Metabolic functions of insulin signalling and resistance in the brain

Rationale 

Eight out of 10 men and seven in 10 women will be overweight or obese by 2020. These individuals are more likely to be insensitive to insulin (insulin resistant) and develop diabetes.

The brain collects inputs from around the body to regulate glucose metabolism of an individual and signals back to the peripheral organs to ensure a balanced hormonal response. Alteration of these hormonal and metabolic processes can lead to metabolic diseases and vice versa. Restoring the brain’s ability to modulate metabolic functions could be very important to overcome disease conditions associated with obesity and diabetes. We aim to study how insulin resistance occurs in a specific area of the brain called the Dorsal Vagal Complex, which regulates metabolic functions and glucose levels in the blood. 

Plan of work and impact of our studies  

To understand the molecular mechanism involved in the development of insulin resistance in the brain we will insert a cannula into a specific area of the rat brain and we will either inject small molecule inhibitors or introduce engineered proteins to affect specific metabolic pathways. Using this approach, we will study the effect that loss of insulin sensitivity has on feeding behaviour and glucose metabolism. 

To study glucose metabolism, we will perform pancreatic clamp or intravenous glucose tolerance tests that require infusion of substances, for which the jugular vein and artery will be catheterized.

Our goal is to identify which molecules are involved in responding to insulin in the brain and to find new pharmacological approaches to prevent the incurrence of insulin resistance and diabetes.

Animal welfare

Rats are the best animal models to perform the proposed metabolic studies. Rat glucose levels are stable and the brain surgery is easy to perform in rats due to their anatomy which is well understood.

All surgical procedures will be performed under balanced general anaesthesia and under sterile conditions. Even if rats are subjected to either one or two surgical procedures, they recover well and we do not expect that any animals will suffer beyond moderate severity which will be alleviated through close monitoring, medical treatment (ie painkillers) and high standards of animal care. We will minimise the number of animals necessary to see a significant result and to further reduce numbers of animals, we will perform work using cells and in tissues where possible. 

Non-technical summary 

Read metabolic functions of insulin signalling and resistance in the brain non-technical summary (PDF).

This PDF may not be suitable for users of assistive technology. If you need an accessible version please email h.o.admin@leeds.ac.uk.