Come Get Your NMN (not MNM’s): The NAD+ Precursor Treats the Damaging Effects of Diet- and Age-Induced Diabetes

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NMN Treats the Damaging Effects of Diet- and Age-Induced Diabetes

Type 2 diabetes has become an epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our metabolic pathways. One such pathway is mediated by the rate-limiting enzyme in the mammalian synthesis of the essential molecule nicotinamide adenine dinucleotide (NAD+) called nicotinamide phosphoribosyltransferase (NAMPT) and proteins dependent on NAD+ to function. But how nutritional and environmental perturbations as well as age affect this metabolic network had been unclear up until some seminal research roughly 10 years ago.

Thanks to research from Yoshino and colleagues in 2011, we now know that high-fat diets and aging compromise NAMPT-mediated NAD+ biosynthesis, contributing to the disease development of type 2 diabetes. This influential, decade-old research also provided evidence that promoting NAD+ biosynthesis by using nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD+ intermediate, could be an effective intervention against diet- and age-induced type 2 diabetes. “These findings provide critical insights into a potential nutriceutical intervention against diet- and age-induced type 2 diabetes,” concluded the authors.

Metabolic Malleability in the Modern World

Our bodies have various mechanisms that mediate metabolic adaptation, which have evolved in response to nutritionally scarce conditions like famine and drought. But in our modern, sedentary lifestyle with calorie-rich diets, fast-food, and delivery apps, such adaptive mechanisms could be seriously overwhelmed, causing an epidemic of obesity and type 2 diabetes worldwide.

One such mechanism comprises NAD+ biosynthesis that is mediated by NAMPT and the NAD+-dependent protein SIRT1, which has been linked to longevity. NAMPT-mediated NAD+ biosynthesis and SIRT1 together play critical roles in regulating a variety of biological processes that include metabolism, stress response, cellular differentiation, and circadian rhythm. These two also mediate adaptive responses to limited energy intake, such as fasting and diet restriction.

For example, in skeletal muscle, both nutritional deprivation and exercise increase Nampt activity, enhancing NAD+ biosynthesis and SIRT1 activity. Both NAMPT-mediated NAD+ biosynthesis and SIRT1 regulate pancreatic β cells, which are the cells that synthesize, store, and release insulin and hormones to maintain circulating glucose concentrations. Also, in the liver and white adipose tissue — the fat that sits on our waist, hips, and thighs and stores energy — NAMPT and SIRT1 comprise a feedback loop for the regulation of circadian rhythm, a powerful effector for metabolism.

NMN Nixes Diabetes Damage

In their 2011 paper, Yoshino and colleagues demonstrate that NAMPT-mediated NAD+ biosynthesis is compromised by high-fat diets and aging, contributing to the disease development of type 2 diabetes. They also provide proof of the concept that promoting NAD+ biosynthesis by administering NMN can be an effective intervention to treat the pathophysiology of diet- and age-induced type 2 diabetes.

In both diabetic models, NMN administration dramatically ameliorated impaired glucose tolerance by restoring normal NAD+ levels and enhancing either insulin sensitivity or insulin secretion, supporting our conclusion that underlying defects in NAMPT-mediated NAD+ biosynthesis play an important role in the pathogenesis of diet- and age-induced type 2 diabetes. Although the short-term NMN administration was unable to achieve a significant improvement of fasted glucose levels, NMN is still effective at normalizing multiple metabolic pathways, such as oxidative stress, inflammatory response, circadian rhythm, and glucose-stimulated insulin secretions.

NMN administration dramatically ameliorated impaired glucose tolerance by restoring normal NAD+ levels and enhancing either insulin sensitivity or insulin secretion

Some NMN a Day May Keep Diabetes Away

“Our results provide an interesting implication that NMN supplementation might also be effective in human type 2 diabetes patients if they have defects in NAMPT-mediated NAD+ biosynthesis,” concluded the authors. Because NMN is an endogenous compound, this is rather a nutriceutical approach to type 2 diabetes.

Metabolic tissues and organs seem to utilize NMN and convert it to NAD+ efficiently. So, an adequate and consistent supply of this key NAD+ intermediate must be critical to maintaining normal liver insulin sensitivity and glucose-stimulated insulin secretion in pancreatic β cells. To assess beneficial and possible adverse effects of NMN more comprehensively, Yoshino and colleagues proposed a follow-up study with long-term NMN supplementation experiments in different dietary conditions.

Nonetheless, there is a lot of interest in whether the effects of NMN are synergistic with those of small chemical SIRT1 activators, particularly in aged, diabetic individuals. Yoshino and colleagues anticipate that long-term NMN administration might be a highly effective way to sustain enhanced SIRT1 activity in tissues and organs where NAMPT-mediated NAD+ biosynthesis is compromised and to combat the disconcerting epidemic of type 2 diabetes.

Show references

Yoshino J, Mills KF, Yoon MJ, Imai S. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011;14(4):528-536. doi:10.1016/j.cmet.2011.08.014 

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