Researchers at Washington University School of Medicine in St. Louis have restored normal blood sugar metabolism in diabetic mice using a compound the body makes naturally.
The finding suggests that it may one day be possible for people to take the compound in pill form to treat or even prevent type 2 diabetes. The naturally occurring enzyme, Nicotinamide Mononucleotide – NMN – plays an important role in how cells use energy.
Researcher Shin-ichiro Imai says this discovery holds promise for people because the mechanisms that NMN influences are largely the same in mice and humans ::::
“After giving NMN, glucose tolerance goes completely back to normal in female diabetic mice,” says Shin-ichiro Imai, MD, PhD, associate professor of developmental biology. “In males, we see a milder effect compared to females, but we still see an effect. These are really remarkable results. NMN improves diabetic symptoms, at least in mice.”
Kathryn F. Mills, research lab supervisor said, “We also injected older healthy mice and found that they weren’t adversely affected. It’s good to know that even if the mice are not diabetic, giving NMN is not going to harm them.”
Consuming a high fat diet and aging are contributors to diabetes. The researchers say a fatty diet and aging is also associated with lower levels of nicotinamide mononucleotide, slowing the body’s production of NAD leads to abnormal metabolic conditions such as diabetes. NAD could not be given to the mice directly because of toxic effects. But after administering NMN, levels of NAD rise and the diabetic mice show dramatically improved responses to glucose. In some cases, they return to normal.
All cells in the body make NMN in a chain of reactions leading to production of Nicotinamide Adenine Dinucleotide – NAD – a vital molecule that harvests energy from nutrients and puts it into a form cells can use. Among other things, NAD activates a protein called SIRT1 that has been shown to promote healthy metabolism throughout the body, from the pancreas to the liver to muscle and fat tissue.
NMN is vital for the production of NAD, which is an oxidizing agent that has several roles in metabolism. One of the functions of NAD is activation of a protein called SIRT that boosts insulin sensitivity in the body. NAD is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups, with one nucleotide containing an adenine base and the other containing nicotinamide. Nicotinamide adenine dinucleotide, like all dinucleotides, consists of two nucleotides joined by a pair of bridging phosphate groups. The nucleotides consist of ribose rings, one with adenine attached to the first carbon atom and the other with nicotinamide. The nicotinamide moiety can be attached in two orientations to this anomeric carbon atom. Because of these two possible structures, the compound exists as two diastereomers. It is the B-nicotinamide diastereomer of NAD that is found in organisms.
“But whether this mechanism is equally compromised in human patients with type 2 diabetes is something we have to check,” Imai says. “We have plans to do this in the very near future.”
In younger healthy mice with diabetes induced by a high fat diet, NMN boosted NAD levels to normal levels in females, but not completely in males. The researchers say they’re not certain why. “…sex hormones, such as estrogen, may be important downstream for NAD synthesis.” Yoshino says. The investigators are studying the effect of the natural compound on diabetic mice when it’s added to their drinking water
“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, MD, PhD, postdoctoral research associate. “Plus, the fact that the body naturally makes NMN is promising for translating these findings into humans.”
Imai and his colleagues found that young, healthy mice on a high-fat diet developed diabetes in six months or less. In these mice, they found that NAD levels were reduced. But after administering NMN, levels of NAD increased and the female mice had normal results in glucose tolerance tests — a measure of how well the body moves glucose from the blood to the organs and tissues for use. Glucose tolerance was also improved after male diabetic mice received NMN but did not quite return to normal. The researchers are interested in learning more about these differences between male and female mice.
“We don’t have a clear answer, but we are speculating that sex hormones, such as estrogen, may be important downstream for NAD synthesis,” Yoshino says.
In older mice, they observed that about 15 percent of healthy males fed a normal diet developed diabetes.
Imai says few studies have examined normal mice that naturally develop diabetes as a simple result of aging because the experiments take so long. In an interesting twist, few elderly female mice developed diabetes at all. But after switching to a high fat diet, older female mice quickly developed severe diabetes.
“Again, when we injected these females with NMN, we came up with a completely normal glucose tolerance curve,” Mills says. “We can also see that the NMN has completely reversed and normalized the levels of cholesterol, triglycerides and free fatty acids.”
In the current study, one injection of nicotinamide mononucleotide reversed symptoms of diabetes by returning glucose tolerance to normal in the female mice, the enzyme also improved lipid profiles in the mice. “Once we can get a grade of NMN that humans can take, we would really like to launch a pilot human study,” Imai says.
Imai’s group is now conducting a long-term study of diabetic mice that get NMN dissolved in their drinking water. Imai calls this work a first step toward a possible “nutriceutical” that people could take almost like a vitamin 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.
source: cell metabolism
Credit and Abstract:>
Authors: Yoshino J, Mills KF, Yoon MJ, Imai SI. Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metabolism. Online Oct. 4, 2011.
This work was supported in part by the National Institute on Aging, the Ellison Medical Foundation, the Longer Life Foundation, the Washington University Nutrition Obesity Research Center, the Washington University Diabetes Research and Training Center. Jun Yoshino is supported by the Japan Research Foundation for Clinical Pharmacology, the Manpei Suzuki Diabetes Foundation, and the Kanae Foundation for the Promotion of Medical Science.
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.