A novel insulin receptor-signaling platform and its link to insulin resistance and type 2 diabetes.

Abstract

Insulin-induced insulin receptor (IR) tyrosine kinase activation and insulin cell survival responses have been reported to be under the regulation of a membrane associated mammalian neuraminidase-1 (Neu1). The molecular mechanism(s) behind this process is unknown. Here, we uncover a novel Neu1 and matrix metalloproteinase-9 (MMP-9) cross-talk in alliance with neuromedin B G-protein coupled receptor (GPCR), which is essential for insulin-induced IR activation and cellular signaling. Neu1, MMP-9 and neuromedin B GPCR form a complex with IRβ subunit on the cell surface. Oseltamivir phosphate (Tamiflu®), anti-Neu1 antibodies, broad range MMP inhibitors piperazine and galardin (GM6001), MMP-9 specific inhibitor (MMP-9i), and GPCR neuromedin B specific antagonist BIM-23127 dose-dependently inhibited Neu1 activity associated with insulin stimulated rat hepatoma cells (HTCs) that overly express human IRs (HTC-IR). Tamiflu, anti-Neu1 antibodies and MMP-9i attenuated phosphorylation of IRβ and insulin receptor substrate-1 (IRS1) associated with insulin-stimulated cells. Olanzapine, an antipsychotic agent associated with insulin resistance, induced Neu3 sialidase activity in WG544 or 1140F01 human sialidosis fibroblast cells genetically defective in Neu1. Neu3 antagonist 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) and anti-Neu3 antibodies inhibited sialidase activity associated with olanzapine treated murine Neu4 knockout macrophage cells. Olanzapine attenuated phosphorylation of IGF-R and IRS1 associated with insulin-stimulated human wild-type fibroblast cells. Our findings identify a novel insulin receptor-signaling platform that is critically essential for insulin-induced IRβ tyrosine kinase activation and cellular signaling. Olanzapine-induced Neu3 sialidase activity attenuated insulin-induced IGF-R and IRS1 phosphorylation contributing to insulin resistance.

• Authors: Farah Alghamdi, Merry Guo, Samar Abdulkhalek, Nicola Crawford, Schammim Ray Amith, Myron R Szewczuk
• Journal: Cellular signalling (Cell Signal) Vol. 26 Issue 6 Pg. 1355-68 (Jun 2014) ISSN: 1873-3913 [Electronic] England
• PMID: 24583283 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014. Published by Elsevier Inc.

Chemical References

• Antipsychotic Agents
• IRS1 protein, human
• Insulin
• Insulin Receptor Substrate Proteins
• Benzodiazepines
• Receptor, IGF Type 1
• Receptor, Insulin
• NEU1 protein, human
• Neu3 protein, human
• Neuraminidase
• MMP9 protein, human
• Matrix Metalloproteinase 9
• Olanzapine

Topics

• Animals
• Antipsychotic Agents (pharmacology)
• Benzodiazepines (pharmacology)
• Cell Line, Tumor
• Diabetes Mellitus, Type 2 (metabolism)
• Humans
• Insulin (physiology)
• Insulin Receptor Substrate Proteins (metabolism)
• Insulin Resistance
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Neuraminidase (metabolism)
• Olanzapine
• Phosphorylation
• Protein Processing, Post-Translational
• Protein Transport
• Rats
• Receptor, IGF Type 1 (metabolism)
• Receptor, Insulin (metabolism)
• Signal Transduction