistance without baseline hyperinsulinaemia. However, physical activity can ameliorate this condition. These observations offer avenues for personalized interventions and targeted preventive strategies. In Greenlandic Inuit, a TBC1D4 loss-of-function mutation increases type 2 diabetes risk by tenfold. Carriers show severe muscle insulin resistance, impaired glucose disposal and reduced muscle GLUT4, yet exercise mitigates these defects, offering potential for personalized lifestyle interventions.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 12","pages":"2254-2266"},"PeriodicalIF":18.9000,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01153-1.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature metabolism","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s42255-024-01153-1","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
Abstract
In the Greenlandic Inuit population, 4% are homozygous carriers of a genetic nonsense TBC1D4 p.Arg684Ter variant leading to loss of the muscle-specific isoform of TBC1D4 and an approximately tenfold increased risk of type 2 diabetes1. Here we show the metabolic consequences of this variant in four female and four male homozygous carriers and matched controls. An extended glucose tolerance test reveals prolonged hyperglycaemia followed by reactive hypoglycaemia in the carriers. Whole-body glucose disposal is impaired during euglycaemic-hyperinsulinaemic clamp conditions and associates with severe insulin resistance in skeletal muscle only. Notably, a marked reduction in muscle glucose transporter GLUT4 and associated proteins is observed. While metabolic regulation during exercise remains normal, the insulin-sensitizing effect of a single exercise bout is compromised. Thus, loss of the muscle-specific isoform of TBC1D4 causes severe skeletal muscle insulin resistance without baseline hyperinsulinaemia. However, physical activity can ameliorate this condition. These observations offer avenues for personalized interventions and targeted preventive strategies. In Greenlandic Inuit, a TBC1D4 loss-of-function mutation increases type 2 diabetes risk by tenfold. Carriers show severe muscle insulin resistance, impaired glucose disposal and reduced muscle GLUT4, yet exercise mitigates these defects, offering potential for personalized lifestyle interventions.
期刊介绍:
Nature Metabolism is a peer-reviewed scientific journal that covers a broad range of topics in metabolism research. It aims to advance the understanding of metabolic and homeostatic processes at a cellular and physiological level. The journal publishes research from various fields, including fundamental cell biology, basic biomedical and translational research, and integrative physiology. It focuses on how cellular metabolism affects cellular function, the physiology and homeostasis of organs and tissues, and the regulation of organismal energy homeostasis. It also investigates the molecular pathophysiology of metabolic diseases such as diabetes and obesity, as well as their treatment. Nature Metabolism follows the standards of other Nature-branded journals, with a dedicated team of professional editors, rigorous peer-review process, high standards of copy-editing and production, swift publication, and editorial independence. The journal has a high impact factor, has a certain influence in the international area, and is deeply concerned and cited by the majority of scholars.