Inhibiting glucagon/beta-catenin signalling in the liver with niclosamide as a novel therapy for Type 2 diabetes

GC Smith, MKH Chowdhury, N Turner and M Morris

UNSW Australia, Sydney, Australia

T2D is a complex metabolic disorder characterised by hyperglycaemia which has now reached epidemic levels. It has been predicted that the current prevalence of 400 million people worldwide will double over the next 20 years. T2D also doubles the risk of a wide range of cardiovascular disease, like coronary heart disease and stroke, but also non-vascular disease like cancer, mental and nervous system disorders, infections and liver disease. The current pathophysiological evidence describes T2D as a spectrum disorder characterised by variable degrees of insulin resistance and β-cell dysfunction which leads to hyperglycaemia. But despite many years of research into insulin signalling and T2D no fully effective solution to treat this metabolic disorder has been discovered. Currently drugs used to treat T2D target the symptoms of this disease but over time lead to undesirable side effects and even drug resistance. Here we propose that inhibiting glucagon signalling, that is elevated in people with T2D, represents a new approach in the treatment of this disease. We found a novel link between glucagon and β-catenin signalling that is regulated by cAMP levels in the liver that may provide a novel metabolic link for the development of newer drugs to treat the cause of T2D. We have used a drug called niclosamide that works as a mitochondrial uncouplier to reduce the production of cAMP and found this drug inhibits glucagon/β-catenin signalling and improved glucose metabolism in obese animals. Because of the excellent safety profile in humans and other animals and long-term oral treatment (from months to a year in rats and dogs) showing no adverse effects, niclosamide could be re-purposed for the treatment of T2D. By re-purposing niclosamide for the treatment of T2D our research would have immediate health impact.