Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women, Science, April 22, 2021
NAD+ is the critical cellular component for cellular homeostasis, which declines during the aging process. Various studies have shown that decreased NAD+ levels are associated with age-related metabolic disorders, including obesity and diabetes. Nicotinamide mononucleotide (NMN) is a precursor of NAD+ and the production of NMN is the key rate-limiting factor in mammalian NAD+ biosynthesis. Studies in model organisms have shown that NMN supplementation can increase the NAD+ level in multiple tissues and rescues age-related abnormalities (e.g., improves glucose tolerance, insulin sensitivity, and β-cell function). However, it hasn’t been systematically tested in humans until recently.
The first NMN trial in humans
On April 22, 2021, the first NMN trial in humans, led by Dr. Samuel Klein’s group at Washington University, was published in Science. They conducted a 10-week trial to evaluate the effect of NMN supplementation on metabolic function in 25 postmenopausal women with prediabetes who were overweight or obese. Note that this is a randomized, placebo-controlled, double-blind trial – the most rigorously controlled type of trial that could provide the causal relationship between NMN supplementation and metabolic health in humans. And indeed, the result demonstrates that NMN increases muscle insulin sensitivity, insulin signaling, and remodeling in humans. This study provides the first evidence that MNM provides metabolic benefits in humans.
Twenty-five postmenopausal women with prediabetes who were overweight or obese were included in this study. 12 were randomized to the placebo group and 13 to the NMN group (250 mg/day). Multiple tests were conducted before and after ten weeks of treatment to assess the outcome, including body composition measurement, insulin sensitivity test, and cellular effects analysis using the muscle biopsies. Note that this is a small-scale study with a relatively low dose, short period trial on a small group of people; therefore, the statistical power is very limited. In other words, only considerable changes after NMN supplementation can be detected with statistical significance based on this study design. To obtain a complete picture of the effects of NMN, a larger study is needed in the future.
NMN treatment increased NAD+ levels in the blood
After ten weeks of NMN treatment, the N-methyl-2-pyridone-5-carboxamide (2PY) and N-methyl-4-pyridone-5-carboxamide (4PY), which are metabolites produced by NMN, significantly increased in blood plasma. Moreover, the cellular NAD+ levels inside the blood cells (PBMC) was also significantly increased after NMN treatment. These results confirmed that oral NMN supplementation could indeed increase NAD+ levels in the blood.
NMN treatment increased NAD+ turnover in muscle
The NAD+ levels in muscle biopsies was not increased after NMN treatment. However, NMN metabolites 2PY and 4PY were significantly increased, suggesting NMN treatment increased muscle NAD+ turnover. In other words, NMN may promote both the rate of production and the rate of consumption of NAD+ in muscle. Therefore, although it may appear that overall NAD+ levels were unchanged after treatment, there was potentially more NAD+ produced and consumed compared to the placebo group.
NMN treatment increased muscle insulin sensitivity
Insulin resistance is one of the hallmarks of age-related metabolic disorders. In healthy people, when blood glucose levels increase, the pancreatic islets B cells will secret insulin to promote the incorporation of glucose in major metabolic tissues, including skeleton muscle. Therefore, glucose will be taken up by the tissues and the blood glucose level will decrease. However, in people with metabolic disorders such as obesity and type II diabetes, the metabolic tissues do not respond well to insulin, and the blood glucose level remains high even with a high blood insulin level. This phenomenon is called insulin resistance, or decreased insulin sensitivity, which will exacerbate metabolic disorders.
In this trial, the muscle insulin sensitivity was assessed as the rate of insulin-stimulated glucose disposal per kg of fat-free mass during the clamp procedure. In plain words, they measured how quickly and efficiently the glucose is taken up from blood in response to the insulin. A higher insulin-stimulated glucose disposal rate suggests higher insulin sensitivity, which is metabolically healthier.
After 10 weeks of NMN supplementation, but not placebo, the insulin-stimulated glucose disposal rate increased by 25 ± 7% in the subjects. This improvement in muscle insulin sensitivity is clinically relevant and is similar to the improvement observed after ~10% weight loss (equivalent to roughly 20 pounds weight loss in the subjects). This result suggests that NMN administration improved insulin sensitivity and potentially metabolic health by increasing NAD+ turnover instead of changing muscle NAD+ concentration.
Notably, the effect of NMN was specific to insulin sensitivity in muscle. It did not affect other important variables associated with insulin resistance, including indices of liver and adipose tissue insulin sensitivity, intra-abdominal adipose tissue volume, intrahepatic triglyceride content, and fasting plasma glucose, insulin, and adiponectin concentrations. These results demonstrate that NMN has selective beneficial effects on insulin-mediated glucose metabolism in skeletal muscle.
NMN treatment up-regulated muscle remodeling/regeneration related genes
Finally, the researchers used RNA-sequencing to evaluate global gene expression of muscle samples after NMN treatment. Compared with placebo, NMN caused a 60-fold increase in the number of differentially expressed genes during insulin infusion. The PDGF binding pathway was the most highly enriched, and muscle PDGFRβ and downstream targets of PDGF signaling were significantly up-regulated during insulin infusion after NMN treatment.
The PDGF is a growth factor that regulates cell growth and division, which plays an important role in muscle growth and regeneration. In addition, NMN treatment increased insulin-stimulated mTOR phosphorylation (another master regulator of cell growth) and gene expression of selected markers of myogenic genes, which together indicate increased skeletal muscle remodeling and regeneration.
NR did not improve insulin sensitivity in previous trials
Another notable fact is that in contrast to the insulin-sensitizing effects of NMN shown in this study, the results from several randomized controlled trials conducted in middle-aged and older-adult men found that treatment with nicotinamide riboside (NR) did not affect whole-body or muscle insulin sensitivity. Even though, compared with the administration of 250 mg NMN in this trial, these NR trials used a higher dose of NR with a similar time: 2000 mg for 12 weeks in Dollerup et al. (2018); 1000 mg for 3 and 6 weeks in Elhassan et al. (2019) and Remie et al. (2020).
“Insulin sensitivity, endogenous glucose production, and glucose disposal and oxidation were not improved by NR supplementation.” (r)
“There were no changes in body weight, blood pressure, lipid profile, fasting glucose and insulin (Table S1), and homeostatic model assessment of insulin resistance…NR did not produce this effect in our trial “(r)
“However, no effects of NR were found on insulin sensitivity, mitochondrial function, hepatic and intramyocellular lipid accumulation, cardiac energy status, cardiac ejection fraction, ambulatory blood pressure, plasma markers of inflammation, or energy metabolism.”(r)
This may indicate that NMN, as the rate-limiting factor in NAD+ synthesis, provides more metabolic benefits than NR. However, due to the complexity of population heterogeneity and limitation of sample size, further studies are needed to address this question.