Dynamic insulin-stimulated mTOR/GSK3 signaling in peripheral immune cells: Preliminary evidence for an association with lithium response in bipolar disorder

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.