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R E S E A R C H A R T I C L E Open Access
Role of Fenugreek in the prevention of
type 2 diabetes mellitus in prediabetes
Arpana Gaddam
1*
, Chandrakala Galla
1
, Sreenivas Thummisetti
1
, Ravi Kumar Marikanty
1
, Uma D. Palanisamy
2
and Paturi V. Rao
1
Abstract
Background: It is hypothesized that dietary supplementation with Fenugreek modulates glucose homeostasis and
potentially prevents diabetes mellitus in people with prediabetes. The objective of present study is to determine
whether Fenugreek can prevent the outcome of T2DM in non diabetic people with prediabetes.
Methods: A 3-year randomized, controlled, parallel study for efficacy of Fenugreek (n= 66) and matched controls
(n= 74) was conducted in men and women aged 30–70 years with criteria of prediabetes. Fenugreek powder, 5 g
twice a day before meals, was given to study subjects and progression of type 2 diabetes mellitus (T2DM) was
monitored at baseline and every 3 months for the 3-year study.
Results: By the end of intervention period, cumulative incidence rate of diabetes reduced significantly in Fenugreek
group when compared to controls. The Fenugreek group also saw a significant reduction in fasting plasma glucose
(FPG), postprandial plasma glucose (PPPG) and low density lipoprotein cholesterol (LDLc) whereas serum insulin
increased significantly. It was observed that controls had 4.2 times higher chance of developing diabetes compared
to subjects in the Fenugreek group. The outcome of diabetes in Fenugreek group was positively associated with
serum insulin and negatively associated with insulin resistance (HOMA IR).
Conclusions: Dietary supplementation of 10 g Fenugreek/day in prediabetes subjects was associated with lower
conversion to diabetes with no adverse effects and beneficial possibly due to its decreased insulin resistance.
Keywords: Fenugreek, Prediabetes, Impaired fasting glucose, Impaired glucose tolerance
Background
An epidemic of diabetes threatens the health of a large
number of individuals in developed and developing
countries alike [1]. Recent data from the USA indicate
that the prevalence of prediabetes is 34.6 %, impaired
fasting glucose (IFG) is 19.4 %, impaired glucose toler-
ance (IGT) is 5.4 % and that of IFG and IGT is 9.8 % in
the adult population [2]. The epidemic of prediabetes is
likely to compound the existing diabetes crisis as many
individuals with IGT will develop type 2 diabetes melli-
tus (T2DM) in the future. It is estimated that approxi-
mately 316 million people worldwide are with IGT and
this is predicted to rise to 471 million by 2035. Accord-
ing to the estimates of International Diabetes Federation
(IDF) in 2013, India alone has 65.1 million people living
with diabetes; this places India second to China [3].
Plants provide an excellent source of drugs and a large
proportion of currently-available drugs have been either
derived directly or indirectly from plant sources. Present
literature suggests the existence of more than 800 plants
that may possess hypoglycemic activity [4]. The use of
medicinal plants in most developing countries, as a
normative basis for the maintenance of good health, has
been observed extensively. There is a growing global inter-
est in herbal and other forms of traditional medicine [5].
An effective strategy to restrict global impacts of
T2DM is by limiting the number of prediabetics [6]. It’s
our focus to identify new effective therapeutic agents,
with relatively low cost and low toxicity that can be used
regularly to control a progression of T2DM in the predi-
abetic population. Thus, dietary supplements that can
modulate glucose homeostasis and potentially improve
* Correspondence: dr.arpanag@gmail.com
1
Department of Endocrinology and Metabolism, Nizam’s Institute of Medical
Sciences University, Punjagutta, Hyderabad 500082, India
Full list of author information is available at the end of the article
© 2015 Gaddam et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Gaddam et al. Journal of Diabetes & Metabolic Disorders (2015) 14:74
DOI 10.1186/s40200-015-0208-4
lipid parameters would be desirable. Although numerous
herbs are reported to possess antidiabetic activity, a
significant amount of research and traditional usage sug-
gests that Fenugreek seeds (Trigonella foenumgraecum)
are among the best in terms of safety and efficacy [7].
Seeds of Fenugreek are a rich source of fiber and have
multiple benefits in patients with diabetes [8]. Research
in the past two decades has shown that Fenugreek seeds
help to lower blood glucose in patients with diabetes. Its
role as an antidiabetic, by reducing fasting blood glucose
levels and improved glucose tolerance in human subjects
was reported [9]. Fenugreek is currently available as a
nutraceutical with claims to reduce hyperglycemia [10].
Patients, who already manifest abnormalities of glu-
cose handling, could benefit from a low-risk, inexpen-
sive, food-based intervention aimed at normalizing their
metabolic milieu. From the literature it is observed that
Fenugreek is a dietary supplement that may hold prom-
ise in this regard. Though the hypoglycemic and hypo-
lipidemic effects of Fenugreek were evaluated in animal
and human models with T2DM [11], no study has been
reported in prediabetics. The present study assesses the
ability of Fenugreek to prevent T2DM in prediabetics
having IGT/IFG. The objective of present study is to
determine whether Fenugreek can prevent the outcome
of T2DM in non diabetic people with prediabetes. If
pharmacotherapy for prediabetes is initiated, it is import-
ant to realize that any therapy will require a long-term
commitment by both subject and provider. In addition, it
is important to review with the patient that there are lim-
ited data demonstrating the long-term health benefits of
pharmacological intervention compared with lifestyle
intervention [12]. Therefore the present Fenugreek inter-
ventional study was carried out for a period of 3 years.
Methods
The institutional ethics committee reviewed and ap-
proved the research protocol and the informed consent
vide review letter No. IRB/NIMS/080/2010. It is also
confirmed that the ethics committee of Nizam’s Institute
of Medical Sciences is constituted and functions as per
Good Clinical Practice guidelines issued by Central Drug
Standard Control Organisation and Ethical guidelines
for Biomedical research on Human subjects, issued by
Indian Council of Medical Research.
Selection of the subjects
The proposed study was carried out in the Diabetes
Day Care Center of the University Department of
Endocrinology and Metabolism at Nizam's Institute of
Medical Sciences, Hyderabad. The research protocol
and the informed consent was reviewed and approved by
the Institutional Ethics Committee of Nizam’sInstituteof
Medical Sciences University, Hyderabad, India.
Men and women aged between 30–70 years with body
mass index (BMI) ≥19 kg/m
2
, fasting plasma glucose
(FPG) 100–125 mg/dl (IFG) (or) post 75 g oral glucose
load, plasma glucose (oral glucose tolerance test, OGTT)
140–199 mg/dl (IGT) and those who were willing to give
informed consent form were included in the study. Type 1
diabetes subjects, those who were taking drugs that could
alter glucose tolerance, whose fasting triglycerides (TG)
were >400 mg/dl, those who had a history of cancer or
any major illness of the liver, kidney and central nervous
system and women who were pregnant, breast feeding or
planning a pregnancy during the course of the study were
excluded from the study.
Study design
A single blinded (subjects were blinded to allocation), 3-
year follow-up of randomized controlled trial of Fenu-
greek in 66 control and 74 study (Fenugreek) subjects
was initiated in nondiabetic people with prediabetes
(Fig. 1 and Tables 1 and 2). The proposed study design
included investigation of long-term intake of Fenugreek
intervention in persons with prediabetes. Study subjects
and matched-controls were selected and monitored once
Fig. 1 Subject disposition
Gaddam et al. Journal of Diabetes & Metabolic Disorders (2015) 14:74 Page 2 of 10
in every 3 months, for identifying study-specific changes
during and after study period.
All subjects in control as well as study groups were
given similar instructions of physical activity and diet
(adaptation of standard life style measures advised were,
on dietary modification appropriate for weight and activ-
ity, weight reduction as necessary and exercise/physical
activity for at least 30 minutes every day for a minimum
of 5 days every week). Control and study subjects were
counseled once in 3 months with advice on appropriate
lifestyle and dietary practices.
Randomization procedures
After steps of consenting, screening, and diet and life-
style training, all subjects were randomly assigned to
either the Fenugreek group or control group using a
fixed randomization scheme with assignment based on
computer-generated random numbers performed by an in-
dependent researcher. The allocation scheme was sealed in
opaque and consecutively numbered envelopes. Envelopes
were opened sequentially by the independent person.
Fenugreek intervention program
The use of Fenugreek has been limited by its bitter taste
and pungent odor. Isolation of biologically active com-
ponents or production of a debitterized extract, which
would allow greater use of the plant, has been investi-
gated [13]. Debitterized, defatted and deodorized Fenu-
greek fiber with vitamins, minerals and amino acids was
supplied (single batch) by SMS Pharmaceuticals limited
(Jeedimetla, Hyderabad, India). The compound was in
the form of a fine powder. Fenugreek powder (debitter-
ized and processed) 5 g twice a day, was given to the
subjects along with 200 ml of water half an hour before
meals and they were asked to follow the same dosage re-
gime up to the end of study. Number of Fenugreek
packs supplied to and returned by the subjects at the
follow-up visit was reported to calculate the compliance
Table 1 Incidence rate of diabetes during the study period in controls
Control group
Baseline (n= 66) ½ yr (n= 64) 1 yr (n= 59) 1 ½ yrs (n= 50) 2 yrs (n= 38) 2 ½ yrs (n= 32) 3 yrs (n= 27)
NGT 0 11 (17.19) 16 (27.12) 15 (30.00) 9 (23.68) 11 (34.38) 5 (18.52)
IFG 23 (34.85) 14 (21.88) 11 (18.64) 4 (8.00) 4 (10.53) 6 (18.75) 5 (18.52)
IGT 16 (24.24) 6 (9.38) 10 (16.95) 13 (26.00) 10 (26.32) 7 (21.88) 5 (18.52)
IFG + IGT 27 (40.91) 26 (40.63) 13 (22.03) 11 (22.00) 9 (23.68) 3 (9.38) 10 (37.04)
No; for analysis 66 57 50 43 32 27 25
NDDM 0 7 (10.94) 9 (15.25) 7 (14.00) 6 (15.79) 5 (15.63) 2 (7.41)
Known DM 0 0 7 16 23 29 34
Drop outs 0 2 0 0 5 5 5
NDDM newly diagnosed diabetes mellitus, NGT normal glucose tolerance, IFG impaired fasting glucose, IGT impaired glucose tolerance, DM diabetes mellitus. NGT:
FPG <100 and PPPG <140 mg/dl, IFG: FPG 100–125 mg/d l, IGT 140–199 mg/dl, DM: FPG > 125 and PPPG > 200 mg/dl
Figures in parenthesis represent the percentage (%)
Table 2 Incidence rate of diabetes during the study period in Fenugreek group
Fenugreek group
Baseline (n= 74) ½ yr (n= 73) 1 yr (n= 68) 1 ½ yrs (n= 63) 2 yrs (n= 60) 2 ½ yrs (n= 54) 3 yrs (n= 52)
NGT 0 16 (21.92) 21 (30.88) 16 (25.40) 19 (31.67) 19 (35.19) 18 (34.62)
IFG 27 (36.49) 7 (9.59) 12 (17.65) 5 (7.94) 13 (21.67) 6 (11.11) 10 (19.23)
IGT 19 (25.68) 11 (15.07) 6 (8.82) 7 (11.11) 4 (6.67) 13 (24.07) 6 (11.54)
IFG + IGT 28 (37.84) 37 (50.68) 26 (38.24) 32 (50.79) 22 (36.67) 14 (25.93) 13 (25.00)
No; for analysis 74 71 65 60 58 52 47
NDDM 0 2 (2.74) 3 (4.41) 3 (4.76) 2 (33.33) 2 (3.70) 5 (9.62)
Known DM 0 0 2 5 8 10 12
Drop outs 0 1 4 6 6 10 10
NDDM newly diagnosed diabetes mellitus, NGT normal glucose tolerance, IFG impaired fasting glucose, IGT impaired glucose tolerance, DM diabetes mellitus. NGT:
FPG <100 and PPPG <140 mg/dl, IFG: FPG 100–125 mg/d l, IGT 140–199 mg/dl, DM: FPG > 125 and PPPG > 200 mg/dl
Figures in parenthesis represent the percentage (%)
Gaddam et al. Journal of Diabetes & Metabolic Disorders (2015) 14:74 Page 3 of 10
of study medication. Efficacy parameters were assessed
at each visit.
Data collection and measurable methods
Measurements were made at baseline (before treatment)
and once in every 3 months during the study period.
Demographic data was recorded at the baseline; a ques-
tionnaire on medical history and medication was admin-
istered, and body weight, height, and vital signs were
measured. Height, weight, BMI, waist-to-hip ratio
(WHR), FPG, post prandial plasma glucose (PPPG), lipid
profile - serum cholesterol, serum triglycerides (TG),
high density lipoprotein cholesterol (HDLc), low density
lipoprotein cholesterol (LDLc) and serum insulin were
recorded at baseline and during follow-up visits.
By measuring with tape horizontally, the WHR was
calculated, waist as the minimal abdominal circumference
located midway between the lower rib margin and the iliac
crest and hip as the widest circumference over the great
trochanters. The diagnosis of CAD (coronary artery dis-
ease), based on the presence of angina symptoms and ab-
normalities in resting electrocardiogram, was also assessed
at baseline and after each year during the follow-up.
Hypertension was determined by history of high blood
pressure (≥130/85 mmHg).
Dyslipidemia was defined by any of the following: total
cholesterol ≥200 mg/dl, triglycerides ≥150 mg/dl, HDL
cholesterol ≤35 mg/dl, and/or LDL cholesterol ≥100 mg/dl
or taking lipid-lowering drugs. OGTT at 2 h was performed
in all subjects by taking 75 g oral glucose solution after
overnight fasting; and then 2 h later, blood glucose level
was measured. Blood was collected at 8:00 AM from the
antecubital vein while the subjects were in the recumbent
position after an overnight fasting. FPG, HbA1c, total chol-
esterol, triglyceride, HDLc, LDLc and serum insulin levels
were measured according to the standard procedures and
thesampleanalysesweredoneatVimtaLabsLtdwhichis
approved by the College of American Pathologists.
HOMA-IR was calculated to assess change of IR.
Statistical analysis
It was assumed that during a 3-year follow-up period,
36 % subjects with prediabetes (IFG or IGT) develop
clinical diabetes, with annual incidence rates of conver-
sion ranging between 10 and 12 % [14–16]. In the pro-
posed 3-year study it is expected that administration of
Fenugreek reduces the risk of diabetes development in
14 % study subjects. Assuming the risk errors of α= 0.05
and β= 0.20, sample size was calculated based on the
normal approximation to the binominal and was found
to be 73 subjects per group including 20 % drop outs
during the study.
For analysis of outcome variables, values of mean (SD)
at baseline and at the end of 3 years were presented for
both the groups. Statistical analysis was performed by
two-tailed paired t-test for numerical variables, chi-square
test for ordinal variables as appropriate, multivariate ana-
lysis; significance was set at p< 0.05. Cumulative incidence
rate of diabetes during the study period was calculated as
the proportion of individuals who developed diabetes for
every six months (E/N, number of events (E)/number of
persons (N)). Relative risk reduction rate (RRR, control
event rate―study event rate/control event rate) for devel-
oping diabetes was calculated at the end of 3 years. Insulin
secretion and insulin sensitivity were calculated using a
pre-validated formula, homeostasis model assessment
(HOMA). Statistical analysis was performed using the
Statistical Package for Social Sciences 13.0 software ((SPSS
Inc., Chicago, IL).)
Results
Cumulative incidence rate and relative risk reduction of
diabetes
Cumulative incidence rates of diabetes at every six months
for the length of 3 years were 10.6, 24.2, 34.9, 43.9, 51.5
and 55.0 % respectively in the control and 2.7, 6.7, 10.8,
13.5, 16.2 and 23.0 % respectively in the Fenugreek group
(Fig. 2). By the end of the 3-year intervention period, the
cumulative incidence rate of diabetes reduced significantly
Fig. 2 Cumulative Incidence Rate of Diabetes. During the study period at ½, 1, 1½, 2, 2½ and 3 years cumulative incidence rates in control and
Fenugreek groups are represented
Gaddam et al. Journal of Diabetes & Metabolic Disorders (2015) 14:74 Page 4 of 10
in Fenugreek group compared to the control (chi-
square = 13.4; p< 0.01). RRR for developing diabetes at
the end of 3 years was 0.6 in Fenugreek group.
Anthropometric measurements
At baseline and at the end of 3 years, there were no sig-
nificant differences in body weight, BMI, WHR, SBP and
DBP (mean ± SD) within control and Fenugreek groups
(Table 3).
Biochemical parameters
Blood glucose
Subjects within control group had similar FPG and
PPPG by the end of study period. In Fenugreek group,
FPG (103.7 ± 9.5 vs 99.7 ± 11.4 mg/dl; p< 0.05) and
PPPG (142.9 ± 26.6 vs. 129.0 ± 29.6 mg/dl; p< 0.01) had
reduced significantly at the end of 3 years (Table 3).
Lipid profile
When compared with baseline, serum cholesterol, TG,
HDLc were comparable in controls and Fenugreek
group at the end of study period.
However, LDLc was observed to reduce significantly at
the end of 3 years in the Fenugreek group whilst this
was not the case in the control group (117.6 ± 26.3 vs.
110.9 ± 23.9 mg/dl; p< 0.05) (Table 3).
Serum insulin
Serum insulin levels and insulin resistance (HOMA IR)
were similar in control group throughout the study
period (Table 3). This was not the same in the Fenu-
greek group, both serum insulin levels (10.2 ± 4.5 vs.
12.0 ± 5.6 mU/l; p< 0.01) and HOMA IR (2.6 ± 1.1 vs.
2.9 ± 1.5; p< 0.05) increased significantly at the end of
study period (Table 3).
Multivariate analysis
Multiple regression analyses for associations between
presence of diabetes and conventional risk variables in
diabetes viz. gender (both men and women) (Odds Ratio,
OR 0.96, 95 % Confidence Interval, CI 0.21–4.43), inter-
ventional groups (OR 4.18, 95 % CI 1.34–13.09; p<
0.05), age (30–70 years) (OR 1.05, 95 % CI 0.99–1.12),
BMI (OR 0.96, 95 % CI 0.75–1.23), waist circumference
(OR 0.97, 95 % CI 0.85–1.11), hip circumference (OR
1.00, 95 % CI 0.88–1.14), SBP (OR 0.98, 95 % CI 0.94–
1.03), DBP (OR 1.00, 95 % CI 0.93–1.06), serum choles-
terol (OR 1.00, 95 % CI 0.98–1.03), serum TG (OR 1.00,
95 % CI 0.99–1.01), HDLc (OR 0.97, 95 % CI 0.90–1.04),
serum insulin (OR 1.98, 95 % CI 1.30–3.02; p< 0.01) and
HOMA IR (OR 0.07, 95 % CI 0.02–0.30; p< 0.001) were
estimated.
Parameters entered into the model showed a significant
change in 2 log likelihood ratio (p<0.001). The overall p
value for the logistic regression analysis (p= 0.0002) indi-
cates that the independent variables significantly predicts
change in the outcome variable, which is onset of
diabetes.
The odds ratio of 4.18 (p= 0.01) for the intervention
group indicates that subjects in control group have 4.2
Table 3 Mean anthropometric and biochemical measurements in control and Fenugreek groups during the study period
Controls (n= 27) Fenugreek (n= 52)
Baseline 3 years
a
Baseline 3 years
a
Weight, kg 68.53 (10.08) 68.34 (10.09) 69.13 (7.95) 68.79 (8.43)
BMI, kg/m
2
25.95 (3.04) 25.91 (3.38) 26.62 (2.82) 26.43 (3.00)
WHR 0.92 (0.06) 0.91 (0.06) 0.92 (0.07) 0.92 (0.06)
SBP, mmHg 124.56 (14.89) 119.80 (24.66) 124.36 (18.80) 125.09 (18.58)
DBP, mmHg 80.72 (8.62) 77.72 (7.07) 79.36 (11.51) 80.36 (10.64)
FPG, mg/dl 102.8 (9.4) 100.6 (11.04) 103.7 (9.5) 99.7 (11.4)
*
PPPG, mg/dl 146.1 (30.3) 147.3 (32.6) 142.9 (26.6) 129.0 (29.6)
**
S.CHOL, mg/dl 185.5 (38.0) 179.9 (28.5) 183.1 (30.8) 183.9 (34.0)
S.TG, mg/dl 154.4 (78.1) 152.0 (50.6) 152.1 (73.0) 155.1 (69.6)
HDLc, mg/dl 36.5 (7.4) 38.1 (9.2) 37.9 (7.2) 36.4 (6.6)
LDLc, mg/dl 119.0 (28.3) 111.4 (23.3) 117.6 (26.3) 110.9 (23.9)
*
S.Insulin, mU/l 12.2 (7.8) 10.9 (6.9) 10.2 (4.5) 12.0 (5.6)
**
HOMA IR 3.2 (2.2) 2.7 (1.8) 2.6 (1.1) 3.0 (1.5)
*
Values are presented in Mean (Standard Deviation); BMI body mass index, WHR waist to hip ratio, SBP systolic blood pressure, DBP diastolic blood pressure. Data
were calculated by dependent sample ttest
a
No significant difference between baseline and 3 years study for both control and Fenugreek groups. Data were calculated by dependent sample ttest.
*
p < 0.05,
**
p < 0.01: chang e from baseline within the control and Fenugreek groups. FPG fasting plasma glucose, PPPG post prandial plasma glucose, S. CHOL serum
cholesterol, S.TG serum triglyceride, HDLc high density lipoprotein cholesterol, LDLc low density lipoprot ein cholesterol, VLDLc very low density lipoprotein
cholesterol, S.Insulin serum insulin, HOMA IR insulin resistance
Gaddam et al. Journal of Diabetes & Metabolic Disorders (2015) 14:74 Page 5 of 10
times higher chance of developing diabetes when com-
pared to the subjects in Fenugreek group. It was ob-
served that the outcome of diabetes in Fenugreek group
was positively associated with serum insulin (OR 1.98,
95 % CI 1.30–3.02; p< 0.01) and negatively associated
with HOMA IR (OR 0.07, 95 % CI 0.02–0.30; p< 0.001)
(Fig. 3 and Table 4). The results of regression analysis
i.e., the individual odds ratio and their confidence inter-
vals are represented graphically by Forest plot based on
logistic regression (Fig. 3).
Drug compliance
Drug compliance was calculated by pill count method at
every follow-up visit as the percentage of difference be-
tween number of Fenugreek packs supplied and returned
by the subject divided by the total study medication that
subject has to take. Compliance varied at each follow-up
visit with maximum number of subjects having good and
acceptable compliance (Table 5).
Discussion
Globally, T2DM has an enormous impact on the health
care costs and economy, as such it is highly desirable
that this disease be prevented at an early stage. A predia-
betes condition does not necessarily develop into dia-
betes if controlled well. Progression to diabetes can be
prevented by lifestyle interventions and pharmacothera-
peutic modes. There are several effective pharmacological
regimens with encouraging results [17–19] however these
regimens are either not usually economically accessible or
not well tolerated by all [20]. Hence a need to focus on
indigenous, inexpensive food-based regimens.
Traditional plant medicines are used throughout the
world as alternative therapies to control diabetes. Al-
though numerous herbs are reported to possess some
degree of anti-diabetic activity [21], a significant amount
of research, as well as traditional usage suggest that
Fenugreek may be among the best in terms of efficacy
and safety [7]. Though many studies evaluated the
hypoglycemic and hypolipidemic effects of Fenugreek in
animal and human models with type 1 and type 2 dia-
betes, no study is reported in prediabetes till date. Further
this is a first study conducted employing a commercially
debitterized Fenugreek powder in the prevention of
diabetes in subjects with IFG/IGT. The rate of progression
to diabetes during the intervention in controls and Fenu-
greek group is determined in the present study.
Progression to diabetes
It was observed that the conversion rate from IFG and
IGT to diabetes by the end of 3 years reduced signifi-
cantly in Fenugreek group when compared to controls
(Fig. 2). At 3 years, glucose levels have normalized in
18.52 % of controls and 34.62 % of Fenugreek subjects.
In a 11-year follow up study it was stated that many
people with prediabetes (a quarter or more) may revert
to normal glucose tolerance on long term, and after a
protracted follow-up, only about 50 % of people with
IGT or IFG will develop diabetes [22]. In our study the
conversion rate from IFG and IGT to diabetes in con-
trols was similar to the study quoted above. Therefore
this indicates that progression to diabetes from prediabe-
tes stage is subsided by the consumption of Fenugreek as
Fig. 3 Forest plot for multivariate analysis between independent predictor variables and the outcome
Gaddam et al. Journal of Diabetes & Metabolic Disorders (2015) 14:74 Page 6 of 10
the conventional conversion rate of diabetes is lowered
from 55 to 23 % at the end of 3 years due to Fenugreek.
Anthropometric parameters
It was observed that body weight, BMI, SBP and DBP
were unaltered in both control and Fenugreek groups.
Simiarly the patient’s weight, BMI and other clinical pa-
rameters measured were found to be almost stationary
when the dose-dependent effects of Fenugreek in dia-
betes with dyslipidemia were studied [23].
Biochemical parameters
Hypoglycemic effects
During the study period FPG (p< 0.05) and PPPG (p<
0.01) reduced significantly at the end of 3 years in Fenu-
greek group.
The hypoglycemic effect of Fenugreek seed powder
discussed in our study is well supported by few studies
[9, 11, 24, 25] which showed hypoglycemic effect in both
type 1 and type 2 diabetes subjects. In vivo study by
Kumar RV et al. [26] depicted a significant reduction
(p< 0.001) in the postprandial blood glucose levels in
the diabetic rats on treatment with Fenugreek formula-
tion AF40.
Hypolipidemic effects
In this study, serum cholesterol and TG levels were
almost similar by the end of study period within control
and Fenugreek groups, which is in contrast to the stud-
ies which reported that cholesterol and TG levels were
lower in Fenugreek treated animals over untreated dia-
betic animals (p< 0.05) [27, 28]. The small changes in
serum cholesterol and TG levels could be due to the fact
that the mean data for these variables are already in the
normal range.
Within controls and Fenugreek group there were no
significant changes in HDLc throughout the study
period. Analogous to these results few studies also re-
ported that Fenugreek did not alter HDLc levels [23, 29].
The LDLc reduced at the end of 3 years (p< 0.05) in
Table 4 Independent predictors of diabetes on Multinomial logistic regression at the end of the study (3 years)
Independent
variables
B coefficient Odds ratio 95 % CI p- value
Lower bound Upper bound
Gender −0.04 0.96 0.21 4.43 ns
Groups 1.43 4.18 1.34 13.09 0.01
*
Age, yrs 0.05 1.05 0.99 1.12 ns
BMI −0.04 0.96 0.75 1.23 ns
Waist, cm −0.03 0.97 0.85 1.11 ns
Hip, cm 0.00 1.00 0.88 1.14 ns
SBP, mmHg −0.02 0.98 0.94 1.03 ns
DBP, mmHg 0.00 1.00 0.93 1.06 ns
S.CHOL, mg/dl 0.00 1.00 0.98 1.03 ns
S.TG, mg/dl 0.00 1.00 0.99 1.01 ns
HDLc, mg/dl −0.03 0.97 0.90 1.04 ns
S.Insulin, mU/l 0.69 1.98 1.30 3.02 0.001
**
HOMA IR −2.67 0.07 0.02 0.30 0.0004
***
95 %CI 95 % confidence interval, Groups Control and Fenugreek groups, S.CHOL serum cholesterol, S.TG serum triglyceride, HDLc high density lipoprotein
cholesterol, S.Insulin serum insulin, HOMA IR insulin resistance
*
p< 0.05,
**
p< 0.01,
***
p< 0.001
Table 5 Compliance reported during the intervention period
Compliance ½ yr (n:73) 1 yr (n:68) 1 ½ yrs (n:63) 2 yrs (n:60) 2 ½ yrs (n:54) 3 yrs (n:52)
n% n% n% n% n% N%
Poor 3 4.11 6 8.82 6 9.52 1 1.67 2 3.70 9 17.31
Average 8 10.96 7 10.29 3 4.76 5 8.33 9 16.67 7 13.46
Good and acceptable 62 84.93 55 80.88 54 85.71 54 90.00 43 79.63 36 69.23
If % of Drug Compliance: < 50 % - Non-Compliant, 50–70 % - Poor Compliant, 70–80 % - Average, > 80 % - Good and Acceptable
Gaddam et al. Journal of Diabetes & Metabolic Disorders (2015) 14:74 Page 7 of 10
Fenugreek group. Fenugreek seeds contain a gel-like
soluble fiber which combines with bile acid and lowers
triglyceride and LDL cholesterol levels [30].
Insulinotropic effects
In controls, serum insulin levels remained same during
the study period whereas in Fenugreek group, at the end
of 3 years, serum insulin had increased significantly (p<
0.01) in Fenugreek group. Various studies [31, 32] sug-
gested that Fenugreek seeds act as insulin secretor, as
they reported increased insulin secretion in animal stud-
ies. Yadav et al. [33] also suggested that Fenugreek seeds,
more precisely the water extract, act as an insulin secre-
tor but they did not monitor insulin levels.
As serum insulin levels have increased in Fenugreek
subjects, insulin resistance was assessed by HOMA. In-
sulin resistance (HOMA IR) was not different in control
group during the intervention period but within Fenu-
greek group HOMA IR increased significantly at the end
of 3 years (p< 0.05). This is in contrary with the study
which reported that the action of Fenugreek is mediated
by improving insulin sensitivity and decreasing insulin
resistance apart from the known mechanisms of reduced
glucose absorption [11]. The data obtained on insulin re-
sistance in our study are not in agreement with the study
where anti-diabetic properties of 4-hydroxy isoleucine, the
active compound in Fenugreek were seen for its insulino-
tropic action and for extrapancreatic insulin-sensitizing
effects [34]. The studies reported above were done in type
2 diabetes subjects and it cannot be assumed that Fenu-
greek actually increases insulin resistance in prediabetes,
because the serum insulin levels in our study subjects
were within the normal range. In addition, the HOMA-IR
level in the Fenugreek group at the end of 3 years was
within the normal insulin resistance category (<3). Regres-
sion analysis outcome of diabetes in Fenugreek group was
positively associated with serum insulin (p< 0.01) and
negatively associated with HOMA IR (p< 0.001). Fenu-
greek may exert its therapeutic effect through its alkaloids
content by modulation of insulin secretion. The amino
acid 2S,3R,4S, 4-hydroxyisoleucine, purified from Fenu-
greek seeds, showed insulinotropic effects which increased
peripheral glucose uptake in vitro [35].
Strengths, limitations and avenues of the study for future
research
This is a prospective, randomized controlled study con-
ducted in men and women, having different life-styles and
socio-cultural backgrounds but satisfying the inclusion
and exclusion criteria mentioned. Though the sample size
had diversified demographics, their anthropometric, clin-
ical and biochemical parameters were similar at baseline.
This study could target large populations more cost effect-
ively. So far there was no systematic long term study in
prediabetes and as such this is a conventional interven-
tion, carried out for the first time in a different group of
population (prediabetes). No study until now has reported
the incidence conversion rate to diabetes with the inter-
ventional Fenugreek powder in prediabetes. The strength
of this intervention lies on the complexity of data analysis
which illuminates the statistical correlation between inde-
pendent risk factors towards the onset or progression to
diabetes.
Our estimate of the effect of the intervention can be
considered conservative for two reasons. First, data was
analyzed according to the intention-to-prevent principle,
even though some subjects in the intervention group did
not follow the recommendations about Fenugreek con-
sumption. Second, for ethical reasons, all subjects assigned
to the control group also received general health advice and
counseling on dietary patterns at base line and at annual
follow-up visits and may have benefited from this advice.
Participants who dropped out before the end of the
1 year intervention period were not included in the ana-
lysis because if their last observation had been carried
forward, the differences between the two groups would
have been artificially maintained over the follow-up
period. Carrying the last observation forward assumes that
assigning a no-change status is a conservative analysis,
which is not the case, because weight change over time is
nonlinear.
Despite of supplying debitterized processed Fenugreek
powder to the study group, few subjects have skipped
their doses due to its unacceptable palatability. Because
of this reason they were advised to consume it along
with some flavoring agents. This perhaps, could alter the
plasma glucose levels and was found to be one of the
limitations of the study. Though there were many rea-
sons for subject dropouts, one of the reasons was their
unwillingness towards the consumption of Fenugreek on
long term basis due to its undesirable taste. In addition,
subjects did not receive any incentives during the study
due to which there was a lost to follow-up and the drop-
out rate in study group was recorded as 13.5 %.
An alternative prediabetic intervention study can be
carried out with the supplementation of tulsi with Fenu-
greek, which can be used to mask the bitter taste of
Fenugreek. In addition, the role of Fenugreek in different
population groups should also be carried out.
Conclusions
This study provides evidence for the use of Fenugreek to
delay the onset of diabetes in subjects with prediabetes.
Fenugreek powder is useful to lower the blood glucose in
prediabetes. From the results it can be concluded that
Fenugreek showed hypocholesterolemic effects by redu-
cing LDLc levels but without affecting serum TG, HDLc
levels. Our results strongly suggest that the enhancement
Gaddam et al. Journal of Diabetes & Metabolic Disorders (2015) 14:74 Page 8 of 10
of serum insulin levels is due to insulinotropic effects. In
conclusion, our results show that hypoglycemic effects are
due to increasing levels of serum insulin and we suggest
here that the mode of action of Fenugreek may be caused
by their contents of alkaloids.
Abbreviations
BMI: Body mass index; CI: Confidence interval; DBP: Diastolic blood pressure;
FPG: Fasting plasma glucose; HDLc: High density lipoprotein cholesterol;
HOMA: Homeostasis model assessment; ICMR: Indian Council of Medical
Research; IDF: International Diabetes Federation; IFG: Impaired fasting
glucose; IGT: Impaired glucose tolerance; LDLc: Low density lipoprotein
cholesterol; OGTT: Oral glucose tolerance test; OR: Odds ratio; PPPG: Post
prandial plasma glucose; RRR: Relative risk reduction; SBP: Systolic blood
pressure; TG: Triglycerides; VLDLc: Very low density lipoprotein cholesterol;
WHR: Waist to hip ratio.
Competing interests
The authors declare that they have no competing interests.
Authors’contributions
GA screened and examined all the recruited subjects, researched and
analyzed data, and wrote and edited the manuscript. GC, TS and RKM
analyzed data, contributed to the discussion and reviewed the manuscript.
UDP reviewed and edited the manuscript. PVR conceptualized and designed
the study, and reviewed the manuscript. GA is the guarantor of this work
and, as such, had full access to all the data in the study and takes
responsibility for the integrity of the data and the accuracy of the data
analysis. All authors read and approved the final manuscript.
Acknowledgements
We are thankful to Indian Council of Medical Research (ICMR) for providing
Senior Research Fellowship during the study. This work was funded by
Research Society for the Study of Diabetes in India (RSSDI); unrestricted
educational grants were received from DiabetOmics India.
Author details
1
Department of Endocrinology and Metabolism, Nizam’s Institute of Medical
Sciences University, Punjagutta, Hyderabad 500082, India.
2
School of
Medicine and Health Sciences, Monash University Malaysia, Selangor,
Malaysia.
Received: 8 September 2014 Accepted: 26 September 2015
References
1. Cheema A, Adeloye D, Sidhu S, Sridhar D, Chan KY. Urbanization and
prevalence of type 2 diabetes in Southern Asia: A systematic analysis. J Glob
Health. 2014;4:010404.
2. Karve A, Hayward RA. Prevalence, diagnosis, and treatment of impaired
fasting glucose and impaired glucose tolerance in nondiabetic U.S. adults.
Diabetes Care. 2010;33:2355–9.
3. International Diabetes Federation 2013. Diabetes Atlas 6
th
edition.
http://www.idf.org/sites/default/files/EN_6E_Atlas_Full_0.pdf.
[Accessed January 21 2014].
4. Patel DK, Kumar R, Laloo D, Hemalatha S. Diabetes mellitus: an overview on
its pharmacological aspects and reported medicinal plants having
antidiabetic activity. Asian Pac J Trop Biomed. 2012;2:411–20.
5. Hong L, Guo Z, Huang K, Wei S, Liu B, Meng S, et al. Ethnobotanical study
on medicinal plants used by Maonan people in China. J Ethnobiol
Ethnomed. 2015;11:32.
6. Hogan P, Dall T, Nikolov P. Economic costs of diabetes in the US in 2002.
Diabetes Care. 2003;26:917–32.
7. Pandey A, Tripathi P, Pandey R, Srivatava R, Goswami S. Alternative therapies
useful in the management of diabetes: a systematic review. J Pharm
Bioallied Sci. 2011;3:504–12.
8. Ansari R, Ansari S. Effectiveness of fenugreek for lowering hemoglobin
(HbA1c) in patients with self-management of type 2 diabetes: a
randomized, controlled trial. In: Croniger C, editor. Medical Complications of
Type 2 Diabetes. Croatia: InTech; 2011. p. 393–412.
9. Neelakantan N, Narayanan M, de Souza RJ, van Dam RM. Effect of fenugreek
(Trigonella foenum-graecum L.) intake on glycemia: a meta-analysis of
clinical trials. Nutr J. 2014;13:7.
10. Roberts KT. The potential of fenugreek (Trigonella foenum-graecum) as a
functional food and nutraceutical and its effects on glycemia and lipidemia.
J Med Food. 2011;14:1485–9.
11. Gupta A, Gupta R, Lal B. Effect of Trigonella foenum-graecum (fenugreek)
seeds on glycaemiccontrol and insulin resistance in type 2 diabetes
mellitus: a double blind placebo controlled study. J Assoc Physicians India.
2001;49:1057–61.
12. Aroda VR, Ratner R. Approach to the patient with prediabetes. J Clin
Endocrinol Metab. 2008;93:3259–65.
13. Madar Z, Stark AH. New legume sources as therapeutic agents. Br J Nutr.
2002;88 Suppl 3:S287–92.
14. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker
EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle
intervention or metformin. N Engl J Med. 2002;346:393–403.
15. Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-
Parikka P, et al. Prevention of Type 2 diabetes mellitus by changes in
lifestyle among subjects with impaired glucose tolerance. N Engl J Med.
2001;344:1343–50.
16. Tabák AG, Herder C, Rathmann W, Brunner EJ, Kivimäki M. Prediabetes: a
high-risk state for diabetes development. Lancet. 2012;379:2279–90.
17. Kesari AN, Kesari S, Singh SK, Gupta RK, Watal G. Studies on the glycemic
and lipidemic effect of Murraya koenigii in experimental animals.
J Ethnopharmacol. 2007;112:305–11.
18. Rydén L, Standl E, Bartnik M, Van den Berghe G, Betteridge J, de Boer MJ,
et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases:
executive summary. Eur Heart J. 2007;28:88–136.
19. Hanley AJ, Zinman B, Sheridan P, Yusuf S, Gerstein HC, Diabetes Reduction
Assessment with Ramipril and Rosiglitazone Medication (DREAM)
Investigators. Effect of Rosiglitazone and Ramipril on beta-cell function in
people with impaired glucose tolerance or impaired fasting glucose: the
DREAM trial. Diabetes Care. 2010;33:608–13.
20. Alam K, Mahpara S. Role of diet, nutrients, spices and natural products in
diabetes mellitus. Pak J Nutr. 2003;2:1–12.
21. Patel DK, Prasad SK, Kumar R, Hemalatha S. An overview on antidiabetic
medicinal plants having insulin mimetic property. Asian Pac J Trop Biomed.
2012;2:320–30.
22. Shaw JE, Zimmet PZ, de Courten M, Dowse GK, Chitson P, Gareeboo H,
et al. Impaired fasting glucose or impaired glucose tolerance. What best
predicts future diabetes in Mauritius? Diabetes Care. 1999;22:399–402.
23. Mitra A, Bhattacharya D. Dose-dependent effects of Fenugreek composite in
Diabetes with dyslipidemia. Internet J Food Safety. 2006;8:49–55.
24. Deng R. A review of the hypoglycemic effects of five commonly used
herbal food supplements. Recent Pat Food Nutr Agric. 2012;4:50–60.
25. Vijayakumar MV, Singh S, Chhipa RR, Bhat MK. The hypoglycaemic activity of
fenugreek seed extract is mediated through the stimulation of an insulin
signalling pathway. Br J Pharmacol. 2005;146:41–8.
26. Kumar RV, Sinha VR. A novel synergistic galactomannan-based unit dosage
form for sustained release of acarbose. AAPS PharmSciTech. 2012;13:262–75.
27. Xue WL, Li XS, Zhang J, Liu YH, Wang ZL, Zhang RJ. Effect of
Trigonellafoenum-graecum (fenugreek) extract on blood glucose, blood
lipid and hemorheological properties in streptozotocin-induced diabetic
rats. Asia Pac J Clin Nutr. 2007;16 Suppl 1:422–6.
28. Hannan JM, Rokeya B, Faruque O, Nahar N, Mosihuzzaman M, Azad Khan
AK, et al. Effect of soluble dietary fibre fraction of Trigonellafoenumgraecum
on glycemic, insulinemic, lipidemic and platelet aggregation status of Type
2 diabetic model rats. J Ethnopharmacol. 2003;88:73–7.
29. Broca C, Gross R, Petit P, Sauvaire Y, Manteghetti M, Tournier M, et al.
4-Hydroxyisoleucine: experimental evidence of its insulinotropic and
antidiabetic properties. Am J Physiol. 1999;277(4 Pt 1):E617–23.
30. Kadan S, Saad B, Sasson Y, Zaid H. In Vitro Evaluations of Cytotoxicity of
Eight Antidiabetic Medicinal Plants and Their Effect on GLUT4 Translocation.
Evid Based Complement Alternat Med. 2013;2013:549345.
31. Devi BA, Kamalakkannan N, Prince PS. Supplementation of fenugreek leaves
to diabetic rats. Effect on carbohydrate metabolic enzymes in diabetic liver
and kidney. Phytother Res. 2003;17:1231–3.
32. Eidi A, Eidi M, Mousa S. Effect of fenugreek (Trigonellafoenum-graecum L)
seeds on serum parameters in normal and streptozotocin-induced diabetic
rats. Nutr Res. 2007;27:728–33.
Gaddam et al. Journal of Diabetes & Metabolic Disorders (2015) 14:74 Page 9 of 10
33. Yadav M, Tomar R, Prasad GBKS, Jain S, Yadav H. Complementary
hypoglycemic and anti-hyperglycemic activity of various extracts of
Fenugreek seeds in rats. Asian J Biochem. 2008;3:182–7.
34. Broca C, Breil V, Cruciani-Guglielmacci C, Manteghetti M, Rouault C, Derouet
M, et al. Insulinotropic agent ID-1101 (4-hydroxyisoleucine) activates insulin
signaling in rat. Am J Physiol Endocrinol Metab. 2004;287:E463–71.
35. Wang Z, Wang J, Chan P. Treating type 2 diabetes mellitus with traditional
chinese and Indian medicinal herbs. Evid Based Complement Alternat Med.
2013;2013:343594.
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