Berberine vs Metformin – RENUE BY SCIENCE – Bioavailable NAD+ Boosters

Berberine vs Metformin


Striking Simularities

Recent studies show striking similarities between the popular diabetes drug metformin and its natural alternative berberine. It’s also as effective as metformin, but without the side effects and long-term implications.

Compared with metformin, berberine exhibited an identical effect in the regulation of glucose metabolism. In the regulation of lipid metabolism, berberine activity is better than metformin. 1

Berberine – A Natural Alternative

Berberine is the most effective natural supplement known to protect against chronic diseases and aging and one of the few supplements shown to be as effective as a pharmaceutical drug. 2

A growing body of research emphasizes that berberine can outperform metformin’s antidiabetic, blood sugar stabilizing and longevity-enhancing effects. 3

A review of 14 studies found that berberine lowered blood sugar levels and seemed to be as effective as metformin. 4

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What is Metformin?

In the past 2 decades, metformin has become a mainstay of type 2 diabetes management and is now the recommended first-line drug for treating the disease in the United States and worldwide.  It has been prescribed to over 120 million people around the world. 5

In the early 2000s, studies at the National Institutes of Health determined that metformin extends lifespan and healthspan in laboratory mice, and shortly thereafter metformin was found in studies to reduce morbidity and mortality from aging-associated diseases in humans. 6

Why are Biohackers Using Metformin?

Metformin is now considered to be one of the new darlings of the anti-aging industry.  Silicon Valley executives, CEOs, well-known pioneers in the longevity field and biohackers have been taking metformin as a prophylactic measure for cancer prevention and a long-term longevity strategy.

Metformin Delays Cell Senescence

Metformin has been shown to delay aging in model organisms and reduces the incidence of age-related diseases in humans by reducing oxidative stress and reducing excessive ROS production in the mitochondria. 7

In addition, metformin activates SIRT3, participates in mitochondrial autophagy and reduces oxidative stress, thereby delaying cell senescence.

Longevity-signaling molecules in human cells, known as mTOR and AMPK, are increased when taking metformin – which helps to reduce fat and sugar storage that support cells to function youthfully. 8

Figure 1:  Metformin can activate the SKN-1 pathway through ROS, which acts as a signaling molecule to delay aging. In addition, metformin activates SIRT3, participates in mitochondrial autophagy and reduces oxidative stress, thereby delaying cell senescence.

The Dark Side of Metformin

Despite its widespread use, not all individuals prescribed metformin derive the same benefit and some develop side effects.

Around 30 percent of people taking metformin in the long-term experience vitamin B-12 deficiency. 9

Some users (especially first-time users) experience the following side effects which could result in them stopping the medication:

  • Nausea and vomiting

  • Diarrhea

  • Abdominal pain

  • Gas and bloating

  • Lack of appetite

  • A metallic taste in the mouth


Metformin Blunts the Health Benefits of Exercise

In the study “Impact of metformin on peak aerobic capacity”, it was shown that metformin can significantly decrease VO2 max (–2.7%), peak heart rate (–2.0%), peak ventilation (–6.2%), peak resting energy expenditure (–3.0%), and actual exercise duration (–4.1%).


Metformin Lowers Endurance

A 2019 study highlights that metformin has also been shown to hamper endurance and limit mitochondrial proliferation in response to an exercise protocol. 11

Metformin’s Negative Impact on Muscle Strength

Studies have shown large doses of metformin negatively impact the response to strength training in healthy older adults. 12


Why is Berberine Replacing Metformin?

Berberine—a natural bioactive compound extracted from several different plants—has been used medicinally for at least four centuries.

The lipid lowering effect of berberine is comparable to conventional lipid pharmaceutical drugs but with low toxicity. 13   Berberine also inhibits the mTOR pathway as metformin does. 14

Berberine Outperforms Metformin

Those with type 2 diabetes and metabolic syndrome stand to benefit the most from berberine because it causes a major reduction in blood sugar levels. 15

One study found that 500 mg of berberine taken twice per day by patients with type 2 diabetes lowered blood glucose, fasting insulin, and blood lipid levels and it was as effective at lowering blood glucose as metformin. 4

Berberine Induces Autophagy, Protects the Epigenome

Berberine is one of the most promising interventions to slow down the accumulation of senescent cells by inducing autophagy. 19

Autophagy is a powerful evolutionary self-preservation mechanism through which the body can remove dysfunctional cells and toxic proteins responsible for many age-related chronic diseases, and recycle parts of them toward cellular repair and cleaning.

Berberine’s benefits extend beyond the induction of autophagy, and include optimizing metabolic pathways, and upregulating the molecules that maintain the epigenome. 20

Berberine Flips the Metabolic Master Switch

Berberine’s primary mechanism of action is through the AMPK (AMP-activated protein kinase) pathway.  Scientists call AMPK the “Metabolic Master Switch” and is found in cells of different organs throughout the body, including heart, brain, kidneys, liver, fat cells, and muscle tissue.

By activating AMPK, berberine improves the body’s ability to metabolize glucose (sugar) for energy. That’s the main reason it’s helpful for people with type 2 diabetes or metabolic syndrome. 16

Berberine also affects DNA transcription (turning genes on or off), receptor expression (controlling the behavior of cells), and the interaction of other molecules with cells in your body. 17


Overcoming Berberine’s Poor Bioavailability with Liposomes

Despite the advantages of berberine, there are some limitations in its clinical applications, the most important of which is its poor aqueous solubility and absorption loss in the gastrointestinal tract. 21

To overcome these limitations, nanotechnology has been considered the main strategy to improving berberine’s low bioavailability.

Liposomes encapsulated with nanoparticles of berberine increase assimilation into the gastrointestinal tract and improve efficacy over conventional supplements.  22

Berberine-loaded liposomes protect the nutrients from degradation by the digestive juices in the gut and the molecule ends up in the intestines where they enter the bloodstream. 23

Liposomal Berberine has a Greater Absorption Rate

  • Enhanced bioavailability and absorption of nutrients to target cells.
  • They are non-invasive. It eliminates the discomfort linked with injections.
  • Increases intracellular delivery
  • They are cost-effective. Liposomes provide effect for a lower dose compared to traditional methods.
  • They are an alternative for those who struggle to take capsules or tablets.
  • They can deliver both hydrophilic (water-soluble) and hydrophobic (fat-soluble) compounds.
  • They have fewer side effects associated with regular oral supplements



  1. Efficacy of Berberine in Patients with Type 2 Diabetes
  2. Efficacy of Berberine in Patients with Type 2 Diabetes
  3. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states
  4. Berberine in the Treatment of Type 2 Diabetes Mellitus: A Systemic Review and Meta-Analysis
  5. Microparticulate and nanoparticulate drug delivery systems for metformin hydrochloride
  6. Metformin as Anti-Aging Therapy: Is It for Everyone?
  7. Metformin: A Potential Candidate for Targeting Aging Mechanisms
  8. Longevity and Aging: A New Approach Using Metformin
  9. Side effects of taking metformin
  10. Impact of metformin on peak aerobic capacity
  11. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults
  12. Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double-blind, placebo-controlled, multicenter trial: The MASTERS trial
  13. Metformin and berberine, two versatile drugs in treatment of common metabolic diseases
  14. Dose-Dependent AMPK-Dependent and Independent Mechanisms of Berberine and Metformin Inhibition of mTORC1, ERK, DNA Synthesis and Proliferation in Pancreatic Cancer Cells
  15. Berberine as a therapy for type 2 diabetes and its complications: From mechanism of action to clinical studies
  16. Berberine Ameliorates High Glucose-Induced Cardiomyocyte Injury via AMPK Signaling Activation to Stimulate Mitochondrial Biogenesis and Restore Autophagic Flux
  17. Comprehensive Study in the Inhibitory Effect of Berberine on Gene Transcription, Including TATA Box
  18. Lipid-lowering effect of berberine in human subjects and rats
  19. Berberine suppresses gero-conversion from cell cycle arrest to senescence
  20. Berberine acts as a putative epigenetic modulator by affecting the histone code
  21. Berberine nanoparticles with enhanced in vitro bioavailability: characterization and antimicrobial activity
  22. Liposome encapsulated berberine treatment attenuates cardiac dysfunction after myocardial infarction
  23. Liposomes as Advanced Delivery Systems for Nutraceuticals