A glucose-responsive network

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It is estimated that 4.5 million people in the UK suffer with diabetes and many of these patients regulate their blood-sugar levels by taking insulin. A major problem with this treatment is that is can lead to repeated bouts of low glucose or "hypos." This is when there is too little glucose in the bloodstream (hypoglycaemia), which can cause serious problems. For example, a patient might start feeling agitated or dizzy, and may even collapse unconscious. These feelings stimulate the body to release natural, protective hormones and alert the patient to eat something sugary. Unfortunately, diabetic patients taking insulin may suffer from bouts of hypoglycaemia so regularly that they start to become unaware of the warning signs, increasing the probability that they may collapse and even fall into a coma. If we are to help these patients in the future, it is critical that we understand how the brain normally detects and responds to hypoglycaemia. We have made the important discovery of a specific type of brain cell, which contains a chemical signal called PACAP. These cells can sense low sugar levels and initiate a series of physiological responses. We have mapped the other parts of the brain with which PACAP cells connect and, importantly, each of these areas has previously been implicated in the brain's response to hypoglycaemia. Thus, together they initiate the release of the protective hormones or produce a change in behaviour (e.g. cause hunger and sugar seeking). Critically, our discovery has provided us with a key to "open up" the brain and understand the complex electrical circuits which sense and respond to hypoglycaemia. Our experiments allow us to make PACAP cells shine under fluorescent light. This means we can cut slices of mouse brain from dead animals and record specifically the electrical activity of PACAP cells. This shows us exactly how PACAP cells respond to low sugar levels and how they then send this information to the other brain areas. Similar techniques also allow us to activate PACAP neurones in living mice, either by shining a light into their brains through an optic fibre or by giving the mice a special "designer" drug by an injection under their skin. The mice do not feel anything unusual, but by activating PACAP cells or other specific cell types in the brain (as happens naturally with hypoglycaemia), we will map the circuits which control the release of protective hormones and cause awareness of hypoglycaemia. By carefully profiling PACAP and other brain cells, we should be able to identify additional key cell types and fit them into our glucose-sensing network. Thus, we will be able to build up a picture of exactly how the brain senses and responds to hypoglycaemia. By understanding the complex circuits in this network, we should begin to understand why patients lose their awareness of hypoglycaemia after long-term insulin treatment. We hope to be able to suggest new ways of detecting and preventing impaired awareness of hypoglycaemia and, thus, improve the safety of diabetic patients.