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Elucidation of the final stages in coupling of insulin signalling to GLUT4 translocation

阐明胰岛素信号转导与 GLUT4 易位耦合的最后阶段

基本信息

批准号：
MR/J003417/1
负责人：
Geoffrey Holman
金额：
$ 50.26万
依托单位：
University of Bath
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FJ003417%2F1
关键词：
Elucidation final stages coupling insulin

项目摘要

Maintenance of blood glucose levels is critically dependent on insulin stimulated glucose transport in adipose tissue, heart and skeletal muscle. Insulin combines with its receptor on target tissues and this initiates a cascade of linked reactions that ultimately result in the fusion of vesicles containing the glucose transporter protein GLUT4 with the plasma membrane. This latter process increases the availability of transporter molecules and thereby increases glucose transport into the cell. Although many of the links in the cascade are well studied, many technical difficulties have prevented detailed study of the final steps in the sequence, namely the fusion process. The proposed project will utilise novel approaches to study the fusion reaction and the extent to which small G-proteins of the Rab family link with the fusion machinery. We have identified many similarities between the membrane fusion reactions that occur in the pancreatic beta cell (which lead to secretion of insulin) and in insulin target tissues (which are involved in GLUT4 vesicle fusion). These similarities will guide the research objectives and experimental plans. These plans will be directed at advancing knowledge of how specific and known components of the fusion mechanism are linked together by effector proteins that are downstream of Rab proteins. This work is important as the fundamental mechanism that links signalling to regulated membrane fusion underlies many processes in biology and is relevant to human health. Elucidation of common mechanisms for pancreatic insulin-vesicle traffic and insulin target cell GLUT4-vesicle traffic will allow a unification of our understanding of those key reactions that are critical for control of blood glucose. These may become dysfunctional by a common route in metabolic disease including obesity and type 2 diabetes.

血糖水平的维持很大程度上依赖于胰岛素刺激的脂肪组织、心脏和骨骼肌中的葡萄糖转运。胰岛素与其靶组织上的受体结合，引发一系列连锁反应，最终导致含有葡萄糖转运蛋白 GLUT4 的囊泡与质膜融合。后一个过程增加了转运分子的可用性，从而增加了葡萄糖转运到细胞中。尽管级联中的许多环节都得到了很好的研究，但许多技术困难阻碍了对序列中最后步骤（即融合过程）的详细研究。拟议的项目将利用新方法来研究融合反应以及 Rab 家族的小 G 蛋白与融合机制的连接程度。我们已经发现胰腺β细胞（导致胰岛素分泌）和胰岛素靶组织（参与GLUT4囊泡融合）中发生的膜融合反应之间有许多相似之处。这些相似之处将指导研究目标和实验计划。这些计划将旨在增进对融合机制的特定和已知成分如何通过 Rab 蛋白下游的效应蛋白连接在一起的了解。这项工作很重要，因为将信号传导与调节膜融合联系起来的基本机制是生物学中许多过程的基础，并且与人类健康相关。阐明胰腺胰岛素囊泡运输和胰岛素靶细胞 GLUT4 囊泡运输的常见机制将使我们能够统一对控制血糖至关重要的关键反应的理解。这些可能会通过肥胖和 2 型糖尿病等代谢疾病的常见途径而变得功能失调。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The causal role of breakfast in energy balance and health: a randomized controlled trial in lean adults.

DOI：
10.3945/ajcn.114.083402
发表时间：
2014-08
期刊：
The American journal of clinical nutrition
影响因子：
0
作者：
Betts JA;Richardson JD;Chowdhury EA;Holman GD;Tsintzas K;Thompson D
通讯作者：
Thompson D

FGT-1 is the major glucose transporter in C. elegans and is central to aging pathways.

DOI：
10.1042/bj20131101
发表时间：
2013-12-01
期刊：
The Biochemical journal
影响因子：
0
作者：
Feng Y;Williams BG;Koumanov F;Wolstenholme AJ;Holman GD
通讯作者：
Holman GD

Developmental programming mediated by complementary roles of imprinted Grb10 in mother and pup.

DOI：
10.1371/journal.pbio.1001799
发表时间：
2014-02
期刊：
PLoS biology
影响因子：
9.8
作者：
Cowley M;Garfield AS;Madon-Simon M;Charalambous M;Clarkson RW;Smalley MJ;Kendrick H;Isles AR;Parry AJ;Carney S;Oakey RJ;Heisler LK;Moorwood K;Wolf JB;Ward A
通讯作者：
Ward A

The causal role of breakfast in energy balance and health: a randomized controlled trial in obese adults.

DOI：
10.3945/ajcn.115.122044
发表时间：
2016-03
期刊：
The American journal of clinical nutrition
影响因子：
0
作者：
Chowdhury EA;Richardson JD;Holman GD;Tsintzas K;Thompson D;Betts JA
通讯作者：
Betts JA

Proteomic Analysis of GLUT4 Storage Vesicles Reveals Tumor Suppressor Candidate 5 (TUSC5) as a Novel Regulator of Insulin Action in Adipocytes.

GLUT4储存囊泡的蛋白质组学分析揭示了抑制肿瘤候选者5（TUSC5）是脂肪细胞中胰岛素作用的新调节剂。

DOI：
10.1074/jbc.m115.657361
发表时间：
2015-09-25
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Fazakerley DJ;Naghiloo S;Chaudhuri R;Koumanov F;Burchfield JG;Thomas KC;Krycer JR;Prior MJ;Parker BL;Murrow BA;Stöckli J;Meoli CC;Holman GD;James DE
通讯作者：
James DE