Updated on April 10, 2023
Although most individuals understand the link between insulin utilization and diabetes, few recognize the risks and symptoms of insulin resistance. Insulin resistance can lead to having a chronically high blood sugar level, which is a contributing factor to developing type II diabetes. Before it develops into diabetes, insulin resistance is correlated with symptoms like brain fog, confusion, dysexecutive syndrome, sleepiness, excessive hunger, thirst, and weight gain. Once insulin resistance is established, it can be hard to reverse because a variety of lifestyle habits contribute to it, such as poor diet and lack of exercise. Given that the primary therapy for insulin resistance is diet modification and exercise, compliance is often subpar, so a better solution is needed.
Unfortunately, even when an individual does make meaningful lifestyle changes, reversing their insulin resistance can be uncomfortable, and sometimes even debilitating, requiring days or weeks of feeling out-of-sorts while their cells acclimatize to normal insulin levels. Only a few pharmacological therapies for insulin resistance exist, but they suffer from weak long-term efficacy and difficult side effects, like vitamin B deficiency. As clinicians and their patients seek better approaches, a recent flurry of promising investigations into berberine would seem to indicate they might not have to look further.
Practitioners and their patients from Western countries are unlikely to be familiar with berberine and its ability to provide nutritional support for insulin resistance.* Berberine is an alkaloid compound produced by a handful of plants ranging from the barberry bush to the prickly poppy, and its alkaloid structure is partially shared with many mainstream pharmaceuticals. Traditional Chinese medicine has used berberine for thousands of years due to its ability to support the body’s natural inflammatory response.* In the last decade, Western medicine has increasingly recognized the potential of berberine, and researchers have now identified the compound as a viable option for addressing insulin resistance owing to its insulin-sensitizing effects.*
Unlike many folk remedies, berberine’s utility has very rarely been viewed with skepticism, so the barriers to utilizing it as a natural remedy for insulin resistance are fairly low. Berberine, which is readily bioactive, has been confirmed to benefit several 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 toward a specific purpose before it is ready. The chief challenge is finding where it is most effective, rather than finding a single case where it is effective at all. Insulin resistance could be the niche where berberine can shine brightly as a natural remedy.
Berberine provides nutritional support for insulin resistance indirectly by diminishing the intensity of cellular feedback loops that generate resistance in the first place.* These feedback loops are at the center of the cellular energy generation system. Insulin is a hormone, which means the body utilizes it to signal cells to perform a specific action. In the case of insulin, the specific action is to moderate cellular glucose uptake and the cellular breakdown of glucose-derived molecules.
Under normal conditions, insulin prompts cells to uptake glucose and process it for energy that the cells use to perform their somatic functions 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 that it regulates depending on the other cellular signals that 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 insulin’s signaling is impaired. On a cellular level, insulin resistance manifests as a downregulation in the number of insulin receptors present on external cellular surfaces. The fewer insulin receptors there are on cellular surfaces, the less physiological impact insulin molecules can have on the cell. In other words, more insulin molecules are needed to accomplish the same physiological activity in an insulin resistant individual than in an individual with normal insulin physiology.
What might cause cells to have fewer insulin receptors? 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 rich in simple sugars—their cells become accustomed to their insulin receptors being activated by insulin very frequently. In this condition, the cells uptake large volumes of glucose and subsequently convert that glucose into lipids when they have more energy than they need to perform their functions in the body. These lipids are secreted from the cell and travel 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 only utilizes a finite amount of lipids at a time, so the excess lipids continue to circulate, awaiting their turn.
When the concentration of these circulating lipids becomes too high, cellular toxicity can result. To avoid toxicity, physiological feedback mechanisms compensate for the rising lipid levels by prompting cells to reduce their concentration of insulin receptors. Fewer insulin receptors means there are fewer glucose molecules metabolized. Decreased 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.
But 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 can be left with so few insulin receptors that they struggle to get the glucose they need to survive, causing the individual to experience lethargy and other symptoms. The patient has thus become insulin resistant.
Breaking the insulin resistance feedback loop described above requires altering the way cells uptake glucose and turn it into energy, and berberine does exactly that.* Berberine has been shown to mitigate 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 that coded for insulin in type II diabetes subjects. The subjects were weaned off their medications over a 2-week period and split into three groups. Two groups received mainstream pharmacotherapies for insulin resistance, whereas the third group received berberine. Over a period of two months, the three cohorts took their group’s prescribed therapy once daily.
After the two months had elapsed, the participants had their blood compared to samples taken at the start of the trial. The subjects who had taken berberine experienced 25.9 percent reduced blood glucose levels compared to the start of the trial. The two mainstream therapies reduced blood glucose levels by 17.6 percent and 30.3 percent. When the researchers examined cell cultures generated from the participants’ blood samples, they found that the serum insulin levels of the berberine group decreased by 28.2 percent, thus providing a significant benefit for insulin sensitivity.* This means that berberine can act as an attractive natural remedy for providing nutritional support to insulin sensitive individuals, including individuals looking to include a natural product with conventional therapies.*
However, the above researchers didn’t stop after elucidating berberine’s benefits for insulin sensitivity. Because many Chinese people suffer from liver issues caused by viral hepatitis B and C infections, the researchers were also interested in determining if berberine would be effective in benefiting individuals with compromised liver function.* This issue is important because the current pharmacotherapies for insulin resistance tend to be harsh on patients’ livers. In this aspect of the clinical study, berberine was also shown to provide significant benefits to liver function.*
Although researchers are still working to understand how berberine exerts these impressive effects, preliminary evidence suggests it is related to berberine’s benefits exerted within the mitochondria of the cell. Because the mitochondria are responsible for producing chemical energy for the cell, inhibiting mitochondrial energy production 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 would be reduced.*As a result, existing insulin resistance is mitigated 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.*
As practitioners and their patients integrate berberine in their management plans, clinical vigilance is necessary. Although side effects of berberine are not yet comprehensively understood, anecdotal reports indicate that low blood sugar and low blood pressure are the most common issues. Patients with diabetes should be especially careful. Some patients report taking a large dose of berberine can cause cramping or diarrhea; spacing usage over the course of a day would be an effective solution to this issue. Individuals with sensitive gastrointestinal tracts should speak with their healthcare provider regarding strategies for mitigating discomfort.
For individuals wishing to utilize berberine supplementation, careful usage is essential; most clinical trials of berberine for insulin resistance tested usage 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 at higher amounts, so usage should be adjusted downward if side effects occur. This should not scare patients away however, because the available evidence does indicate that berberine can be a beneficial form of nutritional support for addressing insulin resistance with relatively low amounts and in short-term courses.* Indeed, published clinical reports indicate that berberine is very well tolerated 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 there is a high potential for drug interactions associated with berberine usage. These interactions could either increase, decrease, prolong, or shorten the effects of other substances processed by the enzyme. To put this into context, however, inhibition of the P450 enzyme is found in a plethora of mainstream therapies that patients use without facing problems. Likewise, individuals with liver issues should use lower amounts of berberine with the expectation that their reduction of blood glucose will be slightly less than in a healthy person. Individuals should discuss berberine supplementation with their doctors before trying it regardless of their liver health.
Ongoing research into berberine will likely elucidate its benefits. In the meantime, patients dealing with insulin resistance should be proactive in learning more about how to use berberine supplementation for their health and wellness.
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Zhang X, Zhao Y, Zhang M, et al. 2012. PlosOne.