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.
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.
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.