Increased monocyte‐derived reactive oxygen species in type 2 diabetes: role of endoplasmic reticulum stress

Abstract

Recent evidence suggests that exposure of human monocytes to glucolipotoxic media to mimic the composition of plasma of patients with type 2 diabetes (T2D) results in the induction of endoplasmic reticulum stress markers and formation of reactive oxygen species (ROS). The extent to which these findings translate to patients with T2D remains unclear. Thus, we first measured ROS (dihydroethidium fluorescence) in peripheral blood mononuclear cells (PBMCs) from whole blood of T2D patients (n=8) and compared to age matched healthy controls (n=8). T2D patients exhibited greater basal intracellular ROS (mean±SD, +3.4±1.4 fold; p<0.05) compared to controls. Next, increased ROS in PBMCs isolated from T2D patients was partially recapitulated in cultured human monocytes (THP-1 cells) exposed to plasma from T2D patients for 36 hours (+1.3±0.08 fold vs. plasma from controls; p<0.05). In addition, we found that increased ROS formation in THP-1 cells treated with T2D plasma was NADPH oxidase-derived and led to increased endothelial cell adhesion (+1.8±0.5 fold; p<0.05) and lipid uptake (+1.3±0.3 fold; p<0.05). Notably, we found that T2D plasma-induced monocyte ROS and downstream functional effects were abolished by treating cells with tauroursodeoxycholic acid, a chemical chaperone known to inhibit ER stress. Collectively, these data indicate that monocyte ROS production with T2D can be, in part, attributed to signals from the circulating environment. Furthermore, an interplay between ER stress and NADPH oxidase activity contributes to ROS production and may be a mechanism mediating endothelial cell adhesion and foam cell formation in T2D.

No effect of ascorbate on cutaneous vasodilation and sweating in older men and those with type 2 diabetes exercising in the heat

“…; Restaino et al. ), which as mentioned above, may result in attenuations in the heat loss responses via mechanisms related to NO. Ascorbate may therefore augment the heat loss responses during exercise in the heat in older adults with type 2 diabetes to a greater extent compared to healthy older adults.…”

“…This is likely secondary to an attenuation in whole-body heat dissipation ) associated with reductions in local cutaneous vasodilation (Wick et al 2006;Sokolnicki et al 2009) and sweating (Fealey et al 1989;Petrofsky et al 2005); albeit due to regional heterogeneity, reductions in local heat loss responses are not always observed (Kenny et al , 2016b. Individuals with type 2 diabetes have been shown to have increased oxidative stress relative to healthy older adults without type 2 diabetes (Folli et al 2011;Casoinic et al 2016;Restaino et al 2016), which as mentioned above, may result in attenuations in the heat loss responses via mechanisms related to NO. Ascorbate may therefore augment the heat loss responses during exercise in the heat in older adults with type 2 diabetes to a greater extent compared to healthy older adults.…”

Superoxide and NADPH oxidase do not modulate skin blood flow in older exercising adults with and without type 2 diabetes

“…However, we did show that NOS is an important regulator of cutaneous vasodilation in all three groups under these conditions. Further, despite typically elevated levels of superoxide and NADPH oxidase in individuals with type 2 diabetes (Folli et al, 2011;Restaino et al, 2017), inhibition of these mechanisms was not associated with augmented cutaneous vasodilation in this population during rest or exercise in the heat. These findings are in stark contrast to responses observed during local heating of the skin wherein intradermal delivery of superoxide scavengers or NADPH oxidase inhibitors consistently improves endothelium-dependent cutaneous vasodilation under several conditions associated with augmented ROS production (DuPont et al, 2014;Fujii et al, 2014;Hurr et al, 2018;Kirkman et al, 2018;Medow et al, 2011).…”

“…Additionally, individuals with type 2 diabetes may demonstrate further reductions in cutaneous vasodilation compared to their healthy age-matched counterparts (Sokolnicki et al, 2009;Wick et al, 2006). Reactive oxygen species (ROS) can scavenge NO during exercise (Dillard et al, 1978) and aging (Donato et al, 2007), type 2 diabetes (Casoinic et al, 2016;Folli et al, 2011;Restaino et al, 2017) and exercise in hot conditions (Sureda et al, 2015) all independently augment ROS production. Consequently, endogenous antioxidant defenses may be overwhelmed in healthy older adults and those with type 2 diabetes during exercise in the heat.…”

“…This effect is associated with increased antioxidant activity via production of superoxide dismutase (SOD), which scavenges superoxide, as well as down-regulation of the pro-oxidant enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Durrant et al, 2009;La Favor et al, 2016). In contrast, type 2 diabetes may be associated with elevated levels of superoxide and NADPH oxidase (Folli et al, 2011;Restaino et al, 2017). Intradermal delivery of superoxide scavengers or NADPH oxidase inhibitors during local heating improves endothelium-dependent vasodilation in the skin under several conditions associated with augmented ROS production (DuPont et al, 2014;Fujii et al, 2014;Hurr et al, 2018;Kirkman et al, 2018;Medow et al, 2011).…”