Dihydroberberine (DHB)

Stefan Filippo
February 3, 2023
3 Scientific References

Key facts:

  • DiHydroBerberine is one of the 17 metabolites of Berberine.
  • DiHydroBerberine has an enhanced bioavailability and half life when compared to Berberine.
  • Both Berberine and DiHydroBerberine support Metabolic Health, though DiHydroBerberine does it better.
  • The dosage of DiHydroberberine is much less than Berberine.

Berberine is a superstar supplement.

It does everything from supporting the health of the microbiome, promoting a healthy gut lining as well as supporting metabolic function via helping to maintain a healthy blood glucose, lowering HbA1c, improving insulin sensitivity, improving fat metabolism, enhancing body composition and more.

With that impressive list of uses, why do we need something better? 

In fact, can we actually do any better than that?

The big downside to Berberine is its low cellular bioavailability, less than 1% [R]. This means that approximately 1% of the Berberine we take in, makes its way into our cells, where it can exert all these beneficial metabolic effects.  

If we are looking to use Berberine to support blood sugar, we’d have to take quite high doses, a standard dose for this is 500mg 3 times per day.

This is all well and good, but this can lead to some unwanted effects, mainly gut distress and potential die off symptoms (brain fog, fatigue, frequent toilet visits and more) [R].

Enter Dihydroberberine (DHB).

Dihydroberberine is one of the 17 metabolites of Berberine. It is a compound that we naturally make in our intestines after we supplement with Berberine [R]. Dihydroberberine has a number of benefits over standard Berberine, including better oral bioavailability and a longer half life [R]. 

💡 Takeaway: Due to the higher bioavailability and longer half life of DHB, a much lower dose is needed, leading to much less GI symptoms.

What is Dihydroberberine used for?

DHB is mainly used as a supplement to improve Metabolic Health, showing greater effectiveness than standard Berberine.

💡 Takeaway: While regular Berberine has strong antimicrobial effects, DHB doesn’t display as much of this due to the much lower dose needed.

What does Dihydroberberine do?

Dihydroberberine benefits

The benefits of Dihydroberberine may include;

  • Enhancing carbohydrate metabolism [R]
  • Activates AMPK [R]
  • Maintains a healthy blood glucose [R]
  • Lowering HbA1c [R]
  • Improving insulin sensitivity [R]
  • Improving fat metabolism [R]
  • Enhancing body composition [R]
  • Lowering inflammation [R]
  • Inhibiting fat cell growth [R]
  • Having antioxidant effects [R]
  • Activating thermogenesis [R]
  • Increasing Adiponectin [R]
  • Supporting Autophagy [R]
  • Improves the composition of the microbiome via enriching Akkermansia genus [R]
  • Anti-fibrotic effects [R]
  • Protects the kidney and liver [R]
  • May increase Acetylcholine levels by inhibiting acetylcholinesterase [R, R
  • Reducing cancer cell growth, inhibiting metastasis & increasing sensitivity of cancer cells to anti-cancer drugs [R, R, R, R

To better understand how DHB supports our metabolic health, it’s useful to have an understanding of how Berberine supports it.

What is Berberine?

Berberine is a bioactive alkaloid found in various plants such as Indian Barberry, Goldenseal, Oregon Grape and Chinese Goldthread as well as Berberis shrubs, which is how it got its name. Berberine containing plants were used medicinally by various traditional cultures, including in Traditional Chinese Medicine.

In the modern day, Berberine is quite a well known compound in the natural health, functional medicine, naturopathic and biohacking spaces. 2 of its broad uses are to help with metabolic health and gut function.

A quick glance at PubMed will show that over 630 papers were published last year (2021) alone for Berberine.

Regarding the gut, Berberine is a potent anti-microbial, being used to eradicate a vast array of pathogens [R, R, R]. 

Beyond that, it can actually support the health of our ‘good’ microbes by doing the following [R]; 

  • Increases the levels of Akkermansia muciniphila (a keystone strain of bacteria)
  • Supports our production of butyrate and other Short Chain Fatty Acids which supports our microbiome
  • Enhancing gastrointestinal motility (making your bowels move better) 
  • Reduces intestinal permeability (leaky gut)
  • Has a pain relieving effect in the gut
  • Lowers Lipopolysaccharide (LPS)

This article will shine a spotlight on the metabolic effects of Berberine, as this is the most important area of comparison between Berberine and DHB. We’ll specifically look at insulin resistance and all the ways Berberine and DHB can support our body in becoming more insulin sensitive.

But first…

What is insulin resistance and insulin sensitivity?

Berberine, Insulin Resistance & Insulin Sensitivity

Before we look at all the ways Berberine supports insulin sensitivity it is helpful to know how a healthy person digests and metabolises carbohydrates.

If you’re well versed in this, skip ahead to (link to next section)

Carbohydrate metabolism for a healthy person

We’ll dive into a bit of biochemistry to look at how our body metabolises sugars and where insulin resistance and insulin sensitivity play into this.

We take in sugar from the foods that we eat. Our Small Intestines are the main organ involved in digesting the sugar into its smallest components, monosaccharides (glucose, fructose and galactose). For simplicity, we’ll focus on glucose here.

After being digested, glucose is then absorbed through our intestinal lining into the bloodstream, which raises blood glucose. Our pancreas detects that there is more sugar in the bloodstream than the baseline level and secretes insulin via the pancreatic beta cells.  The beta cells secretes insulin in a dose-dependent manner, meaning that the more sugar it detects in the bloodstream, the more insulin it will secrete.

Insulin is a hormone that binds to our cells and allows them to open up and take in glucose from the bloodstream, hence we see a decrease in blood glucose. Within the cell the glucose is converted into Adenosine-Triphosphate (ATP), our internal form of energy.

💡 Takeaway: Insulin also helps us to store glucose into our fat and muscle cells.  Because of this, insulin is known as a storage hormone. Where our body stores this energy (muscle, fat etc) is based on a number of factors, but primarily our degree of insulin sensitivity.

Insulin sensitivity and insulin resistance

In a healthy individual (insulin sensitive), a relatively small amount of insulin is secreted to maintain a healthy blood glucose. When a person has compromised metabolic function (insulin resistance) the body now has to secrete more and more insulin to lower blood sugar.

What is insulin resistance and insulin sensitivity?

Simply put, insulin sensitivity is a measure of how well our cells respond to insulin. The more insulin sensitive you are, the healthier your glucose metabolism is. A more insulin sensitive person requires less insulin to maintain a healthy blood glucose.

The other end of the spectrum is insulin resistance, the unhealthier side of glucose metabolism. Here, the cells are less and less responsive to insulin, and require more insulin to allow glucose into the cell.

Why is insulin resistance a problem?

Many reasons.

Insulin resistance puts extra strain on the Pancreatic Beta Cells (the cells of the pancreas that produce insulin). As the cells aren’t responding to a healthy amount of insulin, the Beta Cells need to pump out more insulin to lower blood sugar. Over time, this can lead to a wearing out of these cells, which can lower insulin production over time and lead to heightened blood sugar.

Insulin is a storage hormone, thus insulin resistance, and the elevated insulin production that comes with it can lead to difficulty losing weight or unwanted weight gain. When insulin is elevated it switches off fat burning, it is a storage hormone after all. We need lower levels of insulin to activate fat burning.

💡 Takeaway: Elevated levels of insulin (and blood glucose) lead to metabolic issues, such as cardiovascular disease, obesity, vascular damage, high blood pressure, inflammation, type II diabetes and more.

What causes insulin resistance?

Cells can become insulin resistant for many reasons. Inflammation, cell damage, excessive exposure to insulin, low activity levels, elevated body fat and more. 

What causes low Insulin production?

Pancreatic beta cell damage. This can be from overproduction of insulin for a long time, toxicity, cell damage and more.

Is Berberine good for insulin resistance?

💡 Takeaway: Berberine is a fantastic supplement for supporting the body in improving its glucose metabolism.

Here are the ways that Berberine improves the insulin sensitivity of the cells and overall metabolic health.

How Berberine supports blood sugar Mechanism
Berberine increases blood glucose breakdown and utilization via enhancing insulin sensitivity Berberine activates the cellular pathway AMP-activated protein kinase (AMPK). This pathway enhances blood sugar metabolism and insulin sensitivity [R] as well as stimulating glycolysis (breakdown of sugar into energy) [R]
Berberine enhances fat oxidation / metabolism By activating AMP-activated protein kinase (AMPK) [R]. Enhancing fat oxidation has been shown to improve insulin sensitivity [R].
Berberine inhibits fat cell enlargement By activating AMP-activated protein kinase (AMPK) [R]. Inhibiting fat cell enlargement may lower inflammation and improve insulin sensitivity of visceral and reduce visceral adipose tissue [R].
Berberine lowers gluconeogenesis By activating AMP-activated protein kinase (AMPK) [R]. Gluconeogenesis is the process whereby sugars from non-carbohydrate sources. By lowering gluconeogenesis, Berberine reduces blood glucose [R].
Berberine lowers inflammation and is antioxidant Berberine activates AMP-activated protein kinase (AMPK), mitogen-activated protein kinases (MAPKs), nuclear factor erythroid-2-related factor-2 (Nrf2) pathway, and inhibits the nuclear factor-κB (NF-κB) pathway which lead to both its anti-inflammatory and antioxidant effects [R].
Berberine normalises blood lipids Berberine can normalise total cholesterol, lowering LDL & increasing HDL as well as lower triglycerides. Normalising these values is indicative of an improved metabolic profile [R].
Berberine activates thermogenesis Thermogenesis directly improves insulin sensitivity [R] while also increasing overall energy expenditure (calories burned) [R].
Berberine increases Adiponectin levels [R] Adiponectin is a hormone released from fat cells that plays a role in protecting against insulin resistance, by stimulating fat burning in muscles and inhibiting gluconeogenesis. Adiponectin also plays a role in forming new blood vessels and reducing plaque build-up in arteries (atherosclerosis) [R]. This hormone also lowers inflammation by blocking the effects of TNF-alpha and inhibiting NF-KB signalling [R]. Additionally, Adiponectin stimulates AMPK activation [R].
Berberine supports autophagy Autophagy is a process whereby cells “eat” senescent cells (unhealthy cells) or damaged components of cells [R]. Autophagy enhances insulin sensitivity [R].
Berberine supports liver function The liver is a key organ involved in many metabolic processes that support healthy blood sugar [R]. Thus, by supporting the liver, blood sugar metabolism is enhanced.
Berberine restores pancreatic beta cell function Beta Cells are the cells of the Pancreas that produce insulin. Via activating the miR-204/SIRT1 Signalling pathway, Berberine promotes the healthy function of pancreatic beta-cells and can therefore support healthy levels of insulin secretion [R].

DiHydroberberine vs Berberine

DHB is one of the 17 metabolites of Berberine that we naturally produce in our bodies.

💡 Takeaway: After we take a Berberine supplement, our gut microbes alter Berberine via a reduction process, adding 2 hydrogen molecules to it, making it Dihydroberberine (2 hydrogens + Berberine).  DHB then gets absorbed across the intestinal wall and into the bloodstream. DHB is then converted back to Berberine, through the process of oxidation (losing the 2 hydrogen molecules).  This Berberine can then be absorbed into the cell [R, R].

Curious to know just how DHB stacks up against regular Berberine?

Read on…

But first, what is GlucoVantage DHB?

What is GlucoVantage DHB?

The ingredient we’re using in our Dihydroberberine product is a patented form of DHB, known as GlucoVantage. GlucoVantage is created from pure Berberine, extracted from the herb Berberis aristata (also known as Indian Barberry). It is lab tested to ensure purity and free of contamination with other compounds. This product is produced by NNB nutrition, of which Shawn Wells is a part of. You can hear Shawn speaking about Dihydroberberine and more on Ben Greenfield’s podcast.

A potential issue with Berberine

Shawn Wells tested 40 Berberine supplements in 2015 and found that only 3 contained pure Berberine at the specified dose. The 37 remaining contained other compounds or were underdosed. As mentioned above, Shawn is part of the company NNB which sells the patented form of DHB, so there is a potential conflict of interest here.

Is Dihydroberberine better than Berberine?

There are a few factors to look at with this comparison; bioavailability half life, side effects, metabolic effects, inflammation and more.

Dihydroberberine bioavailability

The chemical structure of DHB (2 hydrogen molecules attached to Berberine) allows for easier absorption than Berberine. In vitro studies estimate 5 times more DHB passes through the intestinal wall than Berberine [R].

For those who have issues with their microbiome, the conversion of Berberine into DHB is negatively affected and this can lower Berberine bioavailability even further. DHB circumvents this issue and still performs well despite an altered microbiome [R]. 

A 2015 study on mice looked at the absorption of DHB in comparison to Berberine and corroborated the above results, DHB had better intestinal absorption. In addition to this result, in mice that lacked the intestinal bacteria to convert Berberine into DHB, it was shown that DHB had even greater absorption comparatively [R].

A 2022 human study then gave further evidence to this, showing that DHB at 40% and 80% of the dose of Berberine, yielded higher absorption of Berberine into the blood [R].

💡 Takeaway: Put simply, DHB gives us more Berberine in our bloodstream than if we supplemented pure Berberine.

Given that DHB is only one of 17 metabolites of Berberine, do we miss out on the other 16 if we take DHB? 

The simple answer is no.

Given that we convert DHB back to Berberine, we get the benefits of these metabolites as well [R]. 

Dihydroberberine half life

In addition to the enhanced bioavailability, DHB also has a longer half life than Berberine. Berberine’s half life is 4 hours while DHB’s is 8 hours [R]. 

Side effects of Berberine and DihydroBerberine

Why does Berberine cause Diarrhea?

Berberine is known as an antimicrobial substance. It can kill pathogenic microorganisms which can lead to some unpleasant symptoms such as brain fog, fatigue and gastrointestinal issues such as diarrhea.

DHB, due to the much lower dose required, doesn’t seem to have as much of this antimicrobial effect.

Does DHB cause stomach upset?

Rodent studies show less stomach upset with DHB, though there are still some GI side effects present [R, R].

💡 Takeaway: Human studies show mixed results and are inconclusive due to the short length of study, study design and low sample size [R].

This is not to say that the antimicrobial effect is a ‘side effect’ of berberine, it is in fact one of the main effects. If you’re looking for more of the metabolic effects DHB appears to be more effective (more on this below) and if you’re looking for the antimicrobial effects, Berberine may be a supplement to use in your stack.

DHB vs Berberine HCl - DHB vs Berberine

And now we look at the rodent and human studies comparing Berberine and DHB for their effectiveness in metabolic conditions.

Metabolic effects - DHB vs Berberine

A 2008 study on mice found that DHB outperformed Berberine for its improvement on metabolic parameters. Mice were fed a diet that would promote obesity and metabolic issues and separated into 2 groups, one given 100mg/kg/day of Berberine and the other given 100mg/kg/day of DHB. At this dose, the DHB group saw improvements in glucose tolerance via a 44% improvement in insulin sensitivity as well as improved markers for adiposity and triglyceride build up, with the Berberine group showing no effect. When Berberine was increased to 560mg/kg/day it showed comparable effects to the 100mg/kg/day DHB group.  The authors postulated that it was the enhanced bioavailability responsible for this effect [R].

A 2014 mice study looked at Berberine and DHB for their effects on atherosclerotic plaques. These plaques are typically seen in the progression of cardiovascular disease and are rooted in metabolic dysfunction. The study found that DHB reduced atherosclerotic plaque formation and improved the stability of the plaque, 2 beneficial results, while Berberine didn’t show this effect [R].

DHB was compared to Berberine for its effects at inhibiting pancreatic lipase [R]. Pancreatic Lipase is an enzyme that is targeted in the treatment of obesity, lowering it is shown to improve outcomes [R].

💡 Takeaway: It was shown that DHB had a higher binding affinity than Berberine which may mean it has better activity at reducing the activity of this enzyme and thus aiding fat and weight loss to a greater degree [R].

Inflammation - DHB vs Berberine

Modulating inflammation is a key target for improving insulin sensitivity & overall metabolic health. Studies comparing the anti-inflammatory effects of Berberine vs DHB show mixed results, sometimes DHB is more effective and sometimes Berberine is more effective.

💡 Takeaway: DHB appears to outperform Berberine at reducing Cardiovascular inflammation [R] and colonic inflammation [R] while Berberine outperformed DHB in rodent cell culture studies [R, R].

Gut lining

A mice study compared the effects of Berberine, DHB and the immunosuppressant medication Azathioprine on outcomes with Ulcerative Colitis. It was found that DHB outperformed Berberine. The DHB group had better gut barrier function through up-regulated tight junction proteins (claudin-1, occludin & junctional adhesion molecules A) and mucins. DHB was also shown to decrease pro-inflammatory cytokines associated with UC by blocking the TLR4/MyD88/NF-κB signalling pathway [R].

Dihydroberberine vs Metformin

Metformin is one of the most prescribed drugs for treating Type II Diabetes. It works to improve insulin sensitivity and enhance carbohydrate and fat metabolism.

To the best of our knowledge, there are no studies directly comparing DihydroBerberine to Metformin. However, there is a study comparing Metformin to Berberine and studies comparing DHB to Berberine (link to above section). Therefore, by extrapolation, we can speculate on how DHB would compare to Metformin.

Berberine vs Metformin for Insulin Resistance

A 2009 human study compared 500mg Berberine 3 times per day to the same dose of Metformin. Berberine and Metformin had identical effects in regards to how well they lowered HbA1c, fasting blood glucose, postprandial blood glucose, fasting insulin and postprandial insulin. However, Berberine outperformed Metformin in regards to fat metabolism as measured by its effects on triglycerides and total cholesterol [R].

As stated above (link to above), DHB outperforms Berberine for supporting both carbohydrate and fat metabolism.

As Berberine appears to be identical to Metformin for carbohydrate metabolism and DHB outperforms Berberine for carbohydrate metabolism, it could be hypothesised that DHB may outperform Metformin.

💡 Takeaway: As Berberine outperformed Metformin for fat metabolism and DHB outperforms Berberine for fat metabolism, it could be hypothesised that DHB may outperform Metformin.

DiHydroberberine vs Ceylon Cinnamon

Ceylon Cinnamon, also known as True Cinnamon (Cinnamomum verum), is a herbal remedy that can improve metabolic health via enhancing insulin sensitivity. Specifically, Cinnamon promotes phosphorylation of insulin receptor tyrosine kinase to increase insulin sensitivity. Additionally Cinnamon may also modulate GLUT4 transporters to mobilize glucose into the cell [R].

Not all Cinnamons are created equally

There are many forms of Cinnamon, with Ceylon Cinnamon appearing to be the safest form of Cinnamon to use, being lower in Coumarins, a compound that can lead to liver toxicity in high amounts.

Berberine vs Cinnamon

Similar to Metformin, there don’t appear to be any studies directly comparing DHB to Ceylon Cinnamon. In fact, there are no studies comparing Berberine to Cinnamon. But, there are studies that look at how Cinnamon can work synergistically with Berberine and positively affect the absorption and efficacy of Berberine.

Berberine with Cinnamon

There is a Traditional Chinese Herbal formula named Jiao-Tai-Wan. It is a combination of Cinnamon Cassia and Coptis Chinensis, a plant that contains Berberine.  The below 4 studies are based on this formulation.

Rodent studies on Cinnamon and Berberine

A 2010 rat study found that cinnamon use changed the distribution of Berberine. Distribution is referring to where in the body the Berberine makes its way to. By itself, the Berberine from Coptis was mainly distributed to the liver. With the addition of Cinnamon, the Berberine was found in higher concentrations in the liver though also in the heart and kidneys [R].

A 2013 study on diabetic mice found that Cinnamon enhanced the uptake of Berberine from Coptis as well as having a synergistic effect. The addition of Cinnamon was found to enhance the blood sugar lowering/insulin sensitising effects of Berberine [R].

A 2018 rat study found that Cinnamon increased the bioavailability and half life of Berberine and other compounds within Coptis [R].

Human studies on Cinnamon and Berberine

A 2011 human study on Jiao-Tai-Wan found similar results to the rodent studies. Cinnamon enhanced blood levels of Berberine, as well as enhancing absorption and half life. This study did not look at blood sugar [R].

💡 Takeaway: Given that these studies are all for Cinnamon Cassia, it is unclear of the exact effect of Ceylon Cinnamon on the absorption of Berberine.

Dihydroberberine with Ceylon Cinnamon

Given everything above, what can be said about Dihydroberberine and Ceylon Cinnamon? It theoretically could increase absorption, though it’s not fully clear.

Given that both ingredients support healthy blood sugar, there may be a synergistic additive effect when combining the 2.

DHB dosage/dose

NNB Nutrition, the patent holders of GlucoVantage, have extrapolated data from rodent studies to come to the dosage recommendations for DHB.

💊 The recommended dose is 100-200mg of DHB 1-2 times per day. This translates to 1-2 capsules 1-2 times per day usually taken in the morning and evening.

When to Take DHB

DHB should ideally be taken 30 minutes before your most blood sugar and insulin spiking meal. This will usually be your highest carbohydrate meal.

The reason for this is to improve insulin sensitivity and glucose metabolism so that the glucose gets shuttled to muscle quickly rather than staying elevated in the bloodstream and leading to the issues described earlier.

Is DHB safe?

Rodent safety studies on DHB

A 2018 rat study looked at transdermal (on the skin) use of Berberine and DHB for 14 days. Firstly, it found that transdermal DHB had greater uptake than both transdermal and oral berberine. On the safety side of things, DHB was found to be safe, there were no changes in kidney and liver biomarkers [R]. 

Human safety studies on DHB

To date there appears to be one study on DHB in humans, published in 2022. It was mainly done to assess the absorption and half life of DHB compared to Berberine. There were 4 treatments, Placebo, 100mg DHB twice per day, 200mg DHB twice per day and 500mg Berberine. The study found that both DHB groups outperformed Berberine with respect to the amount of Berberine absorbed [R].

Regarding blood work, most white blood cells were unaffected from Berberine and DHB supplementation. There was some elevation for lymphocytes (for 100mg DHB compared to 200mg DHB) and monocytes (for 100mg DHB and placebo groups), though these were still within clinically acceptable ranges [R].

Regarding metabolic panels, there were some significant differences with creatinine levels, though these were once again within clinically acceptable ranges [R].

All groups, including placebo, recorded adverse effects. Interestingly, the 100mg DHB treatment saw more self-reported adverse effects than both the 200mg DHB and Berberine groups. The placebo group saw more adverse effects than both the 200mg DHB and Berberine groups [R].

This study has a big limitation, there were only 5 study participants, all cycling through 4 treatments, placebo, 100mg DHB twice daily, 200mg DHB twice daily, 500mg Berberine (known as a crossover trial). A more accurate representation of these supplements would include more participants and for a longer period of time [R].

DHB side effects

The side effects noted for the DHB group in the human study included Nausea, upset stomach, headache, dizziness [R].

The bottom line

On the metabolic side of things, it appears that DiHydroBerberine outperforms Berberine. It is absorbed more easily, lasts longer in the bloodstream, requires a much lower dose, has less side effects and controls blood glucose and other metabolic parameters much more effectively than standard Berberine.

DHB supplement

After reading all of this information (or maybe just skimming through it), you probably have just one question.

Where can I get my hands on DiHydroBerberine supplements?

Thankfully, you have come to the right place (who would have thought the website with the most comprehensive DiHydroBerberine article would also sell DiHydroBerberine?).

Our DiHydroBerberine supplement is free of fillers, vegan friendly, and contains 100mg of DiHydroBerberine per serving, easily enabling you to get the 100-200mg dosage twice per day as recommended by NNB Nutrition.



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DHB Supplement Australia

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