Natural Diabetes Treatments - Berberine

The purpose of using drugs to control blood sugar levels is rooted in the extraordinarily effective use of insulin to treat type I diabetes patients who otherwise would die in diabetic keto-acidosis. Since the discover of insulin, a multitude of pharmaceutical drugs have come on the market, all of which aim to lower blood sugar levels and prolong the life of diabetic patients. In addition, some of the drugs also have an effect on other complications of diabetes, such as vascular disease (arteriosclerosis), heart disease, dementia and chronic infections.

What are we really trying to do when we treat diabetes?

  1. Lower the blood sugar levels – fasting, average and post-prandial (the after-meal spike), so that mean A1C levels are below 6.5 – meaning average glucose levels in the blood are within an adequate reference range, but not too high. “The higher the level of glucose in the blood, the more glycated hemoglobin is formed. Once the glucose binds to the hemoglobin, it remains there for the life of the red blood cell – normally about 120 days. The predominant form of glycated hemoglobin is referred to as A1c. A1c is produced on a daily basis and slowly cleared from the blood as older RBCs die and younger RBCs (with non-glycated hemoglobin) take their place… For monitoring purposes, an A1c of less than 7% indicates good glucose control and a lower risk of diabetic complications for the majority of people with diabetes.”[1] The American College of Endocrinology recommends an A1C of less than 6.5% (or as close to normal as is safe and achievable).[2] There is some disagreement about what A1C levels are optimal, but all agree that lower is better than higher.
  2. Decrease obesity – by any means necessary – to decrease the inflammatory state which is an inherent characteristic of fatty tissues.
  3. Improve diet and lifestyle – all agree that getting rid of fast foods and exercising more is important.
  4. Treat unhealthy mental states – mainly depression and anxiety – to improve overall well-being.
  5. Increase life span and decrease the chances of premature death due to disease.

The biggest disagreements between the “standard-of-care” community and the “alternative medicine” community lie in the means by which the above goals are accomplished.

Metabolism of glucose and production of energy for metabolic functions within our cells is a complex process, made more complex by the fact that we are multi-cellular organisms, each of the cell types serving specific functions different from other cell types. However, the overall common denominator is the need for energy to run the engine, and the need for storage of energy to keep the battery functional.

Conventional drugs for diabetes aim to accomplish specific metabolic tasks in order to decrease average glucose levels.

  1. Restore sensitivity to leptin.
  2. Suppress the secretion of glucagon (which in turn increases insulin secretion). GLP-1 receptor agonists work here – they regulate secretion of both glucagon and insulin, gastric emptying, and urge to eat (caloric intake)
  3. Slow gastric emptying, to increase the feeling of satiety (to feel as though you have eaten something). GLP-1 receptor agonists work here.
  4. Decrease the secretion of ghrelin by the stomach (produced in response to hunger). GLP-1 receptor agonists work here as well.
  5. Decrease the “reward” motivation to eat. GLP-1 receptor agonists work here as well. GLP-1 levels are increased by ingestion of green plant membranes on a regular basis.[3], [4]
  6. Break down incretins faster (including ghrelin) to reduce the degree of hunger we experience, thus reducing the need to eat. DPP-4 inhibitors (gliptins) work here.
  7. Inhibit intestinal enzymes that break down carbohydrate for easier absorption – thus reducing the amount of carbohydrate available to be absorbed as calories. Alpha glucosidase inhibitors work here.
  8. Improve function of lining of blood vessels (endothelial cells) thus reducing the chance of developing vascular disease and the risk of extremity amputation and/or heart attacks and/or strokes.
  9. Improve PPAR gamma function in order to stimulate adiponectin and increase insulin sensitivity – thus allowing the body to make do with less insulin. Thiazolidinediones work here. Other members of this superfamily of PPAR agonists include retinoic acid, estrogen, thyroid, vitamin D, and glucocorticoid receptors, and several other proteins involved in xenobiotic (foreign compound) metabolism.[5]
  10. Increase renal excretion of glucose. Under normal circumstances, our bodies utilize all the glucose we absorb, converting the excess into fat – to provide a source of calories for when food becomes scarce. SGLT2 inhibitors (the gliflozin family of drugs operates here.
  11. Increase the availability of insulin, the hormone which our bodies require in order to transport glucose into our cells where it is used to produce energy for cellular function.
  12. Decrease systemic inflammation to decrease cortisol levels, well known to be associated with increased blood sugar levels. None of the currently available diabetes drugs specifically targets inflammation. Traditional medicines often contain anti-inflammatory components.[6]

Let us look at some of the “traditional” treatments used to control diabetes over the millennia. Our aim will be to determine whether any of the methods are effective in controlling blood sugar, and whether they are safe to use on an ongoing basis.

First, let us examine some of the herbs used traditionally, and what these herbs do metabolically to help in glucose metabolism.

If we can increase levels of adiponectin, that will enable us to improve several related conditions – type 2 diabetes, arteriosclerosis, hypertension and adiposity. Do we have to use drugs to increase adiponectin levels?

undefinedBarberry - berberine

Barberry is an invasive shrub which has taken over much of the forests of the Northeastern United States. It was well known for its effect on diabetes and obesity, even before we knew the words adiponectin. It is cultivated in arid parts of the world – the Middle East (9200 tons of the dried fruit are collected annually in one part of Iran) –

Barberry’s active ingredient is berberine which activates a chemical messenger called AMPK – a protein kinase which acts as a sensor of cellular energy status.[7]

Berberine also promotes the assemblage ofadiponectin molecules into a large molecule called a “multimer” which is very metabolically active, promoting insulin sensitivity in peripheral tissues. Adiponectin is a protein hormone produced by adipocytes (fat cells) that regulates the metabolism of lipids and glucose. It also has anti-inflammatory effects on the cells lining the walls of blood vessels.[8]

It appears that adiponectin in a trimer form (LMW), hexamer form (MMW) have different functions from the multimer HMW) in adipocytes. The HMW adiponectin is more metabolically active and closely associated with peripheral insulin sensitivity. [9]

Adiponectin functions a little like an army, with different assemblies covering different aspects of our metabolism. The multimer covers insulin sensitivity. Other smaller structures cover liver and cellular insulin sensitivity.

Berberine and Metformin (Glucophage®) both are PPAR gamma agonists; both block the activity of mitochondrial respiratory chain complex I.[10] A cancer cell line with a significant complex I defect produces large amounts of reactive oxygen species, potentially resulting in mitochondrial DNA damage, and subsequent nuclear DNA damage eventually resulting in mutations leading to cancer.[11] If berberine can stop the oxidation of glucose within cells, it will decrease the production of molecules related to oxidative stress, and thus indirectly be protective against development of cancer.

Berberine appears to have a protective effect on the liver, at least on rats with diet-induced fatty liver. It also induced autophagy (self-destruction, or death-by-suicide) of liver cancer cells.[12]

Berberine increases insulin sensitivity by stimulating the metabolism of glucose (glycolysis), resulting in lower fasting insulin levels after as little as five weeks of treatment.[13]

Berberine decreases (inhibits) oxygen consumption at the cellular level, increases the release of lactic acid without reducing the cellular levels of ATP – presumably by increasing anaerobic metabolism.13 Since berberine also activates AMPK and promotes the assemblage of adiponectin into the larger conglomerate molecule, this explains the increased muscle uptake of glucose, the lower blood sugars, and the overall beneficial effect on glucose metabolism and insulin sensitivity. Berberine also has a protective effect on the kidneys, reducing kidney damage in diabetic patients.[14] There is even a muscle-protective effect noted – and this includes heart muscle.[15]

To top it all off, berberine appears to have no toxicity to cells, at least as measured by production of LDH, a common conventional measure of cell damage. There appears to be a rate limitation step in oral absorption which made it impossible for one group to measure the LD-50[16] for oral administration of berberine, at least in mice.[17] Berberine is readily available as a supplement, and has been used in Chinese medicine herbal formulations (where it is known as Coptis chinensis) for at least 1500 years, both for treatment of diarrhea and for its blood sugar modulating effects. In a 3-month trial of treatment of patients with type 2 Diabetes, berberine lowered the fasting and prandial (post-meal) blood sugar, triglycerides, fasting insulin, Hemoglobin A1C, total cholesterol and low-density lipoprotein cholesterol (LDL) significantly – at least as well as metformin. There was no liver or kidney damage in any of the patients.[18] There is a report of neurotoxicity of berberine when used in isolated nerve cell culture.[19]

Advantages of metformin: it is a prescription medication, potentially covered by insurance, and acceptable to the “standard-of-care” establishment. It lowers blood sugar, partially restores insulin sensitivity, restores leptin sensitivity, increases secretion of glucagon, reverses fatty liver disease.

Side effects of metformin: common side effects include diarrhea, lactic acidosis, nausea (sometimes vomiting), flatulence (excessive intestinal gas). Long term use leads to vitamin B12 deficiency – B12 is essential for the formation of red blood cells, for neurologic function, and to make DNA. We generally have adequate B12 stores to last at least 2-3 years, so the B12 deficient neurologic state may not be immediately related to the use of metformin (Glucophage®) to treat diabetes.

Metformin can also result in severe hypoglycemia (low blood sugar), especially if there has been strenuous exercise or lack of food intake.

Advantages of berberine: It is not a prescription medication, it is not covered by insurance, and it is only marginally acceptable to the “standard-of-care” establishment. It does all the things that metformin does without the risk of excessive lowering of blood sugar (probably because its absorption by the gastro-intestinal route is poor, thus extremely difficult to take enough to lower the blood sugar excessively.

Can berberine be combined with other “standard-of-care” medications: it appears to be safe in patients who are inadequately controlled by their conventional diabetes medicines.[20]

In summary, it appears that berberine works at least as well as metformin on multiple levels – blood sugar control, blood vessel protection, heart and skeletal muscle protection, liver protection.

[1] This is the clearest explanation I have read, downloaded 10/13/2019 from

[5] ibid

[6] Makarem, A., and N. Khalili R. Asodeh. "Efficacy of barberry aqueous extracts dental gel on control of plaque and gingivitis." Acta Medica Iranica (2007): 91-94.

[8] Ruan, Hong, and Lily Q. Dong. "Adiponectin signaling and function in insulin target tissues." Journal of molecular cell biology 8.2 (2016): 101-109.

[11] Lenaz, Giorgio, et al. "Mitochondrial Complex I: structural and functional aspects." Biochimica et Biophysica Acta (BBA)-Bioenergetics 1757.9-10 (2006): 1406-1420.

[12] Wang, Ning, et al. "Berberine induces autophagic cell death and mitochondrial apoptosis in liver cancer cells: the cellular mechanism." Journal of cellular biochemistry 111.6 (2010): 1426-1436.

[13] Yin, Jun, et al. "Berberine improves glucose metabolism through induction of glycolysis." American Journal of Physiology-Endocrinology and Metabolism 294.1 (2008): E148-E156.

[14] Cha, Ying, et al. "Protective effects of berberine on high fat-induced kidney damage by increasing serum adiponectin and promoting insulin sensitivity." International journal of clinical and experimental pathology 8.11 (2015): 14486.

[16] LD-50 is the dose at which 50% of a test group is killed by the compound administered.

[17] Kheir, Michael M., et al. "Acute toxicity of berberine and its correlation with the blood concentration in mice." Food and Chemical Toxicology 48.4 (2010): 1105-1110.

[18] Yin, Jun, Huili Xing, and Jianping Ye. "Efficacy of berberine in patients with type 2 diabetes mellitus." Metabolism 57.5 (2008): 712-717.

[20] Di Pierro, Francesco, et al. "Pilot study on the additive effects of berberine and oral type 2 diabetes agents for patients with suboptimal glycemic control." Diabetes, metabolic syndrome and obesity: targets and therapy 5 (2012): 213.