Curcumin and diabetes: Mechanisms of action and its anti-diabetic properties

Abstract

Curcumin, a yellow substance derived from the Rhizoma Curcumea Longae, is the main constituent of the spice turmeric. It is a lipophylic polyphenol, a bis-alpha,beta-unsaturated beta-diphenone with the chemical formula C21H20O6 and chemical name of (E,E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5 dione). There are numerous studies documenting curcumin's anti-inflammatory and anti-diabetic properties, among which the inhibition of inflammatory cytokines, such as MCP and TNF-a along with the induction of AMPK through inhibition of MAPK play a pivotal role in its mechanisms of action. In this review, the anti-diabetic properties of curcumin and its potential beneficial effects in the prevention and treatment of diabetes mellitus will be discussed.

Full text

CURRENT TOPICS IN NUTRACEUTICAL RESEARCH Vol. 12, No. 4, pp. 135-142, 2014
ISSN 1540-7535 print, Copyright © 2014 by New Century Health Publishers, LLC
www.newcenturyhealthpublishers.com
All rights of reproduction in any form reserved
CURCUMIN AND DIABETES: MECHANISMS OF ACTION AND ITS ANTI-DIABETIC
PROPERTIES
1Christos Kazazis, 2Natalia G. Vallianou, 2Aris Kollas and 3Angelos Evangelopoulos
1Internist, Horonary Lecturer at Leicester University, Samos, Greece; 2Internist, Evangelismos General Hospital, Athens,
Greece; and 3Biologist, Roche Diagnostics, Athens, Greece
[Received May 27, 2014; Accepted July 29, 2014]
[Communicated by Arrigo F.G. Cicero, MD, PhD]
ABSTRACT: Curcumin, a yellow substance derived from the
Rhizoma Curcumea Longae, is the main constituent of the spice
turmeric. It is a lipophylic polyphenol, a bis-a ,b-unsaturated
b-diphenone with the chemical formula C21H20O6 and
chemical name of (E,E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-
1,6-heptadiene-3,5 dione). ere are numerous studies
documenting curcumin’s anti-inflammatory and anti-diabetic
properties, among which the inhibition of inflammatory
cytokines, such as MCP and TNF-a along with the induction
of AMPK through inhibition of MAPK play a pivotal role
in its mechanisms of action. In this review, the anti-diabetic
properties of curcumin and its potential beneficial effects in the
prevention and treatment of diabetes mellitus will be discussed.
KEY WORDS: AMPK, Curcumin, Diabetes, Inammation,
Obesity
Corresponding Author: Natalia G. Vallianou, MD, PhD, 5
Pyramidon str, Municipality of Marathon, 190 05 Athens,
Greece; E-mail: natalia.vallianou@hotmail.com
INTRODUCTION
Diabetes mellitus constitutes a major public health threat,
especially in low and middle-income countries, as it was
estimated that in 2013 382 million people suered from the
disease, while this number is expected to rise to 592 million by
year 2035, according to the IDF. Obesity is an inammatory
process that includes, among other things, increased production
of adipokines as well as increased and decreased production
of pro and anti-inammatory cytokines, respectively; thus,
contributing to the development of type 2 diabetes mellitus and
cancer (Lee et al., 2013). In this paper, we will discuss the anti-
inammatory and possible anti-diabetic eects of a herb used in
traditional Chinese and Indian medicine- Rhizoma Curcumea
Longae and -in particular- one of its active components derived
from turmeric, curcumin (Xie and Du, 2011).
Curcumin 1, the main constituent of turmeric, is a lipophylic
polyphenol, a bis-α,β-unsaturated -diphenone with the
chemical formula C21H20O6 and chemical name of (E,E)-1,7-
bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5 dione).
While it is not soluble in water, it demonstrates considerable
stability in the stomach’s acidic environment, especially when
it is administered with anti-oxidants like vitamin C. ere are
numerous studies documenting curcumin’s anti-inammatory,
anti-diabetic and anti-cancerous properties (Basnet et al.,
2011; Shehzad et al, 2013; Zhang et al, 2013).
Transition from normal weight to obesity leads to appearance
of a low-grade chronic inammation, which plays cardinal
role in the development of type 2 diabetes mellitus. e
hypertrophic adipose tissue is characterized by large adipocytes,
resistant to insulin, and activated macrophages. Furthermore,
decreased production of anti-inammatory molecules, like
adiponectin, and increased production of inammatory ones,
namely leptin, resistin, IL6, MCP-1, TNF-α, PAI-1, Ang II
takes place. Primary mediators for adipose tissue inammation
are toll-like receptors (TLRs) and nuclear factor-κΒ (NF-κB).
e former activates the latter leading to transcription of
inammatory cytokines like IL-6 and TNF-α (Siriwardhana
et al., 2013).
AGEs also play a role in inammation. ey are the result
of glucose interaction mainly with proteins and to a lesser
extent with nucleic acids. Hyperglycemia results in increased
production of AGEs with deleterious eects inside the cell
and the extra-cellular matrix. AGE receptors also play a role
in the inammatory process, as they have been identied
on monocytes and macrophages, and their activation leads
to production of inammatory cytokines from the latter.
AGE receptors have been also recognized on glomerular
mesangial and vascular endothelial cells and are responsible for
production of reactive oxygen species as well as activation of
NF-κB and p21 ras (Goldstein et al., 2010).

136 Curcumin and diabetes
IN VITRO DATA
Experimental exposure of endothelial and Jurkat
T-lymphoblasts to conditions mimicking diabetes mellitus
(high glucose levels or AGE) and subsequent study of curcumin
action on cell membranes have demonstrated a benecial
eect on membrane uidity and transmembrane potential,
resulting in reduction of inammation, by inuencing levels
of lipid peroxidation and MCP-1 release (Lin et al., 2012).
Curcumin inhibits formation of inammatory cytokines
(MCP, IL-6, TNF-α) either directly or through inhibition
of NF-κB and PGE2. Besides, its benecial eect on
inammation is demonstrated by induction of AMPK and
inhibition of MAPK (Siriwardhana et al., 2013). Curcumin
and dimethoxycurcumin in particular inhibit AGE production
by trapping an AGE precursor-methylglyoxal- a mechanism
also identied in other polyphenols (Lin et al., 2012).
ere is mounting evidence that curcumin plays a protective
role against non-alcoholic steatohepatitis, which often
accompanies type 2 diabetes mellitus, through induction of
AGE-R1 gene expression, leading to clearance of AGEs from
the liver. is is achieved in hepatic stellate cells by inhibition
of extracellular signal-regulated kinase (ERK) activity,
induction of gene expression of PPAR-γ, and stimulation
of its transactivity (Jianguo et al., 2012). In the same cells,
it suppresses RAGE gene expression, mainly by interrupting
the p38 MAPK signaling pathway, canceling in that way
membrane translocation of glucose transporter-2 (GLUT2),
and by stimulating PPARγ activity and de novo synthesis of
GSH resulting in suppression of GLUT2 expression (Margina
et al., 2013). Moreover, gluco-conjugates are crucial for life
maintenance polymers of sugars with proteins or lipids.
eir increased hydrolysis involving lysosomal enzymes,
correlates with the levels of oxidative stress, AGE production
and microvascular complications in diabetes mellitus. It is
undeniable that there is a tight link between diabetes and
immune dysfunction (Sparks et al., 2012). On the other hand,
obesity causes endoplasmic reticulum stress, with subsequent
activation of the inammatory cascade, via activation of several
kinases including the c-Jun N-terminal kinase (JNK), leading
to insulin resistance and eventually diabetes (Siriwardhana et
al., 2013).
Curcumin seems to be a potent immune-modulator, as it
promotes apoptotic cell death of activated Jurcat T-cells, by
increasing endoplasmic reticulum stress response, making it
an attractive candidate for treatment of several autoimmune
diseases and diabetes (Zheng et al., 2013).
Accumulation of amyloid in the pancreas, with amylin as
its major component, up-regulated by MCP-1 through JNK,
ERK and NF-κΒ signaling, is also recognized as a factor
contributing to the appearance of insulin resistance and type
2 diabetes (Gota et al., 2010). Curcumin interferes in the
amyloid’s self-assembly, by disassembling the α-helix of the
molecule (Sparks et al., 2012).
A recent study has documented that curcumin signicantly
increases GLP-1 secretion in GLUTag cells in a Ca/Ca
calmodulin-dependent kinase pathway, which is independent
of c-AMP/PKA, PKC and MEK/ERK pathways (Cuomo et
al., 2011). e increased secretion of GLP-1 may be another
mechanism, by which curcumin exerts its anti-hyperglycemic
eects.
Nanocurcumin (curcumin encapsulated PLGA
nanoparticles) demonstrated a better performace in comparison
with curcumin, as far as delay of cataract development is
concerned, in four dierent ways: a) by preventing MDA and
protein carbonyl levels to rise b) by normalizing AR activity
(an enzyme playing a critical role in the polyol pathway) and
subsequently reducing sorbitol levels c) by reducing AGE
formation in soluble protein fraction and d) by improving the
total and soluble protein levels, as protein in-solubilization
is the nal step to lens opacication and cataract (Cai et al.,
2011).
In addition, curcumin is a protein kinase C-a, PKC-β
and ERK1/2 activity suppressor and acts similarly as far as
expression of TGF-β1, CTGF, osteopontin, p300, bronectin
and type IV collagen is concerned (Takikawa et al., 2013).
Furthermore, there is data indicating that curcuming
reduces neuropathic pain by activating the opioid receptors
(Antony et al., 2008). Neuropathic pain, demyelination, nerve
ischemia and reduction of inammation (mainly by inhibiting
phosphorylation of IKK complex and subsequent activation
of NF-κΒ) was augmented by using a SNEDDS curcumin
formulation. is was due to its enhanced bioavailability
compared to the classical formulation, and was attributed to
its globule size, as well as its better dissolution and increased
absorption from the lymphatic system. ese properties were
achieved due to presence of gelucire 44/14, which improves
permeability by inhibiting eux of P-glycoprotein, and
to opening of the tight junctions in Caco-2 cells. On the
other hand, solubilization of curcumin micelles, inhibition
of the eux system, and reduction of curcumin’s intestinal
metabolism, occurred due to vitamin E TPGS in the SNEDDS
formulation (Gramma et al., 2013).
EX VIVO DATA
Despite small sample size (n < 30), a number of studies
has shown that curcumin-treated diabetic rats and diabetic
patients presented with statistically signicant reduction in
blood glucose levels and weight. Animal studies indicate that
curcumin signicantly increases plasma insulin levels and
decreases plasma glucose and glycated hemoglobin levels.
is was attributed to increased hemoxygenase activity in the
pancreas (Tables 1, 2).
Curcumin reduced lysosomal enzyme activity in diabetic
rats by over 65% (Yue et al., 2013). Curcumin seems to
contribute in the prevention of diabetic retinopathy by acting,
among other ways, as an antioxidant and anti-inammatory
agent as well as a VEGF inhibitor. Antioxidant properties are
demonstrated by preventing diabetes-induced decrease in the
retinal antioxidant capacity, inhibition of NF-κB activation
and accumulation of 8-OHdG and nitro-tyrosine, while levels

Curcumin and diabetes 137
of retinal glutathione, superoxide dismutase and catalase are
increased, when curcumin is administered at a dose of 1g/kg
body weight.
Curcumin’s anti-inammatory eects, besides those
mentioned above, are evident in down-regulation
of 5-hydroxy-eicosatetranoic acid, cyclooxygenase,
lipoxygenase and arachidonic acid metabolism.
Regarding curcumin’s eects on angiogenesis, it acts as
a VEGF inhibitor, as well as a VEGF-induced PKCβ II-
translocation inhibitor. In addition, curcumin decreases
levels of stromal cell-derived factor 1 (SDF-1).
Curcumin is also an inhibitor of transcription factor
EGR-1, which encodes a nuclear phospho-protein, vital
for control of several diseases, including diabetes. In this
way, EGR1 and the gene’s expression in endothelial cells,
broblasts and rat retinas is hindered (Wei et al., 2012).
In type 1 diabetic rats, curcumin has contributed
to the prevention of renal brosis by down-regulation
of sphingosine-kinase-1 activity and sphingosine-1-
phosphate production, as this pathway, under conditions
of hyperglycemia, favors overproduction of bronectin
(FN) and transforming growth factor beta (TGF-β). SphK1
expression is blocked due to curcumin’s inhibitory eect
on AP-1 transcriptional activity, and especially, its most
important constituent cJun (Soetikno et al., 2012; Chougala
et al., 2012).
In diabetic rats fed with curcumin at a dose of 100 mg/
kg/day, an approximately 30% reduction in macrophage
inux to the glomerulus was noted. is, was followed by a
twofold reduction in levels of activated NF-κB and reduced
rate of cytosolic IκBα degradation, resulting in reduction
of renal TNF-α and IL-1β mRNA expression by 1.7 and
2.5 fold, respectively. Curcumin has also down-regulated
expression of ICAM-1 and MCP-1 (Aldebasi et al., 2013).
ere is no doubt that accumulation of lipids in the
kidney plays an important role in the pathogenesis of
diabetic nephropathy. In diabetic rats, receiving per os the
same curcumin dose as above, a decrease in plasma and
renal triglyceride levels was noted. is, benecial for the
kidney, eect was attributed to curcumin’s activation of
AMPK, with subsequent suppression of renal regulatory
element-binding protein–1c (SREBP-1c), resulting in
decreased expression of acetyl-CoA-carboxylase, fatty acid
synthase and adipose dierentiation related protein, which
is a marker of triglyceride accumulation in the kidney. An
increase in nephrin expression was also documented (Patel
et al., 2013).
Curcumin is a NADPH-oxidase inhibitor, which is
activated in diabetic neuropathy. It has also reversed
increased MDA concentration and decreased SOD activity
in the spinal cord of STZ-induced diabetic rats, leading to
the reduction of neuropathic pain (Soetikno et al., 2013).
Curcumin has reduced hyperglycemia-induced direct
neuronal damage in rats treated with streptozocin, by acting
as a free radical scavenger in the cerebral cortex, due to its
phenolic -OH groups. Besides, by modulating muscarinic
cholinergic receptors and by down-regulating the α-7
nicotinic receptor and insulin receptor mRNA, it improved
their cognitive performance. Glucose uptake by the cerebral
cortex was also improved through control of increased
GLUT3 expression (Soetikno et al., 2011a).
Neuropathic pain, which is elicited with the help of
TNF-α, among other pro-inammatory cytokines, released
from activated microglia in the dorsal horn of the spinal
TABLE 1. Curcumin-induced changes in glucose levels of diabetic rats
Study Glucose
measured Control Diabetes Diabetes + Cur
100 mg/kg
Diabetes + Cur
150 mg/kg
Diabetes + Cur
200 mg/kg
Huang J, 2013 FBG 5.60±0.64 22.53±3.81 18.34±4.86
Aziz, 2013 FPG 5.06±0.38 16.88±1.73
10.56±0.35
(curcumin 20
mg/kg/d)
Na, 2013 (human
study) FPG 8.4±2.06
(Control group) 7.28±1.77
Yu, 2012 FBG 5.1±0.1 20.6±1.6 13.1±2.2 8.7±1.7
Soetikno, 2012 FPG 6.52±0.33 40.9±0.5 32.8±0.54
Soetikno, 2011 FPG 7.74±1.1 38.49±0.95 32.94±0.93
TABLE 2. Curcumin-induced weight changes in diabetic rats. All values are presented as mean ± S.E.M. C-control group, d – diabetic
rats, d + c – diabetic rats treated with curcumin
Study C D d + cur 100 mg/kg d + c 150 mg/kg d + c 200 mg/kg
Huang J, 2013 490±8.12 362.14±18.14 394.44±19.69
Yu, 2012 401±18 247±19 293±25 332 ± 27
Soetikno, 2011 541±15.05 328.6±12.63 353.2±16.55
Soetikno, 2011 539.5±19.24 325.8±15.98 341.5±15.11

138 Curcumin and diabetes
cord, was reduced in STZ-induced diabetic rats treated
with curcumin, as it was found that its administration
caused reduction in expression of TNF-α receptor, followed
by amelioration of mechanical allodynia and thermal
hyperalgesia (Kumar et al., 2011).
In diabetic rats with cardiomyopathy, curcumin seemed
to contribute in improvement of several echocardiographic
and histologic variables in a statistically signicant manner
in the curcumin treated diabetic rats (Table 4) (Hamind
et al., 2013). e cardiac muscle of STZ-induced diabetic
rats treated with curcumin at a dose of 100 or 200 mg/
kg/day, showed a marked improvement as far as left
ventricular dysfunction (increase in ejection fraction)
and intravetricular septal hypertrophy were concerned
(decreased IVSD). In addition, at the cellular level, it was
proven that curcumin restored histologic abnormalities in
the cardiomyocyte in conjuction with reduction in the rate
of glycogenolysis and reduced hypertrophy and brosis.
At the biochemical level, besides inhibition of markers of
inammation, AGE accumulation and RAGE expression,
decreased levels of myocardial injury markers (CK-MB,
LDH, AST) were noted in the 200 mg/kg/day treated
group. Moreover, cardiomyocyte apoptosis was prevented in
the same group through up-regulation of the anti-apoptotic
protein Bcl-2 and down-regulation of the pro-apoptotic Bax
and caspase-3 proteins. Also, curcumin-induced increased
phosphorylation of Akt and GSK-3β, played a benecial
role in cardiomyocyte’s growth and survival (Rayanta et al.,
2013). Last, but not least, in the cardiac muscle curcumin
acted as an inhibitor of NF-κB, decreased levels of NAD(P)
H oxidase, TGF-β, osteopontin, myocyte enhancer factor-2
and down-regulated protein kinase C-α and β2-mitogen
activated protein kinase (MAPK) pathway, as well as mRNA
expression of transcriptional co-activator p300 (which plays
an important role in cardiac hypertrophy and failure), atrial
natriuretic peptide, accumulation of ECM protein and
increased superoxide production in the left ventricle of
diabetic rats (Wei-Cheng et al., 2014).
Numerous studies on animals, provide insights on
curcumin’s benecial and statistically signicant eects on
renal function and potential underlying mechanisms (Table
3) (Soetikno et al., 2011b; Huang et al., 2013).
HUMAN STUDIES
Recently, a randomized, double-blind, clinical trial
assessed the ecacy of curcumin in delaying the development
of T2DM in the pre-diabetes population (Li-Xin et al.,
2013). A total of 240 participants were assigned to receive
either curcumin (1.5 g/day) or placebo capsules, and
changes in β cell functions (homeostasis model assessment
[HOMA]-β, C-peptide, and proinsulin/insulin), insulin
resistance (HOMA-IR), and anti-inammatory cytokine
(adiponectin) levels were recorded at baseline and at three,
six and nine months of treatment. After nine months,
16.4% of participants in the placebo group were diagnosed
with T2DM, whereas none were diagnosed with T2DM in
the curcumin-treated group. Furthermore, participants in
the curcumin-treated group exhibited a better function of
β cells, with higher HOMA-β and lower C-peptide levels.
e curcumin-treated participants also had lower levels
of HOMA-IR and higher adiponectin concentrations,
compared to the placebo group. erefore, curcumin may
be benecial in a pre-diabetes population to delay or prevent
the development of type 2 diabetes mellitus (Li-Xin et al.,
2013).
Although curcumin has shown ecacy against numerous
human diseases, poor bioavailability due to poor absorption,
rapid metabolism, and rapid systemic elimination have
been documented to limit its therapeutic eects (Lin
et al., 2012). e use of adjuvants, which may block the
metabolic pathway of curcumin is the most common
strategy for increasing the bioavailability of curcumin.
e notion of combining piperine, a known inhibitor of
hepatic and intestinal glucuronidation, was evaluated on
the bioavailability of curcumin in healthy human volunteers
(Jianguo et al., 2012). In humans receiving a dose of 2 g
of curcumin alone, serum levels of curcumin were either
undetectable or very low. On the contrary, concomitant
administration of 20 mg of piperine with curcumin,
resulted in much higher concentrations within 30 min
to 1 h after drug treatment; thus, piperine increased the
bioavailability of curcumin by 2,000%. Other promising
TABLE 3. Curcumin’s eects on renal function parameters. All values are presented as mean ± S.E.M. C-control group, d – diabetic
rats, d + c – diabetic rats treated with curcumin
Study Cur dose
(mg/kg/d)
Plasma
creatinine -
c (mg/dl)
Plasma
creatinine
- d r
Plasma
creatinine
d + c
Ccr - c (ml/
min) Ccr - d Ccr d+c Albuminuria c
(mg / 24 h)
Albuminuria
d
Albuminuria
d+c
Huang,2013 150 0.3 ±
0.06
0.58 ±
0.12
0.36 ±
0.05 14.4 ± 3.56 100 ± 12.87 58.31 ±
14.51
Soetikno,
2013 100 0.3 ±
0.01
2.1 ± 0.1 0.8 ± 0.2 3.9 ± 0.5 0.8 ±
0.2
2.7 ±
0.5
Soetikno,2011 100 0.55 ±
0.02
1.06 ±
0.13
0.69 ±
0.03 3.8 ± 0.9 0.81 ±
0.08
3.61 ±
0.48
Soetikno,
2011 100 0.3 ±
0.01
1.43 ±
0.02
0.36 ±
0.02 3.9 ± 0.7 1.0 ±
0.2
3.0 ±
0.7 13.2 ± 0.6 33.6 ± 5.2 18.8 ± 2.7

Curcumin and diabetes 139
approaches to increase the bioavailability of curcumin
include the use of nanoparticles, liposomes, phospholipid
complexes, and structural analogues (Shoba et al., 1998).
Meriva is a patented phytosome complex of curcumin with
soy phosphatidylcholine that has better bioavailability
than curcumin. e absorption of a curcuminoid mixture
and Meriva was examined in a randomized, double-blind,
human study (Khajehdehi et al., 2012). Total curcuminoid
absorption was about 29-fold higher for the Meriva mixture
than it was for the corresponding unformulated curcuminoid
mixture. Interestingly, the phospholipid formulation
increased the absorption of demethoxylatedcurcuminoids
much more than that of curcumin (Anand et al., 2007).
e bioavailability of curcumin has also been shown to be
greatly enhanced by reconstituting curcumin with the non-
curcuminoid components of turmeric (Te-Yu et al., 2012).
Until now, there are no concerns regarding the safety of
the use of Meriva in human adults (Belcaro et al., 2010).
PERSPECTIVES
Curcumin seems to have a favorable eect in serum
glucose levels, which may be attributed to its ability to inhibit
formation of inammatory cytokines (MCP, IL-6, TNF-α)
either directly or through inhibition of NF-κB and PGE2. In
addition, its benecial eect on inammation is demonstrated
by induction of AMPK and inhibition of MAPK. Studies have
demonstrated a benecial role of curcumin for signicant
diabetic complications, such as diabetic nephropathy,
neuropathy and retinopathy. Further and large-scale studies,
with molecules with better bioavailability, are needed to
conrm its promising potentials in the prevention and
management of diabetes mellitus.
CONFLICTS OF INTEREST STATEMENT
ere is no conict of interest regarding this manuscript.
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142 Curcumin and diabetes