Diabetes is rapidly becoming a global health crisis. Depending on the type of statistical methodology used, theworld-wide incidence of the most common type of diabetes, adult-onset or Type II, is estimated to be in the rangeof 285 million. In both Type I and Type II diabetics glycemic control is paramount as the inability to maintainglycemic 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 areversible, glucose dependent response at the insulin receptor. The full realization of the GRI concept wouldmost closely mimic the benefits of a healthy pancreas and maintain euglycemia, reduce/eliminate the need forconstant monitoring, and ultimately, reduce/eliminate the complications of diabetes. The scope of this proposalis the design and testing of a series of analogs that can bind glucose allosterically and demonstrate differentialresponse at the insulin receptor. This will be achieved through completion of three aims. In Aim 1 we will use anovel computational platform to design and produce a series of GRIs with glucose binding affinity in thephysiological 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 theGRI's in the presence of glucose at physiological concentrations. Completion of these Aims will result in theidentification of several GRI lead candidates with glucose binding in the physiological range and reversibleglucose dependent insulin receptor binding and absence of IGF-1R binding.
Public Health Relevance Statement: 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.
Project Terms: Adult ; 21+ years old ; Adult Human ; adulthood ; Amputation ; Binding Sites ; Combining Site ; Reactive Site ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Blood Glucose ; Blood Sugar ; Calorimetry ; Clinical Trials ; Computing Methodologies ; computational methodology ; computational methods ; computer based method ; computer methods ; computing method ; Diabetes Mellitus ; diabetes ; Insulin-Dependent Diabetes Mellitus ; Brittle Diabetes Mellitus ; IDDM ; Juvenile-Onset Diabetes Mellitus ; Ketosis-Prone Diabetes Mellitus ; Sudden-Onset Diabetes Mellitus ; T1 DM ; T1 diabetes ; T1D ; T1DM ; Type 1 Diabetes Mellitus ; Type 1 diabetes ; Type I Diabetes Mellitus ; insulin dependent diabetes ; juvenile diabetes ; juvenile diabetes mellitus ; ketosis prone diabetes ; type I diabetes ; type one diabetes ; Non-Insulin-Dependent Diabetes Mellitus ; Adult-Onset Diabetes Mellitus ; Ketosis-Resistant Diabetes Mellitus ; Maturity-Onset Diabetes Mellitus ; NIDDM ; Non-Insulin Dependent Diabetes ; Noninsulin Dependent Diabetes ; Noninsulin Dependent Diabetes Mellitus ; Slow-Onset Diabetes Mellitus ; Stable Diabetes Mellitus ; T2 DM ; T2D ; T2DM ; Type 2 Diabetes Mellitus ; Type 2 diabetes ; Type II Diabetes Mellitus ; Type II diabetes ; adult onset diabetes ; ketosis resistant diabetes ; maturity onset diabetes ; type 2 DM ; type II DM ; type two diabetes ; Dialysis procedure ; Dialysis ; dialysis therapy ; Fructose ; Levulose ; Glucose ; D-Glucose ; Dextrose ; Goals ; Human ; Modern Man ; Hypoglycemia ; hypoglycemic ; hypoglycemic episodes ; Incidence ; Insulin ; Humulin R ; Novolin R ; Regular Insulin ; Insulin Infusion Systems ; insulin pump ; Kidney Diseases ; Nephropathy ; Renal Disease ; kidney disorder ; renal disorder ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Leucine ; Ligands ; Maintenance ; Methods ; Methodology ; Molecular Conformation ; Molecular Configuration ; Molecular Stereochemistry ; conformation ; conformational state ; Mutation ; Genetic Alteration ; Genetic Change ; Genetic defect ; genome mutation ; Pancreas ; Pancreatic ; Legal patent ; Patents ; Patients ; Production ; Proteins ; Insulin Receptor ; Insulin Receptor Protein-Tyrosine Kinase ; Insulin-Dependent Tyrosine Protein Kinase ; Retinal Diseases ; Retinal Disorder ; retina disease ; retina disorder ; retinopathy ; Somatomedins ; Insulin-Like Growth Factors ; Sulfation Factor ; insulinlike growth factor ; Testing ; Thermodynamics ; Thermodynamic ; Time ; Toxicology ; Trees ; Valine ; L-Valine ; Xylose ; D-Xylose ; carbene ; methylene ; Measures ; insulin Wakayama ; Caring ; base ; improved ; Phase ; Physiological ; Physiologic ; Series ; Screening procedure ; screening tools ; insight ; diabetic ; analog ; Diabetes Complications ; Diabetes-Related Complications ; Diabetic Complications ; Complications of Diabetes Mellitus ; milligram ; neuropathic ; Neuropathy ; System ; vision loss ; visual loss ; Blindness ; Receptor Protein ; receptor ; receptor bound ; receptor binding ; success ; Cryo-electron Microscopy ; Electron Cryomicroscopy ; cryo-EM ; cryoEM ; Cryoelectron Microscopy ; novel ; vigilance ; cardiovascular risk ; cardiovascular risk factor ; Property ; response ; QSAR ; Quantitiative Structure Activity Relationship ; Quantitative Structure-Activity Relationship ; Molecular Interaction ; Binding ; small molecule ; IGF1 ; IGFI ; IGF1 gene ; global health ; Affinity ; Data ; in vivo ; Ligand Binding ; Monitor ; Characteristics ; Process ; Development ; developmental ; computerized tools ; computational tools ; design ; designing ; glycemic control ; Coupled ; healthy volunteer ; type I diabetic ; type 1 diabetic ; standard of care ; lead series ; drug candidate ; phase 2 study ; phase II study ; screening ; biophysical properties ; biophysical characteristics ; biophysical characterization ; biophysical measurement ; biophysical parameters ; clinical candidate ; lead candidate ; machine learning algorithm ; machine learned algorithm ; euglycemia ; web server ; computational platform ; computing platform ; Type 2 diabetic ; Type II diabetic ; pharmacokinetics and pharmacodynamics ; PK/PD ; in silico ; Rapid screening ;
