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.

Neuraminidase-1: A novel therapeutic target in multistage tumorigenesis

“…It has also been shown that insulin can mediate increases in MMP9 via insulin receptor (IR) activation [148], which fits well within this molecular signaling platform for insulin-induced receptors [59]. The study has also shown that insulin can induce MMP9 upregulation via the mitogenic signaling pathways, and renders the PI3K-dependent signaling pathway unnecessary.…”

“…It is noteworthy that we have reported a striking similarity with this novel receptor signaling platform for nerve growth factor (NGF) TrkA receptors [35], insulin [59, 60] and cell surface TOLL-like receptor (TLR)-4, [34, 61–64] and intracellular TLR7 and TLR9 receptors [65], all of which require receptor dimerization and are regulated by Neu1. Pshezhetsky and Ashmarina [66] have recently summarized the emerging data demonstrating that Neu1, well known for its lysosomal catabolic function, is also localized to the cell surface and assumes the previously unrecognized role as a structural and functional modulator of cellular receptors.…”

“…MMP9 and neuromedin B GPCR (NMBR) are associated with each other on the cell surface, and together form a complex with EGFR [30], TrkA receptors [35], insulin receptor IRβ subunits [59], TLR-4 [34, 61, 62, 64], and TLR7 and −9 [65]. Co-immunoprecipitation experiments using cell lysates from RAW-blue macrophage cells demonstrated that the 80 kDa NMBR isoform forms a complex with the active 88 kDa MMP9 isoform from naïve or lipopolysaccharide (LPS)-stimulated cells [62].…”

Influence of Gut Microbiota on Inflammation and Pathogenesis of Sugar Rich Diet Induced Diabetes

“…Further, adverse effects precipitated by increased fructose intake include negative effects on cardiovascular and kidney functions. Earlier studies reported that high sugar diet can lead to insulin resistance, while defects in the insulinsignaling pathway may be due to high fat diet [24]. In this study, HFD and HSD rats reproduced the changes in blood glucose, plasma triglyceride and cholesterol levels which may leads to insulin resistance and impaired glucose tolerance.…”

Acute Hepatic Insulin Resistance Contributes to Hyperglycemia in Rats Following Myocardial Infarction

“…Insulin-stimulated tyrosine phosphorylation of IR β-subunit, which is correlated with full activation of the IR tyrosine kinase (14,15), did not change significantly in liver tissue between MI and control rats ( Figure 2A). By contrast, insulinstimulated tyrosine phosphorylation of IRS1 decreased by almost 70% more in MI rats than in controls ( Figure 2B).…”