Figure 11.

Summary of the cascade leading to lower nicotinamide adenine dinucleotide (NAD⁺) levels in diabetes. High glucose increases sorbitol levels by aldose reductase. Oxidation of sorbitol, free fatty acid (FFA) and lactate cause production of excess NADH. This leads to a low NAD⁺/NADH ratio (pseudohypoxia), which mainly causes activation of two pathways: diacylglycerol (DAG)–protein kinase C (PKC) and (DAG)–protein kinase D (PKD) cascade, which occur preferentially in type 2 diabetes and high levels of oxidative stress that occur in insulinopenic type 1 diabetes. Both cascades decrease NAD⁺ levels. ATP, adenosine triphosphate; DNA, deoxyribonucleic acid; PARP, poly adenosine diphosphate‐D‐ribosyl polymerase; SIRT1, sirtuin 1.