Cinnamon activates PPARs and pulls . . .

The Antidiabetes Trigger
Going after the biggest problem in the world and its consequences
By Will Block

The spice extends life. The spice expands
consciousness. The spice is vital to space travel . . .
travel to any part of the universe without moving.

— Frank Herbert, Dune (1965)

hat is the biggest single problem in the world? Is it the global economic downturn? The war in the Mideast? Radical weather changes? Politics? The “civilizing” effect of the American film industry (if you laugh at this, you may be warped)?

But wait a moment: I forgot to tell you that this is a trick question. The biggest single problem in the world, literally, is the total amount of excess weight that people carry around. According to the World Health Organization, based on data gathered for 2005, there were approximately 1.6 billion adults (15+ years) pronounced to be overweight on the planet, and at least 400 million of those are obese. Imagine the total mass! Nearly 237 million Americans are currently overweight, an estimated 74.1% of the entire population. That makes the USA number nine in the world list of the fattest countries, the only “developed” country in the top ten.* So among the developed nations, we’re number one!

As of 2006, professional services provider company Aramark reported that the average American weighed 188.3 lb and had an average body mass index of about 29.0, which is approaching the clinically obese level of 30.0. With about 222 million adults, the total weight of all United States adults is 41.8 billion pounds. If the average percentage of fat is about 27%, then the total amount of fat carried by adult Americans is 11.29 billion pounds. That amount of fat would fill the Roman Coliseum about 188 times!

The War Zone of Fat

U.S.A. We’re #1!
The real problem is that once you are overweight, the next stop is obesity—an enormous health problem because it is a major risk factor for insulin resistance in the development of type 2 diabetes. This degenerative disease affects at least 171 million people worldwide, with around 3.2 million deaths every year stemming from complications attributable to it. Compare that figure to the total war deaths on the planet—378,000 global war deaths annually per year, for the last period for which reliable data was available (1985-94).1 If the average has held, you are 8.5 times more likely to die from diabetes than from a bomb, a bullet, or a machete!


*See http://www.forbes.com/2007/02/07/worlds-fattest-countries-forbeslife-cx_ls_0208worldfat_2.html

†According to the American Council on Exercise, obesity is 32+% for women and 25+ for men.

‡The top 10 countries for diabetes, in numbers of sufferers, are India, China, USA, Indonesia, Japan, Pakistan, Russia, Brazil, Italy, and Bangladesh in that order.


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, PPARδ/β is expressed in many tissues. To date, PPARδ/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.2 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.

Although cinnamon use goes back at least 4000 years, it only was shown to have insulin-like biological activity as late as 2000.3 (Insulin was discovered in the early 20th century.) In subsequent studies, cinnamon extract has been found to induce an antidiabetic effect in a special breed of diabetic mice,4 and in humans.5 Other studies have shown that cinnamon oil can increase insulin sensitivity6 and that cinnamon water extract can increase glucose uptake in adipocytes (fat cells).7


What is truly new about the PPAR
Research report is the identification of
an underlying mechanism for the way
that cinnamon produces
antihyperglycemic and
antihyperlipidemic effects.


Nevertheless, it has proven difficult to identify the individual components of cinnamon that display insulin-like or insulin-enhancing activity, let alone the mechanisms by which it occurs. Dr. Richard Anderson and colleagues believe that they have narrowed it down to type-A polyphenols found in cinnamon.8 Type-A polyphenols are water soluble, and because there are fat-soluble components in cinnamon that are potentially harmful in large amounts, such as coumarin and cinnamaldehyde, the water-extract form is preferable and the evidence is convincing. Concerning the mechanism, colleagues of Dr. Anderson have more recently found that the ability of cinnamon to increase insulin sensitivity is mediated through an insulin signaling pathway.9 (See the sidebar “Cinnamon is an Insulin Signal Enhancer.”)

Cinnamon is an Insulin Signal Enhancer

In earlier work, Dr. Anderson et al. reported that improvements of insulin sensitivity by cinnamon were attributable, in part, to enhanced-insulin signaling. Recently he and his colleagues have examined the effects of cinnamon extract on postprandial (after eating a meal) metabolism.1 What they found is that cinnamon water extract could lower the levels of the lipoprotein apoB48, found throughout the body and especially in the intestinal enterocytes (intestinal absorptive cells) of hamsters (hamsters are much more reflective of humans in the production and distribution of this lipoprotein).

Cinnamon increases insulin sensitivity
by enhancing insulin signaling.
ApoB48 contains high amounts of very low-density lipoprotein particles and growing evidence suggests that intestinal overproduction of apoB-containing lipoproteins may contribute significantly to the elevation of circulating triglyceride-rich lipoproteins. This is not good for your health, especially if you’re insulin-resistant. While apoB48 is an essential intestinally-derived structural component, recent research suggests that the excessive accumulation of apoB48 leads to liver dysfunction.

Also in this study, cinnamon was found to decrease triglyceride levels along with the overproduction of total and triglyceride-rich apoB48. When the investigators examined the effects of cinnamon-invoked mechanisms on the expression of insulin signaling pathway genes and lipoprotein metabolism, they found that cinnamon reversed the expression of impaired genes and inhibited the overexpression of enterocytes signaling. Thus, cinnamon was found to improve the insulin sensitivity of intestinal enterocytes by downregulating triglycerides and lipid regulatory proteins. In summary, cinnamon reduces intestinal insulin resistance, a finding that may be beneficial in helping to control the dominance of the wrong types of lipids.

Reference

  1. Qin B, Polansky MM, Sato Y, Adeli K, Anderson RA. Cinnamon extract inhibits the postprandial overproduction of apolipoprotein B48-containing lipoproteins in fructose-fed animals. J Nutr Biochem 2008 Nov 5. [Epub ahead of print]

Cinnamon’s Underlying Mechanism

What is truly new about the PPAR Research report is the identification of an underlying mechanism for the way that cinnamon produces antihyperglycemic and antihyperlipidemic effects on diabetic animals and presumably for type 2 diabetic patients. Using a variety of experimental techniques, it was demonstrated that cinnamon water extract can elevate the expression of both PPARα and γ, and consequently their target genes in fat cells.

Through in vitro studies, the PPAR researchers found that cinnamon water extract stimulated the differentiation of a line of fat cells from preadipocytes to adipocytes. Next they showed that the cinnamon extract treatment not only increased the message transmission of PPARs α and γ but also that it elevated the expression of their target genes (LPL, CD36, GLUT4, and ACO) by thousands of folds in the fat-cell line. Finally, the cinnamon extract increased transactivities of both the full length and ligand-binding domain of PPARα and PPARγ significantly. These observations are all associated with antihyperglycemic and anti-hyperlipidemic effects.


Cardiovascular disease is much more
prevalent among those with
type 2 diabetes.


In vivo studies followed with the researchers using diet-induced obese mice. The mice were fed a 60% fat diet for 5 months causing substantial increases in both body weight and fat weight. As expected, the mice developed insulin resistance and hyperinsulemia, fatty-liver condition, and significantly diminished liver function associated with early type 2 diabetes. However, after 3 weeks of feeding cinnamon water extract, their glucose tolerance and hyperinsulemia improved markedly, compared to untreated mice. The scientists concluded that improved glucose tolerance and lower insulin level contributed to the reduction of insulin resistance.


Ligands (synthetic or natural, such as cinnamon) initiate the intracellular process that regulates the expression of genes. Retinoid X receptors (RXR) bind together with PPARα and γ and affect gene expression.
Furthermore, free-fatty acid levels—known to impair insulin secretion, induce beta-cell lipotoxicity, and inhibit insulin-stimulated glucose uptake into muscle—were also reduced notably in the diet-induced obese mice given cinnamon. In white fat tissue, the gene expression of PPARα and PPARγ in their respected target genes was also elevated, indicating that cinnamon water extract may act as a dual activator of PPARα and PPARγ. This in turn resulted in improved insulin resistance and lower serum lipids. When other in vivo studies were done with mice bred to readily develop diabetes, cinnamon water extract was also found to have hypoglycemic and hypolipidemic effects.

Stemming the Tide to Cardiovascular Disease

Cardiovascular disease is much more prevalent among those with type 2 diabetes. This we know, in part, due to associated higher levels of low-density lipoprotein cholesterol (LDL), a hallmark for atherosclerosis and the risk of cardiovascular disease. Consequently, lowering LDL stems the rising tide that encompasses cardiovascular disease. And indeed, the PPAR researchers showed that cinnamon water extract reduced LDL to normal levels in diet-induced obese mice, firming the case that such an extract of cinnamon may be beneficial for helping to prevent what is still the number one killer in the world.

The Coactivation Connection

In the field of longevity, one member of a group of nuclear receptor coactivator proteins has created quite a stir. That’s the protein with the formidable name peroxisome proliferator-activated receptor gamma coactivator-1α (abbreviated PGC-1α, where the P stands for PPAR). PGC-1α is a transcriptional master regulator, which recently has been discovered to be activated by the sirtuin SIRT1, which in turn is activated by the phytonutrient resveratrol. In effect, resveratrol exerts pharmacological preconditioning by activating PGC-1α.

The reason for all the excitement is that PGC-1α induces mitochondrial biogenesis, a process whereby mitochondria, the energy agents of the cell, are increased. When more energy is produced, the result is less oxidative damage, improved energy efficiency, and an increase in overall health, and perhaps longer life. Resveratrol is a mitochondrial turbocharger.

What is the interconnection between coactivators, such as PGC-1α and the PPARs? Although certain relationships have been established—for example, PGC-1α and PPARα cooperate to activate genes encoding enzymes involved in cardiac fatty oxidation—there is a paucity of knowledge at this time. Answering these questions should help in the design of studies that investigate these relationships. In time, they may lead to the creation of nutrient cocktails—such as perhaps a resveratrol-cinnamon combination—for a spectrum of health benefits unforeseeable at this time.

Another finding of the PPAR study is that cinnamon treatment improved impaired liver function in diet-induced obese mice. Liver enzyme levels were decreased notably with 3 weeks of cinnamon treatment suggesting that cinnamon may play an important role in improving liver function.


Cinnamon water extract exhibited
hypoglycemic and hypolipidemic
effects on both diet-induced obese
and diabetes mice.


Despite the publication of a meta-analysis, based on five randomized clinical trials, showing that the use of cinnamon did not appear to improve glycosylated hemoglobin, fasting blood glucose, or lipid parameters in patients with type 1 or type 2 diabetes,10 the preliminary PPAR study also showed no effect on either type of mouse when cinnamon powder was used without water extraction. However, cinnamon water extract exhibited hypoglycemic and hypolipidemic effects on both diet-induced obese and diabetes mice. These results agreed with the report by Mang et al.,11 demonstrating that the aqueous cinnamon extract had a moderate effect in reducing fasting plasma glucose concentrations in diabetic patients with poor glycemic control.

The PPAR researchers contend that the water extraction process enriched the amount of the active components of cinnamon necessary to trigger both PPARα and PPARγ, without which there would be fewer or no observable beneficial effects. Thus, preparation of cinnamon using water extraction should be considered when designing new clinical trials.

Summarizing the findings, this study demonstrates that cinnamon may be beneficial for type 2 diabetes because it can activate both PPARα and PPARγ, and that the net result is improved insulin resistance, lower blood glucose, and lower serum lipid levels. Also, this was accomplished without weight gain or structural change in white adipose tissue. Finally, cinnamon improved the liver function of obese mice. When all of this is considered, cinnamon can be extremely helpful for managing obesity-related type 2 diabetes and hyperlipidemia, possibly as a supplement and to help prevent spiraling out of control and moving closer to the edge of the obesity-related disease abyss.

References

  1. Obermeyer Z, Murray CJ, Gakidou E. Fifty years of violent war deaths from Vietnam to Bosnia: analysis of data from the world health survey programme. BMJ 2008 Jun 28;336(7659):1482-6. Epub 2008 Jun 19. Erratum in: BMJ 2008 Jun 28;336(7659).
  2. 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. Epub 2008 Dec 11.
  3. Broadhurst CL, Polansky MM, Anderson RA. Insulin-like biological activity of culinary and medicinal plant aqueous extracts in vitro. J Agric Food Chem 2000;48:849–52.
  4. Kim SH, Hyun SH, Choung SY. Anti-diabetic effect of cinnamon extract on blood glucose in db/db mice. J Ethnopharmacol 2006 Mar 8;104 (1-2):119-23.
  5. Khan A, Safdar M, Ali Khan MM, Khattak KN, Anderson RA. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diabetes Care 2003 Dec;26(12):3215-8.
  6. Talpur N, Echard B, Ingram C, Bagchi D, Preuss H. Effects of a novel formulation of essential oils on glucose-insulin metabolism in diabetic and hypertensive rats: a pilot study. Diabetes Obes Metab 2005 Mar;7(2):193-9.
  7. Roffey B, Atwal A, Kubow S. Cinnamon water extracts increase glucose uptake but inhibit adiponectin secretion in 3T3-L1 adipose cells. Mol Nutr Food Res 2006 Aug;50(8):739-45.
  8. Anderson RA, Broadhurst CL, Polansky MM, Schmidt WF, Khan A, Flanagan VP, Schoene NW, Graves DJ. Isolation and characterization of polyphenol type-A polymers from cinnamon with insulin-like biological activity. J Agric Food Chem 2004 Jan 14;52(1):65-70.
  9. Qin B, Nagasaki M, Ren M, Bajotto G, Oshida Y, Sato Y. Cinnamon extract prevents the insulin resistance induced by a high-fructose diet. Horm Metab Res 2004;36:119–25.
  10. Baker WL, Gutierrez-Williams G, White CM, Kluger J, Coleman CI. Effect of cinnamon on glucose control and lipid parameters. Diabetes Care 2008 Jan;31(1):41-3.
  11. Mang B, Wolters M, Schmitt B, Kelb K, Lichtinghagen R, Stichtenoth DO, Hahn A. Effects of a cinnamon extract on plasma glucose, HbA, and serum lipids in diabetes mellitus type 2. Eur J Clin Invest 2006 May;36(5):340-4.


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

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