Berberine Gives Diabetes the

12 Punch
There are few nutrients that have built a justified following
as fast as berberine
By Will Block

T he worldwide adult population of diabetics has more than doubled since 1980. It now

stands at 347 million (a 133% increase) according to an international team of researchers who
have just published a study in the medical journal The Lancet.1 This figure is a far larger
number than previously thought, strongly suggesting that associated costs of treating the
diabetes are about to explode. With all the economic problems of the world economy, this is a
disaster in the making. Especially in the U.S., which is now reported to have the fastest rate of
diabetes increase in men, and the third fastest in women.

A previous recent projection had put the estimated number of diabetics at 285 million
worldwide. But the new study has found that figure woefully short. By evaluating the
worldwide FPG (fasting plasma glucose) records from 2.7 million individuals 25 years of age,
the research team estimated prevalence using advanced statistical methods. Of the 347
million people with diabetes, 138 million are in China and India and another 36 million in the
United States and Russia.

Led by Professor Majid Ezzati, from the School of Public Health at Imperial College London,
and Dr. Goodarz Danaei, from the Harvard School of Public Health, the authors of the new
study attribute 70% of this increase to longer lifespans. As it turns out, the older you are, the
greater your risk is for developing diabetes. Obesity and other risk factors account for the
remaining 30%.

According to Professor Ezzati:

Diabetes is one of the biggest causes of morbidity and mortality worldwide. Our study has
shown that diabetes is becoming more common almost everywhere in the world. This is in
contrast to blood pressure and cholesterol, which have both fallen in many regions. Diabetes
is much harder to prevent and treat than these other conditions. 2

To which Dr. Danaei added:

Unless we develop better programs for detecting people with elevated blood sugar and helping
them to improve their diet and physical activity and control their weight, diabetes will
inevitably continue to impose a major burden on health systems around the world. 2

What is Diabetes and What Can Be Done?

Diabetes mellitus is a group of metabolic diseases that have some commonalities and some
differences. In both of the two principal varieties, type 2 diabetes (about 9095% of all
diabetes in the U.S.) and type 1 diabetes (510% of the diabetes population) high blood
sugar is the common feature. High blood sugar produces the classical symptoms of polyuria
(frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).
However, in type 2 diabetes, cells do not respond to the insulin that is produced, and in type 1
diabetes, the body does not produce enough insulin.

Other differences include the presence of insulin resistancea condition in which cells fail to
use insulin properlysometimes combined with an absolute insulin deficiency in type 2
diabetes (this is why it was previously called non-insulin-dependent diabetes mellitus) and the
need to inject insulin in type 1 diabetes (this is why it used to be called insulin-dependent
diabetes mellitus).

Berberine Helps Both Principal Types of Diabetes

A surprising new study conducted in Taiwan has found that berberine administered to non-
obese diabetic (NOD) mice protects pancreatic islets and serum lipids. 3 In type 1 diabetes,
pancreatic islets are damaged by auto-antibodies in which the immune system is misdirected
to attack proteins, gradually causing chronic complications. This momentous study examined
the effects of berberine on type 1 diabetes in vivo. The NOD mice were grouped and given 50,
150 or 500 mg of berberine/kg of body weight per day* over a 14 weeks week period. During
the span of the investigation, the following measurements were made:

1. Changes in pancreatic islets

2. Levels of serum insulin

3. Levels of berberine

4. Levels of lipids

a. LDL/TC (low density lipoprotein

cholesterol/total cholesterol)

b. HDL (high density lipoprotein cholesterol)

c. HDL/TC (high density lipoprotein cholesterol/total cholesterol)

* The amounts given to the mice, respectively are the human equivalent of 344, 1033, or 3443 mg
of berberine per day for a 187 lb person.

The Arrival of a Two-Fisted Supplement

The results showed that berberine supplementation significantly increased pancreatic islets
cells while raising serum berberine levels in dose-dependent manners. As well, berberine
supplementation also increased insulin levels, but decreased the ratio of LDL-C/TC. (LDL-C is
known as the bad cholesterol.) Furthermore, as serum levels of berberine increased, so did
HDL-C (the good cholesterol) levels along with the HDL-C/TC ratio. This study suggests that
berberine administration protects pancreatic islets and serum lipids in NOD mice. When
combined with prior studies showing a clear benefit of berberine for type 2 diabetes, this gives
rise to a two-fisted supplement, one able to tangle with the causes of two distinct variants of
diabetes (see Berberine is Superior to Metformin in the July, 2011 issue, Berberine
Goldthread Enhances Memory in the April, 2011 issue, Take This Dye for Diabetes in
the November, 2010 issue).

Berberine administration may

alleviate cardio-metabolic
complications in diabetes via
improving serum lipid profiles.

Possible Mechanism of Activity

Unfortunately, the new paper did not perform any tests necessary to clarify the mechanism of
action. However, a previous study indicated that the ability of berberine to act both as an
insulin sensitizer and an insulin secretagogue (releaser) may be due to its modulation of
several signaling pathways and targets.4 This paper choose to investigate berberines function
as a ligand (binder) of a fatty acid receptor GPR40 (G protein-coupled receptor 40), which
stimulates glucose dependent insulin secretion. Berberine was also found to stimulate calcium
mobilization in the GPR40 cell line. Furthermore, berberine stimulated glucose-dependent
insulin secretion from rat pancreatic beta cell line. Together, this data suggests that berberine
functions as an agonist (trigger) of fatty acid receptor GPR40 and might be a novel
antidiabetic mechanism of action for berberine.

Berberine Inhibits H1N1 Influenza A

In another new study,1 researchers tested whether berberine can inhibit the growth of
influenza A. The results showed strong inhibition of the growth of 2 strains of H1N1
influenza A (PR/8/34 and WS/33) in macrophage-like cells, human lung epithelial-derived
cells, and murine bone-marrow-derived macrophages. The authors suggest that the
mechanism of berberine underlying these effects occurs after chemical translation to inhibit
virus protein trafficking/maturation which in turn inhibits virus growth.

Berberine was also assessed for its ability to inhibit production of TNF- (tumor necrosis
factor-alpha, a cytokine mediator involved in systemic inflammation) and PGE2
(prostaglandin E2, a mediator with strong physiological effects, including the regulation,
contraction, and relaxation of smooth muscle tissue) from PR/8/34 infected-macrophage-
like cells. What the researchers found revealed strong inhibition of the production of both
mediators. This effect is probably distinct from the anti-viral effect.

Finally, berberine-containing ethanol extracts of goldenseal at high concentrations also

strongly inhibited the growth of influenza A and production of inflammatory mediators.
However, diluted extracts were somewhat less effective than purified berberine. The results
indicate that berberine may indeed be useful for the treatment of infections with influenza
A.

Reference

1. Cecil CE, Davis JM, Cech NB, Laster SM. Inhibition of H1N1 influenza A virus growth
and induction of inflammatory mediators by the isoquinoline alkaloid berberine and
extracts of goldenseal (Hydrastis canadensis). Int Immunopharmacol 2011 Jun 15.
[Epub ahead of print]

Cinnamon and Berberine: Better Together

Researchers investigated the pharmacokinetics of a mixture of cinnamon granules and
berberine from Rhizoma coptidis granules in healthy male volunteers. The concentration of
berberine in the plasma of healthy male volunteers was determined directly by high
performance liquid chromatography (HPLC) after an oral administration of Rhizoma coptidis
granules alone or combined with cinnamon granules. The plasma concentration-time curves
of berberine were plotted. Based on the finding, the authors suggest berberine granules
combined with cinnamon granules could increase the plasma concentration of berberine,
promote berberine absorption and lengthen the detention time of berberine in healthy male
volunteers. Cinnamon would appear to make berberine work better, longer, and harder.

Islet Cells Protected

Returning to the current study, the central idea was to evaluate the long-term effects of
berberine supplementation on type 1 diabetes. Using a normal species control for the NOD
mice, controls were found to have markedly higher islet cell numbers than those of NOD mice,
and this continued throughout the experimental period. Nonetheless, berberine
supplementation increased the islet cell numbers in a dose dependent manner. And the higher
the doses of berberine, the more significantly increased were the counts compared to the
control group. This suggested that berberine administration protected islet cells from
spontaneous injury in NOD mice.

The serum berberine levels in

berberine-administered groups
significantly increased in a dose-
dependent manner.
Using HPLC (high-performance liquid chromatography, a technique that can analyze the
content of mixture), the Taiwan researchers calculated the berberine levels in individual mice
and compared these to the reflected peak berberine standard. It was shown that the serum
berberine levels in berberine-administered groups significantly increased in a dose-dependent
manner, offering persuasive evidence that that berberine is readily absorbable via the
digestive tract. Oral berberine supplementation enriched the body and serum concentrations,
indicating that the bioavailability of berberine supplementation was proven. Yet, the relative
distribution in different body organs remains to be further clarified.

Berberine Altered Serum Insulin Levels

When the changes in insulin levels were determined, it was found that the controls had
markedly higher levels of insulin than the groups receiving berberine. Yet the insulin levels of
the NOD mice increased throughout the experiment. But berberine reversed the lower levels of
insulin in NOD mice, allowing the researchers to conclude that berberine increased insulin
secretion levels via a reawakened use of pancreatic islets. Unfortunately, serum insulin levels
were up just slightly, but not significantly through the 14-week experimental period. Thus the
scientists thought that berberine administration at the indicated concentrations in this study
could not fully reverse the spontaneous injury to pancreatic islet -cells in the NOD mice. But
NOD mice were designed to finish their days with type 1 diabetes.

Berberine Changes Serum Lipids Mostly for the Better

Berberine administration did not significantly influence serum lipid levels, including serum
triglycerides (TG), TC, HDL-C, and LDL-C levels. Nevertheless, NOD mice had significantly
higher ratios of LDL-C/HDL-C and LDL-C/TC compared to the controls throughout the study.
This argues that relatively higher LDL-C levels existed initially in the NOD mice. Of importance,
the different doses of berberine markedly decreased the raised LDL-C/TC ratio.

Evidently, a decrease in TG, TC, LDL-C serum levels with an increase in HDL-C (good
cholesterol) in vivo is favorable to good health and avoids diabetic complications, at least for
type 2 diabetes. In summary, the results propose that berberine administration improved
serum lipid profiles in NOD mice principally through relatively decreasing LDL-C serum levels.

Correlating Berberine levels, Islet Cell Numbers, and Lipid Levels

To more fully understand the relationship among berberine, pancreatic islet cell numbers, and
lipid levels in the experimental NOD mice, the correlations between these factors were
determined using a technique called Pearsons correlation coefficients (a measurement of the
correlation between two variables). The results demonstrated a significantly positive
correlation between berberine and HDL-C levels, along with a significantly positive correlation
between the berberine and HDL-C/TC ratios.

The researchers hypothesize that

berberine inhibited pancreatic islets
cell death, particularly through its
potent anti-inflammation potential.
At the same time, a significantly negative correlation between berberine serum levels and the
LDL-C/HDL-C ratios was found. Also, there was a slightly positive correlation between the
berberine serum levels and pancreatic islet cell numbers. These results further suggested that
berberine administration, whatever the level of ingestion, could not fully protect pancreatic
islets from spontaneous injury.

Serum fasting glucose levels and oral glucose tolerance test (OGTT) were determined and
showed that NOD mice developed type 1 diabetes, notwithstanding berberine absorption via
the digestive tract. Berberine is an alkaloid with moderate water soluble property, and this
characteristic may have enhanced its bioavailability in the study.

And the higher the berberine serum levels the greater the protective effects from spontaneous
pancreatic islet cell injury. Accordingly, these higher levels raised the decreased islet cell
numbers in a dose dependent manner. As they have been designed to do, the NOD mice
spontaneously developed type 1 diabetes, accompanied by chronic inflammation resulting in
apoptosis (cell death), especially in their pancreatic islet cells.

It is reasonable to assume that the prevention of pancreatic islet insulin-producing cells from
selective destructionsuch as through anti-apoptotic effects on the islets in the early stage
may cure or delay type 1 diabetes. Regrettably, the pancreas cell mass was not directly
determined in this study. Moreover, it is difficult to directly diagnose -cell abnormalities in
vivo because of their small size, as well as the fact that they are deeply and sparsely dispersed
in the pancreas. However, techniques are currently in development to do that. It is believed
that islet cell numbers correlate closely with b cell mass in the pancreas.

In the Taiwan researchers previous studies,5 berberine was found to possess potent anti-
inflammation potential and to inhibit streptozotocin-induced apoptosis in mouse pancreatic
islets. The researchers did not doubt that berberine can protect cells from cell death in NOD
mice. Once absorbed via the digestive tract, berberine can enter pancreatic islet cells and
exert its anti-apoptotic effect possibly using its potent anti-inflammatory and antioxidant
activities, not to mention its ability to down-regulate the Bax/Bcl-2 gene expression ratio
(which helps govern apoptosis).

The researchers hypothesized that berberine inhibited pancreatic islets apoptosis, particularly
through its potent anti-inflammation potential. They found that appropriate insulin secretion
levels were produced by the increased pancreatic islet cells, although insulin levels were still
not significantly changed through the experimental period. Also, they found that NOD mice
showed significantly higher LDL-C/HDL-C and LDL-C/TC ratios, compared to those of controls,
suggesting that relatively higher LDL-C levels exist in NOD mice.

Berberines versatility for combating

a wide range of diabetic
consequences, now includes
protection of pancreatic islets and
the reduction of serum lipids.
Surprisingly, berberine administration at different doses for 14 weeks markedly decreased the
raised LDL-C/TC ratio, demonstrating that berberine administrations improved serum lipid
profiles in NOD mice. Further analysis also showed a significantly positive correlation between
berberine and HDL-C levels, as well as a significantly positive correlation between serum
berberine levels and HDL-C/TC ratios, but a significantly negative correlation between serum
berberine levels and LDL-C/HDL-C ratios in NOD mice.

Research results indicate that berberine administration improved serum lipid profiles in NOD
mice via relatively increasing serum HDL-C, and decreasing LDL-C levels. The results further
clarify that berberine administration may alleviate cardio-metabolic complications in diabetes
via improving serum lipid profiles. In another study, berberine was found to inhibit fatty acid
synthesis via decreasing the acetyl-CoA carboxylase activity in 3T3-L1 adipocytes (fat cells). 6
Nonetheless, this regulatory mechanism of berberine on serum lipid levels and profiles
requires more study.

Unfortunately, cell and tissue analysis of the liver, pancreas and lung were not performed to
further evaluate the protective effects of berberine on type 1 diabetes-induced organ fibrosis.
However, berberine decreased the ratios of pro-/anti-inflammatory cytokine gene expressions
in the liver and kidney of NOD mice. This suggests an anti-inflammatory protection of
berberine on visceral organs.

When taken together, the findings of this study are promising. They support a growing body of
scientific literature, whichalong with anecdotal evidenceshow berberines versatility for
combating a wide range of diabetic consequences, now including protection of pancreatic islets
and the reduction of serum lipids.

References

1. Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ, Lin JK, Farzadfar F,
Khang Y-H, Stevens GA, Rao M, Ali MK, Riley LM, Robinson CA, Ezzati M, on behalf of
the Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group
(Blood Glucose). National, regional, and global trends in fasting plasma glucose and
diabetes prevalence since 1980: systematic analysis of health examination surveys
and epidemiological studies with 370 country-years and 27 million participants The
Lancet 25 June 2011 DOI: 10.1016/S0140-6736(11)60679-X.

2. Imperial College London (2011, June 25). 350 million adults have diabetes: Study
reveals the scale of global epidemic. ScienceDaily. Retrieved June 26, 2011, from
http://www.sciencedaily.com/releases/2011/06/110625142633.htm

3. Chueh WH, Lin JY. Berberine, an isoquinoline alkaloid in herbal plants, protects
pancreatic islets and serum lipids in non-obese diabetic mice. J Agric Food Chem 2011
Jun 22. [Epub ahead of print]

4. Rayasam GV, Tulasi VK, Sundaram S, Singh W, Kant R, Davis JA, Saini KS, Ray A.
Identification of berberine as a novel agonist of fatty acid receptor GPR40. Phytother
Res 2010 Aug;24(8):1260-3.
 5. Lin WC, Lin JY. Five bitter compounds display different anti-inflammatory effects
through modulating cytokine secretion using mouse primary splenocytes in vitro.
J Agric Food Chem 2011;59:184-92.

6. Kim HY, Kim K. Protective effect of ginseng on cytokine-induced apoptosis in

pancreatic -cells. J Agric Food Chem 2007, 55, 2816-23.

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