Novel Monoclonal Antibody Is an Allosteric Insulin Receptor Antagonist That Induces Insulin Resistance
| Autor: | Yin Liang, Ken Boayke, Simon A. Hinke, Rupesh Nanjunda, Eilyn R. Lacy, Russell B. Lingham, Jean M. Whaley, Dana L. Johnson, Anthony J. Kihm, Philip Cooper, Stephen Jarantow, Mark L. Chiu, Katharine D'Aquino, Robert Perkinson, Anne M. Cieniewicz, Thomas Kirchner |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Agonist medicine.medical_specialty medicine.drug_class Endocrinology Diabetes and Metabolism medicine.medical_treatment Blotting Western Glucagon-Like Peptide-1 Receptor Cell Line Mice 03 medical and health sciences Insulin resistance Internal medicine Insulin receptor substrate Internal Medicine medicine Hyperinsulinemia Animals Humans Glucose homeostasis Phosphorylation Receptor biology Insulin Antibodies Monoclonal medicine.disease Receptor Insulin Mice Inbred C57BL Insulin receptor 030104 developmental biology Endocrinology Diabetes Mellitus Type 2 Hyperglycemia biology.protein Insulin Resistance Peptides Protein Binding Signal Transduction |
| Zdroj: | Diabetes. 66:206-217 |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | A hallmark of type 2 diabetes is impaired insulin receptor (IR) signaling that results in dysregulation of glucose homeostasis. Understanding the molecular origins and progression of diabetes and developing therapeutics depend on experimental models of hyperglycemia, hyperinsulinemia, and insulin resistance. We present a novel monoclonal antibody, IRAB-B, that is a specific, potent IR antagonist that creates rapid and long-lasting insulin resistance. IRAB-B binds to the IR with nanomolar affinity and in the presence of insulin efficiently blocks receptor phosphorylation within minutes and is sustained for at least 3 days in vitro. We further confirm that IRAB-B antagonizes downstream signaling and metabolic function. In mice, a single dose of IRAB-B induces rapid onset of hyperglycemia within 6 h, and severe hyperglycemia persists for 2 weeks. IRAB-B hyperglycemia is normalized in mice treated with exendin-4, suggesting that this model can be effectively treated with a GLP-1 receptor agonist. Finally, a comparison of IRAB-B with the IR antagonist S961 shows distinct antagonism in vitro and in vivo. IRAB-B appears to be a powerful tool to generate both acute and chronic insulin resistance in mammalian models to elucidate diabetic pathogenesis and evaluate therapeutics. |
| Databáze: | OpenAIRE |
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