Optimizing diabetes therapy: re-engineering insulin as a biased agonist

DESCRIPTION provided by applicant Insulin is essential to the treatment of Type diabetes mellitus DM and is often required for optimal management of Type DM Despite its many decades of clinical use the complex post receptor signaling properties of insulin include both therapeutic and non therapeutic effects The overarching objective of this Phase I SBIR application is to demonstrate proof of principle that the signaling properties of insulin at the cellular level may be selectively re engineered to optimize glycemic control while avoiding undesirable biological actions Such selective re engineering in general designated biased agonism represents a key emerging frontier of molecular pharmacology Nobel Laureates Michael Brown and Joseph Goldstein have highlighted the importance of selective insulin resistance in T DM leading to the classic triad of hyperinsulinemia hyperglycemia and hypertriglyceridemia andquot The concept of selective insulin resistance in the liver assumes increased importance with the realization that elevated fatty acids and triglycerides make detrimental contributions to the diabetic state andquot they note andquot Brute force treatment of type diabetes patients with large doses of wild type insulin can overwhelm the insulin resistance and control the blood sugar but at what price andquot Brown M S andamp Goldstein J L Selective versus total insulin resistance a pathogenic paradox Cell Metab In this paradigm selective resistance to the glucose lowering effects of insulin leaves intact undesirable signaling properties of insulin with respect to lipid synthesis and mitogenicity That signaling through the insulin receptor can in principle lead to biased signaling outcomes has recently been demonstrated in animal studies of a phage display derived peptide agonist Frikke Schmidt H Pedersen T A Fledelius C Olsen G S Bouman S D Fitch M andamp Hellerstein M Treatment of diabetic rats with insulin or a synthetic insulin receptor agonist peptide leads to divergent metabolic responses Diabetes E pub Oct This application builds on the recent structural elucidation of a conserved hormone binding pocket in the ectodomain of the insulin receptor to design a non standard insulin analog with biased agonist properties Preliminary studies suggest that this novel analog retains glucose lowering activity with marked attenuation of its mitogenicity in human cancer cell culture and that in an animal model Sprague Dawley rats cellular signaling is shifted toward glycogen synthesis in muscle Support is requested to enable a more complete analysis of these signaling properties and to characterize the structure and stability of the insulin analog PUBLIC HEALTH RELEVANCE Development of an insulin analog with altered or biased post receptor signaling properties is proposed in relation to the paradigm of selective insulin resistance in Type diabetes mellitus Molecular design exploits a non standard modification penta fluoro Phe in combination with site directed mutagenesis of the A and or B chains to enhance metabolic homeostasis