Summary: Pregnancies complicated by diabetes have largely increased in number over the last 50 years. Pregnancy is characterized by a physiologic increase in insulin resistance, which, associated with increased oxidative stress and inflammations, could induce alterations of glucose metabolism and diabetes. If not optimally controlled, these conditions have a negative impact on maternal and foetal outcomes. To date, one can resort only to diet and lifestyle to treat obesity and insulin resistance during pregnancy, and insulin remains the only therapeutic option to manage diabetes during pregnancy. However, in the last years, in a variety of experimental models, inositol and antioxidants supplementation have shown insulin‐sensitizing, anti‐inflammatory, and antioxidant properties, which could be mediated by some possible complementary mechanism of action. Different isomers and multiple combinations of these compounds are presently available: Aim of the present review article is to examine the existing evidence in order to clarify and/or define the effects of different inositol‐ and antioxidant‐based supplements during pregnancy complicated by insulin resistance and/or by diabetes. This could help the clinician's evaluation and choice of the appropriate supplementation regimen.

Myo-inositol (Myo) improves insulin resistance, glucose metabolism, and helps gestational diabetes (GDM) management. GDM is associated with a pro-inflammatory state and increased oxidative stress, which are both involved in vascular damage in diabetes. Our aim was to study Myo anti-inflammatory/antioxidant potential effects on an in vitro model of human umbilical vein endothelial cells (HUVECs). To this end, monocyte cell adhesion to HUVECs, adhesion molecule membrane exposure, and oxidative stress levels were determined in cells from control (C-) and GDM women treated during pregnancy either with diet only (GD-) or with diet plus Myo (GD+Myo). To deeply study the vascular effects of Myo, the same evaluations were performed in C- and GD-HUVECs following 48 h in vitro stimulation with Myo. Notably, we first observed that GD-HUVECs obtained from women assuming Myo supplementation exhibited a significantly decreased number of monocytes that adhered to endothelial cells, less adhesion molecule exposure, and lower intracellular reactive oxygen species (ROS) levels in the basal state as compared to GD-HUVECs obtained from women treated by diet only. This Myo anti-inflammatory/antioxidant effect was confirmed by 48 h in vitro stimulation of GD-HUVECs as compared to controls. Altogether, these results strongly suggest that Myo may exert protective actions against chronic inflammation induced by endothelial dysfunction in diabetes.

Diabetes has been shown to accelerate vascular senescence, which is associated with chronic inflammation and oxidative stress, both implicated in the development of endothelial dysfunction. This condition represents the initial alteration linking diabetes to related cardiovascular (CV) complications. Recently, it has been hypothesised that the acetyltransferase, p300, may contribute to establishing an early vascular senescent phenotype, playing a relevant role in diabetes-associated inflammation and oxidative stress, which drive endothelial dysfunction. Specifically, p300 can modulate vascular inflammation through epigenetic mechanisms and transcription factors acetylation. Indeed, it regulates the inflammatory pathway by interacting with nuclear factor kappa-light-chain-enhancer of activated B cells p65 subunit (NF-κB p65) or by inducing its acetylation, suggesting a crucial role of p300 as a bridge between NF-κB p65 and the transcriptional machinery. Additionally, p300-mediated epigenetic modifications could be upstream of the activation of inflammatory cytokines, and they may induce oxidative stress by affecting the production of reactive oxygen species (ROS). Because several in vitro and in vivo studies shed light on the potential use of acetyltransferase inhibitors, a better understanding of the mechanisms underlying the role of p300 in diabetic vascular dysfunction could help in finding new strategies for the clinical management of CV diseases related to diabetes.

TRIB3, a mammalian tribbles homologue, affects insulin signalling and action by inhibiting Akt phosphorylation. A TRIB3 Q84R gain-of-function polymorphism has been associated with insulin resistance both in vitro and in vivo and with several atherosclerotic phenotypes, including increased carotid intima–media thickness (IMT). We wanted to replicate this latter association and, if so, to get deeper insights about the molecular mechanisms underlying the role of the TRIB3 Q84R polymorphism in atherosclerosis. In 430 Caucasians of European ancestry, carotid IMT was increased in QR (n = 116) and RR (n = 15) when compared with QQ (n = 299) subjects (P= 0.009), thus replicating similar data recently obtained among Asians. In human umbilical vein endothelial cells (HUVECs) naturally carrying the QQ genotype, 24 h insulin stimulation increased monocyte adhesion, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression, and mitogen-activated protein kinase (MAPK) kinase (MEK)–MAPK activation. Conversely, QR- and RR-HUVECs had increased unstimulated monocyte adhesion, VCAM-1 and ICAM-1 expression, and MEK–MAPK activation which did not increase further upon insulin stimulation. In addition, QQ-, QR-, and RR-HUVECs showed similar basal Akt phosphorylation and nitric oxide synthase activity which, however, were significantly increased by insulin only in QQ cells. The TRIB3 R4 variant is associated with increased carotid IMT also in Caucasians, thus replicating previous data obtained in Asians. In addition, in HUVECs, this variant is associated with unbalanced insulin signalling. This abnormality may favour vasoreactivity, intima–media thickening, and plaque formation and may, therefore, underlie the deleterious role exerted by the variant on the susceptibility to atherosclerosis.