Nicotinamide Mononucleotide Prevents Free Fatty Acid-Induced Reduction in Glucose Tolerance by Decreasing Insulin Clearance

Int J Mol Sci. 2021 Dec 8;22(24):13224. doi: 10.3390/ijms222413224.


The NAD-dependent deacetylase SIRT1 improves β cell function. Accordingly, nicotinamide mononucleotide (NMN), the product of the rate-limiting step in NAD synthesis, prevents β cell dysfunction and glucose intolerance in mice fed a high-fat diet. The current study was performed to assess the effects of NMN on β cell dysfunction and glucose intolerance that are caused specifically by increased circulating free fatty acids (FFAs). NMN was intravenously infused, with or without oleate, in C57BL/6J mice over a 48-h-period to elevate intracellular NAD levels and consequently increase SIRT1 activity. Administration of NMN in the context of elevated plasma FFA levels considerably improved glucose tolerance. This was due not only to partial protection from FFA-induced β cell dysfunction but also, unexpectedly, to a significant decrease in insulin clearance. However, in conditions of normal FFA levels, NMN impaired glucose tolerance due to decreased β cell function. The presence of this dual action of NMN suggests caution in its proposed therapeutic use in humans.

Keywords: SIRTs; free fatty acids; glucose tolerance; insulin clearance; insulin resistance; type 2 diabetes.

MeSH terms

  • Animals
  • Fatty Acids, Nonesterified / blood*
  • Glucose / adverse effects*
  • Glucose Intolerance / blood
  • Glucose Intolerance / chemically induced
  • Glucose Intolerance / drug therapy*
  • Hep G2 Cells
  • Humans
  • Infusions, Intravenous
  • Insulin / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NAD / metabolism
  • Nicotinamide Mononucleotide / administration & dosage*
  • Nicotinamide Mononucleotide / pharmacology
  • Oleic Acid / adverse effects*
  • Sirtuin 1 / metabolism
  • Up-Regulation


  • Fatty Acids, Nonesterified
  • Insulin
  • NAD
  • Nicotinamide Mononucleotide
  • Oleic Acid
  • Sirtuin 1
  • Glucose