Metformin

Category: other

Pharmacological Mechanism

Mitochondrial complex I inhibition (see oxidative phosphorylation); ampk signaling activation; reduced hepatic gluconeogenesis.

Half-Life (t½)

PO: 4h

Dosing Guidelines

• PO: Typical 500 (Range: 250–2000)

Target Organ Systems

• digestive

Interactions

• Berberine (synergistic): Same AMPK/Complex I axis — additive glucose-lowering + additive GI intolerance.
• Vitamin B12 (caution): Chronic metformin depletes B12 — monitor at ≥4 years.
• Dapagliflozin (synergistic): Standard dual-therapy pairing.
• Empagliflozin (synergistic): Standard dual-therapy pairing in T2D; complementary mechanisms, no PK interaction.
• Sitagliptin (synergistic): Standard dual-therapy combination; Janumet combines the two.

Notes

Take with food. Monitor B12 on chronic use.

Pathways It Modulates

• Alzheimer disease (inhibitor) — tau hyperphosphorylation via AMPK + insulin sensitization (observational signal)
• AMPK energy sensor (activator) — AMPK (indirect via complex I → ↑AMP)
• Autophagy (macroautophagy) (activator) — AMPK → ULK1 (mTOR-independent autophagy induction)
• Bile acid (activator) — ↑Akkermansia + alters BA pool composition (gut-mediated)
• Brown adipose thermogenesis (activator) — AMPK → mitochondrial biogenesis + BAT recruitment
• Cellular senescence / SASP / senolytics (inhibitor) — AMPK-mediated SASP suppression + mTOR damping
• cGAS-STING cytosolic DNA sensing → type I IFN (inhibitor) — AMPK → ↓cGAS-STING tonic activation
• Circadian clock (inhibitor) — AMPK → CRY1 → peripheral clock
• FXR / TGR5 bile-acid receptor signaling (activator) — FXR (indirect — alters BA pool composition + microbiota)
• Gluconeogenesis (inhibitor) — hepatic gluconeogenesis (Complex I + mGPD inhibition reduces cytoplasmic NADH for the GAPDH-reverse step)
• Hepcidin / ferroportin iron regulation (inhibitor) — hepcidin (modest)
• Hippo / YAP-TAZ signaling (inhibitor) — AMPK → LATS activation → YAP suppression (preclinical anti-cancer signal)
• Insulin signaling + glucose homeostasis (inhibitor) — mitochondrial complex I + AMPK (hepatic)
• Microbiome short-chain fatty acid signaling (activator) — butyrate-producer abundance (Akkermansia, Faecalibacterium)
• Mitophagy (activator) — AMPK → mitophagy enhancement
• NAD+ / sirtuin / longevity axis (activator) — AMPK (downstream NAD+/AMPK convergence node)
• NAFLD / MASH (inhibitor) — hepatic gluconeogenesis + AMPK → ↓steatosis (modest)
• Necroptosis (inhibitor) — necroptosis (AMPK-mediated; preclinical IRI models)
• Neuroinflammation (inhibitor) — AMPK → ↓microglial NLRP3
• Oxidative phosphorylation (inhibitor) — Complex I (mild) — basis for hepatic gluconeogenesis suppression + lactic acidosis risk
• p53 / MDM2 DNA-damage response (activator) — AMPK → mTORC1 inhibition + p53 modulation (anti-cancer signal)
• PI3K / AKT signaling (inhibitor) — PI3K/AKT indirect (via AMPK → TSC2 → ↓mTORC1)
• Pyroptosis (inhibitor) — NLRP3 + AMPK → autophagy clearance of inflammasome
• Telomere maintenance + shelterin complex (activator) — AMPK → telomere length preservation (epidemiologic signal)
• Unfolded protein response / ER stress (inhibitor) — UPR (chronic; via AMPK-mediated ER stress reduction)
• Wnt / β-catenin canonical signaling (inhibitor) — Wnt/β-catenin (AMPK-mediated)

Chemical Identifiers

• PubChem CID: 4091
• Formula: C4H11N5
• Molecular weight: 129.16 g/mol
• InChIKey: XZWYZXLIPXDOLR-UHFFFAOYSA-N
• SMILES: CN(C)C(=N)N=C(N)N

References

• PMID 24843017