title: Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice.
abstract: Type 2 diabetes (T2D) has become 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.
authors: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Jun
authors: J
authors: Yoshino
authors: Kathryn F
authors: KF
authors: Mills
authors: Myeong Jin
authors: MJ
authors: Yoon
authors: Shin-ichiro
authors: S
authors: Imai
mesh_terms: D000375:Aging; D000818:Animals; D002940:Circadian Rhythm / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D009243:NAD / Q000096:biosynthesis*; D009537:Nicotinamide Mononucleotide / Q000494:pharmacology*; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: D016207:Cytokines; D007004:Hypoglycemic Agents; D007328:Insulin; D009243:NAD; D009537:Nicotinamide Mononucleotide; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D005947:Glucose