Most patients understand the link between insulin utilization and diabetes, but few patients recognize the risks and symptoms of insulin resistance. Insulin resistance leads to high blood sugar, which is a contributing factor to developing type II diabetes. Before it develops into diabetes, insulin resistance is correlated with a slew of symptoms like brain fog, confusion, dysexecutive syndrome, sleepiness, excessive hunger, thirst, and weight gain. Once insulin resistance is established, it can be hard to revert because patients are often beset by a variety of lifestyle habits that contribute to insulin resistance, such as poor diet or a lack of exercise. Given that the primary treatment for insulin resistance is diet modification and exercise, treatment compliance is often subpar and patients need a better solution.
Unfortunately, even if patients are diligent with altering their lifestyle to treat insulin resistance, reversing the resistance can be uncomfortable or even debilitating, requiring days or weeks of feeling out-of-sorts while their cells acclimatize to normal insulin levels. A sparse few pharmacological therapies for insulin resistance exist, but they suffer from weak long-term efficacy and difficult side effects like vitamin B deficiency. However, patients and clinicians continue to seek superior treatments. With a recent flurry of promising investigations on a chemical called berberine, they may not have to look any further.
The Multifunctional Berberine
Clinicians and patients from Western countries are unlikely to be familiar with berberine and its applications 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 pharmaceutical drugs like codeine. Traditional Chinese medicine has used berberine for thousands of years for its antimicrobial and anti-inflammatory effects. In the last decade, Western medicine has increasingly recognized the potential of berberine and researchers have now identified the compound as a unique therapy for insulin resistance owing to its insulin-sensitizing effects.
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.
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