*3.2. The Sirtuins Pathway*

Another pathway that also consumes NAD<sup>+</sup> is the sirtuin proteins [88,89] (Figure 3B), which remove acetyl groups from acetylated proteins using NAD<sup>+</sup> as a substrate. This pathway may play an important role in lowering NAD<sup>+</sup> levels in early stages of diabetes, but at advanced stages of diabetes, sirtuin protein contents tend to be down regulated [90]. Therefore, it is likely that sirtuin deficiency in advanced stages of diabetes contributes less to NAD+ depletion in diabetes.

### *3.3. The CD38 Pathway*

CD38 is an NADase that catalyzes the degradation of NAD<sup>+</sup> [91–93] (Figure 3C). This enzyme has been shown to be upregulated in a variety of diseases as well as aging [92,94], leading to decreased content of NAD<sup>+</sup> that would impair the function of sirtuins and poly ADP ribosylase [95,96]. CD38-driven NAD<sup>+</sup> deficiency has been shown to be responsible for organ fibrosis and diabetic kidney dysfunction [97]. Conversely, CD38 inhibitors have been shown to mitigate mitochondrial oxidative stress in DKD via restoration of NADH/NAD+ redox balance [98].
