If it was a drug, its benefits would be proclaimed in worldwide headlines, because . . .

Cinnamon Swoops Down
to Retard Diabetes

Cinnamon extract significantly increases
insulin sensitivity, reduces serum and hepatic lipids,
improves hyperglycemia and hyperlipidemia, and
lowers abdominal fat weight

By Will Block

Great birds, they say, bring the sticks which we Greeks, taking the word from the Phoenicians, call cinnamon, and carry them into the air to make their nests.
— George Rawlinson, History of Herodotus
Herodotus

H

erodotus (circa 484–425 BC) is often thought of as “The Father of History,” yet the phoenix story attributed to him was probably a flight of fancy, filtered through Pliny (23–79 BC), a frequent critic of Herodotus, and also a historian. Pliny should have known better because, in addition to the profession he shared with Herodotus, he was a naturalist. Yet the fables connected with cinnamon are more a flight of the mind’s eye, reflecting evidence of the ancient world’s interest, not only for the culinary aspects of cinnamon but for its medicinal relevance too.

In reality, nutritional utilization often prefaces medical application. The use of cinnamon as a food additive, condiment, and flavoring agent is indebted to its antioxidant, preservative, and carminative (gastrointestinal) properties. Underlying these uses are mechanisms which provide the reasons behind cinnamon’s applications in herbal medicine, where traditionally it has been used for dyspepsia, blood circulation, appetite stimulation, digestion, and even heart disease.1

In the present, despite reports showing that the use of herbal supplements has increased dramatically, the precise mechanisms of actions of their active ingredients are infrequently understood. But there are exceptions and cinnamon extract is certainly one of those in the scientific forefront, with a succession of studies showing that it can increase insulin sensitivity, reduce serum and hepatic lipids, and improve hyperglycemia and hyperlipidemia, possibly by regulating the PPAR-medicated glucose and lipid metabolism … as shall be explained.2

Cinnamon Grand Slam

In a new study, conducted at Kyung Hee University’s College of Pharmacy, in Seoul, Korea, the effect of cinnamon extract on hyperglycemia and hyperlipidemia was studied by measuring the blood glucose levels, serum insulin, adiponectin levels, serum and hepatic lipids, and PPARα mRNA expression in liver and PPARγ mRNA expression in adipose tissue.2

Twenty male diabetic mice were divided into a cinnamon extract treated group and a diabetic group (10 each) and given 200 mg/kg of body weight orally (treated) or not (controls).* Among their findings, the researchers reported that fasting and postprandial (measured 2 hours after supplementation) blood glucose levels were significantly lower in the cinnamon treated group compared to those in the control group. As well, the serum insulin and adiponectin levels were significantly higher in the cinnamon treated group versus the control group. Furthermore, serum lipids and hepatic lipids were improved in the mice receiving cinnamon. To top this off, the nuclear receptors PPARα mRNA (as measured in the liver) and PPARγ mRNA (as measured in white adipose fat tissue) expression levels were increased significantly in the cinnamon treated group. (See the sidebar, “Therapeutic Target for Dyslipidemia and Diabetes.”)


*Calculating the human equivalent dose (see sidebar table in “The Universal Cause of Aging” in the February 2009 issue), 200 mg/kg for a mouse translates to about 16.2 mg/kg for a human (e.g, that would be 1.4 g of cinnamon extract for a person weighing 85 kg or 187 lb).


Therapeutic Target for Dyslipidemia and Diabetes

In molecular biology, peroxisome proliferator-activated receptors (PPARs) are a family of receptor proteins that operate in the cell nucleus as transcription factors, regulating the expression of genes. Thus PPARs are essential and intimately involved in directing some of the most important aspects of higher organisms, including cellular development, differentiation, and metabolism. Starting in the early 1990s, PPARs have been recognized as therapeutic targets for dyslipidemia (disruption in the amount of lipids in the blood) and diabetes. Since then, PPARs have been found to play a major role in processes and pathological conditions associated with aging, obesity, diabetes, inflammation, immunity, cancer, and fertility.

PPARs are divided into three related forms: PPARα (alpha), PPARγ (gamma), and PPARδ/β (delta/beta, usually referred to as delta). PPARα is expressed principally in brown adipose (fat) tissue and liver, whereas PPARγ is mainly expressed in white adipose (fat) tissue. The last one, PPAR&delta/β is expressed in many tissues. To date, PPAR&delta/β is the least interesting of the isoforms.

When activated, PPARα lowers triglycerides (bad) and elevates HDL (good) cholesterol levels, while the activation of PPARγ increases insulin sensitivity and results in antidiabetic effects. Consequently, these PPARs are of enormous interest. The question of how to activate them has split in two directions: seeking out natural ligands (molecular binders) and inventing synthetic ones. For reasons that you can guess, most studies to date have set out with the goal of developing synthetic PPAR ligands. Because synthetic PPARs can be patented, it clearly has been in the interest of Big Pharma to finance much of the research . . . but herein lies the rub.

Limitations of Synthetic Activators

The results of PPAR drug development have been problematic. Among the PPARα agonists (a type of ligand or drug that binds and alters the activity of a receptor) for treating insulin resistance and dyslipidaemia are fibrates, a class of amphipathic (possessing affinity for both fat and water) carboxylic acids. Commonly prescribed fibrates are bezafibrate, biprofibrate, blofibrate (largely obsolete due to side-effect profile, e.g. gallstones), gemfibrozil, and fenofibrate. While studies have found that fibrates can be beneficial for a broad range of lipid management, there are serious side effects, including myopathy (muscle pain) and rhabdomyolysis (muscle destruction, leading to renal failure), especially when used with statins, a commonly used class of drugs for lowering cholesterol levels.

Among the PPARγ agonists found to be of some value in the management of insulin resistance and type 2 diabetes are the class of drugs known as thiazolidinediones (also called glitazones). Included in that class are troglitazone (recently withdrawn from the market due to severe liver toxicity), rosiglitazone (accused by FDA’s Dr. David Graham of possibly causing as many as 205,000 heart attacks and strokes from 1999 to 2006) and pioglitazone. As noted, these agonists can produce moderate to serious side effects including edema, weight gain, congestive heart failure, and liver damage.

Cinnamon, a Natural Trigger for Activating PPARs

While it has been know for some time that omega-3 polyunsaturated fatty acids, long-chain fatty acids, and prostaglandins can serve as PPAR ligands, little work has been done to explore natural ligands. So it is good news to report a study published in PPAR Research finding that the popular spice cinnamon—known as a traditional antidiabetes remedy—improves insulin resistance and lipid metabolism by triggering into activation both PPARα and PPARγ.1 Remember that these PPARs are expressers of genes in brown and white fat, as well as in the liver. When triggered, PPARα is positively beneficial for lowering triglycerides and raising HDL cholesterol levels, both of which are highly desirable. When PPARγ is triggered, insulin sensitivity improves as do other antidiabetic effects. The finding that cinnamon is a PPAR activator opens the door to PPAR benefits without the unwelcome side effects of the PPAR drugs.

Reference

  1. Sheng X, Zhang Y, Gong Z, Huang C, Zang YQ. Improved insulin resistance and lipid metabolism by cinnamon extract through activation of peroxisome proliferator-activated receptors. PPAR Res 2008;2008:581348.

Altogether, these results suggest that cinnamon extract significantly (1) increases insulin sensitivity, (2) reduces serum lipids, (3) lowers hepatic lipids, and (4) improves hyperglycemia and (5) hyperlipidemia possibly by regulating PPAR-mediated glucose and lipid metabolism. By any measure, the findings of this study amount to the equivalent of a grand slam, as in contract bridge where the expression is used to mean winning all the tricks in a hand.

Cinnamon Decreases Abdominal Fat Weight

After 12 weeks of the regimen, the differences in the changes of body weight and food intake of the mice treated with cinnamon extract and control were not significant. However, the liver index of the cinnamon group was significantly lower than that of the controls. Moreover, the abdominal fat weight showed a significant decrease in the cinnamon group compared to the control group, strongly suggesting that cinnamon inhibited the accumulation of hepatic and abdominal fat lipids.


Fasting and postprandial
blood glucose levels
were significantly lower in the
cinnamon treated group compared to
those in the control group.


Cinnamon Enhances Blood Glucose, Plasma Insulin, and Adiponectin Levels


Figure 1. Each value represents the mean ± S.D.
The researchers reported that the fasting blood glucose level in the cinnamon group was significantly lower than that in the control group and this result continued throughout the experiment. In fact, the fasting blood glucose level in the cinnamon group at 2 weeks was similar to what was normal for the controls. They also found that cinnamon produced a significant decrease in the postprandial blood glucose levels (measured 2 hours after supplementation) compared to the control group. As the same time, the serum insulin concentration in the cinnamon treated mice was substantially higher than those in the control group. Following 12 weeks of cinnamon, the serum insulin level in the cinnamon extract treated mice increased by 74% compared to controls. Remarkably, the level of serum adiponectin significantly increased by 1.9-fold in the group treated with cinnamon. (See Fig. 1.) Although other researchers have hypothesized this effect, this is the first time it has been shown to be true in vivo. In a recent study conducted by leading cinnamon researchers including Dr. Richard Anderson, Wistar rats fed a high-fructose diet, an extract of cinnamon given at 50 mg/kg* did not result in a significant increase in adiponectin.3


*That’s the equivalent of 25 mg/kg for a mouse, or 1/8th the amount of cinnamon used in the current study.


Adiponectin Can Correct the Hyperglycemia Associated with Obesity

Adiponectin is an adipocyte (fat cell)-derived hormone that is synthesized and secreted by the activation of the nuclear receptor PPARγ (see sidebar above, “Therapeutic Target for Dyslipidemia and Diabetes”). It is involved in the regulatory processes of inflammation, metabolism, and cardiovascular disease. However, its production is reduced by eating too many calories, through a mechanism which is thought to be associated with leptin deficiency or resistance. But once released, adiponectin can directly increase fatty-acid transport, and reduce the levels of intramuscular lipid content, through oxidation and dissipation in skeletal muscle, thus amplifying insulin signaling. Adiponectin can also increase liver cells' sensitivity to insulin, directly or indirectly, by lowering the level of the circulating lipids owing to its action on the muscles. When administered, adiponectin can improve insulin sensitivity and glucose tolerance, and can correct the hyperglycemia associated with obesity. Judging from the results of the current study, adiponectin may be produced and released by cinnamon.


Serum insulin and adiponectin levels
were significantly higher in
the cinnamon group.


Cinnamon Has a Positive Effect on Hyperlipidemia

With regard to lipids, cinnamon was found to lower triglycerides by 38.5% compared to controls. Also, the total cholesterol level in the cinnamon extract treated group was significantly lower than that in the control group. Moreover, the HDL-cholesterol level in the cinnamon group was significantly higher than those in the control group. And the HDL-cholesterol/total cholesterol ratio was higher in the cinnamon group than in the control group. The hepatic level of free fatty acids in the group of mice treated with cinnamon was 65.6% lower than in the control group. It was conclusive that cinnamon extract had a positive effect on hyperlipidemia.


The abdominal fat weight
showed a significant decrease in the
cinnamon group.


Cinnamon Alters PPARα and PPARγ mRNA Expression

The PPARγ mRNA level in the cinnamon treated group increased significantly, by 1.2 fold compared to those in the control group, offering a strong suggestion that cinnamon extract upregulated the expression of this nuclear receptor in white adipose tissue. In the liver, the PPARα mRNA level in the cinnamon treated group was approximately 11.4% higher than those in the control group. Altogether, these results suggest that cinnamon extract exercises beneficial effects on hepatic lipid accumulation through the increased expression of PPARα in the liver. Further investigation will help to clarify these findings. Indeed they are needed because these findings are new to cinnamon research, or for that matter other natural substances.


The HDL-cholesterol level in
the cinnamon group
was significantly higher.


A Candidate for Type II Diabetes?

One thing is certain, a correlation exists between blood glucose, serum insulin, and adiponectin concentration. This may help explain the anti-diabetic mechanism of cinnamon extract.

The PPARγ mRNA expression was up-regulated in adipose tissue by the cinnamon extract. PPARγ is highly expressed in adipose tissue and plays an important role in insulin sensitivity and the secretion of adipocytokines such as adiponectin. As the major regulator of adipogenesis, PPARγ stimulates the production of insulin-sensitive adipocytes. When adiponectin is produced, it acts in adipose tissue to increase whole-body insulin sensitivity.


The level of serum adiponectin
significantly increased by 1.9-fold in
the group treated with cinnamon.


Also, insulin sensitivity improvements were associated with decreased triglyceride content in the muscle and liver, and increased fatty acid oxidation in the muscle. These improvements were accompanied by the increased expression of genes for proteins involved in fatty acid transport and utilization. Adiponectin also suppressed glucose production by insulin by acting directly on the liver. The higher the level of adiponectin in serum, the lower the body weight and abdominal fat weight. Thus, the researchers anticipated that cinnamon extract would behave similarly to a PPARγ agonist.

Cinnamon is a Naturally Occurring
Anti-Angiogenesis Agent

Angiogenesis is a process whereby new blood vessels are formed from pre-existing vessels. On the surface, that sounds like a good thing, but in reality, it is not. That’s because angiogenesis provides a support system for tumors, and without the growth of new blood vessels, tumors would not be able to grow and metastasize.

This process is tightly regulated by a complex balance between a variety of stimulators and inhibitors, and one of these, vascular endothelial growth factor (VEGF), is perhaps the single most critical and specific angiogenesis factor regulating normal physiological and tumor angiogenesis.

VEGF induces angiogenesis by binding to its two receptors expressed on endothelial cells, which are required mainly for cell division and chemically directed responses, and which contribute to endothelial cell morphogenesis (organism shaping). Thus, VEGF initiates a signal cascade that orchestrates a variety of processes that are required for forming new blood capillaries, including endothelial cell proliferation, migration, and survival.1

VEGF is viewed as an attractive therapeutic target for novel anticancer agents, and a variety of approaches to inhibit VEGF activity are currently being assessed in preclinical and clinical trials. Serious side effects, such as hypertension, bleeding and gastrointestinal perforation, have been associated with currently available anti-VEGF agents, raising the red flag of caution and limiting chronic use. Consequently, there has been a renewed interest in identifying natural food sources’ anti-VEGF agents, given the advantage of proven safety for human use, and also because eating a plant-based diet has been found to have implications for the prevention of cancer development and progression.

The use of certain polyphenols, especially flavonoids, is well-recognized to be beneficial. They are found in a variety of foods, including tea, coffee, fruits, vegetables, soybeans, seeds, grains, and spices. This recognition has been extended to polyphenols extracted from various plants, including soy, berry, pomegranate, grape seed extract and green tea. These additional polyphenols have been found to be potent inhibitors of angiogenesis. Nevertheless, the benefits of dietary components on VEGFR (VEGF receptor) has not been sufficiently elucidated. However, there is good news. Data has revealed a novel activity in cinnamon that allows it to act as a natural VEGF inhibitor that could potentially be useful in cancer prevention and treatment. Thus, cinnamon is an angiogenesis inhibitor.

Reference

  1. Lu J, Zhang K, Nam S, Anderson RA, Jove R, Wen W. Novel angiogenesis inhibitory activity in cinnamon extract blocks VEGFR2 kinase and downstream signaling. Carcinogenesis 2010 Mar;31(3):481-8.

The up-regulation of serum adiponectin, insulin, and the significant decrease in the blood glucose levels caused by cinnamon extract may result from the increased expression of PPARγ. At the same time, body weight and abdominal fat weight gains were significantly lowered by the increased level of serum adiponectin in the cinnamon group.

As well, the present study showed that cinnamon extract is effective in retarding the progress of type 2 diabetes, possibly by improving the lipid metabolism through the up-regulation of PPARα expression.

PPARα agonists (promoters) are known to stimulate the mitochondrial oxidation and cellular uptake of free fatty acids by modifying the expression of genes such as the acyl-CoA synthetase gene and fatty acid transport protein gene. PPARα ligands (receptor binders) also increase the expression of the lipoprotein lipase gene and reduce the expression of the gene encoding for apo-C, which is an inhibitor of lipoprotein lipase, resulting in the anti-hyperlipidemia effect.


Cinnamon significantly decreased
blood glucose levels
by increasing the levels of
insulin and adiponectin through
PPARγ expression in adipose tissue.


In the study, the researchers confirmed that cinnamon extract would behave similarly to a PPARα agonist. In liver tissue, PPARα transactivation corresponded with decreased serum lipids and liver weight in the cinnamon group, indicating that cinnamon regulates lipid metabolism through PPARα activation in the liver, where PPARα may play an important role for the regulation of hyperlipidemia and hyperglycemia.

In conclusion, cinnamon extract significantly decreased the blood glucose levels by increasing the levels of insulin and adiponectin through PPARγ expression in adipose tissue. Also, the serum and liver lipids were lowered by the up-regulation of PPARα expression in the liver. Therefore, cinnamon extract, which controlled hyperglycemia and hyperlipidemia in the mice, may be a successive candidate for type II diabetes.

Cinnamon Safety and Consideration

Cinnamon extract has proven itself to be quite safe. So when you consider the results of the current study, which are increasingly supported by a growing succession of other studies, supplement takers concerned about the problems of hyperglycemia and hyperlipidemia, not to mention fat disposition, should fine-tune their choices. In keeping with what they are already doing, they could feather their nutritional nests moreso with cinnamon extract.

References

  1. Ravindran PN, K Nirmal-Babu K, Shylaja M, eds. Cinnamon and Cassia: The Genus Cinnamomum. Boca Raton, FL: CRC Press; 2003.
  2. Kim SH, Choung SY. Antihyperglycemic and antihyperlipidemic action of Cinnamomi Cassiae (Cinnamon bark) extract in C57BL/Ks db/db mice. Arch Pharm Res 2010 Feb;33(2):325-33.
  3. Qin B, Polansky MM, Anderson RA. Cinnamon extract regulates plasma levels of adipose-derived factors and expression of multiple genes related to carbohydrate metabolism and lipogenesis in adipose tissue of fructose-fed rats. Horm Metab Res 2010 Mar;42(3):187-93.


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

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