ROS can lead to inactivation of insulin gene transcription [28] and insulin secretion is further impaired by hypoxia-induced loss of the adaptive unfolded protein response (UPR) which normally prevents accumulation of misfolded or unfolded proteins (such as proinsulin) in the endoplasmic reticulum [29, 30], leading to a vicious circle of hyperglycaemia exacerbating cellular hypoxia through production of mitochondrial ROS [6]. This evidence concerns the gene INS and Hyperglycemia.