PMID- 33864716
OWN - NLM
STAT- MEDLINE
DCOM- 20220419
LR  - 20220419
IS  - 1399-5618 (Electronic)
IS  - 1398-5647 (Linking)
VI  - 24
IP  - 1
DP  - 2022 Feb
TI  - Dynamic insulin-stimulated mTOR/GSK3 signaling in peripheral immune cells: 
      Preliminary evidence for an association with lithium response in bipolar 
      disorder.
PG  - 39-47
LID - 10.1111/bdi.13081 [doi]
AB  - INTRODUCTION: A key mechanism of lithium is the inhibition of glycogen synthase 
      kinase-3beta (GSK3beta) 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 GSK3beta 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 microg) 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 pGSK3beta. In contrast, functional PBMC responses to 5 min of insulin 
      stimulation demonstrated robust increases in pGSK3beta (87.05 +/- 43.41%) and pmTOR 
      (105.7 +/- 66.48%) in the lithium responsive group only. This contrasted observed 
      decreases in pGSK3beta (34.08 +/- 16.12%) and pmTOR (37.84 +/- 14.39%) 5 mins 
      post-insulin in non-responders. CONCLUSIONS: Dynamic increases in pmTOR and 
      pGSK3beta 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.
CI  - (c) 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
FAU - Tye, Susannah J
AU  - Tye SJ
AUID- ORCID: 0000-0003-1291-4304
AD  - Mayo Clinic Depression Center, Department of Psychiatry and Psychology, Mayo 
      Clinic, Rochester, MN, USA.
AD  - Queensland Brain Institute, The University of Queensland, St Lucia, Qld, 
      Australia.
AD  - Department of Neurosurgery, Mayo Clinic, Rochester, MN, USA.
FAU - Borreggine, Kristin
AU  - Borreggine K
AD  - Mayo Clinic Depression Center, Department of Psychiatry and Psychology, Mayo 
      Clinic, Rochester, MN, USA.
FAU - Price, J Blair
AU  - Price JB
AUID- ORCID: 0000-0002-6806-7899
AD  - Mayo Clinic Depression Center, Department of Psychiatry and Psychology, Mayo 
      Clinic, Rochester, MN, USA.
AD  - Department of Neurosurgery, Mayo Clinic, Rochester, MN, USA.
FAU - Sutor, Shari L
AU  - Sutor SL
AD  - Mayo Clinic Depression Center, Department of Psychiatry and Psychology, Mayo 
      Clinic, Rochester, MN, USA.
FAU - Cuellar-Barboza, Alfredo B
AU  - Cuellar-Barboza AB
AUID- ORCID: 0000-0002-7663-913X
AD  - Mayo Clinic Depression Center, Department of Psychiatry and Psychology, Mayo 
      Clinic, Rochester, MN, USA.
AD  - Department of Psychiatry, Autonomous University of Nuevo Leon School of Medicine, 
      Monterrey, Mexico.
FAU - McElroy, Susan L
AU  - McElroy SL
AD  - Lindner Center of HOPE, Mason, OH, USA.
AD  - Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati 
      College of Medicine, Cincinnati, OH, USA.
FAU - Biernacka, Joanna M
AU  - Biernacka JM
AUID- ORCID: 0000-0001-9350-4440
AD  - Mayo Clinic Depression Center, Department of Psychiatry and Psychology, Mayo 
      Clinic, Rochester, MN, USA.
AD  - Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
FAU - Frye, Mark A
AU  - Frye MA
AD  - Mayo Clinic Depression Center, Department of Psychiatry and Psychology, Mayo 
      Clinic, Rochester, MN, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210513
PL  - Denmark
TA  - Bipolar Disord
JT  - Bipolar disorders
JID - 100883596
RN  - 0 (Insulin)
RN  - 9FN79X2M3F (Lithium)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
SB  - IM
MH  - *Bipolar Disorder/drug therapy
MH  - Glycogen Synthase Kinase 3
MH  - Glycogen Synthase Kinase 3 beta
MH  - Humans
MH  - Insulin
MH  - Leukocytes, Mononuclear/metabolism
MH  - *Lithium/pharmacology/therapeutic use
MH  - TOR Serine-Threonine Kinases/metabolism
OTO - NOTNLM
OT  - GSK3
OT  - insulin
OT  - lithium
OT  - mTOR
EDAT- 2021/04/18 06:00
MHDA- 2022/04/20 06:00
CRDT- 2021/04/17 17:04
PHST- 2021/04/18 06:00 [pubmed]
PHST- 2022/04/20 06:00 [medline]
PHST- 2021/04/17 17:04 [entrez]
AID - 10.1111/bdi.13081 [doi]
PST - ppublish
SO  - Bipolar Disord. 2022 Feb;24(1):39-47. doi: 10.1111/bdi.13081. Epub 2021 May 13.