Metabolic Syndrome (MS) is defined as a cluster of inter-related symptoms including central obesity, insulin resistance, dyslipidemia, and hypertension that promote the development of type 2 diabetes mellitus, cardiovascular diseases and certain cancers. In this project a pharmacological strategy was developed that could alleviate the vicious circle of hyperglycemia (elevated blood glucose) and elevated insulin observed in metabolic syndrome that accelerates the onset of type 2 diabetes. We identified a new protein that participates in insulin-dependent increase in glucose uptake from the blood. Loss of this protein leads to reduced insulin dependent glucose uptake and a metabolic syndrome like disease in mice. In this project small molecules that modulate the function of the protein were developed and evaluated. New chemical matter was developed that showed suitable in vivo availability and appeared largely non-toxic when both in vitro and in vivo. A lead model compound was developed that when administered to mice that were obese and appeared to improve glucose homeostasis and restrict weight gain. New molecules based on this initial lead were synthesised and will in the next stage be optimized for their potential to be used in humans. These molecules that enhance glucose uptake into cells could be potentially powerful new tools to reverse insulin resistance a key pathology of metabolic syndrome that can accelerate the onset of type 2 diabetes.
