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Depletion of NAD+ (Metabolic pseudohypoxia)

Background

Metabolic pseudohypoxia has been proposed as a hypothesis to explain biochemical dysfunction associated with diabetic complications. The supporting evidence was an observed increase in the cytosolic L-lactate/pyruvate ratio in cells suffering intracellular hyperglycaemia (capillary endothelial cells and pericytes, red blood cells). From this it was inferred that the increased ratio of cytosolic L-lactate/pyruvate ratio reflected an increased ratio of cytosolic NADH/NAD+. The associated decreased concentration of NAD+ lead to a decrease in the in situ activity of glyceraldehyde-3-phosphate dehydrogenase activity (GA3PDH). The concomitant increase in triosephosphates could initiate the de novo formation of DAG in PKCβ activation and increased formation of methylglyoxal and associated AGE formation implicated in the development of diabetic complications.

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The problem with this hypothesis, however, is that cytosolic L-lactate/pyruvate ratio in cells suffering intracellular hyperglycaemia does not reflect the cytosolic NADH/NAD+ concentration ratio. The concentrations of NAD+ and NADH both decrease in hyperglycaemia. It is therefore probably the decrease in NAD+ concentration per se that leads to the accumulation of triosephosphates in hyperglycaemia, rather than chnage in NADH/NAD+ ratio. The decrease in NAD+ may be caused by several factors:

  • Activation of poly(ADP-ribose) polymerase (PARP) following DNA damage
  • Reduction of NAD+ to NADH in the polyol pathway
  • Glycation
  • Other mechanisms

References

  1. Williamson,J.R., Chang,K., Frangos,M., Hasan,K.S., Ido,T., Kawamura,T., Nyengaard,J.R., van den Enden,M., Kilo,C., and Tilton,R.G. 1993. Hyperglycaemic pseudohypoxia and diabetic complications. Diabetes 42:801-813.
  2. Soriano,F.G., Virag,L., Jagtap,P., Szabo,E., Mabley,J.G., Liaudet,L., Marton,M., Hoyt,D.G., Murthy,K.G.K., Salzman,A.L. et al. 2001. Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nature Medicine 7:108-113.
  3. Thornalley,P.J. and Stern,A. 1984. The effect of glyceraldehyde on red blood cells. Haemoglobin status, oxidative metabolism and glycolysis. Biochim.Biophys.Acta 804:308-323.