Fig. 1

a Melatonin improves diabetic cardiomyopathy through inhibiting mitochondrial fission by activation of SIRT1‐PGC1α pathway, increasing mitochondrial biogenesis by activation of cGMP-PKGIα, SIRT1 and AMPK-PGC1α-SIRT3 signaling pathways, inhibiting cardiac hypertrophy by reduction of the expression of VEGF-A, inhibiting apoptotic pathway by decrease the expression of caspase-3, -9, -8, Bax, PERK, Syk/MC1/SERCA, IRS-1/Akt and MAPK signaling pathways and inhibiting oxidative stress by increase the activity of SOD, CAT, GPx, cGMP-PKGIα and Nrf-2-HO-1 signaling pathways and the level of GSH and reduction of ROS, MDA and NO levels. b Melatonin reduces diabetic retinopathy through inhibiting oxidative stress by reduction of ROS, MDA and NO levels and activation of CAT and PI3K/Akt-Nrf2 pathway, improving blood-retinal barrier by reduction of the expression of HIF-1α, VEGF-A and PEDF, inhibiting apoptotic pathway by decrease the expression of caspase-3, Bax and MAPKs pathways, and inhibiting inflammation by inhibition of the expression of TNF-α, NOS and the activity of NFκB. c Melatonin ameliorates diabetic neuropathy through inhibiting oxidative stress by increasing CAT, SOD and GPx activity and GSH level and activating Nrf-2-HO-1 pathway, inhibiting inflammation by reduction of TNF-α, iNOS, IL-6 and COX-2 expressions and the activity of NFκB, inhibiting apoptotic pathway by alleviation of the expression of caspase-3 and -9, Bax, PARP, and p38 MAPKs and elevation of PINK-1 level, and increasing the level of GABA and decreasing astrogliosis, which this effect leads to the improvement of memory and cognitive ability. d Melatonin improves diabetic nephropathy through inhibiting fibrotic process by reduction of the expression of TGF-β, inhibiting oxidative stress by enhancement of mitochondrial complex III, CAT, SOD, GPx and GST activities and reduction of NOX activity and MDA and NO generation, inhibiting inflammation by decreasing the level of IL-β, IL-6 and IL-33, inhibiting apoptosis by reduction of caspase-3 and Bax expression and JAK/STAT activity, inducing autophagy pathway by enhancement of the expression of Beclin-1, and inhibiting EMT by elevation the level of miR-49, which results in the alleviation of the level of ROCK. SIRT sirtuin, PGC1α peroxisome proliferator-activated receptor gamma coactivator 1α, AMPK 5′ AMP-activated protein kinase, cGMP Cyclic guanosine monophosphate, PKGIα Protein kinase G Iα, VEGF-A Vascular endothelial growth factor-A, Syk Spleen tyrosine kinase, SERCA sarcoendoplasmic reticulum calcium transport ATPase, Nrf2 erythroid 2‐related factor 2, HO-1 heme oxygenase-1, IRS‐1 insulin receptor substrate, Akt Protein kinase B, GPx glutathione peroxidase, CAT catalase, SOD superoxide dismutase, NOS NO synthase, iNOS inducible NOS, MDA malondialdehyde, COX-2 cyclooxygenase-2, ROS reactive oxygen species, NF‐κB nuclear factor-κB, TNF-α tumor necrosis factor α, IL interleukin, mTOR mammalian target of rapamycin, GSH glutathione, NO nitric oxide, JAK janus kinase, STAT signal transducer and activator of transcription, GABA gamma-aminobutyric acid, PARP poly(ADP-ribose) polymerase, MAPK mitogen-activated protein kinase, TGF-β transforming growth factor-β, EMT endothelial-to-mesenchymal transition, ROCK RhoA/Rho kinase, GST glutathione S-transferases, NOX NADPH oxidase