**3. Pathways of NAD+ Consumption in Diabetes**

#### *3.1. The Poly ADP Ribosylase Pathway*

While NADH is over-supplied in diabetes, NAD+ could be depleted in diabetes. One major pathway utilizing NAD+ is the poly ADP ribosylase catalyzed reaction (Figure 3A), which is activated due to DNA damage by ROS in diabetes and uses NAD+ as a substrate thereby leading to degradation of NAD<sup>+</sup> [83–85]. The contribution of this pathway to the pathogenesis of diabetes has been confirmed by studies using poly ATP ribosylase deficient mouse, in which lack of the enzyme prevents development of diabetes [86,87], demonstrating the detrimental effects of NAD<sup>+</sup> depletion in diabetes.

**Figure 3.** Major pathways that consume NAD+. Shown are (**A**) the poly ADP ribosylase reaction; (**B**) the sirtuin-catalyzed deacetylation reaction; (**C**) the CD38 NAD<sup>+</sup> degradation pathway; (**D**) the NAD kinase pathway converting NAD+ to NADP+. All the shown pathways or reactions use NAD+ as the respective enzyme's substrate.
