# Nicotinamide Riboside--The Current State of Research and Therapeutic Uses
## 3 Effects of NR on Metabolism and Age-Associated Pathophysiology  
### Effects on Insulin Sensitivity, Liver Health and Other Metabolic Functions  
Along with its intermediates, NAD\({}^{+}\) plays an essential role in metabolism, and evidence suggests that an increase in NAD\({}^{+}\) levels can exhibit ameliorating effects on metabolic disorders, such as type 2 diabetes (T2D), metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD) [14; 41; 42]. Furthermore, NR is one of the NAD\({}^{+}\) intermediates that also serves as a precursor of NADH, as well as hepatic NADP\({}^{+}\) and NADPH [14]. Since the hepatic NAD\({}^{+}\) metabolome is regarded as a function of prediabetic (PD) and T2D mouse models, NADP\({}^{+}\) and NADPH can be used to assess the progression of the disease. Namely, both NADP\({}^{+}\) and NADPH are important for resistance to oxidative stress, while NADPH is thought to be the major contributor to insulin resistance [42]. The significantly decreased levels of hepatic NADP\({}^{+}\) and NADPH in PD and T2D mice are restored with supplementation of NR [41]. In mice models, NR can increase NAD\({}^{+}\) metabolism and thereby improve glucose tolerance, reduce weight gain, and exhibit neuroprotective effects against diabetic neuropathy and liver steatosis [41]. Similarly, in mice models of high-fat-induced obesity, a dose of dietary NR as small as 400 mg/kg/day was shown to improve insulin sensitivity and protect mice from weight gain [37]. However, these results have not yet been replicated in humans, as 12-week supplementation of NR with a dose of 2000 mg/day was not able to improve insulin sensitivity and other metabolic parameters in insulin-resistant, obese men [43]. Additional research is required to determine the long-term effects of NR on insulin sensitivity [43]. On the other hand, there is evidence that NR administration in mice models increases the activity of SIRT1, an important factor in the prevention of T2D and preservation of insulin sensitivity [37; 44]. Moreover, SIRT1 inhibits effects of oxidative stress in T2D mice [45], promotes glucose-stimulated insulin secretion from pancreatic \(\beta\)-cells [46; 47], and protects against insulin resistance in peripheral tissues [48], whilst SIRT1 overexpression promotes fatty acid oxidation and inhibits lipogenesis, protecting the liver from steatosis. In addition, sirtuins are downregulated in NAFLD patients, a state characterized by liver steatosis [49]. NAFLD is widely considered a hepatic manifestation of metabolic syndrome as it is found to be associated with T2D, obesity, and insulin resistance [50]. Via activation of SIRT1 and additional factors associated with cholesterol homeostasis, NR could potentially reduce cholesterol levels and improve liver health [51; 52; 53; 54]. Fat accumulation is also potentially reduced through a mechanism that involves the induction of the mitochondrial unfolded protein response [44]. In regenerating liver, NR reduces lipid accumulation, promotes hepatocyte replication, and increases hepatic ATP content leading to a faster regaining of liver weight in mice [55]. Moreover, dietary supplementation of NR was able to restore NAD+ levels caused by impaired biosynthesis in a mouse model of hepatocellular carcinoma, and thereby prevent both DNA damage and tumorigenesis [56]. Altogether, there is sufficient evidence indicating that increasing NAD+ content with NR supplementation can be considered a promising therapeutic strategy for metabolic dysfunctions, including T2D and NAFLD.