New findings show that berberine has antiobesity effects and that …

Berberine is Superior to Metformin
Metformin is a widely used first-line antidiabetic drug
prescribed by doctors for the treatment of
type 2 diabetes, particularly in the overweight and obese.
By Will Block

A

new review focuses on several studies showing that the plant alkaloid berberine can lower blood glucose as effectively as the drug metformin at similar doses (500 mg, taken 3 times/day), and perhaps even better in some ways.1

Berberine is found in Coptis chinensis (goldenthread), Berberis aquifolium (Oregon grape), Berberis vulgaris (barberry), Hydrastis canadensis (goldenseal), and Berberis aristata (tree turmeric). Traditionally, it has been used for more than 2500 years in both Ayurvedic and Chinese medicine, with growing interest in its effects in metabolic and cardiovascular disease in the Western world in the last decade. Berberine has a wide range of healthful uses that include cardiovascular, anti-inflammatory, and antimicrobial (it acts against bacterial diarrhea, intestinal parasites, fungal infections, Candida albicans, yeast, and possibly methicillin-resistant Staphylococcus aureus).

Berberine for Diabetes Mellitus Type 2

As we have already reported (see “Take This Dye for Diabetes” in the November 2010 issue), two recent studies (also covered in the recent review) show the effectiveness of berberine compared to metformin for type 2 diabetes.2 In the first study, 36 adults with newly diagnosed type 2 diabetes were randomly assigned to treatment with berberine or metformin (500 mg 3 times/day) in a 3-month trial. The hypoglycemic effect of berberine was similar to that of metformin. Metformin is a widely used first-line antidiabetic drug prescribed by doctors for the treatment of type 2 diabetes, particularly in the overweight and obese, and those with normal kidney function. Significant changes were observed in the berberine group:

  • Hemoglobin A1c (glycosylated hemogblobin, an AGE*) decreased from 9.5% to 7.5% (about a 21% reduction)
  • Fasting blood glucose (FBG) decreased from 190.8 to 124.2 mg/dl
  • Postprandial blood glucose (PBG) decreased from 356.4 to 199.8 mg/dl
  • Plasma triglycerides from 100.5 to 79.2 mg/dl


* Advanced glycation end-products (AGEs) result from a chain of chemical reactions after an initial glycation reaction. The intermediate products are known, variously, as Amadori, Schiff base, and Maillard products (named after the researchers who first described them). Side products generated in intermediate steps may be oxidizing agents (such as hydrogen peroxide), or not (such as beta amyloid proteins). “Glycosylation” is sometimes used for “glycation” in the literature, usually as “non-enzymatic glycosylation.”


The researchers were surprised that the glucose-lowering effects of berberine were found to be very similar to that of metformin. In fact, it was superior in several ways.

In the second study, 48 adults with poorly controlled type 2 diabetes were supplemented with berberine in a 3-month trial:

  • Hemoglobin A1c decreased from 8.1% to 7.3% (about a 10% reduction)
  • In the first 7 days of treatment, berberine led to a reduction in FBG from 172.8 to 140.4 mg/dl and PBG from 266.4 to 210.6 mg/dl
  • During the second week, FBG and PBG declined further, reaching a low point that was 38 mg/dl below the baseline of 135 mg/dl for FBG and 60 mg/dl below the baseline of 189 mg/dl for PBG, and remained at these levels thereafter
  • Fasting plasma insulin was reduced by 28.1%
  • The homeostasis model assessment of insulin resistance index was reduced by 44.7%
  • Total cholesterol and low-density lipoprotein cholesterol were decreased significantly


The researchers were surprised that
the glucose-lowering effects of
berberine were found to be very
similar to that of metformin. It was
superior in several ways.


Of further interest, both fasting and postprandial proinsulin C-peptides increased significantly in patients when berberine was used together with insulin. These peptides facilitate the efficient assembly, folding, and processing of insulin in the endoplasmic reticulum, and their increase suggests that long-term berberine treatment may improve insulin secretion of the patients. During the trial, 20 patients experienced transient gastrointestinal adverse effects. Functional liver or kidney damages were not observed in any patients.

Berberine Decreases Cholesterol and Triglyceride

Another recent study, covered in the review, showed that berberine benefits type 2 diabetes.3 In this study, 116 patients with type 2 diabetes and dyslipidemia were randomly allocated to receive berberine (1 g daily) or placebo for 3 months. In the berberine group,

  • Hemoglobin A1c decreased from 7.5% to 6.6% (about a 12% reduction)
  • FBG decreased from 7.0 to 5.6 mm/L (126 to 100.8 mg/dl)
  • PBG decreased from 12.0 to 8.9 mm/L (216 to 160.2 mg/dl)
  • Triglycerides decreased from 2.51 to 1.61 mm/L (220 to 141 mg/dl)
  • Total cholesterol decreased from 5.31 to 4.35 mm/L (205 to 168 mg/dl)
  • LDL cholesterol decreased from 3.23 to 2.55 mm/L (124.9 to 98.6 mg/dl)

The glucose disposal rate was increased after berberine treatment, although no significant change was found between berberine and placebo groups. Mild to moderate constipation was observed in 5 participants in the berberine group. Transient gastrointestinal adverse effects with berberine were fairly common and may be related to its antimicrobial action. Berberine may be particularly useful in cases involving both type 2 diabetes, dyslipidemia, and possibly infection.

Berberine Offers Antiobesity Effects

Obesity is a major cause of metabolic syndrome and is due to an increase in the number and hypertrophy (volume increase) of adipocytes. But if the differentiation and proliferation of adipocytes is inhibited, then metabolic syndrome may be treated and prevented. A new study investigated the effects of 50 commonly used Kampo (the Japanese study and adaptation of Traditional Chinese medicine) preparations on the differentiation of 3T3-L1 preadipocytes to search for a drug with an antiobesity effect.4


Long-term berberine treatment
may improve insulin secretion.


Kampo medicines were screened, and the strongest differentiation-inhibitory effect was noted with Orengedokuto (OGT). To explore the active ingredients in OGT, the effects of four crude components of OGT were investigated, and it was found that the differentiation-inhibitory effects of OGT was accounted for by Coptidis rhizome and Phellodendri cortex, both of which contain berberine, which upon examination also showed a differentiation inhibitory effect.

In fact, berberine was found to inhibit the mRNA and protein expression of PPARγ (see “Cinnamon Swoops Down to Retard Diabetes” in the May 2010 issue) as well as the CCAAT/enhancer binding protein α (C/EBPα).* Moreover, berberine inhibited lipid accumulation in adipocytes. These findings suggest that an antiobesity effect could be a new indication for OGT and that its active ingredient is berberine, with a mechanism involving the inhibition of PPARγ and C/EBPα expression. This means that berberine could reduce the size of your fat cells and cut down on their number as well.


* C/EBPα is a member of a family of transcription factors, composed of six members. They promote the expression of certain genes through interaction with their promoter. C/EBPα is required for both adipogenesis (fat cell creation) and normal adipocyte (fat cell) function.


Berberine for Memory Too

We should not forget that berberine has also recently been found to enhance memory function in rats. In research done in India, berberine is reported to inhibit cholinesterase (ChE) activity and increase glucagon-like peptide (GLP-1) release.5 ChE is the enzyme that breaks down the memory molecule acetylcholine, a neurotransmitter that is crucial for the important memory activities of focus and concentration. GLP-1, as recent evidence suggests, plays an imperative role in diabetes, along with cognitive dysfunction, learning, and neuroprotection.


Berberine could reduce
the size of your fat cells
and cut down on
their number as well.


Based on the unavailability of prior research for the influence of berberine on streptozotocin (STZ)-induced memory impairment, the researchers designed their study to investigate if there could be any benefits. The researchers used the Morris water maze model as a measure of memory. In the Morris test, rats are trained to find a submerged platform in a tank of water. Around the sides of the tank are symbols, and the goal entails (pun intended) that the rats remember the location of the platform, to save themselves from exerting energy to stay afloat by refinding the platform and emerging from the water.

Also, lipid peroxidation and glutathione levels (as parameters of oxidative stress) and ChE activity (as a marker of cholinergic function) were assessed in the cerebral cortex and hippocampus. The greater the activity of ChE, the less effective is the cholinergic system, as ChE breaks down acetylcholine. Thirty days after diabetes induction with STZ, rats showed a severe deficit in learning and memory associated with increased lipid peroxidation, decreased reduced glutathione, and elevated ChE activity.

In contrast, diabetic rats treated chronically with orally administered berberine at doses of 25, 50, or 100 mg/kg, but especially the 50 and 100 mg dose, twice daily for 30 days, and then subjected to the Morris water maze test, were all found to have improved cognitive performance, along with lowered hyperglycemia, oxidative stress, and ChE activity. Also administered was vitamin C (100 mg/kg) or metformin (500 mg/kg) or vehicle (1 ml/kg) as placebo, twice daily. Both vitamin C and metformin were comparable in effects to berberine.

Diabetes Implicated in Cognitive Dysfunction

Prior studies have identified that when memory impairment is induced in rats, changes consequently occur in the central nervous system that are secondary to hyperglycemia, including impaired oxidative stress, cholinergic dysfunction, and changes in GLP-1. Indeed, in a model of treatment that uses antihyperglycemics, antioxidants, and cholinergic agonists, beneficial effects have been produced.

In the second leg of the Indian study, 30 days after confirmation of diabetes, berberine was given at the same dose range given during training trials in the Morris water maze that lasted 5 days (days 31–35). Alternatively, vitamin C at 100 mg/kg or metformin at 500 mg/kg, or donepezil (an AChEI that is similar to the plant nutrient galantamine) at 3 mg/kg or placebo at 1 ml/kg were also used. The result for berberine ingestion was improved learning and memory, with lowered hyperglycemia, oxidative stress, and ChE activity. Chronic treatment (30 days) with vitamin C, or metformin, or donepezil during training trials also improved diabetes-induced memory impairment and reduced oxidative stress and/or cholinesterase activity. In a prior study with berberine, its effects were found to be very similar to metformin, and this was upheld in the current study.

Significant Beneficial Effect on Diabetes

Berberine has been shown to have a significant beneficial effect on type 2 diabetes, and may be as effective, or more so, than metformin. Berberine acts through several mechanisms, including mimicking insulin; improving insulin action by activating AMPK; reducing insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression; inducing glycolysis; and on incretins by promoting GLP-1 secretion and modulating its release, and by inhibiting DPP-4 (see sidebar).

Berberine’s Probable and Possible
Mechanisms of Action

The studies encompassed by the review that is the central topic of the article “Berberine is Superior to Metformin” (of which this sidebar is a part) have found that berberine is beneficial for glucose metabolism and insulin activity through a number of distinct mechanisms:

Mimicking insulin action1

Berberine mimics insulin action by increasing glucose uptake ability by 3T3-L1 adipocytes (fat cells) and L6 myocytes (muscle cells) in an insulin-independent manner. Furthering this mimicking process, berberine inhibits activity of protein tyrosine phosphatase 1B (an important negative regulator of insulin and leptin signaling in vivo). It also increases phosphorylation in 3T3-L1 adipocytes. In diabetic mice, berberine lowers hyperglycemia and improves impaired glucose tolerance, but does not increase insulin release and synthesis. The results suggest that berberine represents a different class of anti-hyperglycemic agents.

Improving insulin action by activating AMPK2-5

AMPK (AMP-activated protein kinase) is an enzyme that plays a role in cellular energy homeostasis. Principally, the effect of AMPK activation is stimulation of hepatic fatty acid oxidation and ketogenesis,* inhibition of cholesterol synthesis, lipogenesis (the formation of fat), and triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, stimulation of skeletal muscle fatty acid oxidation and muscle glucose uptake, and modulation of insulin secretion by pancreatic beta-cells.6

AMPK is expressed in a number of tissues, including the liver, brain, and skeletal muscle, where it acts as a “metabolic master switch” that regulates several intracellular systems, including the cellular uptake of glucose, the beta-oxidation of fatty acids, and the biogenesis of glucose transporter 4 (GLUT4).7


* Ketogenesis is the process by which ketone bodies are produced as a result of fatty acid breakdown. Glucose is usually used by cells for energy. But, when there’s no insulin to help it transport out of the blood and into the cells, the body has an “energy crisis” and starts to break down body fat into ketones as an alternative fuel source. This is called ketosis.


Reducing insulin resistance through protein kinase C (PKC)-dependent up-regulation of insulin receptor (InsR) expression8,9

Berberine induced InsR gene expression through a PKC-dependent activation of its promoter. Inhibition of PKC abolished berberine-caused InsR promoter activation and InsR mRNA transcription. In animal models, treatment of type 2 diabetes mellitus rats with berberine lowered fasting blood glucose and fasting serum insulin, increased insulin sensitivity, and elevated InsR mRNA as well as PKC activity in the liver.

Inducing glycolysis10

Berberine has recently been reported to activate AMPK and increase its phosphorylation, which was associated with persistent elevation in AMP/ATP ratio and reduction in oxygen consumption. An increase in glycolysis was observed with a rise in lactic acid production. The results of this suggest that berberine enhances glucose metabolism by stimulation of glycolysis, which is related to inhibition of glucose oxidation in mitochondria. Berberine-induced AMPK activation is likely a consequence of mitochondria inhibition that increases the AMP/ATP ratio.

Promoting GLP-1 secretion and modulating its release11,12

Glucagon-like peptide (GLP)-1 is a potent glucose-dependent insulinotropic gut hormone released from intestinal L cells. GLP-1 is one of the incretins, a group of gastrointestinal hormones that cause a short-term increase in the amount of insulin released from the beta cells of the Islets of Langerhans (which also produce insulin in the pancreas) after eating (see above image). Several approved drugs act on incretins, but there are many side effects, a significant number of which are gastrointestinal. This is ironic because berberine has been used to treat gastrointestinal problems.

Berberine increased GLP-1 secretion in streptozotocin-induced diabetic rats. In vivo, 5-week treatment of berberine enhanced GLP-1 secretion induced by glucose load and promoted proglucagon mRNA expression as well as L cell proliferation in intestine. In vitro, berberine concentration-dependently stimulated GLP-1 release in NCI-H716 cells. Berberine also promoted both prohormone convertase 3 and proglucagon mRNA expression. This demonstrates that berberine showed its modulation on GLP-1 via promoting GLP-1 secretion and GLP-1 biosynthesis.

Inhibition of DPP-413

Berberine was investigated as an inhibitor of human dipeptidyl peptidase IV (DPP IV) in an attempt to explain its anti-hyperglycemic activities. The investigation included simulated docking experiments to fit berberine within the binding pocket of DPP IV. Berberine was found to readily fit within the binding pocket of DPP IV in a low energy orientation characterized with optimal electrostatic attractive interactions bridging the isoquinolinium positively charged nitrogen atom (berberine) and the negatively charged acidic residue of glutamic acid-205 (GLU205) of DPP IV.

Experimentally, berberine was found to inhibit human recombinant DPP IV in vitro with IC(50) = 13.3 microM. These findings suggest that DPP IV inhibition is, at least, one of the mechanisms that explain the anti-hyperglycemic activity of berberine. The fact that berberine was recently reported to potently inhibit the pro-diabetic target human protein tyrosine phosphatase 1B (h-PTP 1B) discloses a novel dual natural h-PTP 1B/DPP IV inhibitor.

Inhibition of hepatic gluconeogenesis14

Berberine is a compound originally identified in a Chinese herbal medicine Huanglian (Coptis chinensis French). It improves glucose metabolism in type 2 diabetic patients. The mechanisms involve in activation of adenosine monophosphate activated protein kinase (AMPK) and improvement of insulin sensitivity. However, it is not clear if berberine reduces blood glucose through other mechanism. In this study, we addressed this issue by examining liver response to berberine in diabetic rats, in which hyperglycemia was induced in Sprague-Dawley rats by high fat diet. We observed that berberine decreased fasting glucose significantly. Gluconeogenic genes, Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase), were decreased in liver by berberine. Hepatic steatosis was also reduced by berberine and expression of fatty acid synthase (FAS) was inhibited in liver.

Activities of transcription factors including Forkhead transcription factor O1 (FoxO1), sterol regulatory element-binding protein 1c (SREBP1) and carbohydrate responsive element-binding protein (ChREBP) were decreased. Insulin signaling pathway was not altered in the liver. In cultured hepatocytes, berberine inhibited oxygen consumption and reduced intracellular adenosine triphosphate (ATP) level.

The data suggest that berberine improves fasting blood glucose by direct inhibition of gluconeogenesis in liver. This activity is not dependent on insulin action. The gluconeogenic inhibition is likely a result of mitochondria inhibition by BBR. The observation supports that berberine improves glucose metabolism through an insulin-independent pathway.

References

  1. Chen C, Zhang Y, Huang C. Berberine inhibits PTP1B activity and mimics insulin action. Biochem Biophys Res Commun Jul 2 2010;397(3):543-7.
  2. Turner N, Li JY, Gosby A, et al. Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action. Diabetes May 2008;57(5):1414-8.
  3. Lee YS, Kim WS, Kim KH, et al. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes Aug 2006;55(8):2256-64.
  4. Ma X, Egawa T, Kimura H, et al. Berberine-induced activation of 5’-adenosine monophosphate-activated protein kinase and glucose transport in rat skeletal muscles. Metabolism 2010 Nov;59(11):1619-27.
  5. Hwang JT, Kwon DY, Yoon SH. AMP-activated protein kinase: a potential target for the diseases prevention by natural occurring polyphenols. N Biotechnol Oct 1 2009;26(1-2):17-22.
  6. Winder WW, Hardie DG. AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol Jul 1999;277(1 Pt 1):E1-10.
  7. Viollet B, Mounier R, Leclerc J, Yazigi A, Foretz M, Andreelli F. Targeting AMP-activated protein kinase as a novel therapeutic approach for the treatment of metabolic disorders. Diabetes Metab Dec 2007;33(6):395-402.
  8. Zhang H, Wei J, Xue R, et al. Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism Feb 2009;59(2):285-92.
  9. Kong WJ, Zhang H, Song DQ, et al. Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression. Metabolism Jan 2009;58(1):109-19.
  10. Yin J, Gao Z, Liu D, Liu Z, Ye J. Berberine improves glucose metabolism through induction of glycolysis. Am J Physiol Endocrinol Metab Jan 2008;294(1):E148-56.
  11. Lu SS, Yu YL, Zhu HJ, et al. Berberine promotes glucagon-like peptide-1(7-36) amide secretion in streptozotocin-induced diabetic rats. J Endocrinol Feb 2009;200(2):159-65.
  12. Yu Y, Liu L, Wang X, Liu X, Xie L, Wang G. Modulation of glucagon-like peptide-1 release by berberine: in vivo and in vitro studies. Biochem Pharmacol Apr 1 2009;79(7):1000-6.
  13. Al-masri IM, Mohammad MK, Tahaa MO. Inhibition of dipeptidyl peptidase IV (DPP IV) is one of the mechanisms explaining the hypoglycemic effect of berberine. J Enzyme Inhib Med Chem Oct 2009;24(5):1061-6
  14. Xia X, Yan J, Shen Y, Tang K, Yin J, Zhang Y, Yang D, Liang H, Ye J, Weng J. Berberine improves glucose metabolism in diabetic rats by inhibition of hepatic gluconeogenesis. PLoS One 2011 Feb 3;6(2):e16556.


The result for berberine was
improved learning and memory,
with lowered hyperglycemia,
oxidative stress, and ChE activity.


Plus, berberine is likely to have an antiobesity effect, and to operate as a memory enhancer. Thus, you are less likely to forget the connection that can help cut down on your weight, reduce the likelihood of metabolic syndrome, and possibly help prevent type 2 diabetes, or allow you to live more easily with it, with fewer consequences and better health. Not bad!

References

  1. Steriti R. Berberine for diabetes mellitus type 2. Natural Medicine Journal 2010 October;2(10):5-6.
  2. Yin J, Xing H, Ye J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism May 2008;57(5):712-7.
  3. Zhang Y, Li X, Zou D, et al. Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J Clin Endocrinol Metab Jul 2008;93(7):2559-65.
  4. Ikarashi N, Tajima M, Suzuki K, Toda T, Ito K, Ochiai W, Sugiyama K. Inhibition of Preadipocyte Differentiation and Lipid Accumulation by Orengedokuto Treatment of 3T3-L1 Cultures. Phytother Res 2011 May 9. doi: 10.1002/ptr.3493. [Epub ahead of print]
  5. Bhutada P, Mundhada Y, Bansod K, Tawari S, Patil S, Dixit P, Umathe S, Mundhada D. Protection of cholinergic and antioxidant system contributes to the effect of berberine ameliorating memory dysfunction in rat model of streptozotocin-induced diabetes. Behav Brain Res 2011 Jun 20;220(1):30-41.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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