title: Insulin Modulates In Vitro Secretion of Cytokines and Cytotoxins by Human Glial Cells.
abstract: Alzheimer's disease (AD) is the most common form of dementia worldwide. Type 2 diabetes (T2D) has been implicated as a risk factor for AD. Since T2D is a peripheral inflammatory condition, and AD brains exhibit exacerbated neuroinflammation, we hypothesized that inflammatory mechanisms could contribute to the observed link between T2D and AD. Abnormal peripheral and brain insulin concentrations have been reported in both T2D and AD. The neurotrophic role of insulin has been described; however, this hormone can also regulate inflammatory responses in the periphery. Therefore we used in vitro human cell culture systems to elucidate the possible effects of insulin on neuroinflammation. We show that human astrocytes and microglia express both isoforms of the insulin receptor as well as the insulin-like growth factor (IGF)-1 receptor. They also express insulin receptor substrate (IRS)-1 and IRS-2, which are required for propagation of insulin/IGF- 1 signaling. We show that at low nanomolar concentrations, insulin could be pro-inflammatory by upregulating secretion of interleukin (IL)-6 and IL-8 from stimulated human astrocytes and secretion of IL-8 from stimulated human microglia. This effect dissipates at higher insulin concentrations. In contrast, insulin at a broader concentration range (10 pM - 1 μM) reduces the toxicity of stimulated human microglia and THP-1 monocytic cells towards SH-SY5Y neuronal cells. These data show that insulin may regulate the inflammatory status of glial cells by modulating their select functions, which in turn can influence the survival of neurons contributing to the observed link between T2D and AD.
authors.forename: Lindsay J
authors.initials: LJ
authors.lastname: Spielman
authors.forename: Manpreet
authors.initials: M
authors.lastname: Bahniwal
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Little
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Walker
authors.affiliation: Department of Biology, University of British Columbia Okanagan Campus, 3187 University Way, Kelowna, BC, Canada, V1V 1V7. andis.klegeris@ubc.ca.
authors.forename: Andis
authors.initials: A
authors.lastname: Klegeris
mesh_terms: D001253:Astrocytes / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003603:Cytotoxins / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D017628:Microglia / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D015213:Neuroimmunomodulation / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D016207:Cytokines; D003603:Cytotoxins; C000597236:IGF1R protein, human; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D020033:Protein Isoforms; D017451:Receptors, Somatomedin; D011994:Recombinant Proteins; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin