Figure 2.

Shows the tryptophan–melatonin pathway (gold shade). Tryptophan is converted by tryptophan hydroxylase (TPH2 stabilized by 14-3-3e) to serotonin (5-HT), which is the necessary precursor for the melatonergic pathway. 5-HT can also be provided by neuronal inputs and other cellular sources, including platelets. In the presence of acetyl-CoA, 5-HT is converted by 14-3-3 stabilized AANAT to N-acetylserotonin (NAS), which is then converted to melatonin by AANAT. Under inflammatory conditions, as in T1DM, cytokines increase indoleamine 2,3-dioxygenase (IDO) and TDO, which converts tryptophan to kynurenine, suppressing tryptophan levels. Kynurenine also activates the aryl hydrocarbon receptor (AhR), which can increase the NAS/melatonin ratio, as well as suppress available melatonin. NAS increases BDNF and can activate the TrkB receptors. Melatonin has many protective effects as well as suppressing oxidative stress and MHC-1 linked autoimmunity, including in pancreatic B-cells. Abbreviations: 5-HT: serotonin; AANAT: aralkylamine N-acetyltransferase; AhR: aryl hydrocarbon receptor; ASMT: N-acetylserotonin O-methyltransferase; CYP: cytochrome P450; IDO: indoleamine 2,3-dioxygenase; MHC-1 major histocompatibility complex-class 1; NAS: N-acetylserotonin; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; PINK1: PTEN-induced kinase 1; TDO: tryptophan 2,3-dioxygenase; TrkB-FL: tyrosine receptor kinase B-full length; TrkB-T1: tyrosine receptor kinase B-truncated.