Molecular mechanisms of impaired glucose transport in insulin resistance

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.

Insulin resistance, a condition where the hormone insulin no longer efficiently lowers blood glucose, is a risk factor for the development of type 2 diabetes, and is also linked to development of cardiovascular disease, some cancers and neurodegenerative diseases. Insulin promotes glucose uptake into adipose and muscle tissue through the redistribution of the glucose transporter GLUT4 from intracellular stores to the cell surface. This process is defective in insulin resistance. The overall aim of my fellowship is reveal the molecular mechanisms for impaired insulin-stimulated GLUT4 trafficking in insulin resistance. This comprises three specific aims. First, I will use proteomics and develop a high-throughput screening platform to find changes in protein localisation and/or protein expression that contribute to impaired GLUT4 trafficking in insulin resistance. Second, I will use microscopy techniques and trafficking assays to study the how the protein TRARG1, a recently identified regulator of GLUT4 trafficking, controls GLUT4 trafficking and whether impaired in signalling to TRARG1 plays a role in insulin resistance. Finally, I will follow up on my recent work that supports a key role for reactive oxygen species in mitochondria in insulin resistance by using phospho- and redox proteomics to map the pathway that connects mitochondrial reactive oxygen species to impaired GLUT4 trafficking in the cytosol. These studies have potential to reveal new information on how insulin regulates GLUT4 trafficking in health, and how this process becomes defective in insulin resistance.
These studies may reveal rational therapeutic options for correcting glucose transport in insulin resistance. This is significant since there are currently no medications for type 2 diabetics that target glucose transport to aid glycaemic control. In the longer term, such medications may help alleviate the development of type 2 diabetes and burden of other insulin resistance-associated disorders.

The following groups will benefit from my research programme and activities:

- Life sciences research community
- Clinicians and patients
- Pharmaceutical industry and life sciences companies
- General public (incl. school children)
- Research group

Life sciences research community
As described in more detail in the academic beneficiaries section, the research findings and method development as part of this project will benefit academics in a number of life sciences fields.

Clinicians and patients
The overall goal of my project is to increase our understanding of the causes of insulin resistance and metabolic disease to find new ways to improve metabolic health. While insulin resistance now appears to be a risk factor for a range of diseases, it is most commonly associated with type 2 diabetes. It is known that the efficacy of drugs (e.g metformin) to help type 2 diabetics control their blood glucose varies considerably between patients. In addition, there are currently no therapeutic options for type 2 diabetics that directly improve glucose uptake into muscle or adipose tissue, where my research is focused. Therefore, using the knowledge gathered from my studies to find new therapies to improve insulin action will improve options for clinicians, giving them a greater chance to find a combination of drugs that help each patient to control their blood glucose, and so improve patients' quality of life. While this impact will not be realised during my fellowship, this represents the major long-term impact of my proposed work.

Pharmaceutical industry and life sciences companies
This project has the potential to reveal new insight into how to improve insulin sensitivity or overcome insulin resistance by correcting/increasing insulin-stimulated glucose transport. Such therapies would also benefit those with type 2 diabetes. With > 3 million people diagnosed with type 2 diabetes in the UK in 2017 and >400 million worldwide in 2014, these findings will be of interest to the pharmaceutical industry and may attract R&D investment. In addition, during this fellowship I will generate technologies (e.g. high-throughput screen for regulators of GLUT4) and reagents (e.g. phospho-specific antibodies) that may be of commercial interest to either the pharmaceutical industry or life sciences companies.

General public (incl. school children)
This fellowship will provide me with the opportunity to engage with the general public to increase their knowledge about metabolic research and the importance of metabolic health, and to inspire students to consider medical research as a career option.

Research group
Studies within this proposal will form the basis of the early post-doctoral career or PhD studies of post-doctoral researchers and students recruited to my future group. My proposed studies address key questions and use innovative technologies, both of which will provide the best opportunity for post-doctoral researchers and students to develop their skillsets and generate data for high impact publications.