@article{2569c2bb477b4256a9e041d0807fcde0,
title = "Dynamic insulin-stimulated mTOR/GSK3 signaling in peripheral immune cells: Preliminary evidence for an association with lithium response in bipolar disorder",
abstract = "Introduction: A key mechanism of lithium is the inhibition of glycogen synthase kinase-3β (GSK3β) and activation of mammalian target of rapamycin (mTOR), two contributors to insulin signaling. We explored the relationship between these markers and clinical response to lithium in bipolar disorder (BD). Methods: Thirty-four subjects with BD who had been taking lithium for ≥2 years and had a maintenance lithium Alda score defined as either high (≥7; n = 20) or low (≤2; n = 14) were included in the study. Baseline protein expression of GSK3β and mTOR (total and phosphorylated (p)) was obtained from a buffy coat. Peripheral blood mononuclear cells (PBMCs) from a subset of each group (n = 11) were stimulated with insulin (10 µg) and change in protein expression was determined using Western blot. Results: In buffy coat samples, significantly higher levels of pmTOR were present in subjects with an Alda score ≤2 (lithium non-responsive), relative to those with scores ≥7 (lithium-responsive). No differences were observed for pGSK3β. In contrast, functional PBMC responses to 5 min of insulin stimulation demonstrated robust increases in pGSK3β (87.05 ± 43.41%) and pmTOR (105.7 ± 66.48%) in the lithium responsive group only. This contrasted observed decreases in pGSK3β (34.08 ± 16.12%) and pmTOR (37.84 ± 14.39%) 5 mins post-insulin in non-responders. Conclusions: Dynamic increases in pmTOR and pGSK3β post-insulin stimulation may reflect an immunometabolic state that facilitates lithium response. Further prospective analyses are needed to replicate and extend these preliminary findings and further investigate the role of insulin signaling in lithium response in BD.",
keywords = "GSK3, insulin, lithium, mTOR",
author = "Tye, {Susannah J.} and Kristin Borreggine and Price, {J. Blair} and Sutor, {Shari L.} and Cu{\'e}llar-Barboza, {Alfredo B.} and McElroy, {Susan L.} and Biernacka, {Joanna M.} and Frye, {Mark A.}",
note = "Funding Information: SJT has received grant/research support from the State of Minnesota, TEVA pharmaceuticals, International Bipolar Foundation, and Mayo Clinic Center for Individualized Medicine. MAF has served as a consultant to Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Co, Myriad Genetics, Sunovion, Supernus Pharmaceuticals, and Teva Pharmaceuticals. MAF has also received grant support from AssureRX, Janssen Research & Development, LLC, Mayo Foundation, Myriad, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institute of Mental Health (NIMH), and Pfizer, and has received CME/travel support from the American Physician Institute and CME Outfitters. SLM has been a consultant to or a member of the scientific advisory boards of Allergan, Avanir, Bracket, F. Hoffmann‐La Roche Ltd., Mitsubishi Tanabe Pharma America, Myriad, Opiant, Shire, and Sunovion. She has been a principal or co‐investigator on studies sponsored by Allergan, Avanir, Azevan, Brainsway, Marriott Foundation, Medibio, Myriad, Neurocrine, Novo Nordisk, Shire, and Sunovion. She is also an inventor on U.S. Patent No. 6,323,236 B2, Use of Sulfamate Derivatives for Treating Impulse Control Disorders, and along with the patent's assignee, University of Cincinnati, Cincinnati, Ohio, has received payments from Johnson & Johnson, which has exclusive rights under the patent. Funding Information: Funding for this study was provided by the Marriott Family and the Ken Fredrickson Family. The families had no further role in the study design and did not participate in analysis or interpretation of the data, writing of the report, or in the decision to submit the paper for publication. Funding Information: SJT has received grant/research support from the State of Minnesota, TEVA pharmaceuticals, International Bipolar Foundation, and Mayo Clinic Center for Individualized Medicine. MAF has served as a consultant to Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Co, Myriad Genetics, Sunovion, Supernus Pharmaceuticals, and Teva Pharmaceuticals. MAF has also received grant support from AssureRX, Janssen Research & Development, LLC, Mayo Foundation, Myriad, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institute of Mental Health (NIMH), and Pfizer, and has received CME/travel support from the American Physician Institute and CME Outfitters. SLM has been a consultant to or a member of the scientific advisory boards of Allergan, Avanir, Bracket, F. Hoffmann-La Roche Ltd., Mitsubishi Tanabe Pharma America, Myriad, Opiant, Shire, and Sunovion. She has been a principal or co-investigator on studies sponsored by Allergan, Avanir, Azevan, Brainsway, Marriott Foundation, Medibio, Myriad, Neurocrine, Novo Nordisk, Shire, and Sunovion. She is also an inventor on U.S. Patent No. 6,323,236 B2, Use of Sulfamate Derivatives for Treating Impulse Control Disorders, and along with the patent's assignee, University of Cincinnati, Cincinnati, Ohio, has received payments from Johnson & Johnson, which has exclusive rights under the patent. Funding for this study was provided by the Marriott Family and the Ken Fredrickson Family. The families had no further role in the study design and did not participate in analysis or interpretation of the data, writing of the report, or in the decision to submit the paper for publication. Publisher Copyright: {\textcopyright} 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd",
year = "2022",
month = feb,
doi = "10.1111/bdi.13081",
language = "English (US)",
volume = "24",
pages = "39--47",
journal = "Bipolar disorders",
issn = "1398-5647",
publisher = "Blackwell Munksgaard",
number = "1",
}