Development of Novel Therapeutic Agents to Enhance Insulin Secretion

Worldwide, 8.5% of adults now have diabetes. Importantly, being overweight or obese increases the chance of developing the most common type of diabetes, type 2 diabetes. In fact, obesity is believed to account for 80-85% of the risk of developing type 2 diabetes, while recent research suggests that obese people are up to 80 times more likely to develop type 2 diabetes than individuals who are lean. The UK currently ranks as the country with the highest level of obesity in Europe, with more than 1 in 4 (28.1%) adults obese and nearly two out of three (63.4%) overweight. Crucially, over the next 20 years, the number of obese adults in the country is forecast to soar to 26 million people. According to health experts, such a rise would result in more than a million extra cases of type 2 diabetes, heart disease and cancer. Whilst the causal link between obesity and diabetes is clear, at the cellular and molecular level there is however much that remains unknown. Research in the Turner group focuses on the impact of high glucose and high fat on the development of diabetes, and on designing new drugs to prevent or treat T2D. This is particularly important, as over time existing treatments typically become less effective, resulting in a search for new compounds that can increase insulin secretion and insulin sensitivity through different mechanisms.

Insulin secretion is known to decrease when pancreatic cells are exposed to chronic elevated concentrations of glucose and fatty acids. Recent research from the Turner group showed that activation of a subset of the trace amine associated receptor family of G-protein coupled receptors (GPCRs) was however able to partially reverse this effect by increasing insulin secretion from the pancreas. However, physiological trace amines are rapidly degraded by enzymes called monoamine oxidases (MAO) in the body, and typically have a half-life of only ~30 sec in vivo. This therefore makes them unsuitable candidates to use therapeutically. Instead, in order to generate more effective and longer-lasting increases in insulin secretion, we need to develop pharmacological agents that are resistant to MAO breakdown, but which are still able to retain their ability to selectively activate trace amine associated receptors. This studentship project will directly address this aim, and will involve a combination of medicinal synthetic chemistry, biological screening, and cell signalling biochemistry.