Complex I inhibitor
Mitochondrial complex I inhibitor
- Energetic stress → activates AMPK
- ↓ hepatic gluconeogenesis
- Excess inhibition impairs oxidative phosphorylation → lactate accumulation
Complex I inhibitor (1/2)
- Principal mechanism — sequence of events
- ➔ ↓ glucose production by the liver
- ➔ ↑ insulin sensitivity of body tissues
- ➔ ↓ fat accumulation
- ➔ ↑ mitochondrial biogenesis
- Example of hormesis
- ➔ low doses of a stressor stimulate beneficial adaptive responses, while higher doses are harmful
Complex I inhibitor (2/2)
- Mechanistically related drugs
- ➔ Hypoglycemia in ~10% of cases
- ➔ Survival is common with aggressive support (IV fluids, hemodialysis)
Drugs with this mechanism (2)
- Metformin — First-line diabetes drug; weight-neutral, sometimes used for antipsychotic weight gain.
- Metformin ER — Extended-release biguanide; often rescues GI intolerance to immediate-release therapy.
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