Targeting the insulin ‘handbrake.’ 30 June 2021 Dr Kim Loh has gone in the opposite direction of most diabetes researchers, and has discovered a promising new drug for treating type 2 diabetes. Through his research into what he calls “the insulin handbrake”, Dr Kim Loh, head of the Diabetes and Metabolic Disease Laboratory at St Vincent’s Institute of Medical Research, has discovered a promising drug for treating type 2 diabetes, thanks to a research grant from Diabetes Australia. In type 2 diabetes, which accounts for 85-90% of all diabetes cases, the body’s ability to respond to insulin is reduced. “The pancreas has to produce excessive amounts of insulin to maintain normal blood glucose levels. Over a prolonged period, the beta cells that produce insulin become exhausted and can’t produce sufficient amounts. So eventually, a patient with type 2 diabetes will need insulin injections.” Dr Loh says while many researchers are focused on stimulating the body’s release of insulin, he has gone in a different direction. “My focus is on the molecules that stop the beta cells from producing insulin: what I call the insulin handbrakes.” After identifying one of these “handbrakes” in mice, his team received a Diabetes Australia grant to undertake further research in 2019. They have now confirmed that this “handbrake” also exists in humans. “Our institute has access to human pancreatic cells, so by looking at cells from healthy donors and donors with type 2, we found this insulin ‘handbrake’ is accelerated in people with type 2 diabetes,” says Dr Loh. The Diabetes Australia grant has also led to another important discovery, a drug that was initially used to treat obesity, but was unsuccessful, has “released this handbrake” and improved blood glucose management in mice. “It makes sense that if you release this handbrake, you improve glucose management,” says Dr Loh. He now wants to carry out clinical trials in humans as well as work with chemists to improve the selectivity of the compounds and increase the drug’s efficacy. Dr Loh says most of the drugs that are used to treat type 2 diabetes work to maintain blood glucose levels rather than treating the condition’s underlying causes. He says all the drugs have their advantages and disadvantages. “For example, metformin is one of the safest drugs used to treat type 2, but it does not improve beta cell function. Many people with type 2 start off taking metformin but eventually they inject themselves with insulin.” He says that by targeting insulin suppression, this obesity drug targets a very different pathway to the other drugs, so he hopes that further down the track they can look at combining it with other drugs to potentially lead to improvements. “If you have drugs that currently stimulate insulin production and you have this handbrake that keeps suppressing the insulin release, I hypothesise that by combining these drugs with one that releases the handbrake, you will have better glucose management,” he says. Dr Loh says although there are many drugs available to treat type 2 diabetes, there are still clinical needs that are not being met. “The more we know, the more we can design better drugs to treat type 2,” he says.