Targeting the hypothalamic purinergic system for the regulation of whole body glucose homeostasis
Dr Craig Beall aims to identify cell surface receptors that are activated by the energy-sensing enzyme AMPK in the brain. He wants to understand their role in the regulation of appetite, blood glucose and energy balance, which affect both Type 1 and Type 2 diabetes.
Background to research
Episodes of severe hypoglycaemia (or hypos) are a major concern for people with diabetes and their carers. Over time they can lead to ‘hypoglycaemia unawareness’, where the body struggles to detect and respond to low blood glucose levels, but unfortunately the signalling mechanisms and cell types that control this process are currently unknown. To extend our knowledge, Dr Craig Beall has been studying the hypothalamus, a small region of the brain that connects signals from the nervous system with hormonal signals that control energy balance. When the energy-sensing enzyme AMPK is activated in this region, it stimulates appetite and helps the body to detect and respond to low blood glucose levels. Dr Beall has uncovered AMPK activity in astrocytes, the abundant star-shaped cells that support and regulate nerve cells in the human brain. He believes that this activity can lead to the activation of specialised ‘purinergic’ receptors on the surface of nerve cells, which in turn leads to nerve cell activity that helps regulate blood glucose and energy balance.
With support from Diabetes UK, Dr Beall aims to improve our understanding of AMPK and its function in astrocyte cells in the hypothalamus. Specifically, he wants to identify purinergic receptors that are activated by AMPK signalling and which play a role in the regulation of blood glucose and energy balance. To do this he will isolate rat astrocyte cells in the laboratory and study their response to low levels of glucose and chemicals that activate or inhibit the function of AMPK. In addition, he will use genetic engineering to alter AMPK activity in the astrocytes of living rats and measure the response to low blood glucose levels and a high fat diet, as well as responses to drugs that modify the function of purinergic receptors.
Potential benefit to people with diabetes
If purinergic receptors are shown to be involved in the control of appetite, blood glucose levels and energy balance, they could provide targets for new drugs to improve the management of both Type 1 and Type 2 diabetes. Potentially, such drugs could help to control blood glucose levels and the detection of low blood glucose levels in Type 1 diabetes or help to regulate appetite and energy balance in Type 2 diabetes. This could help to overcome the lack of existing drugs and the side effects of drugs that do exist. Findings from this research could enable researchers to begin developing these new drugs and help to explain how recurrent low blood glucose levels can cause hypoglycaemia unawareness.