Protein Treatment to Supplement Insulin Therapy for Diabetes Developed
Researchers at University of
Geneva have identified a protein called S100A9 which does away with the harmful
effects of insulin treatment and helps control blood sugar in diabetic
As early as 2010, Roberto Coppari’s team, a professor at the Diabetes Centre of the UNIGE Faculty of Medicine, highlighted the gluco- and lipid-regulatory properties of leptin, a hormone involved in hunger control. “However, leptin has proved difficult to use pharmacologically in human beings due to the development of leptin resistance”, says Roberto Coppari. “In order to overcome this problem, we shifted our focus on the metabolic mechanisms triggered by leptin rather than on the hormone itself.”
An effective protein despite its bad reputation
The scientists observed changes in the blood of insulin-deficient mice to whom they administered leptin and noted the abundant presence of the S100A9 protein. “This protein has a bad reputation because, when it binds to its sister protein S100A8, it creates a complex called calprotectin that causes the symptoms of many inflammatory or autoimmune diseases,” says Giorgio Ramadori, a researcher at the Dia-betes Centre of the UNIGE Faculty of Medicine and the first author of this work. “However, by over-expressing S100A9, we can, paradoxically, reduce its harmful combination with S100A8, hence dampening calprotectin levels.”
The researchers then administered high doses of S100A9 to their insulin-deficient diabetic mice and found improved glucose mana-gement and better control of ketones and of lipids, two metabolic abnormalities that are common in people with insulin deficiency.In order to better understand how this mechanism translates to human beings, Professor Coppari’s team is currently conducting a clinical observation study, in collaboration with the Geneva University Hospitals, in patients with type 1 and type 2 diabetes presenting very high glucose and ketones levels. They want to identify the correlations between the level of S100A9 in the blood and the severity of symptoms. “In human beings, previous studies already indicated that increased S100A9 levels correlate with reduced diabetes risks; hence, these results further bolster the clinical relevance of our data.
“As such, we are currently working to progress to phase I human clinical trials to directly test the safety and efficacy of S100A9 in insulin deficiency”, says Roberto Coppari. Towards combined treatments. The team then made a second discovery: S100A9 protein only appears to work in the presence of TLR4, a receptor located on the membrane of certain cells, including adipocytes or immune system cells. “Why? For the moment, it remains mysterious”, says Roberto Coppari. The researchers are currently working on a treatment that would combine low doses of insulin and S100A9 to better control glucose and ketones and limit high-dose insulin side effects. “We also want to decipher the exact role of TLR4 in order to offer a therapeutic strategy that achieves the delicate balance of optimal blood glucose, ketone and lipid control.”
Use of insulin leads to increased risk of life-threatening hypoglycaemia, and it does not restore metabolic balance. The stakes are high: tens of millions of people take insulin every day throughout their lives, a treatment that is often difficult to balance for both patients and caregivers. The new therapeutic strategy pro-posed by Roberto Coppari and his team could greatly improve their quality of life.