Even in a society that lives for the quick fix, a daily pill that could help prevent Type II diabetes sounds too good to be true. But a team of researchers at Washington University School of Medicine claims to be taking the first steps to making such a compound a reality.

Type II diabetes (T2D) has become a health concern of epidemic proportions in recent years. And while the disorder is thought to develop as our bodies' metabolic pathways become overwhelmed by high-calorie diets, many of the details surrounding how these pathways function and break down remain unclear.


Now, a team of researchers has shed new light on the mechanism of one of nature's most important metabolic pathways. And here's the kicker: they've revealed that one of the molecules in this pathway can actually help reverse the symptoms of diabetes in mice, opening new and promising avenues of therapeutic research.

Note: This research was funded by the NIH, and the findings are available free of charge in the journal Cell Metabolism.


One of the most important molecules in energy metabolism is nicotinamide adenine dinucleotide, or NAD+ for short. If you've ever taken a biochemistry class, you're familiar with the myriad roles that this indispensable molecule plays, transporting energy throughout your body's metabolic organs, and facilitating countless chemical reactions in the process.

NAD+ also activates a protein called Sirtuin 1 (SIRT1), which has been shown to promote healthy metabolism throughout the body.

But in people with Type 2 diabetes, the body's NAD+ supplies are lower than normal, such that the molecule is spread too thin to carry out its biological duties effectively. SIRT1 levels, for example, plummet in the absence of NAD+. Lack of SIRT1, in turn, is thought to contribute to a whole host of metabolic problems, including hallmark symptoms of diabetes like glucose intolerance.


But as anyone who has studied it will tell you, the web of molecules that collaborate to carry out our bodies' metabolic processes is a vast and multifarious one (click the image [via] to have your mind blown, metabolically). Consequently, explicit links between high calorie diets, T2D, and specific pathways — like one responsible for NAD+ production — can remain unexplored for years.

To examine the T2D/NAD+ connection more carefully, researchers at Washington University School of Medicine took to the laboratory, where they stuffed otherwise healthy mice full with a high-fat diet (HFD). And then they waited and watched.


The researchers found that mice fed a HFD developed overt diabetes within six months, but they also showed that the mice's food consumption compromised their NAD+ biosynthesis, contributing to the development of the disorder. Their results reveal how so-called "nutritional perturbations" (i.e. a HFD) affect the system dynamics of NAD+ and SIRT1 production, and, by extension, onset of type 2 diabetes.

On its own, showing that a HFD compromises NAD+ production, thereby contributing to the pathogenesis of type 2 diabetes, might not sound particularly groundbreaking.


But by identifying a definitive link between the three, the researchers were able to hypothesize that a precursor molecule in the synthesis of NAD+ called nicotinamide mononucleotide (aka "NMN," shown here), might be capable of not only ameliorating defects in the body's NAD+ production, but treating symptoms of diabetes, as well.

When the researchers administered NMN to the diabetic mice, they found that it was converted to NAD+ almost immediately.

When they administering the molecule in portioned doses over several days, it was able to make up for much of the underlying defect in NAD+ production.


NMN was also shown to reverse HFD-induced effects on biological pathways and genes related to oxidative stress, inflammatory response, immune response, and lipid metabolism — all of which are known to contribute to insulin resistance in the liver.

And, at least in female mice, NMN was found to completely restore blood sugar metabolism. The scientists have described this last result as particularly striking.

"I'm very excited to see these results because the effect of NMN is much bigger than other known compounds or chemicals," says first author Jun Yoshino. "Plus, the fact that the body naturally makes NMN is promising for translating these findings into humans."


Why NMN has a more dramatic affect on female mice than males remains unclear, though the researchers suspect that sex hormones like estrogen may play an unknown role in NAD+ synthesis.

According to lead researcher Shin-ichiro Imai, the lab is currently trying to reproduce their results, only this time the mice will be receiving NMN via their drinking water, rather than by injection. Imai says his lab's most recent work represents a first step toward what he calls a "nutriceutical," a compound not unlike a daily vitamin that people could take to treat, or even prevent, type 2 diabetes.


"Once we can get a grade of NMN that humans can take, we would really like to launch a pilot human study," Imai says.

The researchers' findings are published in the latest issue of Cell Metabolism, and are available free of charge.