Molecular mechanisms of impaired glucose transport in insulin resistance

胰岛素抵抗中葡萄糖转运受损的分子机制

• 批准号: MR/S007091/1
• 负责人: Daniel Fazakerley
• 金额: $ 159.62万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS007091%2F1
• 关键词: Molecular; mechanisms; impaired; glucose; transport

Type 2 diabetes represents one of the major worldwide health challenges, with more than 400 million people diagnosed. Insulin resistance, a condition where the hormone insulin is no longer able to efficiently control blood glucose levels, is a primary risk factor for the development of type 2 diabetes. In addition, insulin resistance is also linked to a number of other chronic diseases including cardiovascular disease, some cancers and neurodegenerative disorders. Therefore, treatments to overcome insulin resistance would provide new therapeutic options for type 2 diabetes and could help reduce the burden of other insulin-resistance associated diseases.Insulin lowers blood glucose levels, in part, by increasing glucose transport into fat and muscle tissue where it can be utilised or stored. One of the underlying causes of insulin resistance is a defect in the transport of glucose from the blood into these tissues. The processes within fat and muscle cells that are required for insulin to increase glucose transport in healthy individuals is well known. However, is not known how or which of these processes are impaired in insulin resistance. The aim of my fellowship proposal is to address this gap in knowledge by leading studies to identify the reason that the transport of glucose into fat and muscle tissue is disrupted in insulin resistance. The longer-term goal of my work is to use this information to identify rational ways to combat insulin resistance. Improving or restoring glucose transport into fat and muscle tissues to treat insulin resistance will have two major implications for human health. Firstly, this will address a current gap in treatment options for type 2 diabetes since there are no current medications that directly target glucose transport. Secondly, since insulin resistance is now linked to a several other chronic diseases, new therapies to overcome insulin resistance may have significant implications beyond type 2 diabetes.

2型糖尿病是全球主要的健康挑战之一，有超过4亿人被确诊。胰岛素抵抗是一种激素胰岛素不再能够有效控制血糖水平的状况，是2型糖尿病发展的主要风险因素。此外，胰岛素抵抗还与许多其他慢性疾病有关，包括心血管疾病，某些癌症和神经退行性疾病。因此，胰岛素抵抗的治疗将为2型糖尿病提供新的治疗选择，并有助于减少其他胰岛素抵抗相关疾病的负担。胰岛素降低血糖水平，部分是通过增加葡萄糖转运到脂肪和肌肉组织中，在那里它可以被利用或储存。胰岛素抵抗的根本原因之一是葡萄糖从血液运输到这些组织中的缺陷。脂肪和肌肉细胞内胰岛素增加健康个体葡萄糖转运所需的过程是众所周知的。然而，不知道如何或这些过程中受损的胰岛素抵抗。我的奖学金提案的目的是通过领导研究来解决这一知识空白，以确定葡萄糖向脂肪和肌肉组织的运输在胰岛素抵抗中被破坏的原因。我工作的长期目标是利用这些信息来确定对抗胰岛素抵抗的合理方法。改善或恢复葡萄糖向脂肪和肌肉组织的转运以治疗胰岛素抵抗将对人类健康产生两个主要影响。首先，这将解决目前2型糖尿病治疗选择的差距，因为目前没有直接针对葡萄糖转运的药物。其次，由于胰岛素抵抗现在与其他几种慢性疾病有关，因此克服胰岛素抵抗的新疗法可能具有超越2型糖尿病的重要意义。

项目成果

A high-content endogenous GLUT4 trafficking assay reveals new aspects of adipocyte biology.

• DOI: 10.26508/lsa.202201585
• 发表时间: 2023-01
• 期刊: LIFE SCIENCE ALLIANCE
• 影响因子: 4.4
• 作者: Diaz-Vegas, Alexis;Norris, Dougall M.;Jall-Rogg, Sigrid;Cooke, Kristen C.;Conway, Olivia J.;Shun-Shion, Amber S.;Duan, Xiaowen;Potter, Meg;van Gerwen, Julian;Baird, Harry J. M.;Humphrey, Sean J.;James, David E.;Fazakerley, Daniel J.;Burch, James
• 通讯作者: Burch, James

Trafficking regulator of GLUT4-1 (TRARG1) is a GSK3 substrate.

• DOI: 10.1042/bcj20220153
• 发表时间: 2022-06-17
• 期刊: The Biochemical journal

Integrating adipocyte insulin signaling and metabolism in the multi-omics era.

• DOI: 10.1016/j.tibs.2022.02.009
• 发表时间: 2022-06
• 期刊: TRENDS IN BIOCHEMICAL SCIENCES
• 影响因子: 13.8
• 作者: Calejman, C. Martinez;Doxsey, W. G.;Fazakerley, D. J.;Guertin, D. A.
• 通讯作者: Guertin, D. A.

The role of mitochondrial reactive oxygen species in insulin resistance

线粒体活性氧在胰岛素抵抗中的作用

• DOI: 10.17863/cam.78138
• 发表时间: 2022
• 作者: Ayer A