Sustained release dihydroberberine (DHB) is a dietary supplement that has therapeutic value for the prevention and treatment of a wide range of diseases associated with chronic inflammation, including pre-diabetes and diabetes, heart diseases, viral infections, chronic neuroinflammatory diseases, lung diseases, kidney diseases, liver diseases, and as adjunctive treatment in a variety of cancers. This article describes the rationale for such use, relevant research, add-on therapies, and suggested treatment protocols.

Prevalence of Diabetes

More than 46% of the U.S. adult population – about 120 million people – have pre-diabetes or diabetes,i making this category the proverbial mother of all diseases. Moreover, diabetes is often associated with hypertension, heart disease, cancer, vascular damage, and liver damage.ii Diabetic retinopathy is the leading cause of blindness.iii Moreover, diabetes increases the risk of developing neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease, the latter of which is now referred to as “type 3 diabetes.”iv

Diabetes and Inflammation

Chronic inflammation plays a key role in pre-diabetes and diabetes. The DNA of macrophages and other inflammatory cells is wrapped around spool-like histone proteins. When acute inflammation occurs, these proteins become acetylated by the enzyme histone acetyl transferase (HAT), which eliminates the positive charge of histones. This is the on-switch for acute inflammation. The negatively charged DNA then loosens from the histones, which allows for the transcription of inflammatory genes that produce inflammatory gene products and products of oxidative and nitrosative (O/N) stress.

Macrophages, in particular, become activated and generate peroxynitrite. This highly toxic peroxide can further react with carbon dioxide to produce an even more reactive product called peroxynitrite carbonate, which is a strong nitrating compound. As this inflammatory state continues for weeks to months to years, an increasing number of macrophages produce peroxynitrite in excess. This damages histone deacetylase 2 (HDAC2) — the “off switch” for acute inflammation — and allows peroxynitrite or its carbonate to continuously signal chronic inflammation.

Type 1 Diabetes

When acute inflammatory type 1 diabetes begins, T lymphocytes are stimulated and produce interleukins and chemokines that help trigger the chronic inflammatory state in macrophages described above. This state is toxic to pancreatic beta cells that produce and release insulin. The excessive peroxynitrite kills the beta cells, so insulin is not produced. Alpha cells replace the dead beta cells and begin to produce excessive glucagon that, when released, increases glucose in the blood. Without insulin’s ability to allow glucose to enter certain organs and tissues like muscle and fat, the high blood glucose becomes very toxic to tissues and blood vessels.

In type 1 diabetes, the proper amount and kinds of insulin must be given at the proper time of day. Insulin must be given to maintain healthy blood glucose levels and sustain life. Most often, treatment is a combination of short- and long-acting insulin to maintain normal blood glucose levels. But nothing is given to control the O/N stress that is toxic to mitochondria, the cellular organelle response for normal glucose and fat metabolism.

Type 2 Diabetes

Type 2 diabetes is the most common form of diabetes, accounting for about 90-95% of all diagnosed cases of diabetes. It is associated with insulin resistance, a condition where the insulin released is damaged and fails to be effective.

Theodore Banting, the co-discoverer of insulin, originally addressed the key question of what causes diabetes. In his 1920s Nobel address he said, “Insulin is not the cure for diabetes.” Since insulin helps control glucose and lipid levels in the blood and tissues, a logical inference from his idea is that glucose and fats are also not completely responsible for diabetes since they can be held in check by insulin. In addition, many children who eat considerable amounts of candy and sugary sweets do not develop diabetes. If sugars, which contain glucose, do not cause diabetes, how is it involved in the disease?

O/N Stress and Diabetes

Certainly, multiple metabolic pathways that control carbohydrate and lipid metabolism are involved in diabetes. Almost all the drugs used to treat type 2 diabetes work by controlling the metabolism of carbohydrates or lipids like cholesterol and triglycerides, or they stimulate the production or release of insulin. Some do both. While these antidiabetic drugs may be partially effective to control symptoms, they fail to cure the disease or completely prevent the damage it causes.

We and others have demonstrated that O/N stress is a key cause of diabetes. Since excessive blood glucose and insufficient insulin activity (insulin resistance) increase O/N stress, antidiabetic drugs that control glucose and insulin also reduce some, but not all, of the damage from O/N stress.

Interestingly, people with type 2 diabetes often develop profound insulin resistance that requires large dosages of insulin. We have shown that peroxynitrite can lead to nitration of one or more of the four tyrosine residues on the insulin molecule. Others have shown that peroxynitrite can also damage the insulin receptor as a result of nitration of tyrosine residues in its active site. This causes insulin to be less effective in lowering blood glucose levels.

Use of SR Niacinamide

Decades ago, Professor Robert Elliott of the University of Auckland, New Zealand, reported that 500 mg of sustained-release niacinamide (Endurance Products Company; Sherwood, Oregon, USA) taken twice daily may have clinical value in helping to delay the onset of type 1 diabetes in young school-aged children. This is attributed to DNA repair and the need for large amounts of niacinamide. The repair enzyme requires a high level of NAD-dependent, ribose-ADP dependent polymerization. Since NAD is required to make more ATP, its depletion causes cell death. If beta cells fail to produce sufficient insulin, they die and metabolism controlled by insulin is lost. Thus, to live a nearly normal lifespan, a person with type 1 diabetes must continuously replace insulin from external sources and carefully manage their diet and lifestyle. It is crucial that they ingest supplements that produce targets for peroxynitrite. This can control peroxynitrite because the reaction of the two destroys peroxynitrite, which can help control diabetic damage. Dihydroberberine produces many metabolites which destroy peroxynitrite.

Use of Metformin & Berberine

Metformin, the drug most often used in the United States to control type 2 diabetes, is thought to stimulate AMP kinase, which is the “master switch” that controls carbohydrate and lipid metabolism in the mitochondria. The sustained-release form of metformin is considered to be the most effective. However, metformin is not without safety concerns. It is toxic to a fair amount of people, it causes kidney damage to some elderly diabetic patients, and it causes digestive upset in sensitive people.v

Over the last five to six years, berberine, a natural plant supplement which has biological activity of a calcium channel inhibitor, has been used by millions of people in the United States and around the world to treat prediabetes and type 2 diabetes. Like metformin, berberine in the form of a hydrochloride salt has been shown to activate AMP kinase. Berberine HCl has been shown to effectively control blood glucose.vi There is no data to suggest that metformin can relieve O/N stress. However, berberine being a charged cation is not well absorbed in some people and therefore is not the best form of this compound ie., an uncharged form would be better absorbed.

Many people with type 2 diabetes who have difficulty controlling their blood glucose with standard antidiabetic drugs have found berberine HCl treatment to work well without noticeable side effects unless high doses are necessary.vii In addition, berberine HCl has been shown to lower cholesterol and triglyceride levels equal to or better than metformin but without the drug’s known toxicity, and it is metabolized into effective antioxidants if it can become absorbed.viii

Berberine HCl should be taken three times per day with a typical dose of 400 -500 mg, every 8 hours. Patients tend to remember doses to be taken in morning and at night, but forget to take the afternoon dose. Reducing this multiple-dosing frequency does improve patient compliance for correct dosing, which maintains more constant supplement levels.

Berberine and Gut Bacteria

In collaboration with Nabil Jabbour, we recently investigated the efficacy of berberine HCl in an FDA-approved clinical trial involving approximately 40 older adults with prediabetes or type 2 diabetes with associated eye diseases. The study participants were randomly assigned to take either berberine HCl (400 mg, every 8 hours) or a placebo for 10 weeks. The berberine HCl was 98% pure and prepared to pharmaceutical grade standards (USA).

We assessed fasting blood glucose level, hemoglobin A1C level (a measure of glucose control over a 3-month period), and other physiological parameters (e.g., blood pressure, height, weight and pulse) at baseline and regularly thereafter for several months. Diseases of the eyes were continuously followed.

The two oxygens both need a methyl group -OCH3 to be clear

Surprisingly, about 40% of the patients in the berberine HCl treatment group failed to respond well. This lack of effect may relate to individual differences in gut microflora or because thes patients were elderly with comorbidities.. The berberine HCl molecule carries a quaternary nitrogen in one of its four rings, which gives the molecule a formal charge of +1 (see Figure 1). It is well known that charged molecules do not penetrate membranes well.ix

Human (and animal) studies reveal that some, but not all, people have a gut microflora with bacteria that have nitroreductase.x This enzyme effectively converts the berberine salt into Dihydroberberine (DHB) by adding two hydrogen molecules, eliminating the double bond, and neutralizing the positive charge. Since DHB is both lipid soluble and uncharged, it penetrates through cell membranes and is absorbed from the blood much better than berberine compounds. Once absorbed, DHB reverts back into charged berberine via oxidization and is somewhat trapped via the charge. However, since we know that almost all cells have exit pumps, berberine is likely eventually pumped out of the cell by multidrug resistance (MDR) pumps. Some of the DHB is trapped inside and available to generate multiple metabolites, which occurs in the liver and in bacteria in the gut.xi

Many DHB metabolites are phenolic compounds and excellent antioxidants that can inhibit O/N stress, the main cause of various types of diabetes. Thus, supplementing with DHB eliminates the need to rely on gut bacteria with nitroreductase to ensure optimal absorption. In addition, lower doses of DHB are needed for efficacy, making it an effective antidiabetic therapy for more people without the side effects associated with berberine HCl.

Interestingly, in our study, we noticed berberine HCl was effective in one patient only during the first 6 months of treatment. This is likely because the composition of his gut microflora changed and no longer could convert berberine into DHB.

Further, berberine HCl has been shown to be twice as effective in African people than in Chinese people.xii This difference may be attributed to differences in dietary habits as diet is recognized as the most important factor for modulating the composition and diversity of the gut microbiome, including gut bacteria that produce nitroreductase.

Therapeutic Potential of SR Dihydroberberine

Sustained-release DHB has an amazing potential to treat all of the chronic comorbidities even the comorbitities associated with COVID 19 viral infections including diabetes and hypertension, vascular damage, heart diseases, chronic kidney disease, eye diseases, amputations, and erectile dysfunction, among others. In addition, more than 856 scientific studies regarding the adjunctive use of berberine salts in the treatment of cancers have been published to date. Since DHB does not have to react with bacteria in the intestines to be absorbed, it is a better compound to use. We have studied the effects of sustained-release DHB in an animal model of type 1 diabetes, showing O/N stress is also a major cause of this disease in rats.xiii

Therapeutic Potential of Add-On Therapies

Other supplements, which can be obtained from Endurance Products Company (Sherwood, Oregon), that offer important high quality with solid therapeutic continuous value to help control excessive peroxynitrite levels and reduce O/N stress include vitamin C, preferably in a sustained-release form, mixed tocotrienols, and omega-3 fatty acids from krill oil or flaxseed oil. Coenzyme Q10 with its role in the electron transport chain and energy metabolism makes it an especially important supplement for healthy mitochondria.

Cannabidiol (CBD) from hemp oil, preferably in a sustained-release crystalline form to provide uniform dosing, is an important option to help reduce O/N stress. This polyphenol is an excellent target for peroxynitrite. CBD is helpful for all types of diabetes from early to late stages to protect insulin (i.e., lower insulin resistance). Endurance Products Company is experimenting with a sustained-release CBD product that provides 60 mg of crystalline CBD per tablet. This compound is very effective in controlling pain caused by excessive peroxynitrite levels. Therefore, it can help relieve pain associated with damage to joints like knees, hips, ankles, and wrists when in a pure crystalline form packaged in a sustained-release form.

Combined, these therapies not only help reduce O/N stress, but also help control carbohydrate and lipid metabolism. The result is a more complete and effective treatment regime for various forms of diabetes and prediabetes that is safe and less toxic than drugs or supplements presently used. Moreover, the use of highly bioavailable bioactive ingredients in sustained-release tablet delivery helps overcome the challenge of short plasma half-lives and maintains more constant blood and tissue levels for optimal effectiveness.

A growing body of research indicates that both proper control of metabolism (both fats and carbohydrates) and O/N stress are needed to live a normal life. Excellent control of both comprise the most complete method to treat diabetes of any type while helping to maintain the mitochondrial function critical for normal glucose and fat metabolism.

Novel SR Dihydroberberine Tablet

By working with Endurance Products Company, we have been able to develop a novel sustained-release DHB supplement that requires only twice daily doses. This allows for better absorption and continuous maintenance of the blood level of berberine over longer periods of time.

The tablet is made by combining DHB with the company’s proprietary vegetable wax tablet matrix. Berberine is extracted from plants of the Berberis genus and converted to DHB using sodium borohydride or palladium-catalyzed hydrogenation in solution. (DHB can also be extracted from plants that produce it.) The molecule is purified via extraction and crystallization, resulting in pharmaceutical grade 98% pure crystals. The crystals are then compounded into the tablet matrix, which comprises rice bran and/or carnauba wax, isomalt, stearic acid, magnesium stearate, and silica. All ingredients, except silica, are sourced from plants.

The yellow powder is then compressed using an automated tablet press. Each tablet contains 150 mg of DHB. The usual oral dose for patients with diabetes is two tablets, every 12 hours, for a daily intake of 600 mg of sustained-release DHB. We found this twice daily regime offered better dosing compliance and was easier for patients to remember than immediate-release products. In addition, this non-charged supplement in sustained release form behaves more consistently than standard berberine HCl.

Other Chronic Inflammatory Diseases

Diabetes provides an excellent example of how to control other chronic inflammatory diseases and their associated O/N stress with sustained release, non-toxic polyphenolic compounds and other substances that can act as targets of nitration and oxidation.

O/N Stress and Influenzas

While various types of influenza start with acute inflammation, they can evolve into chronic inflammatory diseases. The most startling example is the 1918 “Spanish flu” — the original H1N1 strain of respiratory influenza — that killed about five percent of the world’s population. It was transmitted from human to human in respiratory fluids. Usually, an infected person would sneeze and release tiny virus-laden droplets into the air. Once inhaled by people nearby, the virus would bind to receptors on lung cells, begin to infect, replicate and eventually pass into more people. It is a single-stranded positive RNA envelope virus, a type of virus that exists in a variety of forms, is genetically diverse, and recombines over time to create new viruses. At least two major forms exist: A and B. Presently, the A form predominates, but the B form has occurred more recently.

Interestingly, more people with weak immune systems survived the Spanish flu than those with strong immune systems. This oddity may be attributed to the fact that a strong immune system generates excessive peroxynitrite and other cytokine inflammatory mediators and tremendous O/N stress, which results in extreme edema. In effect, healthy people were drowning in their own lung fluid. Cartoonist and Pogo creator Walt Kelly said it best, “We have met the enemy, and he is us.”

Many of these single-stranded positive RNA viruses infect humans such as the cold virus, SARS coronavirus (2002), MERS-CoV coronavirus (2012), Marburg virus, Dengue virus, Rotavirus, HIV virus, and most recently, the SARS-CoV2 coronavirus responsible for the COVID-19 pandemic.

When vaccines are used against these viruses, their success is limited because of the constant genetic recombinations of the viruses. Yet, these viruses can often be inhibited during the early stage of infection if treatment with anti-inflammatory steroids occurs during the acute stage of inflammation.

Combining steroidal anti-inflammatory drugs with multiple antioxidant substances offers more therapeutic value because the combination inhibits the inflammatory system necessary for these viruses to replicate. My patented combination of antioxidants and steroids has been shown to be an effective cure for feline immunodeficiency virus (FIV) and feline leukemia virus and greatly inhibit HIV in humans.

The H1NI virus and its genetic variations are also susceptible to similar supplement and anti-inflammatory drug combinations. These retroviruses are dependent on the transcription factor nf-kappa B, which is greatly inhibited by steroidal anti-inflammatory drugs such as methylprednisolone acetate (Depo-Medrol®), dexamethasone, prednisone, and prednisolone.

Tetrandrine, a bisbenzyisoquinoline alkaloid, has anti-inflammatory actions that inhibit the infection of Ebola virus. A small dose of this calcium channel-blocking compound would be protective particularly with the use of steroids and antioxidants as proposed above. Tetrandrine can help prevent DHB, CBD and other supplements from being pumped out of cells to help maintain correct intracellular concentrations. This helps prevent drug exit and produces primary drug or primary supplement potentiation.

Sustained-release vitamin C, N-acetyl cysteine and other sustained-release antioxidants are particularly effective. Phenolic supplements such as sustained-release DHB, which metabolize to mono-, di- and polyphenols, and sustained-release CBD are also beneficial because they act as targets and neutralize the peroxynitrite radical, the main controller of chronic inflammatory diseases. By targeting the underlying chronic inflammation caused by these deadly lung-acting viruses, these therapies provide a more complete and effective treatment regime. See Table 1 for a suggested prophylactic regime to reduce the risk for or progression of infection by one of these viruses.

Presently, a group in Germany is developing adjuvants that could increase immunity to the SARS-CoV coronavirus. This approach, which stimulates an immune response, is likely the wrong thing to do, based on the 1918 Spanish flu experience in which people with stronger immune systems were more likely to die. I believe this approach will wind up killing people needlessly because of what happened with H1N1 infection in 1918. The people with strong immune systems died quickly, while those with weak immune systems survived. It is a cautionary tale that portends that those who do not learn from history are likely to repeat it.

Separately, the present drug combinations proposed to treat COVID-19 fail to adequately treat older people with multiple chronic diseases or comorbidities. The use of sustained-release DHB if given early in the disease state will likely help. For example, the antimalarial drug chloroquine has been approved for treatment with COVID 19 patients. Using sustained-release DHB in conjunction with this drug may help improve drug efficacy. Moreover, using sustained-release DHB with an antimalarial drug would treat comorbidities like hypertension, type 2 diabetes, heart diseases, lung diseases, and cancer. Substantial evidence exists in the literature and complete reviews are available on request.

Table 1. Suggested Prophylactic Regime for Prevention and Treatment of Influenza Caused by Single-Stranded Positive RNA Viruses
Therapy	Route	Dose (Dosage)
SR Dihydroberberine	Oral	300 mg, every 12 hours (600 mg/day)a
SR Cannabidiolb	Oral	60 mg, every 12 hours (120 mg/day)
Methylprednisolone acetatec,d	Injectable	low dose
SR Vitamin C	Oral	2 g, every 12 hours (4 g/day)
SR Inosinee	Oral	(3 g/day)
SR Niacinamide	Oral	750 mg, every 12 hours (1.5 g/day)
SR Tetrandrinef	Oral	(50-100 mg/day)
Mixed d-Tocotrienols	Oral	Once daily (50 mg/day)
100% Pure Krill Oil	Oral	(500 mg/day)
Coenzyme Q10 + PQQ	Oral	(100 mg/day + 10 mg/day)
SR indicates sustained-release; PQQ, pyrroloquinoline quinone. a Dihydroberberine could possibly be administered in a proper non-toxic solvent as an inhalant. A standard fluid could be used to dissolve DHB so various doses could be tried to ascertain which would be most helpful. Additionally, a steroid could be dissolved with DHB to slow inflammation caused by the virus. b For a period of time to protect against viruses. c Prescription only. d Budesonide and other over-the-counter steroidal inhalers are also available. e Produces sodium urate, one of the body’s most important antioxidants. f Calcium channel blocker that inhibits ATP-dependent multidrug resistance pumps from causing the early exit of important supplements from the cells such as dihydroberberine and cannabidiol.

O/N Stress and Cancer

Chronically activated macrophages and neutrophils underlie all chronic diseases. As described above, the resulting O/N stress can damage many types of cells, including the master molecule DNA. It’s a chronic inflammatory system gone astray that can lead to DNA mutation, irreparable cell damage, and ultimately cancer. This happens because chronic inflammatory diseases are caused by excessive peroxynitrite or its bicarbonate. Indeed, chronic inflammation is estimated to cause or stimulate one out of five cancers. Perhaps administering sustained-release DHB in combination with various anti-cancer drugs could provide synergistic benefits such that a lower drug dosage provides efficacy with less toxic side effects.

O/N Stress and Neurodegenerative Diseases

Diseases like Alzheimer’s and Parkinson’s diseases, multiple sclerosis, and Huntington’s chorea as well as physical brain damage are linked to chronic inflammatory damage of the brain. Not surprisingly, other chronic diseases like diabetes are very often linked to inflammatory vascular damage.

The blood-brain barrier (BBB) normally acts like a selective filter, allowing needed nutrients to enter the brain while preventing the passage of unwanted materials. Various neurodegenerative diseases, however, can damage the BBB and disrupt its integrity.xiv The resulting “leakiness” of the BBB most often happens as adults enter their later years. Yet, healthy lifestyle and dietary habits, including supplementation, can go a long way to help maintain a person’s healthy neurology. For this reason, O/N stress must be controlled throughout the life span, but especially as a person enters older age.

One option that may help prevent damage to the vascular system and the BBB is a combination of antioxidants and substances that generate nitric oxide (NO). NO is generated by two common pathways in the body. The first pathway involves L-arginine and its metabolite L-citrulline. Both provide efficient enzymatic production of NO. The second major pathway involves the nitrate/nitrite pathway, which can be viewed as a non-enzymatic pathway that only requires bacterial enzymes in saliva to convert nitrate into nitrite. Once swallowed, the salivary nitrite generates NO when exposed to stomach acid. Separately, some physicians use sodium nitrate to quickly produce NO in NO deficiency or anaerobic conditions.

To generate significant amounts of NO from L-arginine, it is helpful to use a sustained release form. For example, I use both sustained released L-arginine (3 g) and immediate-release L-arginine (1 g) in the morning and at night for a total daily intake of 8 g. This regimen effectively helps me maintain a normal blood pressure in the range of 100/80 mmHg.

Other therapies offer potential benefits to prevent damage to the vascular system and the BBB. For example, DHB, CBD, tocotrienols, and krill oil components readily penetrate the BBB and may offer therapeutic value in the treatment of chronic neuroinflammatory diseases that damage the BBB and generate excessive peroxynitrite. See Table 2 for a suggested prophylactic regime.

To paraphrase Ben Franklin, an ounce of prevention is worth much more than a pound of cure. I have spent most of my adult life studying various diseases. One thing is clear: To live a healthy life, it is paramount that we protect our vascular system from damage. It starts with a healthy lifestyle and dietary habits, including dietary supplementation.

Table 2. Suggested Prophylactic Regime for Prevention and Treatment of Neuroinflammation (Oral Administration)
Therapy	Dose (Dosage)
SR Dihydroberberine	300 mg every 12 hours (600 mg/day)
SR Cannabidiol	60 mg every 12 hours (120 mg/day)
SR Vitamin C	2 g every 12 hours (4 g/day)
SR L-arginine + IR L-arginine	3 g every 12 hours (6 g/day) + 1 g every 12 hours (2 g/day)
SR Inosine	500-1,000 mg every 12 hours (1-3 g/day)
Krill Oil (100% pure)	350 mg/day
Mixed Tocotrienol	200 mg/day
SR Niacinamide	500-750 mg every 12 hours (1.5 g/day)
SR indicates sustained-release.

Conclusion

Dietary supplements and other oral therapeutic interventions delivered in sustained-release forms provide a more complete treatment for the prevention and treatment of diabetes and other chronic inflammatory disease. Not only does this delivery form overcome pharmacokinetic limitations, it also provides a steady release of active ingredients over time so they are readily available to combat the continuous production of oxidants and nitrosants and reduce the O/N stress that characterizes chronic inflammatory diseases. Chronic diseases, including chronic inflammatory diseases, generally do not relent. For this reason, regardless of individual’s genetic predisposition to a disease, a regular regime of continuous protection would be the best option to help prevent or control chronic inflammatory diseases.