Tier 2 — strong

Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women

Mihoko Yoshino, Jun Yoshino, Brandon D. Kayser, Gary J. Patti, Michael P. Franczyk, Kathryn F. Mills, Miriam Sindelar, Terri Pietka, Bruce W. Patterson, Shin-Ichiro Imai, Samuel Klein
Science 2021 372(6547), 1224-1229

Bibliography

PubMed
PMID 33888596
PubMed Central
PMC8550608
DOI
10.1126/science.abe9985
Funding
Supported by NIH grants DK56341, DK104995, AG037457 and AG047902; UC San Diego IGM Genomics Center resources supported by NIH SIG grant S10 OD026929; and support from the Tanaka Fund and Foundation for Barnes-Jewish Hospital. Oriental Yeast Co., Ltd. provided placebo and NMN capsules.
Competing interests
Shin-Ichiro Imai receives part of patent-licensing fees from MetroBiotech and Teijin through Washington University and serves as an Invited Chief Scientist at the Institute for Biomedical Research and Innovation in Kobe. Jun Yoshino is an inventor on an NMN-related patent application (#20180228824). Samuel Klein receives research support from Janssen Pharmaceuticals and serves on a scientific advisory board for Merck Sharp & Dohme Corp. Other authors reported nothing to disclose.

Study snapshot

Design10-week randomized, placebo-controlled, double-blind parallel trial with detailed metabolic phenotyping, hyperinsulinemic-euglycemic clamps and skeletal-muscle biopsies.
ModelPostmenopausal women with prediabetes who were overweight or obese (BMI 25.3-39.1 kg/m²).
Sample25 completed: 13 NMN and 12 placebo.
InterventionNMN 250 mg/day for approximately 10 weeks versus placebo; capsules supplied by Oriental Yeast Co., Ltd.
Duration10 weeks.
EndpointsInsulin-stimulated glucose disposal by hyperinsulinemic-euglycemic clamp; Skeletal-muscle insulin signaling: AKT and mTOR phosphorylation; PBMC NAD+ content and NMN metabolites; Skeletal-muscle gene expression and PDGFRβ signaling; Body composition and liver/adipose insulin sensitivity; Muscle mitochondrial respiratory capacity and physical function

What the study showed, in plain terms

This placebo-controlled trial studied a very specific population: postmenopausal women with prediabetes and overweight or obesity. Participants took 250 mg/day of NMN or placebo for 10 weeks and underwent gold-standard clamp testing plus muscle biopsies.

After NMN, insulin-stimulated glucose disposal in skeletal muscle increased, along with insulin-stimulated AKT and mTOR signaling. Basal NAD+ in PBMCs increased, and several NMN metabolites rose in muscle, although steady-state muscle NAD+ itself did not.

The metabolic effect was selective. Body composition, fasting glucose and insulin, liver and adipose-tissue insulin sensitivity, muscle mitochondrial respiratory capacity and measured physical function did not improve. The trial therefore provides evidence for a muscle-specific insulin-sensitizing signal in this population, not a broad demonstration of metabolic or anti-aging benefit.

Key findings

  • Muscle insulin sensitivity measured by insulin-stimulated glucose disposal was 25±7% greater after NMN than before treatment (p<0.01), while placebo showed no comparable pre/post change.
  • Insulin-stimulated AKT and mTOR phosphorylation increased after NMN, consistent with enhanced skeletal-muscle insulin signaling.
  • Basal PBMC NAD+ content increased after 10 weeks of NMN; the 240-minute PBMC NAD+ area under the curve was 43% greater in the NMN group because of the higher basal level.
  • Muscle NAD+ concentration did not change, but NMN-related metabolites increased, suggesting greater muscle NAD+ turnover.
  • Body composition, fasting plasma glucose/insulin, liver and adipose insulin sensitivity, muscle mitochondrial oxidative capacity and muscle physical-function tests did not materially change.
  • No adverse events or standard blood-test abnormalities were reported.

What this study can and cannot tell us

Only 25 postmenopausal women with prediabetes and overweight/obesity completed the study, so results cannot be generalized to men, younger adults, metabolically healthy people or other disease groups.

The trial lasted only about 10 weeks and was designed around mechanistic metabolic endpoints rather than clinical outcomes such as diabetes incidence, cardiovascular events or long-term functional change.

The effect was tissue-specific: improvements were observed in skeletal-muscle insulin action, while several other metabolic and physical-function outcomes did not change.

Citation network

Articles citing this research paper

9 articles

Biohack Blueprint analyses that reference this study in their evidence base.

Editorial review

Reviewed by the Biohack Blueprint research team

Last verified

Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology