title: Insulin-Dependent Regulation of mTORC2-Akt-FoxO Suppresses TLR4 Signaling in Human Leukocytes: Relevance to Type 2 Diabetes.
abstract: Leukocyte signaling in patients with systemic insulin resistance is largely unexplored. We recently discovered the presence of multiple Toll-like receptor 4 (TLR4) signaling intermediates in leukocytes from patients with type 2 diabetes or acute insulin resistance associated with cardiopulmonary bypass surgery. We extend this work to show that in addition to matrix metalloproteinase 9, hypoxia-inducible factor 1α, and cleaved AMPKα, patient leukocytes also express IRS-1 phosphorylated on Ser(312), Akt phosphorylated on Thr(308), and elevated TLR4 expression. Similar signaling intermediates were detected in leukocytes and neutrophils treated with lipopolysaccharide (LPS), a ligand of TLR4, in vitro. In contrast, insulin, but not LPS, induced mammalian target of rapamycin complex 2 (mTORC2)-dependent phosphorylation of Akt on Ser(473) and FoxO1/O3a on Thr(24/32) in leukocytes and neutrophils. Insulin suppressed LPS-induced responses in a dose- and time-dependent manner. AS1842856, a FoxO1 inhibitor, also suppressed TLR4 signaling. We propose that insulin is a homeostatic regulator of leukocyte responses to LPS/TLR4 and that the signaling intermediates expressed in leukocytes of patients with type 2 diabetes indicate TLR4 signaling dominance and deficient insulin signaling. The data suggest that insulin suppresses LPS/TLR4 signals in leukocytes through the mTORC2-Akt-FoxO signaling axis. Better understanding of leukocyte signaling in patients with type 2 diabetes may shed new light on disease causation and progression.
authors.affiliation: Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ.
authors.forename: Louis F
authors.initials: LF
authors.lastname: Amorosa
authors.affiliation: Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ.
authors.forename: Susette M
authors.initials: SM
authors.lastname: Coyle
authors.affiliation: Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Macor
authors.affiliation: Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
authors.affiliation: Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ.
authors.forename: Leonard Y
authors.initials: LY
authors.lastname: Lee
authors.affiliation: Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ haimovic@rwjms.rutgers.edu.
authors.forename: Beatrice
authors.identifier: 0000-0001-9726-8254
authors.initials: B
authors.lastname: Haimovich
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D008070:Lipopolysaccharides; D046912:Multiprotein Complexes; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9