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Role of pseudohypoxia in the pathogenesis of type 2 diabetes

Authors Song J, Yang X, Yan LJ

Received 24 January 2019

Accepted for publication 23 April 2019

Published 5 June 2019 Volume 2019:7 Pages 33—40

DOI https://doi.org/10.2147/HP.S202775

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Thomas Kietzmann

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Dörthe Katschinski


Jing Song,1,2 Xiaojuan Yang,1,3 Liang-Jun Yan1

1Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA; 2School of Public Health, Shanxi Medical University, Taiyuan, People’s Republic of China; 3Department of Geriatrics, First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan, People’s Republic of China

Abstract: Type 2 diabetes is caused by persistent high blood glucose, which is known as diabetic hyperglycemia. This hyperglycemic situation, when not controlled, can overproduce NADH and lower nicotinamide adenine dinucleotide (NAD), thereby creating NADH/NAD redox imbalance and leading to cellular pseudohypoxia. In this review, we discussed two major enzymatic systems that are activated by diabetic hyperglycemia and are involved in creation of this pseudohypoxic condition. One system is aldose reductase in the polyol pathway, and the other is poly (ADP ribose) polymerase. While aldose reductase drives overproduction of NADH, PARP could in contrast deplete NAD. Therefore, activation of the two pathways underlies the major mechanisms of NADH/NAD redox imbalance and diabetic pseudohypoxia. Consequently, reductive stress occurs, followed by oxidative stress and eventual cell death and tissue dysfunction. Additionally, fructose formed in the polyol pathway can also cause metabolic syndrome such as hypertension and nonalcoholic fatty liver disease. Moreover, pseudohypoxia can also lower sirtuin protein contents and induce protein acetylation which can impair protein function. Finally, we discussed the possibility of using nicotinamide riboside, an NAD precursor, as a promising therapeutic agent for restoring NADH/NAD redox balance and for preventing the occurrence of diabetic pseudohypoxia.

Keywords: diabetes, fructose, nicotinamide riboside, oxidative stress, poly (ADP ribose) polymerase, polyol pathway, pseudohypoxia, redox imbalance, reductive stress


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