Cinnamon as a natural supplement is intended for use in
conjunction with diet and exercise to
assist in achieving goal blood sugar levels, and possibly blood lipid
levels, in people with
pre-diabetes or Type 2 diabetes.
Cinnamon spice comes from the bark of trees in the genus
Cinnamomum. This genus has over 300 species distributed in tropical and
subtropical regions of North America, Central America, South America,
Asia, Oceania, and Australia.(6)
There are two notable species
from which most commercial cinnamon is harvested. The first one is
Cinnamomum verum, the "true cinnamon", or also known as C. zeylanicum or
Ceylon Cinnamon. The second is Cinnamomum aromaticum, which is more
commonly known as Cinnamomum cassia. C. zeylanicum is highly regarded but
is relatively expensive and less available than C. cassia, which dominates
the world market. C. cassia is native to southern China and mainland
Southeast Asia west to Myanmar and is a close relative to the Cinnamomum
zeylanicum.
Cinnamomum cassia is the most investigated species for
potential benefits to diabetes care. At least one animal study has
compared the relative efficacy of C. cassia and C. zeylanicum, finding
that C. cassia is superior to C. zeylanicum, and also finding that the
cassia extract was only slightly more efficacious than using the ground
bark of C. cassia.(7)
The interest in cinnamon for blood sugar
control in diabetes has evolved out of cell line and animal research, and
human clinical investigations.
Laboratory Background Supporting
Cinnamon Use in Diabetes
Beginning in 1998, Imparl-Radosevich
et al reported that cinnamon had bioactive compound(s) that could
potentiate insulin activity, measured by enhanced glucose oxidation in the
rat epididymal fat cell assay.(8) Broadhurst et al also using the rat
epididymal adipocyte model reported in March of 2000 that in their
evaluation of 49 herb, spice, and medicinal plant extracts, cinnamon was
the most bioactive of the 49 plants for enhancing insulin-dependent
utilization of glucose.(9) Following from these initial findings, a number
of researchers between 1999 and 2006 have documented in animal models an
ability of cinnamon to enhance glucose uptake and otherwise modulate
insulin sensitivity.(10-14)
Investigations to determine the nature
of the anti-diabetic bioactives in cinnamon have concentrated on
water-soluble components in the aqueous extract. Jarvill-Taylor et al
reported in 2001 on the insulin-mimetic effects in the 3T3-LI adipocyte
cell line of a specific cinnamon constituent originally identified as a
methylhydroxychalcone polymer (MHCP), which is a member of the flavonoid
family of polyphenols.(15) Subsequently in 2004, Anderson et al reported
that watersoluble polyphenolic type-A polymers were thought to be
responsible for the in vitro insulin-dependent enhancement of glucose
oxidation.(16) Irrespective of this initial mislabeling of the
bioactive(s), the Jarvill-Taylor et al and Anderson et al studies have
demonstrated that aqueous extract of cinnamon has the ability in vitro to
cause insulin-like responses in glucose metabolism. Anderson et al found
that cinnamon extract increased insulin-dependent in vitro glucose
metabolism essentially 20-fold. The findings of the Jarvill-Taylor et al
study are given in more detail below. Aqueous cinnamon extract was
compared to insulin in regards to the following five insulin mediated
metabolic parameters:
1. Insulin induces glucose uptake and
glycogen synthesis; The Cinnamon Finding: Treatment with cinnamon
extract indeed stimulated glucose uptake, but with a lag phase compared to
insulin. Stimulation of cells with insulin gave a linear uptake slope over
the 60-minute treatment window, whereas the cinnamon extract stimulation
yielded only a slight effect at 10 minutes, with a dramatic rise in uptake
observed between 30 and 60 minutes. Glycogen synthesis was accomplished to
a similar level as produced by insulin. Furthermore, when the cinnamon
extract was tested with insulin, it demonstrated a capacity for insulin
potentiation in glucose uptake and glycogen synthesis.
2.
Insulin induces auto-phosphorylation of the insulin receptor; [Note:
Insulin-induced auto-phosphorylation of specific tyrosine residues in the
intracellular portion of the insulin receptor á-subunit creates a tyrosine
kinase domain. Auto-phosphorylation of the á-subunit is the critical step
for initiating the cascade of biological effects of insulin]. The Cinnamon
Finding: Analysis of the insulin receptor á-subunit demonstrated that the
receptor was rapidly auto-phosphorylated upon exposure to the cinnamon
extract.
3. Insulin induces activation of the enzyme
phosphatidylinositol-3-kinase (PI-3-kinase); [Note: Activation of the
insulin-receptor tyrosine kinase domain by insulin-induced
auto-phosphorylation results in the rapid recruitment of PI-3-kinase
enzymatic phosphorylation of signaling complexes that then mediate the
biological effects of insulin, including the up-regulation of glucose
uptake and glycogen synthesis.(17)] The Cinnamon Finding: Test results
conclusively showed that PI-3-kinase was recruited upon insulin receptor
á-subunit auto-phosphorylation induced by the cinnamon extract.
4. Insulin induces activation of Glycogen synthase (GS); The
Cinnamon Finding: Glycogen synthase assays documented greater enzyme
activity due to the cinnamon extract.
5. Insulin induces down
regulation of glycogen synthase kinase-3beta (GSK-3á); [Note: GSK-3á
normally down regulates glycogen synthase in a homeostatic manner. Its
unbalanced down regulation of glycogen synthase is characteristic of Type
2 diabetes and this imbalance is considered to be a component in the
cluster of factors described as insulin resistance. If insulin cannot down
regulate GSK-3á, then liver and muscle glycogen formation cannot
adequately drive post-prandial blood sugar lowering to normal.] The
Cinnamon Finding: Treatment with cinnamon extract resulted in an
inhibition of GSK-3á activity at a level greater than produced by insulin.
After a 60-minute incubation, the cinnamon extract inhibited GSK-3á at
54%, insulin at 25% and the combination treatment of cinnamon extract and
insulin, 56%. Jarvill-Taylor et al concluded that their results
demonstrated that cinnamon possesses an effective water-soluble mimetic of
insulin and that it may be useful in the treatment of insulin resistance
and in the study of the pathways leading to glucose utilization in
cells.
Investigations of Cinnamon Efficacy in Human
Subjects
The results of the first human investigation of the
usefulness of cinnamon (Cinnamomum cassia) for improving blood glucose
levels and lipid levels in Type 2 diabetic subjects were published in
Diabetes Care in December, 2003.(1) Lipid changes were included in the
study because insulin also plays a key role in lipid metabolism and the
effects of cinnamon as a proposed insulin mimetic on lipid metabolism
would be important. The study was conducted in the Department of Human
Nutrition, NWFP Agricultural University, Peshawar, Pakistan.
The
selection criteria for the study specified Type 2 diabetic subjects
who: - Were greater than 40 years old, - Were not on insulin
therapy, - Were not taking medications for any other health
condition, and - Had fasting blood glucose levels between 7.8 and 22.2
mmol/l.
Thirty men and thirty women were enrolled with a mean age
of 52.0 ñ 6.87 years in the placebo group and 52.0 ñ 5.85 years in the
group consuming cinnamon. The duration of diabetes was 6.73 ñ 2.32 years
for the placebo group and 7.10 ñ 3.29 years for the cinnamon treated
group. There were an equal number of men and women in the placebo and
cinnamon treated groups. All subjects were taking sulfonylurea medication
(glibenclamide) and medication did not change during the study.
The study was run for 60 days. The 60 subjects were randomly divided into
six groups of 10 subjects each.
- Group 1 consumed 1 gram of
cinnamon per day [500 mg BID, immediately after lunch and immediately
after dinner]. - Group 2 consumed 3 grams per day [2 X 500 mg TID,
immediately after each meal]. - Group 3 consumed 6 grams per day [4 X
500 mg TID, immediately after each meal]. - Groups 4, 5, and 6
received a suitable placebo capsule with corresponding dosing
instructions.
Cinnamon or placebo was consumed each day for 40
days, after which no cinnamon or placebo was consumed between days 41 and
60 to measure the effects of cinnamon after a washout period. On days 0,
20, 40, and 60, 5 ml of fasting blood was collected from each of the 60
subject.
The Results in the Mean Fasting Plasma Glucose (FPG)
Values
The use of 1, 3, or 6 grams of cinnamon per day for 40
days led to a significant decrease in blood sugar, with the following
observations: - There was no evidence of a dose response - all three
doses produced a similar response. - By day-20, values of reduced FPG
were significant only in Group 3, who received 6 grams of cinnamon per
day. - By day-40, values of reduced FPG were significant in Groups 1
through 3 - decreases in FPG ranged from 18 to 29 percent. - There
were no significant reductions in FPG at any time point in the placebo
groups. - By day-60, FPG levels remained significantly lower only in
Group 1, who received 1 gram of cinnamon per day.
The Results
in the Mean Fasting Serum Lipid Values
Regarding Triglycerides
(TG): - By day-20, TG values were significantly lower only in Group 3
(6 grams/day). - By day-40, TG values were significantly lower in
Groups 1 through 3 - decreases ranged from 23 to 30 percent. - By
day-60, decreases in the TG values of Group 1 (1 gram/day) and Group 2 (3
grams/day) remained significantly lower than they were on day-0. - By
day-60, decreases in the TG values of Group 3 (6 grams/day) no longer
remained significant. - There were no changes in TG in the placebo
groups.
Regarding Total Cholesterol (TC): - By day-20
decreases in TC were significantly lower in Groups 1 through 3. - By
day-40, decreases in TC were significantly lower in Group 1 and 6, with
the TC of Group 3 continuing to fall. - Decreases in TC ranged from
13 to 26 percent. - By day-60, decreases in the TC remained
significant. - There were no changes in the TC in the placebo groups.
Regarding LDL-Cholesterol (LDL): - By day-40, decreases in
LDL were significant in Group 2 (3 grams/day) and Group 3 (6 grams/day),
with 10% and 24% decreases respectively. - LDL decreases in Group 1
(1 gram/day) were not significant by day-40, but continued to decline
through days 21-60, achieving significance by day-60. - There were no
significant LDL reductions in the placebo groups.
The results of
the Khan et al Pakistani study are consistent with the understanding that
cinnamon acts as a mimetic of insulin, as indicated by in vitro and animal
studies. These results are dramatic, but are found in subjects with
baseline fasting plasma glucose levels that ranged between 7.8 and 22.2
mmol/l, much higher than normally seen in Western diabetes control.
In the second human study, Mang et al have published the first
randomized, placebo-controlled, double-blind study to evaluate the effects
of an aqueous cinnamon extract (Cinnamomum cassia) on fasting plasma
glucose, HbA1c, and serum lipids in Western people with Type 2 diabetes.2
The study encompassed the results of 65 patients from the Hannover region
of Germany with an average age of 63 and body mass index (BMI) of 29 to
30. The treatment consisted of an aqueous cinnamon extract taken for four
months, dosed at 1 capsule TID of 112 ml, corresponding to 3 grams of
whole cinnamon powder per day. Patients were excluded from the study if
they were on insulin therapy, but dietary/exercise (23.1%) or oral
anti-diabetic therapies were permitted. In addition, 49.2 percent of
patients were on anti-hypertensive medication and 20 percent were on
medications for dyslipidemia.
After 4 months, the researchers
found that Cinnamomum cassia does indeed significantly reduce FPG similar
to the results found in the Khan et al study, but differing in degree of
FPG reduction. The mean percentage difference between the baseline FPG
values and the post-treatment FPG values for the two groups were: -
Cinnamon group - 10.3 ñ 13.2%, - Placebo group - 3.37 ñ 14.2% (P =
0.046).
Mang and his co-workers attribute the difference between
their 10.3 percent reduction in FPG and the 18 to 29 percent FPG reduction
found in the Khan et al study to the fact that the FPG baseline in the
German population was lower than in the Pakistani population. In fact, the
initial FPG levels in the Mang et al study were comparable to the
post-treatment concentrations of the Khan et al study.
Current
guidelines for the treatment of diabetes recommend maintaining the HbA1c
at < 7%.(18) In the Mang et al study, the mean baseline HbA1c for the
whole study population was 6.79 and no meaningful further reductions were
observed with cinnamon treatment.
In contrast with the Khan et al
study, there were no significant changes in total cholesterol, LDL, or
triglyceride concentrations. Better glycemic control is expected to
improve blood lipids, but Mang et al did not observe this effect. The
researchers suggest that the smaller reductions in FPG and the lack of
effect on the HbA1c may indicate that cinnamon intervention in well
controlled diabetic patients may not offer the strong effects seen in the
Khan et al study.
A third human study by Vanschoonbeek et al was
published in 2006 and provides insight on how cinnamon may be precluded
from having an insulin mimetic effect in postmenopausal Type 2 diabetic
women.(19) Cinnamomum cassia was investigated to determine its effects on
insulin sensitivity and/or glucose tolerance, and blood lipid profiles in
25 postmenopausal patients with an average age of 62.9 ñ 1.5 years and
body mass index of 30.4 ñ 0.9 kg/m2. The study was performed in a 6-week
period and the participants consumed either 1.5 grams of cinnamon per day
or a placebo. During the study were determined blood lipid profiles and
multiple indices of whole-body insulin sensitivity. After the realted six
weeks, researchers found that cinnamon supplementation at 1.5 grams daily
did not improve whole-body insulin sensitivity or oral glucose tolerance
and did not modulate blood lipid profiles in the postmenopausal
population.
The Vanschoonbeek et al study results at first glance
may seem to indicate that the cinnamon effects on glucose metabolism
demonstrated by in vitro and animal studies do not consistently apply to
human subjects. And indeed the significant differences in outcome between
the Khan et al and Mang et al studies do suggest that there is a potential
range of efficacies, depending on how well diabetes is controlled at the
outset of initiating cinnamon supplementation. However, the Vanschoonbeek
et al study is confounded by the postmenopausal nature of the study
population. Typically, after menopause, women gain abdominal fat and
become less sensitive to insulin.(20)
In the postmenopausal years,
fat cells, as well as other cells, convert endogenous adrenal
androstenedione into estrone. From estrone, an equilibrium is established
for estradiol and estriol, which augments the reduced ovarian estrogen
contribution. Gaining greater weight as fat can affect the postmenopausal
levels of the respective estrogens, resulting in increased insulin
resistance. Hormone replacement therapy has been documented to increase
insulin resistance.(20,21)
In 2000, Collison et al observed that
numerous studies had suggested a relation between sex hormones and insulin
sensitivity, but the ability of sex hormones to directly influence insulin
action in peripheral tissues had not been investigated.(22) They examined
the effects of estriol, estradiol and estrone on insulin action in
cultured 3T3-L1 adipocytes, finding that estrogens produced a
statistically significant reduction in the ability of insulin to stimulate
glucose transport independently of a reduction in total cellular GLUT-4
content. This diminished ability of insulin to stimulate glucose transport
was accompanied by a reduction in the total cellular content of insulin
receptor substrates -1 and -2 (IRS-1/IRS-2) and the p85 alpha subunit of
phosphatidylinositol 3'-kinase. By contrast, the cellular content of
protein kinase B was unchanged by hormone treatment, but the magnitude of
insulin-stimulated kinase activity was statistically significantly reduced
after incubation with each of the sex hormones. They further showed that
treatment of 3T3-L1 adipocytes with the estrogens alters the intracellular
distribution of insulin receptor substrate proteins such that the
particulate and soluble pools of these proteins were differentially
affected by hormone treatment. They concluded that estrogens can directly
induce a state of insulin resistance in 3T3-L1 adipocytes in culture, due
in part to decreased cellular content and altered intracellular
distribution of insulin receptor substrate proteins which in turn results
in a reduction in insulinstimulated signalling cascades.
Thus, one
can postulate that in postmenopausal women, circulating estrogen levels
related to the magnitude of body fat can impose a reduction in insulin
sensitivity that cinnamon was unable to overcome in the Vanschoonbeek et
alstudy at 1.5 grams of cinnamon per day. It remains unclear if any dose
of cinnamon would be beneficial in women who have been postmenopausal for
approximately 10 years, as was the case in the Vanschoonbeek et al study.
Other Related Benefits in Diabetes
Cinnamaldehyde
may be a promising anti-thrombotic agent, and its anti-thrombotic activity
may be due to anti-platelet aggregation activity.(5) Since diabetes is
associated with increased risk of platelet aggregation, cinnamon may be
important in some diabetics to prevent inappropriate blood clotting.
In summary
There is much about the actions and
value of cinnamon in diabetes care that is not yet known. However, it
would appear that cinnamon can be helpful in achieving goal blood sugar
levels. Its usefulness might be best realized in people who are newly
discovered to have diabetes, with high levels of FPG and elevated blood
lipid values. Since diabetes care calls for serious life-style changes,
cinnamon can be an initial helping hand in the transition period of life
when new knowledge about food choices and exercise levels is being put
into practice. And for some people, diabetes under good control may still
benefit from cinnamon supplementation. For those who continue to struggle
with poor control, cinnamon may remain an important part of their
regimentation. As to how helpful cinnamon can be in a postmenopausal
diabetic person, perhaps higher daily amounts of cinnamon than 1.5 grams,
as used in the Vanschoonbeek et al study, will offer practical
benefits.
While judicious use of
cinnamon with insulin therapy may provide better control in insulin
treated Type 2 diabetes, and in Type 1 diabetic patients with significant
insulin resistance,
caution is required. Not enough practical information is available to know
how to
recommend such use without physician guidance.
Contraindications
Exposure to cinnamaldehyde from C. cassia
is contraindicated in patients receiving antiplatelet
medications. There is a theoretical concern that cinnamaldehyde in the oil
portion
of C. cassia could potentiate anti-platelet medications. Cinnamaldehyde
has been
reported to inhibit in vitro aggregation in human and rabbit platelets,
but little is known
about the anti-thrombotic activities of cinnamaldehyde in vivo.(5) Huang
et al have demon-
strated that cinnamaldehyde can inhibit collagen-induced and
thrombin-induced platelet
aggregation in vitro in a concentration-dependent manner. In mice,
cinnamaldehyde is
able to markedly prolonged hemorrhage and coagulation times and
effectively reduce
the mortality rate of collagen-epinephrine-induced acute pulmonary
thromboembolism.
Cinnamaldehyde can also significantly inhibit collagen-induced platelet
aggregation in
the rat platelet-rich plasma (PRP).
Use of this product at its recommended amounts during pregnancy or during
the time of
nursing is contraindicated since the full implications to the fetus or to
the newborn are
not known.
Higher amounts of cinnamon used with other natural
substances that lower blood sugar
may present a theoretical risk for relative hypoglycemia in some people.
Examples of such
supplements include chromium, alpha-lipoic acid, bitter melon, Gymnema
sylvestre, garlic,
fenugreek, and Panax ginseng.
Higher amounts of cinnamon used with pharmaceutical medications that lower
blood
sugar may have a sufficient additive effect to present a risk for
hypoglycemia.
No adverse effects have been associated with the oral
use of cinnamon in either a water
extraction or as ground cinnamon in its clinical investigations for
diabetic blood sugar
control. In one study, ground cinnamon was given orally in capsules to 30
patients divided
into three treatment groups, each group receiving a different daily dose,
either 1 or 3
or 6 grams per day, for 40 days.(1) In another study published in 2006, 40
patients received
an aqueous cinnamon extract on a TID basis corresponding to 3 grams of
whole cinnamon
per day for four months with no reported adverse effects.(2) Of particular
note, no
cases of observed clinical or relative hypoglycemia have been mentioned in
these clinical
investigations.
The amount of essential oil in ground Cinnamomum cassia bark is reported
to be 1 to 2
percent, of which 75-90 percent is cinnamaldehyde.(3) Contact with
cinnamaldehyde can
be irritating to mucous membranes and is a potential skin irritant
sensitizer.(4) Since cinnamaldehyde
is volatile and subject to oxidation, some have doubted that it is able to
exert a practical pharmacological effect when commercially prepared as
grounded bark.(3)
However, used in greater amounts than used for cuisine, a residual
presence of cinnamaldehyde
may be relevant.
1. Khan, Alam. et al, Cinnamon improves glucose and
lipids of people with Type 2 diabetes, Diabetes Care, December,
26(12):3215-3218, 2003
2. Mang, B., et al, Effects of a cinnamon extract on plasma glucose, HbA,
and serum lipids in diabetes mellitus type 2, Eur J Clin Invest, May,
36(5):340-344, 2006
3. Newall, Carol A., Linda A. Anderson, J David Phillipson, Herbal
Medicines A Guide for Health-Care Professionals, The Pharmaceutical Press,
London, 1996, pp63-64
4. Jellin, J.M., et al, Pharmacist's Letter/Prescriber's Letter Natural
Medicines Comprehensive Database, 6th ed., Stockton, CA: Therapeutic
Research Faculty
5. Huang, J. et al, Cinnamaldehyde reduction of platelet aggregation and
thrombosis in rodents, Thromb Res, 2006 Apr 17; E-published ahead of
print; refer to PMID:16626787
6. http://en.wikipedia.org/wiki/Cinnamomum
7. Verspohl, E.J., et al, Antidiabetic effect of Cinnamomum cassia and
Cinnamomum zeylanicum in vivo and in vitro, Phytother Res, Mar;
19(3):203-206, 2005
8. Imparl-Radosevich, J., et al, Regulation of PTP-1 and insulin receptor
kinase by fractions from cinnamon: implications for cinnamon regulation of
insulin signalling, Horm Res, 50(3):177-182, 1998
9. Broadhurst, C.L., et al, Insulin-like biological activity of culinary
and medicinal plant aqueous extracts in vitro, J Agric Food Chem, Mar;
48(3):849-852, 2000
10. Onderoglu, S., et al, The evaluation of long-term effects of cinnamon
bark ;and olive oil on toxicity induced by streptozotocin administration
to rats, J Pharm Pharmacol, Nov; 51(11):1305-12, 1999
11. Qin, B. et al, Cinnamon extract (traditional herb) potentiates in vivo
insulin-regulated glucose utilization via enhancing insulin signaling in
rats, Diabetes Res Clin Pract, Dec; 62(3):139-148, 2003
12. Qin, B., et al, Cinnamon extract prevents the insulin resistance
induced by a high-fructose diet, Horm Metab Res, Feb; 36(2):119-125,
2004
13. Verspohl, E.J., et al, Antidiabetic effect of Cinnamomum cassia and
Cinnamomum zeylanicum in vivo and in vitro, Phytother Res, Mar;
19(3):203-206, 2005
14. Kim, S.H., et al, Anti-diabetic effect of cinnamon extract on blood
glucose in db/db mice, J Ethnopharmacol, Mar; 104(1-2):119-123, 2006
15. Jarvill-Taylor, Karalee J., et al, A hydroxychalcone derived from
cinnamon functions as a mimetic for insulin in 3T3-L1 adipocytes, J Am Col
Nutri, 20(4):327-336, 2001
16. Anderson, R.A, et al, Isolation and characterization of polyphenol
type-A polymers from cinnamon with insulin-like biological activity, J
Agric Food Chem, 52:65-70, 2004
17. Shepherd, Peter R., et al, Phosphoinositide 3-kinase: the key switch
mechanism in insulin signaling, Biochem J, 333:471-490, 1998
18. American Diabetes Association, Standards of Medical Care of Diabetes -
2006, Diabetes Care, January; 29 (Suppl):S4-S42, 2006
19. Vanschoonbeek, Kristof, et al, Cinnamon Supplementation does not
improve glycemic control in postmenopausal Type 2 biabetes patients, J
Nutri, 136:977-980, 2006
20. Sites, C.K., et al, The effect of hormone replacement therapy on body
composition, body fat distribution, and insulin sensitivity in menopausal
women: a randomized, double-blind, placebo-controlled trial, J Clin
Endocrinol Metab, May; 90(5):2701-2707, 2005
21. Goodrow, G.J., et al, Predictors of worsening insulin resistance in
postmenopausal women, Am J Obstet Gynecol, February; 194(2):355-361,
2006
22. Collison, M., et al, Sex hormones induce insulin resistance in 3T3-L1
adipocytes by reducing cellular content of IRS proteins, Diabetologia,
November; 43(11):1374-1380, 2000
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