Insulin is essential to the treatment of Type 1 diabetes mellitus (DM) and is often required for optimal management of Type 2 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 T2 DM leading to the classic triad of hyperinsulinemia, hyperglycemia, and hypertriglyceridemia. "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," they note. "Brute-force treatment of type 2 diabetes patients with large doses of [wild-type] insulin... can overwhelm the insulin resistance and control the blood sugar, but at what price?" (Brown, M.S., & Goldstein, J.L. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 7, 95-6. (2008)). 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., & Hellerstein, M. Treatment of diabetic rats with insulin or a synthetic insulin receptor agonist peptide leads to divergent metabolic responses. Diabetes (E-pub Oct. 14, 2014)). 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 Statement: 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 2 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.
NIH Spending Category: Autoimmune Disease; Biotechnology; Breast Cancer; Cancer; Diabetes
Project Terms: Agonist; analog; Animal Model; Animals; Arts; Atherosclerosis; Attenuated; attenuation; basal insulin; base; Binding (Molecular Function); Biological; Blood Glucose; Breast Cancer Cell; Buffers; cancer cell; Cell Culture Techniques; Cell Proliferation; Cells; Charge; chemical stability; chemical synthesis; Clinical; Color; Competence; Complex; Deoxyglucose; design; Development; Diabetes Mellitus; diabetes mellitus therapy; diabetic; diabetic rat; Digestion; Dimerization; Dose; Drug Formulations; Drug Kinetics; Electrostatics; Engineering; Euglycemic Clamping; Fatty Acids; Female; Foundations; frontier; Functional disorder; Generations; globular protein; Glucose; Glucose Clamp; glucose disposal; glucose metabolism; glucose output; glucose uptake; glycemic control; Glycogen; Gold; Gray unit of radiation dose; Hepatic; Homeostasis; Hormone Receptor; Hormones; Human; Hydrophobicity; Hyperglycemia; Hyperinsulinism; Hypertriglyceridemia; improved; in vivo; Infusion procedures; Insulin; insulin dimers; Insulin Receptor; Insulin Resistance; Insulin, Lispro, Human; Insulin-Dependent Diabetes Mellitus; interest; Lead; Life; Ligands; Light; Lipids; Liver; Malignant Neoplasms; MCF7 cell; Mediating; Metabolic; miniproinsulin; Modeling; Modification; Molecular; Muscle; Non-Insulin-Dependent Diabetes Mellitus; novel; NPM1 gene; Nude Mice; Obesity; Outcome; pandemic disease; Patients; Pentas; Peptides; Peripheral; Phage Display; Pharmacodynamics; Pharmacology; Phase; phase 1 study; Phenylalanine; Phosphorylation; Phosphotransferases; Physical condensation; physical property; Positioning Attribute; Price; Property; Proteins; public health relevance; Rattus; receptor; Receptor Signaling; Relative (related person); Resistance; response; Risk; Sampling; Side; Signal Pathway; Signal Transduction; Site-Directed Mutagenesis; Skeletal muscle structure; Small Business Innovation Research Grant; Solubility; Sprague-Dawley Rats; Streptozocin; Structure; Sulfur; Technology; Testing; Therapeutic Effect; Time; Tissues; Triad Acrylic Resin; Triglycerides; Trypsin; tumor progression; Variant; Xenograft procedure
