title: Endotoxaemia resulting from decreased serotonin tranporter (5-HTT) function: a reciprocal risk factor for depression and insulin resistance?
abstract: Depression and diabetes are serious diseases with an increasing global prevalence. Intriguingly, recent meta-analyses have highlighted an asymmetrical relationship between the two conditions as depressed patients were found to display a higher risk of developing type 2 diabetes than those individuals suffering from diabetes are to become depressed. Based on recent findings, we favor a hypothesis where by decreased peripheral serotonin (5-HT) transporter (5-HTT) function is a reciprocal risk factor for the co-morbidity of depression and diabetes, as it can trigger inflammatory pathogenetic mechanisms of both conditions. Higher intestinal levels of 5-HT and 5-HT3 receptor stimulation lead to increased intestinal permeability in 5-HTT deficient mice, which is viewed one of the most relevant animal models of depression. We hypothesize that this leakage of bacterial endotoxins can activate both central and peripheral Toll-like receptor 4 (TLR4), which inhibits insulin signaling and IRS1/PI3K/Akt and thus, contribute to the pathogenesis of diabetes and depression that are associated with this pathway. Antidepressant therapies, which also suppress intestinal 5-HTT, may have potentiating effects on the association between depression and diabetes. It is also of interest that high carbohydrate and fat intake ("cafeteria-type diet") increases intestinal 5-HT leading to TLR4 activation. Thus, endotoxaemia and inflammation owing to increased intestinal 5-HT may underpin the depression and diabetes association, where the risk of the latter pathology becomes particularly preeminent after the onset of depression and not vice versa. The evidence presented here shows the further investigation into peripheral mechanisms that linked diabetes to depression is clearly warranted.
authors.affiliation: Buddha Biopharma Oy, Horsemakuja 10, FI-01300 Vantaa, Finland.
authors.forename: Igor A
authors.initials: IA
authors.lastname: Pomytkin
authors.affiliation: CNRS, UMR6265, Université de Bourgogne, CSGA, 9E boulevard Jeanne d'Arc, 21000 Dijon, France; INRA, UMR1324, Université de Bourgogne, CSGA, 9E boulevard Jeanne d'Arc, 21000 Dijon, France; Université de Bourgogne, CSGA, 9E boulevard Jeanne d'Arc, 21000 Dijon, France.
authors.forename: Brandon H
authors.initials: BH
authors.lastname: Cline
authors.affiliation: Department of Pharmacology, Oxford University, Mansfield Road, OX1 3QT Oxford, UK.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Anthony
authors.affiliation: Department of Neuroscience, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 40, NL 6229 ER Maastricht, Netherlands.
authors.forename: Harry W
authors.initials: HW
authors.lastname: Steinbusch
authors.affiliation: Department of Neuroscience, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 40, NL 6229 ER Maastricht, Netherlands; Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Fuechsleinstrasse 15, 97080 Wuerzburg, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: Department of Neuroscience, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 40, NL 6229 ER Maastricht, Netherlands; Institute of Physiologically Active Compounds RAS, Severnii proesd 1, 142432 Chernogolovka, Moscow region, Russia; Institute for Hygiene and Tropical Medicine, New University of Lisbon, Rua da Junqueira, 96, 1349-008 Lisboa, Portugal. Electronic address: t.strekalova@maastrichtuniversity.nl.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Strekalova
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D015897:Comorbidity; D003863:Depression / Q000453:epidemiology* / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000378:metabolism*; D019446:Endotoxemia / Q000209:etiology*; D006801:Humans; D007249:Inflammation / Q000209:etiology; D007333:Insulin Resistance; D011972:Receptor, Insulin / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000928:Antidepressive Agents; D044406:Receptors, Serotonin, 5-HT3; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D011972:Receptor, Insulin
keywords: 5-HT; Antidepressant; Depression; Endotoxemia; Inflammation; Insulin resistance