First Human Trial of Its Kind Finds NMN Improves Glucose Metabolism in Women
Affecting one in three American adults, prediabetes — blood glucose (sugar) levels that are higher than normal, but not high enough to be considered diabetic — is a serious warning bell that should not be ignored. As 70% of people with prediabetes will go on to develop type 2 diabetes, paying attention to this internal alarm before you cross the diagnostic line can greatly improve your health and longevity. Type 2 diabetes — especially when it’s uncontrolled — can cause a whole host of severe health problems, ranging from blindness to nerve loss to foot amputations to kidney failure. As a major modern health epidemic, many researchers are searching for ways to mitigate the metabolic dysfunction that is characteristic of diabetes — and one answer may lie with the compound NMN (nicotinamide mononucleotide), a precursor to the essential coenzyme NAD+ (nicotinamide adenine dinucleotide) that is needed by every cell in the body.
In this April 2021 study, published in Science and authored by Yoshino and colleagues, a research team based out of Washington University School of Medicine in St. Louis, Missouri, demonstrate that supplemental NMN improves several markers of skeletal muscle glucose metabolism that are commonly dysregulated in people with obesity or type 2 diabetes. Being the first clinical trial testing the effectiveness of NMN on human metabolism, co-author Shin-ichiro Imai, MD, Ph.D. states, "This is one step toward the development of an anti-aging intervention, though more research is needed to fully understand the cellular mechanisms responsible for the effects observed in skeletal muscle in people."
The Metabolic Malfunctions Manifesting in Diabetes
Type 2 diabetes and prediabetes are characterized by several metabolic dysfunctions like dysregulated responses to insulin, causing high blood sugar levels. Insulin is a pancreas-made hormone that shuttles sugar from the food we eat, taking it from the bloodstream into various cells. Eighty percent of glucose uptake occurs in skeletal muscle cells, with the rest going to fat tissue and liver cells. Normally, our cells respond immediately when insulin comes around after a meal, which allows for blood sugar to stay in a healthy range.
However, the cells of people with prediabetes or diabetes don’t have the same quick response time. While insulin still rushes to the scene, the cells of a diabetic or prediabetic don’t respond in the same way, becoming resistant to insulin’s inclination for taking glucose away from the blood — known as “insulin resistance.” When this resistance happens, the pancreas pumps out more and more insulin, trying to get our cells to listen. Unfortunately, as this resistance keeps growing, the pancreas can’t keep up with the insulin demand. Blood sugar stays chronically high, setting the stage for prediabetes and, eventually, type 2 diabetes if left uncontrolled.
Linking Low NAD+ Levels To Insulin Resistance
With age, NAD+ levels markedly decline; these low levels are implicated in many, if not all, chronic diseases. In animal and cell-based studies, NMN increases NAD+ stores and is linked to improved cardiovascular, brain, metabolic, muscle, reproductive, and bone health. Although the evidence for NMN’s positive effects on animals is continually growing, we still don’t have a wealth of evidence of how NMN affects human health. While a recent trial did find short-term supplemental NMN to be safe for human consumption, researchers have yet to publish clinical trials of NMN and human health outcomes — until now, with Yoshino and colleagues looking at how NMN plays a role in insulin resistance and glucose metabolism.
While many factors play a role in insulin resistance, including obesity, genetics, and aging, one often overlooked factor is low NAD+ levels in skeletal muscle — the muscular tissue that allows us to move and perform all of our daily activities. With the knowledge that skeletal muscle in aging adults tends to be both low in NAD+ and prone to insulin resistance, Yoshino and colleagues aimed to uncover if supplementing with NMN could improve these muscular metabolic malfunctions that are seen in people with prediabetes — and, with that, potentially open doors for a new therapeutic option for treating this disease.
NMN Supports Healthy Skeletal Muscle Glucose Metabolism
In this clinical trial, the research team took a group of 25 overweight or obese postmenopausal women with prediabetes in their early 60s, using this subset of women due to previous research finding that supplemental NMN improved metabolic health in older female mice with diabetes more than males. Splitting the group randomly into two, the women received either a placebo pill or 250 mg of supplemental NMN per day. At baseline and after 10 weeks, Yoshino and colleagues measured dozens of health markers, including body composition, skeletal muscle metabolic function, insulin resistance, NAD+ levels, and gene activity.
After 10 weeks of taking NMN, the women experienced several significant health benefits. Although some outcomes, like body weight, body fat, blood pressure, fasting blood glucose levels, were not impacted, the NMN-treated group did have 25% greater insulin sensitivity (the opposite of insulin resistance) and boosted levels of several key components of the insulin signaling pathways that regulate how well our bodies uptake glucose into cells. This 25% increase in insulin sensitivity in the muscles is a clinically relevant number, resulting in the same metabolic improvements that losing 10% of one’s body weight or taking a common diabetes medication would cause. Improving insulin sensitivity allows for blood sugar to migrate down towards healthier levels, reducing the risk of prediabetes turning into diabetes.
In this trial, NMN also led to improved muscle remodeling — a process that is dysregulated in people with diabetes and allows for old or damaged muscle cells to be removed and replaced. Although muscle NAD+ levels did not elevate post-NMN supplementation, blood plasma levels of NMN and NAD+ metabolites were increased, suggesting that NMN boosted the turnover of NAD+ in the muscles. Yoshino and colleagues also looked at gene activity, finding that the NMN-treated women had increased activity of genes involved with muscle remodeling, collagen synthesis, and a growth factor pathway called PDGF that regulates cell growth and division. Inadequate PDGF signaling causes reduced insulin sensitivity and glucose uptake by skeletal muscle cells, contributing to type 2 diabetes development or progression.
Can NMN Open New Doors for Diabetes Therapy?
Although supplemental NMN at a relatively low dose of 250 mg per day did not significantly affect body composition or disease biomarkers like blood pressure and glucose, the NAD+ precursor did prove efficacious to skeletal muscle glucose metabolism and insulin sensitivity. While there are a couple of limitations, including the small sample size and specific subset of postmenopausal, prediabetic, and overweight or obese women, this trial is groundbreaking in that it’s the first one of its kind to study the metabolic effects of NMN in humans.
Future research should look at how NMN affects other groups of people with prediabetes or diabetes — potentially with higher doses of NMN or for more extended study periods. As concluded by the senior investigator on the study, Samuel Klein, MD, "Although our study shows a beneficial effect of NMN in skeletal muscle, it is premature to make any clinical recommendations based on the results from our study." While we don’t yet know for sure that taking NMN will improve diabetes in humans, this study is undoubtedly a step in the right direction for mitigating the currently uncontrolled epidemic of type 2 diabetes in our society.
DeFronzo RA, Tripathy D. Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care. 2009;32 Suppl 2(Suppl 2): S157-S163. doi:10.2337/dc09-S302
Irie J, Inagaki E, Fujita M, et al. Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. Endocr J. 2020;67(2):153-160. doi:10.1507/endocrj.EJ19-0313
Yoshino M, Yoshino J, Kayser BD, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women [published online ahead of print, 2021 Apr 22]. Science. 2021;eabe9985. doi:10.1126/science.abe9985