Novel regulators of insulin-stimulated glucose disposal in humans

Type 2 diabetes is a growing health concern globally, and is associated with a range of complications and increased risk of other diseases such as cardiovascular disease. Therefore, understanding more about the progression to type 2 diabetes and developing new treatments or prevention strategies is a high research priority. Type 2 diabetes has a complex aetiology, initially involving insulin resistance, a state where tissues like muscle no longer respond properly to the hormone insulin, and subsequently impaired production/release of insulin from the pancreas. Insulin plays an important role in controlling blood glucose and dysregulation of these processes results in higher-than-normal blood glucose levels, and eventually type 2 diabetes. This proposal focuses on understanding more about insulin resistance, with a long-term aim of finding new drug targets to improve insulin responses in people with type 2 diabetes, or to mitigate progression to type 2 diabetes.
Insulin lowers blood glucose by targeting a range of tissues; in muscle and fat tissues insulin stimulates glucose uptake into these tissues. We do not have a complete understanding of how insulin controls glucose uptake into muscle and fat cells, nor do we understand why insulin-stimulated glucose uptake is impaired in insulin resistance. As a result, we currently do not have treatments that target insulin-stimulated glucose uptake to improve insulin sensitivity.
Our previous work used a combination of human genetics and laboratory models to find a series of genes that were not previously known to regulate insulin-stimulated glucose uptake. These genes may represent completely novel ways to target insulin-stimulated glucose uptake to overcome insulin resistance. In this proposal, we aim to build on this work using a range of experimental models, and human genetics, to explore how these genes work and whether they also regulate insulin responses in tissues.
This will include answering the following questions:
1. How do prioritised genes-of-interest regulate insulin-stimulated glucose transport?
2. Do these genes also play a role in glucose disposal in muscle in mouse models?
3. Does natural genetic variation in these genes in humans play a role controlling blood glucose and in other diseases?
Alongside these aims, we will also undertake additional discovery genetics analyses in humans to more comprehensively map regions of DNA that regulate insulin responses, and further expand our list of genes-of-interest. New genes identified using this approach are also potential candidates for future research into treatments for type 2 diabetes, and will warrant future investigation when building on this programme of work, beyond this proposal.
If successful, we will generate new insights into the regulation of insulin-stimulated glucose uptake, a critical process in whole body glucose homeostasis. Further we will highlight novel potentially actionable drug targets to overcome muscle and fat insulin resistance, which is currently an unmet clinical need, providing the prospect of novel treatment avenues for this increasingly prevalent condition.