SUMMARY/ABSTRACT Diabetes is a global health crisis. Depending on the type of statistical methodology used, the world-wide incidence of the most common type of diabetes, adult-onset or Type II, is estimated to be in the range of 285 million. In both Type I and Type II diabetics, glycemic control is paramount as the inability to maintain glycemic control results in increased risk of cardiovascular complications as well as several secondary complications including neuropathy, nephropathy and retinopathy, that often lead to amputations, dialysis and blindness. Hypoglycemia is a common adverse effect of insulin therapy and recent data shows that in the US alone almost 100k visits to the emergency department and more than 25K hospitalizations are due to insulin related hypoglycemia. Not surprisingly, exposure to hypoglycemia can induce a form of habituation leading to impaired awareness of hypoglycemia (IAH). IAH is a severe complication that often results in death due to patients being unresponsive and unable to self-administer glucose or emergency glucagon. Currently, there is no available approach to combating IAH. In our preliminary work we have designed and tested a series of novel dual agonist drugs candidates we term molecular artificial pancreas systems (mAPS). Our studies have demonstrated the mechanism of action and the ability of mAPS to prevent hypoglycemia at very high doses. In this Direct-to- Phase II project we will pursue manufacturing, formulation, efficacy validation, and safety studies on 3 lead candidates to identify a first in class dual agonist biologic suitable for safely treating Type I and Type II diabetics experiencing IAH.