Hyperoxia reduces insulin release and induces mitochondrial dysfunction with possible implications for hyperoxic treatment of neonates

Abstract

We previously showed that hyperoxia in vitro negatively affects beta cells of the rat. Here, we tested for possible clinical significance as well as mitochondrial interactions by hyperoxia, using human islets (function and viability), INS‐1 832/13 cells (mitochondrial metabolism), and mouse neonates (effects in vivo). Lastly, we assessed relevant parameters in a cohort of individuals born preterm and then exposed to hyperoxia. Human islets and INS‐1 832/13 cells were exposed to 24 h of hyperoxia (90–92% oxygen). Mouse neonates were subjected to 5 days of continuous hyperoxia. Individuals born preterm were evaluated in terms of glucose homeostasis and beta cell function by HbA1c and the HOMA2 formula. In human islets, hyperoxia significantly reduced glucose‐stimulated insulin secretion by 42.2 ± 5.3% and viability assessed by MTT by 22.5 ± 5.4%. Hyperoxia down‐regulated mitochondrial complex II by 21 ± 5% and upregulated complex III by 26 ± 10.1% and complex IV by 37 ± 10.6%. Partly similar effects on mitochondrial complexes were found in hyperoxia‐exposed INS‐1 832/13 cells. Exposure to hyperoxia swiftly reduced oxygen consumption in these cells and increased mitochondrial uncoupling. Hyperoxia transiently but significantly reduced insulin release in mouse neonates. Individuals born preterm displayed higher HbA1c versus controls, as well as insulin resistance. Thus, hyperoxia exerts negative effects in vitro on human beta cells and results indicate inhibitory effects on insulin secretion in vivo in mouse neonates. Negative effects may be lessened by the demonstrated swift and profound mitochondrial adaptability. Our findings open the possibility that hyperoxia could negatively affect beta cells of preterm human neonates.

Human brain blood flow and metabolism during isocapnic hyperoxia: the role of reactive oxygen species

“…As a main regulator of cerebrovascular tone and CBF, nitric oxide (NO) bioavailability emerges as a potential candidate to explain IH-induced cerebral hypoperfusion (Toda et al 2009). Hyperoxia leads to mitochondrial dysfunction (Turrens, 2003;Hals et al 2017), NADPH oxidase activation (Vignais, 2002), as well as an excessive formation of reactive oxygen species (ROS) and reduced NO bioavailability (Beckman & Koppenol, 1996). In rats, hyperbaric oxygen exposure reduced CBF and brain NO end-products via excessive ROS production (Demchenko et al 2002;Zhilyaev et al 2003), which was abolished in the presence of an increased antioxidant defence (Vucinovic et al 2015).…”

“…Hyperoxia leads to mitochondrial dysfunction (Turrens, ; Hals et al . ), NADPH oxidase activation (Vignais, ), as well as an excessive formation of reactive oxygen species (ROS) and reduced NO bioavailability (Beckman & Koppenol, ). In rats, hyperbaric oxygen exposure reduced CBF and brain NO end‐products via excessive ROS production (Demchenko et al .…”

Hyperoxia induces glutamine-fuelled anaplerosis in retinal Müller cells

“…The effect of hyperoxia on metabolism has mostly been linked to the loss of the mitochondrial complexes of the electron transport chain 11,12 . These studies have used indirect measures of metabolic function such as oxygen consumption or absence of the mitochondrial complex subunit protein levels 13 .…”

Hyperglycemia and Lactic Acidosis Associated with Linezolid Therapy in an Extremely Premature Infant

“…Patients with mitochondrial disease have been shown to have impaired pancreatic beta cell insulin secretion on the oral glucose tolerance test [9]. In addition, Hals et al [10] suggested that hyperoxia induces mitochondrial dysfunction and reduces insulin release, with possible implications for hyperoxic treatment of premature infants. This mitochondrial dysfunction induced by linezolid might lead to hyperglycemia in the extremely premature infant with resistance to insulin who is easily prone to hyperglycemia.…”