Metformin and berberine are often described in the same phrase: "activate AMPK." This is true, but incomplete. Both substances affect the energy metabolism of the cell, but differ in where exactly they accumulate, what additional targets they have, and how the body processes them. It is these differences that determine the different profile of side effects. The editors analyze the mechanisms and compare the safety of the two substances.
Pharmacokinetics: the path of a substance in the body
Metformin is a small hydrophilic molecule that is not metabolized in the liver and is excreted unchanged by the kidneys. It enters the cells using transporters of organic cations (OCT1 in the liver, OCT2 in the kidneys). Because of this, kidney function is critically important for safety: when it decreases, metformin accumulates in the blood.
Berberine, on the other hand, has very low oral bioavailability — estimated to be less than 1%. A significant part of the substance remains in the intestine, where it interacts with the microbiota, and what has been absorbed is actively metabolized in the liver by enzymes of the cytochrome P450 system and excreted by the P-glycoprotein pump back into the lumen of the intestine.
This difference has two consequences. First, a significant part of the effects of berberine is probably realized "from the intestines": due to the change in the composition of the microbiota, the effect on the absorption and secretion of intestinal hormones. Secondly, berberine, unlike metformin, actively interacts with enzymes that metabolize other drugs.
Metformin also acts in the intestines: there its concentration is much higher than in the blood. Research in recent years has linked part of its effects to an increase in the secretion of GLP-1, a change in the microbiota, and the utilization of glucose by the intestinal wall. Therefore, the intestine is a common "battlefield" of both substances.
Mechanism of action of metformin
The main clinical effect of metformin is a decrease in glucose production by the liver. It suppresses gluconeogenesis, that is, the synthesis of new glucose from lactate, amino acids and glycerol. Unlike sulfonylureas, metformin does not stimulate insulin secretion, so it rarely causes hypoglycemia by itself.
At the cellular level, metformin accumulates in mitochondria and inhibits complex I of the respiratory chain. As a result, ATP production decreases and the AMP/ATP ratio increases. This activates AMP-activated protein kinase (AMPK), the cell's “energy sensor” that turns on processes that provide energy and inhibits those that use it (Zhou et al., 2001).
Today it is known that AMPK is not the only pathway. Metformin can reduce gluconeogenesis independently of AMPK: through a change in the redox state of the cell, inhibition of mitochondrial glycerophosphate dehydrogenase, and a decrease in glucagon signaling. Scientists are still debating which of the mechanisms is the main one at therapeutic concentrations.
In muscles, metformin moderately improves glucose absorption, and generally increases insulin sensitivity. It is due to the impact on mitochondria that the weakening of adaptation to training found in older people is explained (Konopka et al., 2019): energy stress signals triggered by exercise are partially "overlaid" by the effect of the drug.
Mechanism of action of berberine
Berberine also inhibits mitochondrial complex I and activates AMPK, which explains the similarity of its hypoglycemic action to metformin. In cell models, it enhances glucose absorption, inhibits gluconeogenesis and lipid synthesis in the liver.
Berberine's unique property is its effect on the LDL receptor. Work by Kong et al (2004) in Nature Medicine showed that berberine stabilizes LDL receptor mRNA in liver cells through the ERK signaling pathway. As a result, the liver more actively captures LDL from the blood. This mechanism is different from that of statins, and in a study berberine lowered LDL and triglycerides in patients with hypercholesterolemia.
Berberine was later shown to reduce levels of PCSK9, a protein that destroys LDL receptors. This further explains its lipid-lowering effect. Metformin does not have such a pronounced effect on LDL.
The intestinal effects of berberine are likely to be of great importance. As an antimicrobial substance, it changes the composition of the microbiota, affects the metabolism of bile acids and short-chain fatty acids. Some scientists believe that it is this, and not the systemic concentration, that explains a significant part of its metabolic effects.
Comparison of side effects
The most frequent side effects of both substances are gastrointestinal. Metformin causes diarrhea, nausea, bloating and a metallic taste in the mouth, especially at the beginning of treatment; slow dose escalation and sustained-release formulations reduce these effects. Constipation, bloating and abdominal discomfort are more typical for berberine, although diarrhea is also possible.
| Side effect | Metformin | Berberine |
|---|---|---|
| Gastrointestinal disorders | Often: diarrhea, nausea | Often: constipation, bloating |
| Hypoglycemia (monotherapy) | Rare | Rare |
| Vitamin B12 deficiency | Yes, with long-term use | Insufficient data |
| Lactic acidosis | Rare but serious (warning in the instructions) | Not described as a typical risk |
| Drug interactions through CYP | Minimal | Significant (CYP3A4, CYP2D6, CYP2C9) |
| Risk to newborns | Used during pregnancy as prescribed | Avoid in infants; concern about kernicterus |
Lactic acidosis is the most serious, though rare, risk of metformin. It occurs mainly in severe renal failure, hypoxia, sepsis, alcohol abuse, and circumstances surrounding iodinated contrast procedures in at-risk patients. That is why the instructions forbid use with an estimated GFR below 30 ml/min/1.73 m² and require an assessment of kidney function.
Vitamin B12 deficiency with long-term metformin use has been confirmed in research and may manifest as anemia and neuropathy. ADA guidelines recommend periodic testing of B12 levels, especially in patients with neuropathy.
Drug interactions and special groups
For berberine, the main risk is interactions. It inhibits CYP3A4, CYP2D6 and CYP2C9 enzymes, as well as P-glycoprotein. This can increase the concentration of many drugs: immunosuppressants (an increase in the level of cyclosporine is described), some statins, anticoagulants, antidepressants. People taking regular medications should consult a doctor or pharmacist before taking berberine.
The combination of berberine with metformin, insulin, or sulfonylureas may enhance the hypoglycemic effect and increase the risk of hypoglycemia. Such combinations should be agreed with the doctor.
- Pregnancy and breast-feeding: berberine is contraindicated because it may displace bilirubin from albumin and increase the risk of kernicterus in infants.
- Renal disease: Metformin requires dose adjustment or withdrawal depending on GFR.
- Alcohol: increases the risk of lactic acidosis during metformin.
- Iodinated contrast procedures: a clinician determines whether metformin needs to be withheld based on kidney function, route of contrast and other risk factors. This is not required for every imaging procedure.
For athletes, it is important that none of the substances are prohibited, but intense prolonged exercise, dehydration and metformin are theoretically an unfavorable combination for people with reduced kidney function. Independent use of metformin by healthy people for pre-competition weight cutting has no evidence base.
Editorial conclusions
Metformin and berberine share a key mechanism—inhibition of mitochondrial complex I with AMPK activation—and both act largely in the gut. However, berberine has an additional target, the LDL receptor, which explains its stronger effect on cholesterol.
Pharmacokinetics determines the risk profile: metformin is excreted by the kidneys and is dangerous in renal failure, while berberine is actively metabolized by the liver and enters into numerous drug interactions.
Gastrointestinal effects are common to both, B12 deficiency and rare lactic acidosis are characteristic of metformin, and contraindications for pregnant women and infants are particularly important for berberine.
We also recommend reading our articles on the general difference between metformin and berberine, on AMPK and exercise, and on lipid profile analysis.
References
- Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167–1174.
- Kong W, Wei J, Abidi P, et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med. 2004;10(12):1344–1351.
- Yin J, Xing H, Ye J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism. 2008;57(5):712–717.
- Konopka AR, Laurin JL, Schoenberg HM, et al. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell. 2019;18(1):e12880.
- UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854–865.
- American Diabetes Association. Standards of Care in Diabetes. Diabetes Care. поÑоÑна ÑедакÑÑÑ.
- U.S. Food and Drug Administration. Glucophage (metformin hydrochloride): prescribing information.
