Journal of Inorganic Biochemistry 146 (2015) 97–103

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Journal of Inorganic Biochemistry

journal homepage: www.elsevier.com/locate/jinorgbio

Focused review

Controlling diabetes by chromium complexes: The role of the ligands

Mei Peng, Xiaoping Yang ⁎
Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, PR China

a r t i c l e i n f o a b s t r a c t

Article history: Diabetes, particularly type II diabetes, is a severe disease condition which affects human health worldwide, with a
Received 3 November 2014 dramatically increasing trend in Asian countries including China. Currently, no efficient drugs other than those
Received in revised form 9 January 2015 with observable side effects are available. Chromium complexes, with the most known representative chromium
Accepted 9 January 2015
picolinate, have been listed as one of most attractive health supplements to attenuate this disease condition in
Available online 19 January 2015
western countries. Recent efforts have been made to develop new chromium complexes with novel ligands.
Keywords:
Although fair amounts of reviews have been published to emphasize the biological activity, preclinical and clin-
Chromium complex ical information of chromium picolinate, this mini-review is trying to cover the entire picture of updated research
Anti-diabetes efforts on various chromium complexes highlighting the role of ligands. Chromium phenylalanine sensitizes
Akt insulin cell signaling pathway via the activation of phosphorylation of Akt (protein kinase B (PKB)) and/or
AMPK AMPK (AMP-activated protein kinase). The biological activities, toxicity, pharmacological features and clinical
implications, including the effect of anti-oxidative capacities, protective effect on obese-induced heart dysfunc-
tion, and efficacy and safety of chromium supplementation in diabetes are discussed as well.
© 2015 Elsevier Inc. All rights reserved.

1. Introduction have a broader therapeutic application and a low risk of causing

The rapid prevalence of diabetes mellitus is becoming a global health
problem as a result of population aging, urbanization and lifestyle
changes [1]. Over the past three decades, the number of people with
diabetes mellitus has dramatically increased, making it one of the
most important public health challenges to all countries [2], estimated
to rise to 439 million by 2030 [3]. Rather than a costly disease in devel-
oped countries decades ago, currently, diabetes mellitus is turning out
to be a major burden in developing countries with 80% of cases of
diabetes mellitus worldwide living in less developed countries and
areas. Asian countries including China, India, Pakistan, Indonesia and
Bangladesh are emerging as the major diabetes mellitus pool in the
world [3]. In particular, 11.6% and 50.1% prevalence of diabetes and
prediabetes, respectively, has been estimated in China [4].
Anti-diabetes drugs possess a tremendous market in pharmaceutical
and health industry. The main products are metformin, DPP-4 inhibi-
tors, GLP-1 receptor agonists, pioglitazone glucosidase inhibitors,
sulfonylureas/glinides, acarbose, and SGLT-2 inhibitors. Metformin,
with the weight neutral trait, lowers blood glucose levels, enhances
glucose uptake into the skeletal muscle and reduces cancer incidence.
However, the main contraindication to metformin is a GFR below 60
mL/min with the risk of lactic acidosis [5–7]. Other unpleasant side
effects, including hypoxic comorbidities are further contraindications.
DPP-4 inhibitors, the gliptins sitagliptin, vildagliptin, or saxagliptin
⁎ Corresponding author. Tel.: +86 731 8431 2071; fax: +86 731 8891 2417.
E-mail address: xpyang008@yeah.net (X. Yang).
hypoglycemia [8]. GLP-1 receptor agonists tend to cause weight loss,
particularly when compared to insulin or sulfonylureas [9]. However,
in rodents treatment with the long-acting GLP-1 receptor agonist
Exendin resulted in acinar cell death and inflammation and in accelerat-
ed metaplasia and lesion formation of pancreatic intraepithelial
neoplasia [10,11]. The thiazolidinediones including rosiglitazone and
pioglitazone have a very favorable pattern of action since they enhance
insulin sensitivity of the skeletal muscle and liver, inhibit hepatic gluco-
neogenesis and are anti-inflammatory in various organs [12]. However,
these thiazolidinediones drugs cause fluid retention with associated
peripheral edema due to altered renal sodium and water reabsorption,
the higher rate of fractures and the weight gain [13,14]. Acarbose in-
hibits intestinal alpha-glucosidases, lowers the insulin requirement
without causing hypoglycemia, and causes neither weight loss nor
weight gain. However, gastrointestinal side effects such as flatulence
and diarrhea, and pneumatosis cystoides intestinalis are often seen in
the application of these drugs [15,16]. Sulfonylureas like glibenclamide,
tolbutamide and glimepiride have been broadly used for treating
diabetes since the 1950s. Increased insulin levels reduce blood glucose
concentration but lead to weight gain, a most undesired effect in the
T2D. Hypoglycemia and high cardiovascular risk are other important
adverse effects [17–19]. SGLT-2 inhibitors are newly developed anti-
diabetic drugs. The first drug, Canagliflozin, has been approved by
the FDA in 2013 for clinical use. These inhibitors lessen renal glucose
resorption and thus cause glycosuria and a resulting insulin-
independent reduction in the blood glucose concentration with weight
loss [20]. However, several side effects of this class of drugs have been

http://dx.doi.org/10.1016/j.jinorgbio.2015.01.002
0162-0134/© 2015 Elsevier Inc. All rights reserved.
98 M. Peng, X. Yang / Journal of Inorganic Biochemistry 146 (2015) 97–103
seen such as urinary tract infections, genital mycotic infections,
increased urination and episodes of hypotension. Thus, novel methods
to treat diabetes are needed to be developed.
Chromium is an essential nutrient required for glucose and lipid
metabolism [21] and improves insulin sensitivity by enhancing intra-
cellular signaling [22,23]. Nevertheless, it is worth mentioning whether
chromium that is essential is still controversial since there are neither
known metabolic pathways nor known proteins requiring chromium.
However, supplemental trivalent chromium taken appears to be a
useful tool in the world's fight against epidemic-like appearances of
various manifestations of the metabolic syndrome, especially obesity
and diabetes. Laboratory and clinical studies indicate that certain
forms of trivalent chromium have various capabilities such as overcom-
ing insulin resistance, ameliorating diabetes, suppressing free radical
formation and decreasing SBP. Although the first and most popularly
used chromium complex, CrPic has been marketed for decades, novel
complexes of trivalent chromium with unique ligands have been
continuously prepared and investigated, indicating that the ligand
plays an important role on improving the performance of this kind of
chromium complexes. Thus, this review summarizes bioactivity,
bioavailability and toxicity of several newly developed chromium
complexes highlighting the importance of ligands. The chemical
structures of chromium complexes and their ligands are listed in Fig. 1.
2. Chromium picolinate
CrPic, the complex of chromium and picolinic acid, is the most
extensively studied anti-diabetic and anti-obese chromium complex.
Although its molecular mechanism and biological activities have been
extensively summarized [24], we mainly highlight the ligand picolinate
and the recent progress of its complex afterwards.
Pic is a very important metabolite in neuroscience and brain tumors.
It has been shown that Pic is able to block the neurotoxic, serving as a
neuro-protective agent [25]. One recent study has shown that cerebro-
spinal fluid Pic levels are higher in old people than that in young people
although circadian even plays a more important role on this [26]. It is
Fig. 1. Chemical structures of chromium complexes and their ligands.
interesting that Pic has been shown to have selective toxicity on
simian-virus transformed cells in Petri dish experiment [27] and antitu-
mor activity in mice as well [28]. As a key metabolite in kyurenine
pathway, the effect of Pic has been summarized in one recent review
[29].
Fan et al. reported that CrPic treatment is able to protect hepatocel-
lular injury [30]. Another report shows that CrPic is able to enhance the
Cr translocation through AMPK pathway in 3T3-L1 adipocytes [31].
Also, CrPic improves the glucose uptake in insulin-resistant 3T3-L1
adipocytes via the activation of P38 pathway [32]. The same group has
reported their findings that CrPic exerts the effect via activation of
AMPK pathway using western blot, ELISA and RT-PCR techniques [33].
Interestingly, it has been shown that the traditional Chinese
medicine, Tianmai Xiaoke tablet consists of CrPic, which improves
blood glucose through activating insulin-signaling pathway and
inhibiting PTP1B and PCK2 in diabetic rats [34].
Staniek et al. have shown that CrCl3, CrPic and chromium propionate
have effects on the Zucker obese and Zucker diabetic fatty rats [35].
CrPic administration has effects on the brain of diabetic rats, mainly
via NF-kB and Nrf/HO1 pathway [36]. Interestingly, the data have
shown that Cr histidinate is superior to CrPic in reducing NF-kB expres-
sion and increasing Nrf2 expression in the brain of diabetic rats. The
same group evaluated the effects of CrPic on serotonergic properties
and carbohydrate metabolism in diabetic rats [37]. Sealls et al. have
shown that CrPic is able to modulate cellular cholesterol homeostasis
and impair ABCA1 functions under the conditions of hyperinsulinemia
[38]. Wang et al. show that picolinate induces translocation of CD36 to
the plasma membrane through the signaling pathways in 3T3-L1
adipocytes [39]. CrPic is able to augment insulin-stimulated protein
synthesis. At the molecular level, insulin significantly increased the
mRNA levels of insulin-like growth factor 1 and insulin-like growth
factor 1 receptor [40]. It has been shown that CrPic increases the glucose
uptake in the insulin-resistant 3T3-L1 adipocytes, which is related to the
activation of p38 MAPK, independent of the effect on GLUT4 transloca-
tion [32]. Further, Qiao et al. has shown that CrPic improves glucose
uptake and metabolism through up-regulating the mRNA levels of
 M. Peng, X. Yang / Journal of Inorganic Biochemistry 146 (2015) 97–103
insulin receptor, GLUT4, glycogen synthase, and UCP3 skeletal muscle
cells [41]. Recently, Cefalu et al. showed that modulation of lipid meta-
bolism by CrPic in peripheral tissues may represent a novel mechanism
of action, independent of effects on weight or hepatic glucose produc-
tion [42]. CrPic activated the AMPK and inhibits resistin secretion in
insulin-resistant 3T3-L1 adipocytes [33]. Tan et al. show that CrPic
may affect the oxidative status of piglet hepatocytes, the appropriate
dose of CrPic can inhibit lipid peroxidation [43].
3. Niacin and its chromium complex
NIA, the water soluble vitamin B3, has been used as hypolipidemic
agent since 1955 [44]. It possesses broad-spectrum lipid modifying
properties [45] in addition to elevating HDL cholesterol [46,47] as well
as decreasing both LDL and total cholesterol [44,48,49]. Zambon A
et al. demonstrated that NIA combination therapy with other drugs
including statins raises HDL cholesterol and decreases dense LDL level
[50]. The most recent research by Singh N et al. found that NIA, a
pharmacological Gpr109a agonist, suppressed colitis and colon cancer
in a Gpr109a-dependent manner [51].
The complex of CrNIA has been studied for decades used as a chro-
mium micronutrient. An early study reported that CrNIA can enhance
immunity response and thus, increase disease resistance in calves
[52]. Later, Jain et al. found that CrNIA is able to decrease blood levels
of TNF-α, IL-6 and plasma lipid peroxidation in streptozotocin-treated
diabetic rats. Interestingly, the inflammation protein CRP, GHb and
plasma cholesterol and triglycerides were significantly dropped and
cholesterol/HDL was improved by CrNIA [53]. More importantly,
CrNIA ameliorates sugar-induced SBP elevations by acting as an ACE
inhibitor and lowers the circulating levels of angiotensin-2, affecting
NO system at the same time [54]. Later, the same group found that
CrNIA lowered SBP in a dose-dependent fashion and caused even faster
and more profound changes in SBP when adding antioxidants and
immune modulators to the chromium regimen [55]. Penumathsa et al.
revealed that CrNIA enhances myocardial protection using the model
of STZ-induced diabetic rats after ischemia–reperfusion injury. The
results of molecular mechanistic studies imply that this cardio-protec-
tive effect is mediated by increased activation of AKT, AMPK and
eNOS, leading to an enhanced translocation of the Glut-4 to the caveolar
raft [56]. In 2011, Preuss et al. reported that CrNIA increases life span in
Zucker fatty rats. The results show that the CrNIA had increased average
lifespan (21.8%), median lifespan (14.1%), 30th percentile survival
(19.6%), and maximum lifespan (22%) [57]. Profoundly, Mehdi et al.
reported that CrNIA can alleviate the negative effects of heat stress on
growth performance, carcass traits, and meat lipid oxidation of broiler
chicks without any adverse impacts on blood constituents [58].
Dr. Rains et al. using a U937 monocyte cell culture model found that
hyperketonemia decreased MMP and demonstrated CrNIA improved
glucose metabolism with the normalization of the MMP [59].
4. Phenylalanine and its chromium complex
Phe is a precursor for tyrosine, the monoamine signaling molecular
dopamine, norepinephrine and epinephrine and the skin pigment
melanin. It is found naturally in the breast milk of mammals. Phe has
been used in the manufacture of food and drink products and sold as a
nutritional supplement for its reputed analgesic and antidepressant
effects. It is a direct precursor to the neuromodulator Phe is a commonly
used dietary supplement. Recent studies have shown that the
derivatives of Phe are potent DPP-4 inhibitors, which exert a novel
anti-diabetic biological activity [60,61]. In contrast, CrPhe has been
directly improved to have a great anti-diabetes activity as shown by
various lines of evidence.In vivo study shows that this complex is able
to enhance the insulin sensitivity by amplifying the phosphorylation
of insulin-induced Akt and increase insulin-stimulated glucose uptake
in adipocyte [62]. However, CrPhe is not able to enhance insulin-
99
induced tyrosine phosphorylation of insulin receptor, meaning that
CrPhe may exert its effect on glucose uptake via the downstream insulin
signaling rather than the direct effect on insulin receptor. More interest-
ingly, unlike CrPic, CrPhe does not induce any DNA damage as shown by
DNA cleavage reaction assay [62]. Further, CrPhe does not produce any
degradation of deoxyribose while either positive control Ferric-EDTA in
the presence of ascorbate or CrPic does, measured by deoxyribose deg-
radation assay. As a matter of fact, phenylalanine ligand per se has the
scavenger capacity of hydroxyl radicals via hydroxylation of the phenyl
ring [63]. The in vivo data about CrPhe exhibit stronger information
about its anti-diabetes activity. Using ob/ob mouse model, Yang et al.
have shown that CrPhe increases the intraperitoneal glucose tolerance
capacity by reducing AUC in glucose challenging assay [62]. Intraperito-
neal insulin challenging assay in the ob/ob animal work delivers similar
information [64]. Serum lipid profile shows that CrPhe-treated ob/ob
mice have reduced total cholesterol but no change in HDL, even an in-
creased triglycerol, compared with non-treated ob/ob mice. Important-
ly, tissue homogenates from CrPhe-treated ob/ob livers exhibited
significant reduced levels of lipid peroxidation and protein carbonyla-
tion, compared with liver homogenates from vehicle ob/ob group mice.
Since diabetes patients are frequently associated with cardiovascular
dysfunctions, Dong et al. tried to explore if there are any benefits of
CrPhe on heart function. In vivo comparison experiment by paralleling
side by side CrPic and CrPhe, Dong et al. found that all mechanical
and intracellular Ca2+ abnormalities were greatly either attenuated or
ablated by CrPhe but not CrPic [65]. CrPhe reverses the reduction of
insulin-stimulated glucose uptake in obese mice and improved
basal phosphorylation of Akt and insulin receptor, as well as insulin-
stimulated phosphorylation of Akt and insulin receptor in ob/ob
myocytes. Heart homogenates from ob/ob mice had enhanced oxidative
stress and protein carbonyl formation compared with the lean group,
which were attenuated by chromium supplements. The data indicates
that CrPhe possesses better cardio-protective and insulin-sensitizing
properties against obesity [65]. Using a hindlimb suspension wild type
C57/B6 mouse model, Dong et al. further confirm that CrPhe-treated
mice have minimized skeletal muscle atrophy [66].
5. Salicylate and its chromium complex
Therapeutic compounds containing salicylate first found in plants
have been used for thousands of years and mainly to treat fever and
pain, later used in defense against infection [67]. It was in 1876 that
Ebstein first demonstrated that sodium salicylate could make the symp-
toms of diabetes mellitus totally disappear. Then Williamson obtained
similar observation in 1901 [68]. Interest in salicylate was renewed
ever since some studies found links between inflammation and the
pathogenesis of T2D [69]. Researchers found that the levels of markers
and mediators of inflammation and acute-phase reactants such as IL-6
and C-protein increased in T2D [70,71]. Goldfine AB et al. investigated
the effects of salicylate targeted on inflammation in the treatment of
T2D and results indicated that it could reduce blood glucose, triglycer-
ide, free fatty acid; increased circulating insulin and adiponectin levels
[72]. Recently, the same team assessed the 1-year efficacy and safety
of salicylate in patients with T2D and they concluded that salicylate
could lower HbA1c and improve glycemia. They further verified that sa-
licylate increased adiponectin and hematocrit levels and decreased
fasting glucose, uric acid and triglyceride levels. However, it raised
weight and LDL cholesterol levels at the same time [73]. Meanwhile,
Yang et al. utilized the virus-inducible biobreeding diabetes resistant
(BBDR) rat model to investigate the effects of salicylate on autoimmune
type I diabetes pathogenesis for the first time. It showed that salicylate
prevented diabetes in a dose-dependent manner by inhibiting the ele-
vations in IL-1β, IL-6, IFN-γ and haptoglobin almost completely, and re-
duced IL-12 levels significantly [74].
Due to various biological activities of salicylate in patients with T2D
or cardiovascular diseases with acceptable safety concerns, people
100 M. Peng, X. Yang / Journal of Inorganic Biochemistry 146 (2015) 97–103
consider it as an important ligand to create a series of compounds such
as chromium(III) bounding salicylates. Based on the research by Nan
et al., they found that chromium salicylates decreased total cholesterol,
triglycerides, LDL and increased HDL significantly in obese mice [75].
Physiological parameters indicated that CrSal reduced blood glucose,
fat content and liver weight markedly at the same time [75].
6. Other chromium complexes
As early as 1950s, brewer's yeast was shown to prevent diabetes in
experimental animals [76]. High-chromium yeast had an improved
effect on blood glucose control and lowered serum lipids in the hyper-
glycemic group [77]. Administration of high-chromium yeast with
high-dose (1000 μg/kg per day) for 15 weeks to diabetic mice exerted
significant improvement on blood glucose, GHb, triglyceride, cholester-
ol and other variables [78].
Poljsak et al. have reviewed the interaction of chromium with yeasts
and fungi [79]. Although they did not focus on the Cr(III) complex of
yeasts and fungi, a clear take home message is that compared to higher
valence Cr metal ions, Cr(III) has much less binding activity with both
yeasts and fungi. Hao et al. examined insulin-sensitizing ability of
marine oligosaccharides oligomannuronate and its chromium(III)
complexes from brown alga using C2C12 skeletal muscle cells [80].
They found that chromium(III) complex of oligomannuronate enhanced
insulin-stimulated glucose uptake and increased the mRNA expression
of glucose transporter 4 and insulin receptor after their internalization
into C2C12 skeletal muscle cells [80]. Furthermore, oligosaccharide
treatment significantly enhanced the phosphorylation of proteins
involved in both AMPK/ACC and PI3K/Akt signaling pathways in
C2C12 cells [80]. Increasing energy expenditure in mitochondria has
been seen in this oligosaccharide treatment, indicating the internaliza-
tion into tested cells. Further, increased expression of transcriptional
regulator peroxisome proliferator-activated receptor c coactivator-1,
carnitine palmitoyl transferase-1, and phosphorylated ACC has been
found in this treatment setting [80]. This treatment has much less toxic-
ity but comparable anti-diabetic effect, compared to well known drug
metformin, indicating that oligomannuonate and its chromium(III)
complexes could be used as dietary supplementary or potential drug
for T2D mellitus.
6.1 . Malate and its complex
MA is a natural organic acid which is present in various plants and
plays important roles in some aspects of their properties. MA possessed
good characteristics of improving mitochondrial respiration [81],
carboxylate metabolism [82] and enhancement of natural anti-oxidant
[83], etc. According to the existing researches, the main feature as
natural anti-oxidant is attributed to that MA can reduce the generation
of ROS, lower the activities of anti-oxidant enzymes such as SOD and
GPx.
7. Comparison of complex with different ligands
In Zucker obese and diabetic fatty rats, Staniek et al. conducted a
very interesting study by examining alterations of metal ions in various
tissues between these rats and lean control rats [35]. They found
that the effects of daily gavage administration of CrCl3 (1 mg Cr/kg
body mass), and CrProp ([Cr3O(propionate)6(H2O)3]+) (33 μg and
1 mg Cr/kg body mass) but not CrPic (1 mg Cr/kg body mass) resulted
in lowering the elevated levels of kidney Cu in Zucker diabetic fatty
rats, suggesting a beneficial effect on this symptom of T2D using CrPic,
at 1 mg Cr/kg. Love et al. found that chromium excretion in urine
challenged by insulin is not a biomarker for chromium status [84]. How-
ever, greater cooperative research interactions between nutritionists,
biochemists, and chemists might be helpful to the earlier issues in
nutritional and biochemical Cr research and is necessary to establish
the potential role of Cr as a therapeutic agent at a molecular level [85,
86].
Laschinsky et al. re-investigated the bioavailability of several major
chromium compounds including CrPic, CrNia, CrPhe, CrProp and CrCl3
[87]. The apparent absorption is generally low (0.04–0.24%) in rats but
with slightly higher values for CrCl3 and CrPhe. They argue the fact
that CrPic has higher absorption of Cr attributes than more stable
organic Cr complex. Interestingly, they found that the bioavailability of
CrPic and CrPhe is higher in humans than in rats.
Li et al. reported the preparation of three novel ligands (rutin, folate
and stachyose) of chromium(III) complexes, and examination of their
bioactivities and toxicities [88]. Their results reveal that chromium
rutin and folate complex can decrease blood glucose level, reduce the
activities of aspartate transaminase, alanine transaminase, alkaline
phosphatase, and increase liver glycogen level. They concluded that
chromium folate complex represents an optimal chromium supplement
to control blood glucose in diabetes and non-toxicity in acute manner.
8. Toxicity
The safety and toxicity issues of CrPic are controversial, depending
on the doses and model systems for examination. Significant concerns
about its side effects, particularly regarding the DNA damage have
been raised [89], However, another study shows that administrating
0–50,000 ppm CrPic for 13 weeks in the diet to F334/N rats and
B6C3F1 mice does not induce any adverse hematological, microscopical
or biochemical changes [90]. Cytotoxicity to lymphocytes, increased
levels of lipid peroxidation and micronuclei formation by administering
low concentrations of 200 μg and 400 μg chromium as CrPic for
12 weeks by oral administration in calves have been reported [91].
Evidence for increased urinary and cellular 8-OHdG levels indicative of
oxidative DNA damage and lipid peroxidation in whole animals has
been presented [92]. A recent report has shown that CrPic induces a
concentration dependent apoptosis by using the cytotoxicity data in
peripheral blood lymphocytes, performed in DNA fragmentation
pattern, Annexin V staining, TUNEL positivity, chromatin condensation
and formation of apoptotic bodies [93]. CrPic treatment leads to collapse
of the MMP, Bax expression, increase in cytosolic cytochrome c content
and active caspase-3 and DNA fragmentation, demonstrating that CrPic
is cytotoxic to lymphocytes with ROS and mitochondrial events
involved. Interestingly, no evidence has shown that CrPic induces any
carcinogenesis for a three month period diet treatment in F344/N rats
and B6C3F1 mice by National Toxicology Program [93]. Interestingly, a
novel idea, the possible oxidation of Cr(III) into the Cr(IV) by biological
oxidants in either obesity or diabetes about the toxicity of CrPic, has
been proposed [94].
Shara et al. evaluated the safety and toxicology of CrNIA comprehen-
sively for the first time [95]. Their study evaluated toxicities of CrNIA on
acute oral, acute dermal, primary dermal irritation and primary eye
irritation. The acute dermal LD50 of CrNIA was found to be N2000
mg/kg. A dose-dependent 90-day subchronic toxicity study demon-
strated no significant changes in selected organ weights individually
and as percentages of body and brain weights. CrNIA supplementation
did not cause changes in hepatic lipid peroxidation or DNA fragmen-
tation after 30, 60 or 90 days of treatment. In a previous study,
one year supplementation of a combination of CrNIA, grape seed
proanthocyanidin extract and zinc methionine significantly lowered
SBP in normotensive aging Sprague–Dawley rats, decreased hepatic,
cardiac and renal lipid peroxidation and lowered HbA1c without
showing signs of toxicity [96]. The same group continued their study
in 2007. They reported the evaluation on the long-term (52 weeks)
safety of CrNIA by orally administering either 0 or 25 ppm or the
human equivalency dose of 1000 μg elemental chromium(III) to male
and female Sprague–Dawley rats. It shows no significant changes in he-
patic lipid peroxidation and DNA fragmentation, hematology and
 M. Peng, X. Yang / Journal of Inorganic Biochemistry 146 (2015) 97–103
clinical chemistry, and histopathological evaluation, indicating relative-
ly long term of safety of this chromium complex [97].
In addition to these animal studies, a number of clinical studies were
conducted to demonstrate the safety and efficacy of CrNIA. Crawford
et al. studied 20 overweight African-American women with moderate
diet and exercise consuming 200 μg chromium(III) as CrNIA t.i.d. for
8 weeks had a significant loss of body fat and sparing of muscle (lean
body mass) and no adverse effects were observed [98]. Some other
studies showed similar outcomes [99–101].
Deshmukh investigated the effects of CrNIA on the reproductive
systems of male and female rats, the postnatal maturation and
reproductive capacity of their offspring, and possible cumulative effects
through multiple generations. Results indicated that dietary exposure of
CrNIA to both parental male and female rats of two generations (F0 and
F1) during the premating and mating periods, did not cause any
significant incidence of mortality or abnormal clinical signs. CrNIA did
not affect reproductive performance at the dose of 7.80 and 8.31
mg/kg body weight/day in male and female rats, respectively [102].
Based on the results of the developmental toxicity study, CrNIA was
found to benon-teratogenic in Sprague–Dawley rat, at the dose levels
of 0.50, 2.0, or 8.0 mg/kg/day, respectively [103].
Successful isolation of LMWCr with chromium(VI) and chromium(III)
proteins allows the beginning of chromium toxicity mechanism study
[104].
Regarding the toxicity of CrPhe, we did not find body weight
changes of CrPhe-treated mice either in C57 control and Ob/Ob groups
during the treatment period [62,64,65,105], indicating that CrPhe does
not cause any toxicity. In contrast, All assays regarding DNA damage,
protein carbonylation and lipid peroxidation assay confirmed that
CrPhe rather increases but attenuates the toxicity induced by oxidative
stress, hydroxyl free radicals etc. [62,64,65,105]. However, no evidence
from human subjects is available yet.
So far, no particular side effects in either chromium(III) yeast
complex or LMWCr have been found at the dose used in experimental
models.
9. Clinical implications
Suksombooon et al. conducted a systematic review and meta-
analysis to assess the effects on metabolic profiles and safety of chromi-
um supplementation in diabetes mellitus [106]. They found a total of 25
Fig. 2. The proposed mechanism of chromium action. Chromium exhibits promotion of insulin-induced glucose uptake via amplifying the activation of Akt.
101
trials with 22 studies having chromium mono supplementation, one
trial with combination of chromium yeast, vitamins C and E, and two
trials with combination of CrPic and biotin. The results show that
chromium mono- and combined supplementation significantly
improved glycemic control. Especially, chromium monotherapy signifi-
cantly reduced triglycerides and increased HDL-C levels, improved
glycemic control and no risk difference of adverse events between
chromium and placebo.
In an early review, Broadhurst et al. have summarized the clinical
data of CrPic [107]. Thirteen of 15 clinical studies with a total of 1690
subjects (1505 in CrPic group) showed significant effects on glycemic
control. Positive clinical results from CrPic supplementation included
reduced blood glucose, insulin, cholesterol, and triglyceride levels and
reduced requirements for hypoglycemic medication. Individually, two
weeks after 200 μg chromium daily has shown the benefits on control-
ling the glucose and exogenous insulin levels in a very early clinical
report [108]. This finding has been further confirmed later by other
clinical data by showing the controlling of carbohydrate and lipid
metabolisms [109–112]. With the concept of total parenteral nutrition,
the essential role of chromium in human nutrition has been proposed
[109]. However, it has been noticed that Cr intake and losses of
total parenteral nutrition should be monitored due to the variety of
chromium contents from the nature food [109]. Further, Anderson RA
mentioned another clinical result with Chinese non-insulin dependent
diabetes mellitus condition subjects [110]. It shows that both dose
and form of chromium play a critical role on improvements in the
glucose/insulin system. This information has been further confirmed
by the data of blood glucose, insulin, cholesterol and HbA1C in T2D
mellitus with more than one year follow-up studies [111]. It seems
like that a higher dose is needed when patients have more overt impair-
ments in glucose tolerance and diabetes [111]. By summarizing
published clinical observations, Power M et al. concluded that although
it is clear that dietary supplementation with chromium complex
alleviates insulin resistance, more clinical trials are needed to determine
the dose and duration for treating patients with metabolic syndrome
[112]. Another review has confirmed that CrPic is able to reduce cardio-
vascular risk and improve insulin resistance via sensitizing the insulin
activity via activating GLUT4 translocation with more clinical informa-
tion [113]. Especially, chromium monotherapy with the form enriched
in yeast significantly reduced triglycerides and increased HDL-C levels,
improved glycemic control and no risk difference of adverse events
102 M. Peng, X. Yang / Journal of Inorganic Biochemistry 146 (2015) 97–103

of T2D patients between chromium and placebo [114]. This study Nrf/HO1 nuclear respiratory factor-2/heme oxygenase 1
provided promising and critical information about its safety, and NF-KB nuclear factor kappa B
efficiency in blood glucose variable and oxidative stress. This group 8-OHdG 8-hydroxy-2′-deoxyguanosine
continued their efforts by determining the effect of the same form of Pic picolinate/picolinate acid
chromium supplement on T2D patients with insulin therapy [115]. PTP1B protein tyrosine phosphatase-1B
The results confirmed that T2D patients with insulin treatment could PCK2 phosphoenolpyruvate carboxykinase 2
benefit from chromium-enriched yeast. Although the recruitment size Phe phenylalanine
is limited with only 11 patients the selected medical condition with PI3K phosphoinositide 3-kinase
insulin therapy feature on determining the effect of chromium supple- ROS reactive oxygen species
mentation is very impressive. RT-PCR reverse transcription polymerase chain reaction
In summary, except for a classical complex of chromium with SOD superoxide dismutase
picolinate, a variety of chromium complexes with different ligands is SBP systolic blood pressure
available for further clinical exploration. The potential mechanism of SGLT-2 sodium-glucose co-transporter 2
the chromium complex is represented in Fig. 2. These novel complexes STZ streptozotocin
exhibit better biological activity and lower toxicity. The molecular TUNEL TdT-mediated dUTP nick-end labeling
mechanism of chromium phenylalanine of activating Akt in insulin T2D type 2 diabetes
cell signaling pathway has been explored although possibility of other TNF-α tumor necrosis factor
mechanisms such as AMPK pathway in chromium complex has been UCP3 uncoupling protein-3
confirmed. These advanced effects are attributed to their unique
chemical structures including strong anti-oxidant stress activities.
Very little is known about the molecular mechanism and the evidence Acknowledgments
of the targeted biological molecule(s) is largely unclear. There is a lot
of correlative data but we really need some data to support exactly This work is supported from special fund (840140-008) for
how chromium is binding, transported, and activates these pathways Xiaoxiang Endowed University Professor of Hunan Normal University
in future. to X. Yang.

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