NMN, Glucose, and the Gut: Boosting NAD+ in the Intestines Supports Healthy Blood Sugar Management, Hormones, and Metabolism in Mice

With almost three-quarters of adults in the United States now classified as overweight or obese, having excess body weight is an increasingly prevalent condition that substantially increases the risk of other health disorders and mortality. Although there are many underlying causes, one is that an unhealthy body weight causes hyperglycemia (high blood sugar). Researchers are not entirely sure why excess body weight induces hyperglycemia, but it’s thought that dysfunctional hormone production in our intestines plays a role.  

One of these hormones is called GLP-1 (glucagon-like-peptide-1), which is markedly reduced in obese people. In a recent study published in Endocrinology, researchers out of Keio University School of Medicine in Tokyo, Japan, may have uncovered one mechanism that links these processes — intestinal levels of the compound NAD+ (nicotinamide adenine dinucleotide). In a series of experiments with mice, Nagahisa and colleagues show how NAD+ biosynthesis is vital to regulating GLP-1 production and, with it, maintaining healthy blood sugar and metabolic function. Further, the researchers exhibit that obese mice reverse their metabolic abnormalities when supplied with NMN (nicotinamide mononucleotide), a precursor to NAD+, suggesting a role for using NAD+ boosters to manage the growing issue of excess body weight and its downstream effects. 

Harnessing Hormones for Healthy Weights

GLP-1 is a naturally occurring hormone responsible for numerous vital aspects of metabolism. Primarily, GLP-1 inhibits caloric intake by acting on the brain’s appetite centers and slowing down gastric emptying — the speed at which food moves from the stomach through the rest of the digestive tract. With slower gastric emptying, food remains in the stomach longer, leading to feelings of fullness, suppressed appetite, and reduced caloric intake. 

GLP-1 is also known to encourage insulin secretion after meals, helping to shuttle glucose (sugar) from the bloodstream into cells to be used as fuel. Conversely, inadequate GLP-1 production leads to feelings of hunger, despite how much food was eaten, which can increase weight gain. Without GLP-1, insulin is reduced, and blood sugar stays elevated, increasing the risk of metabolic disorders.  

NAMPT Proves Necessary for Blood Glucose Control 

In this study, Nagahisa and colleagues looked at GLP-1 production and glucose metabolism in mice without any NAMPT (nicotinamide phosphoribosyltransferase), an enzyme needed to synthesize NAD+. The mice had NAMPT activity removed specifically in their intestinal epithelial cells — the single-cell-thick layer of the intestinal lining that provides a physical barrier between the gut and the rest of the body. These mice exhibited markedly reduced intestinal NAD+ levels, about 45% lower than the control mice, suggesting that NAMPT is a crucial regulator of NAD+ biosynthesis in the intestines.

Further, the NAMPT-deleted mice had significantly reduced insulin secretion and GLP-1 production with higher blood glucose levels, both when fasting and postprandial (post-meal). Whereas fasting glucose is important for establishing a baseline level and diagnosing metabolic disorders, postprandial glucose is a better representation of how our bodies respond to food and nutrient intake. However, body weight and overall food intake were not affected, which was somewhat surprising based on the GLP-1 reduction. 

The loss of NAMPT also led to physical changes in the mice’s digestive tracts. These included shorter small intestines and colons with swelling, thickening, and the accumulation of fibrotic scar tissue — all of which can impact absorption and cause digestive complications. Lastly, a lack of NAMPT led to reductions in ​​Proglucagon activity, a protein that acts as a precursor to GLP-1. 

Supplemental NMN Rescues Metabolic Abnormalities in Mice

The changes seen in the NAMPT-deleted mice indicate that intestinal NAD+ biosynthesis is vital for the proper production and secretion of GLP-1 and insulin, which help to manage blood sugar and metabolism. But the researchers still wanted to know how to mitigate these changes, which they did by administering NMN to two sets of mice. 

First, they supplemented young NAMPT-deleted mice with NMN for 14 days, which significantly increased intestinal NAD+ levels. NMN administration also improved fasting blood glucose levels, raised GLP-1 production, and corrected the dysfunctional postprandial glucose metabolism. 

Next, the Tokyo-based research team supplemented male obese mice with NMN. These mice were first fed a high-fat diet for eight weeks, which naturally reduced NAMPT activity and NAD+ levels in the small intestine. The obese mice showed similar metabolic aberrations as the NAMPT-deleted mice, including high glucose and low insulin and GLP-1 levels. Then, they gave the obese mice NMN for 14 days, which reversed the detrimental metabolic effects. After receiving NMN, the obese mice exhibited higher GLP-1 secretion and Proglucagon activity with lower blood glucose levels. 

High GLP is the Way to Be

These findings demonstrate that impaired intestinal NAD+ synthesis — caused by low NAMPT activity or high-fat diets — is tightly involved with weight-associated dysregulation of GLP-1 production and glucose metabolism. In this study with mice, these abnormalities were mitigated by boosting intestinal NAD+ levels via supplemental NMN. Interestingly, although NAMPT-deleted mice produced less GLP-1, their body weights and overall caloric intake were consistent with the control mice, which differs from what research has shown in humans with low GLP-1. 

It’s possible that NMN exhibited these benefits in the small intestine because the NMN-specific transporter, Slc12a8, is expressed in high levels in this organ, which could allow for NMN to be used readily. This could also mean that other NAD+ precursors, like NR (nicotinamide riboside), would not have the same intestinal effects. To this point, one study with obese male adults found that supplemental NR did not affect GLP-1 secretion or blood glucose levels. 

The authors summarize their findings on a hopeful note, suggesting the potential future use of NMN in obese people or those with glucose-regulating abnormalities. Nagahisa and colleagues state, “In conclusion, the present study provides evidence showing that NAD+ is an important regulator of GLP-1 production, and highlights the capability of the intestine to regulate postprandial glucose metabolism.”

They continue, “Although further studies are required to determine the precise molecular mechanisms that link intestinal NAD+ biology, GLP-1 production, and whole-body glucose metabolism, it would be of great clinical importance to examine whether boosting intestinal NAD+ biosynthesis by oral intake of NMN is a potential therapeutic approach to the treatment of [obese- and metabolic-related dysfunctions].” 

References:

Dollerup OL, Trammell SAJ, Hartmann B, et al. Effects of Nicotinamide Riboside on Endocrine Pancreatic Function and Incretin Hormones. J Clin Endocrinol Metab. 2019;104(11):5703-5714. doi:10.1210/jc.2019-01081 

Nagahisa T, Yamaguchi S, Kosugi S, et al. Intestinal Epithelial NAD+ Biosynthesis Regulates GLP-1 Production and Postprandial Glucose Metabolism in Mice. Endocrinology. 2022;163(4):bqac023. doi:10.1210/endocr/bqac023