Inhibition of mitochondrial complex I improves glucose metabolism independently of AMPK activation.
Level 5 - mechanism / opinion, no new human data
Preclinical laboratory study using cell cultures and animal models without human data
PubMed 29106036 · doi:10.1111/jcmm.13432
What was done
Mitochondrial complex I was inhibited chemically (using rotenone and amobarbital) and genetically (via NDUFA13 gene silencing). Intraperitoneal glucose tolerance and insulin tolerance tests were performed in db/db mice treated with rotenone. In vitro experiments in HepG2 hepatocytes, C2C12 myotubes, and primary hepatocytes evaluated glucose consumption, lactate release, and hepatic glucose output. AMPK dependence was assessed using Compound C and adenoviruses expressing dominant-negative AMPK α1/2, alongside measurements of the cellular NAD+/NADH ratio.
What was found
No quantitative numerical values or effect sizes were reported in the abstract. Rotenone ameliorated hyperglycemia and insulin resistance in db/db mice, stimulated glucose consumption and glycolysis, and suppressed hepatic glucose output. Although rotenone activated AMPK, its metabolic effects persisted after AMPK inactivation. Amobarbital and NDUFA13 gene knockdown similarly increased glucose consumption and decreased hepatic glucose output in vitro, correlating with a reduction in the cellular NAD+/NADH ratio.
Why it matters
The study suggests that mitochondrial complex I inhibition improves glucose metabolism through an AMPK-independent, redox-associated mechanism, shedding light on the pathways of complex I-targeting metabolic agents.
Limits
This is entirely preclinical research conducted in cell lines, primary cells, and a mouse model (db/db). The abstract lacks specific sample sizes (n), dosing details, and numerical data. Known toxicity associated with non-specific complex I inhibitors like rotenone was not evaluated for clinical translation.
Cited by
- supports Berberine acts as a mitochondrial Complex I inhibitor.