Berberine in the Treatment of Type 2 Diabetes Mellitus

Type 2 diabetes is a worldwide health threat and treatment of this disease is limited by availability of effective medications. All of the existing oral hypoglycemic agents have subsequent failure after long term administration. Thus, new oral medications are needed for long-term control of blood glucose in patients with type 2 diabetes. Certain botanical products from generally regarded as safe (GRAS) plants have been widely used in diabetes care because of their anti-oxidation, anti-inflammation, anti-obesity and anti-hyperglycemia properties. However, the drawback of using GRAS plants is the difficulty in control their quality as most of these botanical products are mixtures of multiple compounds. Compared to other products from GRAS plants, berberine is a single purified compound, and has glucose-lowering effect in vitro and in vivo.

Berberine (molecular formula C20H19NO5 and molecular weight of 353.36) is the main active component of an ancient Chinese herb Coptis chinensis French, which has been used to treat diabetes for thousands of years.

Berberine - molecular formula C20H19NO5

Berberine is an Over-the-Counter (OTC) drug, which is used to treat gastrointestinal infections in China. Berberine hydrochloride (B·HCl·nH2O) - the most popular form of berberine, is used in this pilot study. The chemical structure of Berberine and related isoquinoline alkaloids are quite different from the commonly used other hypoglycemic agents, such as sulphonylureas, biguanides, thiazolidinediones, or acarbose. Hence, if the efficacy and safety of berberine are confirmed, it can serve as a new class of anti-diabetic medication.

This pilot study was to assess the efficacy of berberine in human subjects with type 2 diabetes. Berberine was given to both newly diagnosed diabetic patients and poorly controlled diabetic patients alone or combination with other hypoglycemic agents for three months. HbA1c, blood glucose and HOMA index were used to determine the efficacy of berberine.

Berberine and diabetes: Traditional Chinese Medicine (TCM) For Diabetes Has Scientific Backing

One of the most promising all-natural treatment options that have risen to prominence in the literature is berberine, a plant extract that has long been used in traditional Chinese medicine. Following decades of research, researchers have developed a strong understanding of how this natural alkaloid works for patients with type 2 diabetes. The success of the in vitro research has driven animal studies suggesting possible ways in which berberine may have positive clinical effects on a wide range of type 2 diabetes symptoms. In the last few years, the first human studies have gotten underway, and although the clinical research is still in its infancy, it has the potential to clarify the specific benefits of berberine for diabetes patients.

The Cellular Mechanisms Underpinning the Effectiveness of Berberine

As an all-natural therapeutic, berberine stands out because scientists have a solid understanding of the specific cellular pathways through which it works to produce particular benefits for patients with type 2 diabetes.

Specifically, berberine targets AMP-activated kinase (AMPK), an effector protein with a role in a wide range of energy production and utilization pathways. For instance, according to a 2006 study, berberine strongly promotes the phosphorylation of AMPK, which directly increases the AMP-to-ATP ratio in the cell and thereby stimulates glucose uptake. In this way, it can have a direct anti-hyperglycemic effect, which is highly relevant for type 2 diabetes patients.

It is also important to note that there are studies suggesting that berberine works through non-AMPK-related pathways. This is especially intriguing for patients and practitioners looking for a more comprehensive type 2 diabetes treatment option, since it could potentially enhance the AMPK-related effects of berberine as a therapeutic.

For instance, in 2010, researchers at the Chinese Academy of Medical Sciences found that berberine increases the expression of insulin receptors, indicating the potential for a prominent role in reducing insulin resistance in type 2 diabetes patients. There is also research to suggest that berberine may help lower LDL cholesterol by increasing the degradation of PCSK9, a protein that downregulates the low-density lipoprotein (LDL) receptor. Because researchers are continuing to find associations between berberine and a variety of cellular pathways, there is ongoing interest within the research community to elucidate additional mechanisms through which this multifunctional compound may be able to help patients with type 2 diabetes.

The Multifunctional Berberine

Unlike many other folk medicines, the case for berberine’s medical utility has very rarely been viewed with skepticism, so the barriers to operationalizing it as a therapy for insulin resistance are fairly low. Berberine is readily bioactive and has been confirmed to affect a handful of different cellular mechanisms reliably and powerfully. 

This means that berberine is a solution that is looking for problems to solve rather than a precursor product that needs a substantial amount of engineering towards a specific purpose before it is ready; the chief challenge that medical science faces with berberine is finding where it is most effective rather than finding a single case where it is effective at all. Insulin resistance may well be the niche where berberine can shine brighter than other therapies.

The Biochemical Basis of Insulin Resistance

Berberine reduces insulin resistance indirectly by diminishing the intensity of cellular feedback loops which generate resistance in the first place. These feedback loops are at the heart of the cellular energy generation system. Insulin is a hormone, which means that the body utilizes it to signal cells to perform a specific action. In the case of insulin, that action is to moderate cellular glucose uptake and cellular breakdown of glucose-derived molecules.

Under normal conditions, insulin prompts cells to uptake glucose and process it for energy that they use to perform their somatic function in the body. Without this energy, the cells die, so insulin levels are closely associated with cellular activity. As with many other hormones, insulin can either promote or inhibit the cellular functions which it regulates depending on the other cellular signals which the cell receives at the same time. However, cells can’t react to any signal involving insulin if their insulin receptors are malfunctional or absent.

Insulin resistance can thus be understood as a condition in which cells’ ability to receive the signal of insulin is impaired. On a cellular level, insulin resistance manifests as a downregulation in the number of insulin receptors that are present on external cellular surfaces. The fewer insulin receptors on the cellular surfaces, the less physiological impact insulin molecules can have on the cell. In other words, more insulin molecules will be needed to accomplish the same physiological result in an insulin resistant individual than in an individual with normal insulin physiology.

But what might cause cells to have fewer insulin receptors in the first place? The answer lies in the concept of homeostasis. When cells are chronically exposed to high concentrations of insulin—such as when an individual consumes a diet that is rich in simple sugars—they become accustomed to their insulin receptors being activated by insulin very frequently. In these conditions, the cells uptake large volumes of glucose and subsequently convert that glucose into lipids whenever they have more energy than they need to perform their function in the body. These lipids are secreted from the cell and trafficked elsewhere in the body. Significantly, some of these lipids are stored for future use in fat cells, which contribute to weight gain. However, the process of storing lipids in fat cells is slow and can only use a finite amount of lipids at a time, so the excess lipids continue to circulate, awaiting their turn.

When the concentration of soluble lipids becomes too high, cellular toxicity results. To avoid toxicity, physiological feedback mechanisms compensate for rising lipid levels by prompting cells to reduce their concentration of insulin receptors. Fewer insulin receptors means that there are fewer glucose molecules metabolized. Diminished glucose metabolism leads to fewer lipid molecules in circulation, which prevents the toxicity. The body has used its feedback mechanisms to maintain homeostasis in the face of unexpected conditions of toxicity. If lipid toxicity continues despite downregulation of glucose metabolism, the cycle repeats itself; downregulation occurs in successive rounds, leaving cells with fewer and fewer insulin receptors. Eventually, a massive amount of insulin is necessary to produce the same physiological outcome, and downregulation stops. Cells may be left with so few insulin receptors that they struggle to get the glucose that they need to survive, causing the patient to experience lethargy and other symptoms. The patient is thus insulin resistant.

Berberine Controls Insulin Resistance Via the Mitochondria

Breaking the insulin resistance feedback loop requires altering the way that cells uptake glucose and turn it into energy, and berberine does exactly that. Berberine has been shown to reduce insulin resistance in rats, in mice, and in humans. One particularly significant study, conducted by researchers in the Department of Pharmacology at the Chinese Academy of Medical Sciences, measured the level of RNA transcripts which coded for insulin in type II diabetes patients. The patients were weaned off of their medications over a two week period and split into three groups. Two groups of patients received mainstream pharmacotherapies for insulin resistance, whereas the third group of patients received berberine. Over a period of two months, the cohort of patients took their group’s prescribed therapy once per day.

After the two months had elapsed, patients had their blood taken and compared to samples taken at the start of the trial. The patients who had taken berberine experienced 25.9% reduced blood glucose levels compared to the start of the trial. One of the mainstream therapies, rosiglitazone, only reduced blood glucose levels by 17.6%. The other drug, metformin, reduced blood glucose levels by 30.3%. In other words, berberine was more effective than one of the most-prescribed therapies for insulin resistance and within the experiment’s margin of error compared to the other. When scientists examined a cell culture generated from the patients’ blood samples, they found that serum insulin levels of the berberine-treated group decreased by 28.2%, causing drastically increased insulin sensitivity. This means that berberine can act as an attractive alternative to conventional pharmaceuticals both for those who have not found success with mainstream treatments and for those looking to replace conventional therapies with more natural products.

However, the researchers didn’t stop after proving berberine’s efficacy in typical type II diabetes patients. As there are many people in China who suffer from liver issues caused by viral hepatitis B and C infections, the researchers were interested in finding out if berberine would be more effective than the mainstream therapies in individuals with compromised liver function. This question is important because the current pharmacotherapies for insulin resistance tend to be harsh on patients livers. Though berberine’s reduction in blood glucose levels was around 10% less effective in the patients with weakened liver function, the researchers found that the patients’ liver enzymes did not change in a way which would indicate ongoing liver damage. As such, berberine was effective for patients who were put in greater danger by mainstream treatments.

Researchers are still working to understand how berberine might exert these impressive effects, but preliminary investigations suspect that it is related to berberine’s inhibition of the electron transport chain within the mitochondria of the cell. As the mitochondria are responsible for producing chemical energy for the cell, inhibiting its energy production process would lower the cell’s uptake of glucose and subsequent generation of lipids. With fewer circulating lipids, the cellular feedback loop that causes insulin resistance wouldn’t occur. Instead, existing insulin resistance is reduced at the source, and cells must upregulate their quantity of insulin receptors to continue to maintain the same level of activity and perform their physiological purpose thanks to their lower rate of energy production.

Using Berberine in the Clinic

As patients increasingly integrate berberine in their treatment plans, clinical vigilance will be necessary. However, many patients will experience relief from their insulin resistance and only minor concomitant side effects. While side effects of berberine are not yet comprehensively understood, patient reports indicate that low blood sugar and low blood pressure are the most common issues. Patients with diabetes should be especially careful of berberine’s lowering of blood sugar, which could cause problems if unaddressed. Some patients report that if they take a large dose of berberine they experience cramping or diarrhea; spacing doses out over the course of a day seems to be an effective solution to the issue. Patients with sensitive gastrointestinal tracts may want to speak with their healthcare provider regarding other strategies for mitigating discomfort.

For those wishing to try berberine supplementation, careful dosage calibration is essential; most of the clinical trials of berberine for insulin resistance tested dosages in the one gram range. Owing to berberine’s interaction with the mitochondria, it is probable that its side effects will be multimodal and increasingly difficult to tolerate with higher dosages, so patients may need to have their dose adjusted downward if they are uncomfortable. This should not scare patients away whatsoever, as the available evidence shows that berberine can be used to treat insulin resistance with relatively low doses and in a short-term course of treatment. Indeed, published clinical reports indicate that patients tolerate berberine very well in the short term.

Berberine’s extensive effects require a measure of caution, however. There is evidence that berberine inhibits the critical liver enzyme P450, which would likely mean that there is a high potential for drug interactions in patients who use berberine. These interactions could either increase, decrease, prolong, or shorten the effects of other chemicals processed by the enzyme. To put this into context, inhibition of the P450 enzyme is found in a plethora of mainstream drugs which patients use without facing problems. Likewise, patients with liver issues should use lower dosages of berberine with the expectation that their reduction of blood glucose will be slightly less than in a healthy person. Patients should discuss berberine with their doctors before giving it a try regardless of their liver health.

After a course of berberine, patients should be able to experience vastly reduced insulin resistance, giving them more physical energy, restoring clarity of thought, and revitalizing their glucose metabolism system. Ongoing research into berberine will likely elaborate on its use cases alongside other drugs so as to shed light on how it might help patients most effectively. In the meantime, patients struggling with insulin resistance should be proactive in learning more about how to use berberine as a powerful tool for their healthcare.

References:

Zhang X, Zhao Y, Zhang M, Pang X, Xu J, et al. 2012. Structural changes of gut microbiota during berberine-mediated prevention of obesity and insulin resistance in high-fat diet-fed rats. 2012. PlosOne. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042529

Sonksen P and Sonksen J. 2000. Insulin: understanding its action in health and disease. British Journal of Anesthesia. 85(1):69-79. https://bjanaesthesia.org/article/S0007-0912(17)37337-3/fulltext

Zhang H, Wei J, Xue R, Wu JD, Zhao W, et al. 2010. Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism. 59(2):285-292. https://www.sciencedirect.com/science/article/pii/S0026049509003163

Diogo CV, Machado NG, Barbosa IA, Serafim TL, Burgeiro A, et al. 2011. Berberine as a promising safe anti-cancer agent – is there a role for mitochondria? Curr Drug Targets. Jun;12(6):850-859. https://www.ncbi.nlm.nih.gov/pubmed/21269266#

Guo Y, Chen Y, Tan ZR, Klaassen CD, Zhou HH. 2012. Repeated administration of berberine inhibits cytochromes P450 in humans. Eur J Clin Pharmacol. 68(2):213-217. https://www.ncbi.nlm.nih.gov/pubmed/21870106

And if you are looking for a type 2 diabetes solution:  KACHIN DIABETES SOLUTION - East-West Perspective