R43DK126521

SUMMARY/ABSTRACT. Diabetes is rapidly becoming 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 several secondary complications including neuropathy, nephropathy and retinopathy, that often lead to amputations, dialysis and blindness as well as increased risk of cardiovascular complications. For the majority of diabetics glycemic control requires constant vigilance and monitoring of blood glucose levels. The overarching goal of this project is the development of a novel glucose responsive insulin (GRI) with a reversible, glucose dependent response at the insulin receptor. The full realization of the GRI concept would most closely mimic the benefits of a healthy pancreas and maintain euglycemia, reduce/eliminate the need for constant monitoring, and ultimately, reduce/eliminate the complications of diabetes. The scope of this proposal is the design and testing of a series of analogs that can bind glucose allosterically and demonstrate differential response at the insulin receptor. This will be achieved through completion of three aims. In Aim 1 we will use a novel computational platform to design and produce a series of GRIs with glucose binding affinity in the physiological range. In Aim 2 we will determine the glucose binding affinity of the analogues produced in Aim 1. Finally, in Aim 3 we will measure the insulin receptor (IR) and insulin like growth factor (IGF-R1) affinity of the GRI’s in the presence of glucose at physiological concentrations. Completion of these Aims will result in the identification of several GRI lead candidates with glucose binding in the physiological range and reversible glucose dependent insulin receptor binding and absence of IGF-1R binding.NARRATIVE Diabetes is rapidly becoming a global health crisis. In both Type I and Type II diabetics glycemic control is paramount as the inability to maintain glycemic control results in a number of secondary complications including neuropathy, nephropathy and retinopathy, that often lead to amputations, dialysis and blindness. A reversible glucose responsive insulin (GRI) would represent a significant improvement in diabetes care for both T1D and T2D patients. The success of this project will result in clinical candidates that will ultimately supplant basal and prandial insulins while simultaneously improving glycemic control and reducing hypoglycemic incidences known to increase cardiovascular risk as well as secondary complications.