A Decade Strong: 2011 Study Shows NMN Preserves Health of Mice with Diet- and Age-Induced Diabetes

Type 2 diabetes has become an epidemic in our modern lifestyle. The cases of this debilitating disease have skyrocketed due to calorie-rich and high-fat diets — not to mention fast food, sugary drinks, and on-demand delivery options — overwhelming how our bodies adapt to metabolize what we consume.

At the heart of our metabolism — how we convert what we consume into energy — is a pathway that is mediated by an enzyme called nicotinamide phosphoribosyltransferase (NAMPT). This pathway is essential for our cells to synthesize nicotinamide adenine dinucleotide (NAD+), a vital compound that each one of our cells and every living cell out in the world uses to metabolize and generate energy. This pathway is ancient, going back to when most living things were just single cells.

But how does this pathway hold up against modern poor diets? Roughly a decade ago, Yoshino and colleagues published a study showing that high-fat diets compromise NAMPT-mediated NAD+ cellular synthesis, contributing to the damaging effects of type 2 diabetes. Importantly, when they promoted cell synthesis of NAD+ by using nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD+ precursor, they were able to manage the detrimental effects of diet and type 2 diabetes.

This seminal paper provided critical insights into a potential supplement-based intervention against type 2 diabetes. Importantly, this paper was the jumping-off point for research assessing beneficial and possible adverse effects of NMN more comprehensively with long-term NMN supplementation experiments in different dietary conditions.

Rocking the Metabolic Boat

There was a time not long ago when food was not so easy to come by. For eons, we and our ancestors survived without supermarkets and drive-thrus, leading humans to evolve various mechanisms that mediate how our metabolism adapts in response to nutritionally scarce conditions, such as famine and drought. So, can these adaptive metabolic means be seriously overwhelmed by our modern, sedentary lifestyle with calorie-rich diets, causing an epidemic of obesity and type 2 diabetes worldwide?

To get at the crux of the matter, we have to understand in detail how our cells adapt metabolically. Sitting at the heart of these adaptive mechanisms is the pathway cells use to synthesize NAD+ through NAMPT and the activity of a protein SIRT1, which has made headlines the past few years for its link to longevity. Together, NAD+ and SIRT1 play critical roles in regulating a variety of biological processes that include metabolism, stress responses, and circadian rhythm — our body’s clock. We now know that it is this system that also mediates adaptive responses to limited energy intake, such as fasting and diet restriction.

For example, in skeletal muscle, which is the muscle we use to move our body, both nutritional deprivation and exercise increase NAMPT levels, enhancing cell synthesis of NAD+ and, consequently, SIRT1 activity. In the pancreas, which plays an essential role in converting the food we eat into fuel for the body's cells, both cell synthesis of NAD+ by NAMPT and the activity of SIRT1 regulate glucose-stimulated insulin secretion in response to glucose availability. Additionally, in our liver and energy-storing fat (white adipose tissue), NAMPT and SIRT1 regulate the circadian rhythm, which has a lot of control over our metabolism.

Also, inflammation and oxidative stress — when the balance of harmful oxygen-containing compounds and antioxidants goes awry — caused by fatty liver disease or aging appear to trigger the reduction in NAMPT-mediated NAD+ cell synthesis and contribute to the negative effects of type 2 diabetes on the body. This led scientists to wonder what happens to the regulation of NAMPT, NAD+, and SIRT1 when we consume a calorie-rich, high-fat diet, and how is this linked to type 2 diabetes.

A Panacea for Diabetic Mice

In their 2011 paper, Yoshino and colleagues dug into this question, looking at how high-fat diets affected cell synthesis of NAD+ by NAMPT and SIRT1 activity in mice. Strikingly, they showed that NAMPT-mediated NAD+ biosynthesis is severely compromised in organs with key roles in metabolism — like the pancreas, liver, and white adipose tissue — by high-fat diets, contributing to the detrimental effects of type 2 diabetes. 

This begged the question: Can NMN, the NAD+ precursor produced by NAMPT, rescue the metabolic defects in diabetic mice? What they found was that supplementing diabetic mice with NMN ameliorated glucose intolerance of the pancreas and enhanced liver insulin sensitivity. NMN supplementation also restored gene activity related to managing oxidative stress, inflammatory responses, and the circadian rhythm, partly through enhancing SIRT1 activation with elevated levels of NAD+.

In addition to calorie-rich diets, aging is one of the greatest risk factors for developing type 2 diabetes, which has become more prevalent as the human lifespan has increased in recent decades. So, Yoshino and colleagues looked into whether mice with age-induced diabetes underwent similar changes to mice with high-fat-diet-induced diabetes and whether NMN could help mitigate the metabolic deficiencies. What they found was that NAD+ and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced type 2 diabetes mice.

Can NMN End the Diabetes Epidemic?

These results provide an interesting implication that NMN supplementation might be effective in human type 2 diabetes patients if they have defects in NAMPT-mediated NAD+ cell synthesis — whether caused by high-fat diets or aging. Yoshino and colleagues propose that an adequate and consistent supply of the key NAD+ intermediate, NMN, is critical to maintain normal insulin sensitivity of the liver and glucose-stimulated insulin secretion in the pancreas, which is key to keeping diabetes at bay. “We 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 against the disconcerting epidemic of type 2 diabetes.”

References:

Yoshino J, Mills KF, Yoon MJ, Imai S. Cell Metab. 2011;14(4):528-536.