(edited) second revision author changes
1
Cinnamomum burmannii improves insulin serum level in the normal obese subjects :
2
preliminary study
3
4
Flori R. Sari1,*, Hari Hendarto2,*, , Chris Adhyanto3
5
* These authors contribute equally.
6
7
1
8
Islamic State University, Jalan Kertamukti, Pisangan, Ciputat, 15419, Indonesia
9
2
Department of Pharmacology, Faculty of Medicine and Health Sciences, Syarif Hidayatullah
Department of Internal Medicine, Faculty of Medicine and Health Sciences, Syarif
10
Hidayatullah Islamic State University, Jalan Kertamukti, Pisangan, Ciputat, 15419, Indonesia
11
3
12
Islamic State University, Jalan Kertamukti, Pisangan, Ciputat, 15419, Indonesia
Department of Biochemistry, Faculty of Medicine and Health Sciences, Syarif Hidayatullah
13
14
Corresponding author : Flori R. Sari, MD, Ph.D
15
Department of Pharmacology, Faculty of Medicine and Health Sciences, Syarif Hidayatullah
16
Islamic State University, Jalan Kertamukti, Pisangan, Ciputat, 15419, Indonesia
17
Phone : (021) 747-16718
18
Fax : (021) 740-4985
19
e-mail : florirsari@uinjkt.ac.id
20
21
22
23
24
1
1
ABSTRACT
2
Obesity is characterized with excessive accumulation of the body fat which occurs when the
3
energy intake exceeds the expenditure. It is routinely associated with insulin resistance and
4
hyperinsulinemia. Additionally, suppressing insulin level protects female mice from weight
5
gaining. Cinnamon suppresses hyperinsulinemia condition in the type 2 diabetic rat
6
suggesting the possible beneficial role of cinnamon in the obesity. We aimed to investigate
7
the role of cinnamon in the normal obese subjects. In this preliminary cross-over clinical trial,
8
24 normal obese subjects were recruited and divided randomly into two groups, treatment and
9
placebo. Two grams of Cinnamomum burmannii extract were given twice daily for 56 days in
10
the treatment group. Normal obese subjects given placebo were allocated as the placebo
11
group. After finishing the treatment, each of the group ran a one month run-in period, then the
12
groups were cross-overed for the next 56 days. Body Mass Index (BMI), insulin serum level,
13
cholesterol and triglyceride plasma level were measured at the beginning and at the end of the
14
study. No diet restriction nor exercise intervention was given during the study. At the end of
15
the study, BMI in the treatment group were slightly reduced when compared to the placebo
16
group (58% vs. 33%), however, the results did not reach significancies in the statistical level.
17
Moreover, significant reduction in the insulin serum level was observed in 63% subject in the
18
treatment group compared to 33% subject in the placebo group (p < 0.05). Additionally, there
19
were no significant differences of cholesterol and triglyceride plasma level observed in the
20
both group.
21
Conclusion. Cinnamon extract may give beneficial role in the normal obese subjects by
22
suppressing the serum insulin level. Further studies are required to elucidate the specific role
23
of cinnamon in preventing weight gain.
24
Keywords. Cinnamomum burmannii, obesity, insulin, body mass index, lipid profile
2
1
INTRODUCTION
2
Obesity is a metabolic disorder characterized with excessive expansion of adipose
3
tissue due to imbalances between nutrient intake and energetic activity.1 Obesity has
4
remarkably increased worldwide and leads to significant morbidity and mortality related to
5
cardiovascular disease, metabolic syndrome, type 2 diabetes, hypertension, degenerative joint
6
disease and some kinds of cancer. It is affecting 33% of adults in the United States and
7
becomes the most common public health problems.2
8
Some strategies have been proposed to reduce enormous body weight in the obese
9
state by inhibiting fat absorption in the gut or supressing appetite in the brain. Recently, it is
10
found that insulin resistance and hyperinsulinemia are the key characteristics of obesity which
11
contributes to its further complication on health.3-5 In the obese state, compensatory rise of
12
insulin due to hyperglycemia, may lead to insulin resistance.6 Furthermore, hyperinsulinemia
13
may promote obesity, resulting in a vicious cycle between obesity, insulin resistance and
14
hyperinsulinemia.6-11 It has been reported that attenuating hyperinsulinemia in the
15
experimental young female mice provides protection against obesity and reducing insulin
16
secretion may promote weight loss in obese adults with insulin hypersecretion.6,12,13
17
Conclusively, reducing insulin secretion may have beneficial role in the strategy of obesity
18
treatment.
19
Cinnamomum burmannii, widely known as Indonesian cinnamon, Padang cassia or
20
Batavia cassia, is native from Indonesia and has been traditionally used as spices, herb and
21
medicine.14 It is currently marketed as a supplemental herbal for diabetes mellitus,
22
dyslipidaemia and glucose intolerance since experimental and clinical evidence have shown
23
that cinnamon play a role as insulin sensitizing agent. In 3T3L1 adipocyte tissue, cinnamon
24
extract stimulates glucose uptake and glycogen synthesis and further activates glycogen
3
1
synthase.15 Additionally, cinnamon bioactive component stimulates enzymatic reaction of
2
phosphorylation and dephosphorylation, confirming its role as an insulin mimetic.16
3
Furthermore, cinnamon extract may decrease the blood glucose level and stimulate glucose
4
uptake in the experimental type 1 diabetic rat or type 2 diabetic mice.17-20 Recently, evidences
5
have reported that cinnamon component, proanthocyanidin and cinnamaldehyde, improve the
6
formation of pancreatic islet polypeptide and suppress hyperinsulinemia condition in the type
7
2 diabetic rat.21-23
8
In the clinical setting, daily consumption of 1, 3 or 6 g cinnamon supplement
9
reduced the blood glucose level up to 29% in the type 2 diabetic patient24 and routine
10
consumption of 3 g cinnamon supplement in eight weeks reduced body weight and body mass
11
index (BMI) in type 2 diabetic patient.25 These mechanisms may be mediated through the role
12
of cinnamon in improving the body composition and attenuating lipogenic processes in the
13
liver and adipose tissue.26 Conversely, another study reported that 4 month treatment with a
14
dietary supplement containing cinnamon, chromium and carnosine decreased fasting plasma
15
glucose (FPG) and increased fat-free mass, however, there was no difference versus placebo
16
with respect to body weight and body mass index in overweight or obese pre-diabetic
17
subjects.27 Despite our significant understanding of the role of cinnamon in the improvement
18
of diabetes, the roles of cinnamon in obesity and its insulin regulation are largely unknown. In
19
the present study, we investigated the roles of cinnamon in the normal obese subjects.
20
MATERIALS AND METHODS
21
Design
22
The design of this preliminary study was randomized cross-over clinical trial study. The study
23
was divided in two phase, in each of the phase every subject received 56 days of capsules
4
1
(treatment or placebo). Subjects were recruited and allocated randomly into two groups,
2
treatment and placebo. Cinnamomum burmannii extract were given for 56 days in normal
3
obese subjects in the treatment group. Another group of normal obese subjects were given
4
placebo as the placebo group. After finishing 56 days treatment, each of the group ran a one
5
month run-in period, and then the groups were cross-overed for the next 56 days. Subjects
6
were not informed which treatment they have received until the end of the study.
7
Study population
8
This study was conducted in the Faculty of Medicine and Health Science, Islamic State
9
University and was approved by the Ethics Committee and Human Studies Review Board of
10
Faculty of Medicine and Health Science, Islamic State University. Selection criteria for the
11
study were adult normal obese subjects with BMI ≥ 23 kg/m2 and age range from 18 to 70
12
year old. Subjects were excluded from the study if they have
13
(hypertension, diabetes mellitus, coronary artery disease, atherosclerosis), cancer, scheduled
14
diet process, pregnancy, breastfeeding, long term pharmacotherapy (chemotherapy,
15
corticosteroid, insuling sensitizing agent, anti-hypertension and anti-cholesterol).
16
Follow up and outcome measures
17
BMI were measured by dividing body weight (kg) with squared of body height (m). The level
18
of insulin serum was measured by ELISA technique using ELISA insulin kit (Calbiotech,
19
Spring Valley, CA, USA). In brief, subjects sera were incubated for 60 minutes with insulin
20
enzyme conjugate, washed, added with TMB substrat for 15 minutes. After the addition of
21
stop solution, sera were analyzed by ELISA reader. The level of cholesterol plasma was
22
measured by cholesterol esterase/cholesterol oxidase technique using cholesterol kit (Sclavo
23
Diagnostics, Siena, Italy). The level of triglyceride plasma was measured by triglyceride kit
: degenerative disease
5
1
(Diasys Diagnostic System, Holzheim, Germany). Subjects were followed up every 7 days,
2
however, outcome measures were done only on day 1 and day 56. At each visits, the
3
occurrence of study outcomes was ascertained according to the intention-to-treat principle.
4
Cinnamon extract
5
Cinnamon (Cinnamomum burmannii (Ness) Bl. Cortex) was prepared by UD. Rachma Sari
6
and certified by Badan POM Kementerian Kesehatan Republik Indonesia (TR 123365801).
7
Each cinnamon capsules contained 2 g of cinnamon extract. Placebo capsules were packaged
8
as the same as the cinnamon capsule. Both the cinnamon and placebo capsules were packaged
9
in plastic bag containing 14 capsules (two capsules of two gram for 7 days) and prepared for
10
distribution of the subjects. Subjects received two gram of extract twice daily (with the total
11
dose of 4 g/day) for 56 days. The dose were decided based on two studies using dose range
12
from 1 – 6 g/day.24,25 Subjects were evaluated every 7 days for supplement compliance until
13
the end of the study. Compliance was monitored by capsule count, subjects interview and
14
daily diary analysis.
15
Data analysis
16
The variable of this study were the BMI, the level of insulin serum, the level of cholesterol
17
and tryglyceride plasma. All variable data from the recruited patients were incuded in the
18
analyses. Comparison among groups was performed using one-way analysis of variance
19
(ANOVA) or student’s t-test, wherever applicable. Differences were considered as
20
statistically significant at probability value
Cinnamomum burmannii improves insulin serum level in the normal obese subjects :
2
preliminary study
3
4
Flori R. Sari1,*, Hari Hendarto2,*, , Chris Adhyanto3
5
* These authors contribute equally.
6
7
1
8
Islamic State University, Jalan Kertamukti, Pisangan, Ciputat, 15419, Indonesia
9
2
Department of Pharmacology, Faculty of Medicine and Health Sciences, Syarif Hidayatullah
Department of Internal Medicine, Faculty of Medicine and Health Sciences, Syarif
10
Hidayatullah Islamic State University, Jalan Kertamukti, Pisangan, Ciputat, 15419, Indonesia
11
3
12
Islamic State University, Jalan Kertamukti, Pisangan, Ciputat, 15419, Indonesia
Department of Biochemistry, Faculty of Medicine and Health Sciences, Syarif Hidayatullah
13
14
Corresponding author : Flori R. Sari, MD, Ph.D
15
Department of Pharmacology, Faculty of Medicine and Health Sciences, Syarif Hidayatullah
16
Islamic State University, Jalan Kertamukti, Pisangan, Ciputat, 15419, Indonesia
17
Phone : (021) 747-16718
18
Fax : (021) 740-4985
19
e-mail : florirsari@uinjkt.ac.id
20
21
22
23
24
1
1
ABSTRACT
2
Obesity is characterized with excessive accumulation of the body fat which occurs when the
3
energy intake exceeds the expenditure. It is routinely associated with insulin resistance and
4
hyperinsulinemia. Additionally, suppressing insulin level protects female mice from weight
5
gaining. Cinnamon suppresses hyperinsulinemia condition in the type 2 diabetic rat
6
suggesting the possible beneficial role of cinnamon in the obesity. We aimed to investigate
7
the role of cinnamon in the normal obese subjects. In this preliminary cross-over clinical trial,
8
24 normal obese subjects were recruited and divided randomly into two groups, treatment and
9
placebo. Two grams of Cinnamomum burmannii extract were given twice daily for 56 days in
10
the treatment group. Normal obese subjects given placebo were allocated as the placebo
11
group. After finishing the treatment, each of the group ran a one month run-in period, then the
12
groups were cross-overed for the next 56 days. Body Mass Index (BMI), insulin serum level,
13
cholesterol and triglyceride plasma level were measured at the beginning and at the end of the
14
study. No diet restriction nor exercise intervention was given during the study. At the end of
15
the study, BMI in the treatment group were slightly reduced when compared to the placebo
16
group (58% vs. 33%), however, the results did not reach significancies in the statistical level.
17
Moreover, significant reduction in the insulin serum level was observed in 63% subject in the
18
treatment group compared to 33% subject in the placebo group (p < 0.05). Additionally, there
19
were no significant differences of cholesterol and triglyceride plasma level observed in the
20
both group.
21
Conclusion. Cinnamon extract may give beneficial role in the normal obese subjects by
22
suppressing the serum insulin level. Further studies are required to elucidate the specific role
23
of cinnamon in preventing weight gain.
24
Keywords. Cinnamomum burmannii, obesity, insulin, body mass index, lipid profile
2
1
INTRODUCTION
2
Obesity is a metabolic disorder characterized with excessive expansion of adipose
3
tissue due to imbalances between nutrient intake and energetic activity.1 Obesity has
4
remarkably increased worldwide and leads to significant morbidity and mortality related to
5
cardiovascular disease, metabolic syndrome, type 2 diabetes, hypertension, degenerative joint
6
disease and some kinds of cancer. It is affecting 33% of adults in the United States and
7
becomes the most common public health problems.2
8
Some strategies have been proposed to reduce enormous body weight in the obese
9
state by inhibiting fat absorption in the gut or supressing appetite in the brain. Recently, it is
10
found that insulin resistance and hyperinsulinemia are the key characteristics of obesity which
11
contributes to its further complication on health.3-5 In the obese state, compensatory rise of
12
insulin due to hyperglycemia, may lead to insulin resistance.6 Furthermore, hyperinsulinemia
13
may promote obesity, resulting in a vicious cycle between obesity, insulin resistance and
14
hyperinsulinemia.6-11 It has been reported that attenuating hyperinsulinemia in the
15
experimental young female mice provides protection against obesity and reducing insulin
16
secretion may promote weight loss in obese adults with insulin hypersecretion.6,12,13
17
Conclusively, reducing insulin secretion may have beneficial role in the strategy of obesity
18
treatment.
19
Cinnamomum burmannii, widely known as Indonesian cinnamon, Padang cassia or
20
Batavia cassia, is native from Indonesia and has been traditionally used as spices, herb and
21
medicine.14 It is currently marketed as a supplemental herbal for diabetes mellitus,
22
dyslipidaemia and glucose intolerance since experimental and clinical evidence have shown
23
that cinnamon play a role as insulin sensitizing agent. In 3T3L1 adipocyte tissue, cinnamon
24
extract stimulates glucose uptake and glycogen synthesis and further activates glycogen
3
1
synthase.15 Additionally, cinnamon bioactive component stimulates enzymatic reaction of
2
phosphorylation and dephosphorylation, confirming its role as an insulin mimetic.16
3
Furthermore, cinnamon extract may decrease the blood glucose level and stimulate glucose
4
uptake in the experimental type 1 diabetic rat or type 2 diabetic mice.17-20 Recently, evidences
5
have reported that cinnamon component, proanthocyanidin and cinnamaldehyde, improve the
6
formation of pancreatic islet polypeptide and suppress hyperinsulinemia condition in the type
7
2 diabetic rat.21-23
8
In the clinical setting, daily consumption of 1, 3 or 6 g cinnamon supplement
9
reduced the blood glucose level up to 29% in the type 2 diabetic patient24 and routine
10
consumption of 3 g cinnamon supplement in eight weeks reduced body weight and body mass
11
index (BMI) in type 2 diabetic patient.25 These mechanisms may be mediated through the role
12
of cinnamon in improving the body composition and attenuating lipogenic processes in the
13
liver and adipose tissue.26 Conversely, another study reported that 4 month treatment with a
14
dietary supplement containing cinnamon, chromium and carnosine decreased fasting plasma
15
glucose (FPG) and increased fat-free mass, however, there was no difference versus placebo
16
with respect to body weight and body mass index in overweight or obese pre-diabetic
17
subjects.27 Despite our significant understanding of the role of cinnamon in the improvement
18
of diabetes, the roles of cinnamon in obesity and its insulin regulation are largely unknown. In
19
the present study, we investigated the roles of cinnamon in the normal obese subjects.
20
MATERIALS AND METHODS
21
Design
22
The design of this preliminary study was randomized cross-over clinical trial study. The study
23
was divided in two phase, in each of the phase every subject received 56 days of capsules
4
1
(treatment or placebo). Subjects were recruited and allocated randomly into two groups,
2
treatment and placebo. Cinnamomum burmannii extract were given for 56 days in normal
3
obese subjects in the treatment group. Another group of normal obese subjects were given
4
placebo as the placebo group. After finishing 56 days treatment, each of the group ran a one
5
month run-in period, and then the groups were cross-overed for the next 56 days. Subjects
6
were not informed which treatment they have received until the end of the study.
7
Study population
8
This study was conducted in the Faculty of Medicine and Health Science, Islamic State
9
University and was approved by the Ethics Committee and Human Studies Review Board of
10
Faculty of Medicine and Health Science, Islamic State University. Selection criteria for the
11
study were adult normal obese subjects with BMI ≥ 23 kg/m2 and age range from 18 to 70
12
year old. Subjects were excluded from the study if they have
13
(hypertension, diabetes mellitus, coronary artery disease, atherosclerosis), cancer, scheduled
14
diet process, pregnancy, breastfeeding, long term pharmacotherapy (chemotherapy,
15
corticosteroid, insuling sensitizing agent, anti-hypertension and anti-cholesterol).
16
Follow up and outcome measures
17
BMI were measured by dividing body weight (kg) with squared of body height (m). The level
18
of insulin serum was measured by ELISA technique using ELISA insulin kit (Calbiotech,
19
Spring Valley, CA, USA). In brief, subjects sera were incubated for 60 minutes with insulin
20
enzyme conjugate, washed, added with TMB substrat for 15 minutes. After the addition of
21
stop solution, sera were analyzed by ELISA reader. The level of cholesterol plasma was
22
measured by cholesterol esterase/cholesterol oxidase technique using cholesterol kit (Sclavo
23
Diagnostics, Siena, Italy). The level of triglyceride plasma was measured by triglyceride kit
: degenerative disease
5
1
(Diasys Diagnostic System, Holzheim, Germany). Subjects were followed up every 7 days,
2
however, outcome measures were done only on day 1 and day 56. At each visits, the
3
occurrence of study outcomes was ascertained according to the intention-to-treat principle.
4
Cinnamon extract
5
Cinnamon (Cinnamomum burmannii (Ness) Bl. Cortex) was prepared by UD. Rachma Sari
6
and certified by Badan POM Kementerian Kesehatan Republik Indonesia (TR 123365801).
7
Each cinnamon capsules contained 2 g of cinnamon extract. Placebo capsules were packaged
8
as the same as the cinnamon capsule. Both the cinnamon and placebo capsules were packaged
9
in plastic bag containing 14 capsules (two capsules of two gram for 7 days) and prepared for
10
distribution of the subjects. Subjects received two gram of extract twice daily (with the total
11
dose of 4 g/day) for 56 days. The dose were decided based on two studies using dose range
12
from 1 – 6 g/day.24,25 Subjects were evaluated every 7 days for supplement compliance until
13
the end of the study. Compliance was monitored by capsule count, subjects interview and
14
daily diary analysis.
15
Data analysis
16
The variable of this study were the BMI, the level of insulin serum, the level of cholesterol
17
and tryglyceride plasma. All variable data from the recruited patients were incuded in the
18
analyses. Comparison among groups was performed using one-way analysis of variance
19
(ANOVA) or student’s t-test, wherever applicable. Differences were considered as
20
statistically significant at probability value