Metformin: the pathway in the body

This page shows the biochemical pathway of the active substance Metformin: where it arrives in the body, where it acts and which steps are affected by that. Every statement has a source. The page describes general textbook knowledge and says nothing about any individual person.

In brief

Metformin is a biguanide. The body does not convert it; inside the cell it gathers in the mitochondrion and slows the first complex of the respiratory chain. It binds nothing fast — the build-up follows the charge gradient and falls back again.

The pathway step by step

1. Metformin → In the small bowel From the gut contents metformin passes through transporters of the gut cells into the blood. Part of it stays in the gut wall and the gut contents; the label gives an availability of about one half. Source 1, 8
2. In the small bowel → Metformin in the blood In the blood metformin barely binds to protein. The body does not convert it: it leaves unchanged through the kidney, where transporters move it from the blood into the urine. Source 1, 8
3. Metformin in the blood → In the liver cell The transporter OCT1 brings the charged molecule into the liver cell. Without this carrier it would hardly cross the membrane. Source 1, 2
4. In the liver cell → In the matrix · positive charge An electrical gradient lies across the inner mitochondrial membrane. A positively charged molecule follows it and gathers in the matrix — metformin sits there at a higher concentration than outside the cell. Source 2, 3
5. NADH in the matrix → Proton gradient complex I · FMN, coenzyme Q10 Complex I accepts the electrons from NADH and passes them on to coenzyme Q10. In doing so it pumps protons out of the matrix; this creates the gradient across the inner membrane. Source 4
6. Proton gradient → ATP ATP synthase · ADP, phosphate The protons flow back into the matrix through the ATP synthase. Its turning motion joins ADP and phosphate into ATP. Source 4
7. B12 + intrinsic factor → B12 in the gut cell Cubam receptor · calcium The receptor brings the complex into the cell. This step runs only with calcium ions at the cell surface. Source 6, 7
8. B12 in the gut cell → B12 in the blood · transcobalamin The gut cell releases B12 bound to transcobalamin into the blood. In this form cells absorb it and convert it into its two active forms. Source 6
9. AMP and ADP → AMPK LKB1 · AMP binds AMP and ADP bind to the AMP-activated protein kinase. The kinase LKB1 attaches a phosphate to it; AMPK is switched on by that. Source 5
10. AMPK → Malonyl-CoA ACC AMPK attaches a phosphate to acetyl-CoA carboxylase and puts it to rest. That enzyme converts acetyl-CoA into malonyl-CoA; while it rests, less of it arises. Source 5

What this active substance affects

• Vitamin B12 — The Cubam receptor picks up B12 with intrinsic factor; this step at the end of the small bowel runs with calcium Source 6, 7
• Calcium — Carries the uptake step at the Cubam receptor; with more calcium the difference was cancelled out in one study Source 7

What takes part in these steps

• Coenzyme Q10 — Accepts the electrons from NADH at complex I and carries them on through the inner membrane Source 4
• NAD⁺ — As NADH the electron source of complex I; NAD⁺ arises again from it for the citric acid cycle Source 4
• Vitamin B2 (riboflavin) — Forms the FMN in complex I — the site that accepts the electrons from NADH Source 4
• Iron — Complex I carries iron-sulfur centres along which the electrons travel to coenzyme Q10 Source 4

What the prescribing information states

One trial in the United States with 141 adults who received metformin and 145 who received a placebo. Listed are the reactions that occurred in more than 5 of 100 participants and were more common than on placebo. The figures apply to this trial.

How to read the table: this prescribing information lists only reactions that occurred more often on metformin than on placebo — reactions of equal or lower frequency are therefore missing. What matters is the distance within the row: for headache it is one point, for diarrhoea more than forty.

In the same section the prescribing information notes an observation that belongs on this page: in studies over 29 weeks the vitamin B12 value in the blood fell in about 7 of 100 participants who had an unremarkable value before. Reactions reported after approval are not listed here — the prescribing information states that neither a frequency nor a causal relationship can be derived from them.

Sources

1. Graham GG, Punt J et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011 · PubMed 21241070
2. Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia 2017 · PubMed 28776086
3. Foretz M, Guigas B et al. Metformin: from mechanisms of action to therapies. Cell Metab 2014 · PubMed 25456737
4. Sazanov LA. A giant molecular proton pump: structure and mechanism of respiratory complex I. Nat Rev Mol Cell Biol 2015 · PubMed 25991374
5. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 2012 · PubMed 22436748
6. Nielsen MJ, Rasmussen MR et al. Vitamin B12 transport from food to the body's cells — a sophisticated, multistep pathway. Nat Rev Gastroenterol Hepatol 2012 · PubMed 22547309
7. Bauman WA, Shaw S et al. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care 2000 · PubMed 10977010
8. US prescribing information (United States): Metformin Hydrochloride Tablets, DailyMed, version of 21 Sept 2026, sections 12.1 Mechanism of Action and 12.3 Pharmacokinetics · Prescribing information
9. US prescribing information (United States): Metformin Hydrochloride Tablets, DailyMed, version of 21 Sept 2026, sections 6.1 Clinical Studies Experience and 6.2 Postmarketing Experience · Prescribing information

As of 2026-09-25. Draft, written by Claude to schema v2; sources checked in PubMed; expert approval pending
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