Nicotinamide mononucleotide , a key NAD+ intermediate , treats the pathophysiology of diet- and age- induced diabetes in mice

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Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice In this study, Yoshino et al. investigated the role of NMN in an animal model of type 2 diabetes (T2D). The authors induced T2D with a high-fat diet, and then administered 500 mg / kg of NMN over 7 or 10 days. The authors found that in untreated mice with T2D, NAD+ biosynthesis was severely diminished in white adipose tissue (WAT) and hepatocytes. Following NMN administration, the authors observed at 15x increase in intracellular NMN, as well as a 5x increase in hepatocyte nicotinamide riboside (NR). The authors also found that NMN supplementation improved insulin-response in T2D mice, in females by improving insulin sensitivity, while in males by improving glucose-stimulated insulin secretion. They were unsure of the exact reason for gender-specific responses to NMN. They also found that Sirtuin 1 was one of the mediators of the improvements associated with NMN, and that treatment with NMN also improved metabolic complications of T2D in these mice[1].

Article abstract

Type 2 diabetes (T2D) has become an epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ biosynthesis, and the NAD+-dependent protein deacetylase SIRT1. Here we show that NAMPT-mediated NAD+ biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD+ intermediate, ameliorates glucose intolerance by restoring NAD+ levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD+ and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a potential nutriceutical intervention against diet- and age-induced T2D.

Implications

This research helps to define the role of NAD+ and NMN in the pathogenesis of diabetes. It underscores that decline in NAD+ and the resulting metabolic complications of diabetes may be effectively reversed by NMN supplementation. Additionally, the research found that the mechanism by which NMN improves the diabetic phenotype may be different in male and female mice. While further research is needed to confirm these findings and define the sex-specific changes, this work lays the groundwork for that research.

Additional research to be conducted

The authors note that the natural extension of their work would be to attempt to replicate the preliminary results in human trials. Specifically, understanding the changes in NAD+ associated with T2D in humans, as well as the potential role for NMN supplementation. Additionally, they note that future work should focus on investigating the potential for a combination intervention of NMN supplementation with sirtuin-1 activators because of the potential for synergistic improvement in metabolism.

Institution

Dr. Shin-ichiro Imai's lab has been an active contributor to the body of literature investigating NMN and its potential benefits. His lab at Washington University in St. Louis has produced several other manuscripts investigating the role of sirtuins in longevity and insulin sensitivity as well as the metabolism of NAD+[2][3][4].

Funding

This work was supported by the National Institute on Aging (AG02150), the Ellison Medical Foundation, and the Longer Life Foundation to S.I. and by institutional support from the Washington University Nutrition Obesity Research Center (P30DK056341) and the Washington University Diabetes Research and Training Center (P60DK020579). The authors reported individual funding of financial interests with the following: Japan Research Foundation for Clinical Pharmacology, the Manpei Suzuki Diabetes Foundation, the Kanae Foundation For the Promotion of Medical Science, and Sirtris, a GSK company.

Authors/ Researchers

  • Jun Yoshino – Department of Developmental Biology, Washington University of St. Louis
  • Kathryn F Mills – Department of Developmental Biology, Washington University of St. Louis
  • Myeong Jin Yoon - Department of Developmental Biology, Washington University of St. Louis
  • Dr. Shin-ichiro Imai - Department of Developmental Biology, Washington University of St. Louis

References

  1. ↑ 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 Metab. 2011;14(4):528-536.
  2. ↑ Luo J, Nikolaev AY, Imai S ichiro, et al. Negative control of p53 by Sir2α promotes cell survival under stress. Cell. 2001;107(2):137-148.
  3. ↑ Revollo JR, Grimm AA, Imai SI. The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J Biol Chem. 2004;279(49):50754-50763.
  4. ↑ Moynihan KA, Grimm AA, Plueger MM, et al. Increased dosage of mammalian Sir2 in pancreatic β cells enhances glucose-stimulated insulin secretion in mice. Cell Metab. 2005;2(2):105-117.
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