Biometals
DOI 10.1007/s10534-017-9996-y
Zincs role in the glycemic control of patients with type 2
diabetes: a systematic review
Gabrielli Barbosa de Carvalho . Paula Nascimento Brandao-Lima . Carla Soraya Costa Maia .
Kiriaque Barra Ferreira Barbosa . Liliane Viana Pires
Received: 26 December 2016 / Accepted: 22 January 2017
Springer Science+Business Media New York 2017
Abstract Past research has shown the importance of
zinc in several metabolic processes, such as the
glucidic metabolism. The present systematic review
aims to discuss zincs participation in the glycemic
control of type 2 diabetes mellitus (DM2) patients. In
order to accomplish that, a systematic search was
performed in the Pubmed database using the following
indexed and theme-related descriptors: zinc AND
type 2 diabetes mellitus, AND MeSH terms related
to glycemic control combined with the boolean
operator OR. In total, 1078 articles were retrieved
from the research, of which 15 articles of original
studies conducted with DM2 patients were included,
with three being about the effect of mineral
G. B. de Carvalho
Graduation in Nutrition, Department of Nutrition, Federal
University of Sergipe, Sao Cristovao, Sergipe, Brazil
P. N. Brandao-Lima
Health Sciences Post-graduation Program, Department of
Medicine, Federal University of Sergipe, Aracaju,
Sergipe, Brazil
C. S. C. Maia
Department of Nutrition, State University of Ceara,
Fortaleza, Ceara, Brazil
K. B. F. Barbosa
L. V. Pires (&)
Department of Nutrition, Federal University of Sergipe,
Avenida Marechal Rondon, S/N Jardim Rosa Elze,
Sao Cristovao, Sergipe 49100-000, Brazil
e-mail: lvianapires@gmail.com;
lvpires@usp.br
supplementation and 12 reporting observational stud-
ies. The main findings of these studies consisted of low
body contents of zinc and high excretion of zinc in
urine. Hyperglycemia was one of the mechanisms that
caused these alterations owing to its interference in
zinc reabsorption via renal cells. Another evidence
was the negative correlation between the glycated
hemoglobin percentage (%HbA1c) and the plasma
zinc levels. Additionally, it has been observed that
zinc supplementation in DM2 patients has improved
glycemic control, since the %HbA1c significantly
reduced in these individuals. This present review
shows the positive effect of adequate zinc levels on
glycemic control, whether it is through dietetic
ingestion or supplementation, since its role in insulin
homeostasis is clear.
Keywords Zinc
Glycemic control
Diabetes

Insulin
Introduction
Zinc widely participates in physiological processes,
such as glucidic metabolism (Chimienti 2013; Badran
et al. 2016). Highly present in beta cells of the
pancreas (Lemaire et al. 2009), its participation in
glucidic metabolism occurs during the synthesis,
storage, crystallization, and secretion of insulin (Cap-
dor et al. 2013; Shan et al. 2014; Maruthur et al. 2015).
In addition, zinc is involved in the phosphorylation of
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insulin receptors and regulation of signaling by
tyrosine-phosphatase (Wijesekara et al. 2009; Shan
et al. 2014).
Zincs deficiency can lead to an increase in
circulating glucose due to beta cells malfunctioning
and resistance to insulin, which makes it easier for
type 2 diabetes mellitus (DM2) to happen (Kazi et al.
2008; Saharia and Goswami 2013). On the other hand,
the disease can alter this minerals body homeostasis
(Saharia and Goswami 2013).
Individuals with DM2 can present with low
erythrocyte and plasma zinc body concentrations,
combined with hyperzincuria and intestinal malab-
sorption (Jasen et al. 2012; Sinha and Sen 2014). A
few studies showed that the daily supplementation of
zinc is capable of improving fasting glucose, serum
insulin and glycated hemoglobin of individuals with
DM2 (Oh and Yoon 2008; Parham et al. 2008). In
addition to a better glycemic control, zinc can reduce
the emergence of microvascular complications
through the reduction of reactive oxygen species
caused by the action of superoxide dismutase, an
enzyme that depends on zinc in its catalytic center
(Basaki et al. 2012). In this regard, this review
proposes to discuss the participation of zinc in the
glycemic control mechanisms of patients with DM2.
Materials and methods
Literature review or Search strategy
This research consists of a systematic review, aiming
to discuss the main effects of zinc status in the glucidic
control of patients with DM2. The Pubmed database
was used to search for studies published from January
2006 to March 2016.
The search strategy included indexed English terms
from Health Sciences Descriptors (DeCS) and Med-
ical Subject Headings (MeSH), as its informed as
follows: zinc OR blood metal OR trace ele- agreement, 0.600.79 = Substantial agreement, and
ment OR micronutrient; AND type 2 diabetes 0.801 = Almost perfect agreement. The analyses were
mellitus, combined with the boolean operator OR by
similar MeSH terms; AND glucose OR glucose
metabolism OR insulin resistance OR insulin-
resistant OR hyperglycaemia OR glycemic con- Results and discussion
trol OR glycaemic control OR glucose intoler-
ance OR glucose metabolism disorders OR
hyperglycemia.
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Biometals
Selecting studies and evaluation
The observational, casecontrol, and supplementation
studies, performed in humans, which presented data
related to the nutritional state of zinc (Serum, Plasma, or
Erythrocyte) and glycemic control (Fasting Glucose,
Postprandial Glucose, %HbA1c, Serum Insulin, or C
Peptide) were considered eligible. There was no restric-
tion regarding the language used in the publications.
In vitro studies in animals and review studies were
excluded, as well as articles that did not present an
abstract or those published only in an abstract format.
The reading of the titles and abstracts was accom-
plished independently by two reviewers. Selected
articles met the eligibility criteria described above.
The controversial cases were discussed and rated by a
third reviewer. Then, the pre-selected articles were
entirely read by two reviewers and those which did not
answer this primary question were excluded. After the
selection of the eligible articles, an evaluation of their
references lists to include important articles concern-
ing this topic was performed.
The Kappa coefficient was calculated to measure
the inter rater reliability in each selection stage. The
present review was elaborated according to the
guidelines proposed by the PRISMA method (Pre-
ferred Reporting Items for Systematic Reviews and
Meta-analysis). The articles selection stages are
outlined in Fig. 1.
Analysis
Descriptive statistics using the present data in the
articles was carried out in order to characterize the
individuals participating in the study. The agreement
rate among the evaluators was determined by the Kappa
coefficient, according to Landis and Kochs (1977)
classification, considering \01 interval, being
\0 = No agreement, 00.19 = Poor agreement,
0.200.39 = Fair agreement, 0.400.59 = Moderate
executed by using R statistics software (3.2.3 version).
Based on the eligibility criteria, out of 618 articles
found on the search, 33 were selected for full reading
Biometals

Research in PubMed

1078 articles

Exclusion of the studies performed in animals

618 articles found

Articles selected by their titles and abstract

33 articles selected for

full reading
Not meeting the inclusion criteria (n=15)
Full study unavailable or available as an
abstract (n=4)

Eligible articles final selection

14 Articles considered Inclusion of 1 article after checking

eligible the included articles references

15 Articles included in the

review

Fig. 1 Selection of studies about the role of zinc on glycemic control flow chart

with Kappa score of 0.868 (95% 0.7990.937 confi-
dence interval). After full reading of the articles, 15
articles with 0.937 Kappa score (95% confidence
interval: 0.5971.0), were selected, characterizing
almost perfect agreement among the raters from
the selection stages. From 15 articles included in this
review, three (3) are mineral supplementation studies
and the other twelve (12) are observational studies.
In the present review, 1290 individuals with DM2
and 655 healthy individuals, from both sexes, were
evaluated, with an age average of 49.78 8.47 years
for the DM2 group and 36.5 20.38 years for the
healthy group. The main results are presented in
Table 1.
Nutritional status of zinc and type 2 diabetes
mellitus
Studies have suggested that the imbalance in body zinc
levels may play an important role in the pathogenesis

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 Table 1 Main results about zinc status and glycemic control of patients with type 2 diabetes
Author, Study design N Age Studied Main results
year variables

123
Al-Maroof Part 1: Part 1 Control group: 39 9.3 years Dietetic Differences among the averages of zinc ingestion in the groups were not found
and Al- Randomized 101 individuals with DM2 DM2 group: 54.6 9.2 years ingestion Positive correlation between zinc dietetic ingestion and serum zinc concentration in
Sharbatti casecontrol (R24 h) the control group
(2006) study 133 healthy individuals
Serum zinc Lower serum zinc concentration in diabetic and healthy women when compared to
Part 2: Single- Part 2
Fasting men from both groups
blind 43 individuals with DM2 supplemented glucose
interventional with zinc DM2 was associated with the average reduction of 12.56 lg/dL in serum zinc
study %HbA1c concentrations
43 individuals with DM2 supplemented
with placebo Strong inverse correlation between %HbA1c and serum zinc was observed before the
supplementation
During the second part of the study there was a significant %HbA1c reduction in the
supplemented group (0.3%)
Nsonwu Transversal 60 individuals with DM2 DM2 group: 51.8 years Fasting Higher urinary zinc excretion in individuals with DM2 than in control individuals
et al. study 40 control individuals Control group: 50.6 years glucose Lower serum zinc concentration in individuals with DM2 than in control individuals
(2006) Serum zinc 5575 years individuals with DM2 presented higher urinary zinc excretion
Urinary zinc Women with DM2 presented higher serum zinc concentration and lower urinary zinc
excretion when compared to men with DM2
The longer the diabetes duration, the lower the serum zinc concentration and the
longer this mineral urinary excretion
Marreiro Transversal 31 individuals with DM2 2060 years Dietetic Average urinary excretion within normality (300600 lg Zn/24 h)
et al. study ingestion 35.5% of the patients with a high urinary excretion of zinc
(2007) (R24 h)
It was not observed any correlation between urinary zinc and fasting glucose
Urinary zinc
Significant correlation between urinary excretion and dietetic zinc
Fasting
glucose
%HbA1c
Parham Transversal, Part 1 Group 1: 52 9.3 years Fasting Plasma concentration of zinc significantly increased in both groups after the zinc
et al. casecontrol, 42 individuals with DM2, of which: Group 2: 54.5 9.2 years glucose supplementation period
(2008) randomized %HbA1c By the end of the study, only Group 1 presented a significative decrease in the
double-blind 21 individuals with DM2 (Group 1)
supplemented with zinc for 3 months Plasma zinc %HbA1c
studies
21 individuals with DM2 (Group 2) Zinc supplementation decreased microalbuminuria levels in individuals with DM2
supplemented with placebo for
3 months
Part 2Crossover
39 individuals with DM2, of which:
18 individuals with DM2 (Group 1)
supplemented with placebo for
3 months
21 individuals with DM2 (Group 2)
supplemented with zinc for 3 months
Biometals
 Table 1 continued
Author, Study design N Age Studied Main results
year variables
Biometals

Oh and Interventional, 76 individuals with DM2, of which: Individuals with DM2 Fasting Over 40% of the individuals with DM2 had a marginal deficiency of plasma zinc.
Yoon casecontrol 44 individuals supplemented with zinc supplemented: glucose Zinc supplementation effects:
(2008) study 58.7 10.1 years %HbA1c
32 individuals supplemented with placebo 1. Zinc deficiency decreased not only on diabetic individuals, but also on healthy
72 healthy individuals, of which: Individuals with DM2 placebo Serum ones.
group: 58.5 11.7 years insulin 2. Significant %HbA1c reduction on healthy individuals
32 individuals supplemented with zinc
Supplemented non-diabetic C Peptide 3. Significant decrease in both fasting glucose and HbA1c in the DM2 group with
40 individuals supplemented with placebo individuals: Plasma zinc %HbA1c C7.5% before supplementation
53.1 11.7 years
Urinary zinc 4. Fasting glucose decrease after supplementation in less than 4 years diabetic
Non-diabetic control patients
participants:
49.6 10.7 years 5. C peptide and insulin increase in more than 4 years supplemented diabetic patients
6. Individuals with DM2 with lower plasma zinc levels before supplementation
responded to supplementation in a better way, presenting significant changes in
fasting glucose, insulin and C peptide
Masood Casecontrol 42 individuals with DM2 Individuals with DM2: Fasting Significantly lower levels of serum zinc in individuals with DM2
et al. study, non- 42 Control participants 46.55 9.67 years glucose Serum zinc status has not changed considering age, sex and disease duration
(2009) interventional Control participants: Serum zinc Serum zinc concentration has not presented any association with fasting glucose
45.81 10.62 years
Lima et al. Casecontrol 36 individuals with DM2 Individuals with DM2: Dietetic Significantly higher levels of both plasma and erythrocyte zinc in individuals with
(2011) study 37 Control participants 46 7.4 years ingestion DM2
Control participants: (R24 h) Zinc ingestion in individuals with DM2 was higher than recommended
37.2 8.6 years Erythrocyte
zinc
Plasma zinc
Plasma
glucose
Serum
insulin
%HbA1c
HOMA-IR

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 Table 1 continued
Author, Study design N Age Studied Main results
year variables

123
Basaki et al. Non- 20 individuals with DM2 Individuals with DM2: Fasting Reduced levels of serum zinc in individuals with DM2
(2012) interventional 20 Control participants 27 6.2 years serum No correlation among the glycemic control variables was observed when comparing
clinical trial Control participants: glucose both DM2 and Control groups
25 5.3 years Glucose
after 2 h of
an oral
tolerance
test
HOMA-IR
Serum zinc
Yerlikaya Non- 45 obese non diabetic women Control participants: C-reactive Serum zinc was negatively correlated to glucose and HOMA-IR in the diabetic obese
et al. interventional 41 Obese women with DM2 41.37 8.3 years protein women
(2013) Diabetic obese women: Fasting Serum zinc levels negatively correlated to C-reactive protein in both diabetic obese
50 non-obese and healthy women (Control
group) 43.9 9.9 years glucose women and non-diabetic obese ones
Non-diabetic obese women: %HbA1c
39.83 12.2 years Serum
insulin
HOMA-IR
Serum zinc
Saharia and Non- 50 individuals with DM2 Over 30 years Fasting Lower serum zinc levels in individuals with DM2 when compared to the control ones
Goswami interventional 50 Control participants glucose Negative correlation between %HbA1c and serum zinc concentration
(2013) Postprandial
glucose
%HbA1c
Serum zinc
Xu et al. Transversal 137 individuals with DM2 Individuals with DM2: Fasting Reduced serum zinc levels and increased urinary zinc excretion in individuals with
(2013) 50 Control participants 56 years glucose DM2
Control individuals: 55 years %HbA1c Significantly lower levels of serum zinc in individuals with DM2 with complications
Urinary zinc (DR*) when compared to the individuals with DM2 without complications

Serum zinc Increased urinary excretion of zinc in individuals with DM2 with complications
(DPN) when compared to the DM2 without complications one
Khan et al. Non- 76 individuals with DM2 with proteinuria Individuals with DM2 with Fasting Lower levels of serum zinc in individuals with DM2 compared to the Control ones
(2015) interventional 76 individuals with DM2 Proteinuria: glucose Individuals with DM2 presented inverse relationship between zinc levels and
62.2 16.3 years Postprandial proteinuria markers
75 Control participants
Individuals with DM2: glucose
60 16.7 years %HbA1c
Control participants: Serum zinc
50.6 18.9 years
Biometals
 Table 1 continued
Author, Study design N Age Studied Main results
year variables
Biometals

Doddigarla Transversal 50 individuals with DM2 Individuals with DM2: %HbA1c Reduced serum zinc concentration in individuals with DM2
et al. study, non- 50 Control participants 50 4.7 years Serum zinc Inverse correlation between %HbA1c and serum zinc in individuals with DM2 and
(2015) interventional Control participants: control patients
50 7.2 years When analyzing data by using linear regression, it was possible to observe that the
%HbA1c increase was associated to the reduced serum zinc concentration in
individuals with DM2, corroborating the correlation results
Luo et al. Transversal 412 individuals with DM2, of which: Individuals with DM2: %HbA1c Reduced serum zinc concentration in patients with microvascular complications
(2015) study 271 with microvascular complications 56 14 years C peptide Individuals with reduced zinc levels presented higher diabetic microvascular
141 without microvascular complications (fasting) complications prevalence (DR*, DPN e DN)
C peptide Individuals with lower zinc levels presented higher age, longer diabetic time, higher
(2 h) %HbA1c, lower C peptide numbers
Serum zinc Serum zinc concentration negatively correlated to age, diabetes duration, %HbA1c
and DN prevalence
Badran Observational 40 individuals with DM2 Individuals with DM2: Fasting Significant decrease in serum zinc concentration in individuals with DM2 when
et al. 36 healthy individuals 53.41 7.62 years (men) glucose compared to the healthy one
(2016) and 51.78 8.75 years Serum zinc Serum zinc concentration presented significant negative correlation with the fasting
(women) glucose levels in individuals with DM2
Healthy individuals:
52.47 6.41 years (men)
and
53.86 5.82 years(women)
*
DR Diabetic retinopathy, DPN Diabetic peripheral neuropathy, DN Diabetic nephropathy

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of diabetes mellitus (Viktornova et al. 2009; Badran
et al. 2016), just as this mineral homeostasis can be
affected by the presence of the disease (Basaki et al.
2012) and actively participates in the synthesis process
and insulin storage (Salgueiro et al. 2001; Viktornova
et al. 2009). The results from several studies per-
formed worldwide are examples of this; individuals
with DM2 presented lower serum concentrations of
zinc, which is associated with alterations in this
minerals biodisponibility in this population (Masood
et al. 2009; Basaki et al. 2012; Saharia and Goswami
2013; Xu et al. 2013; Doddigarla et al. 2015; Badran
et al. 2016).
In regular conditions, only 30% of dietetic zinc is
absorbed by the intestine, from where it is distributed
to the skeletal muscle, bones, liver, pancreas, and other
organs (Kambe et al. 2014). The SLC30 (ZnTs)
proteins are responsible for excluding and pushing
zinc out of the cytoplasm or the cellular compart-
ments, while SLC39 proteins (ZIPs) are responsible
for the influx of this mineral to the cytoplasm. Both
transport proteins alongside metallothioneins control
intra- and extra-cellular zinc distribution, allowing the
maintenance of basal zinc levels (Fukada et al. 2011;
Jeong and Eide 2013; Kambe et al. 2014).
Among the SLC29 family transporters (ZIPs), ZIP4
stands out. It is expressed at the plasma membrane of
pancreatic beta cells, allowing the capture of zinc
through the cell (Dufner-Beattie et al. 2003). During
the low dietetic supply of zinc, the absorption of zinc is
mainly performed by ZIP4, which carries the intestinal
lumen mineral to the intracellular compartments
(Mafra and Cozzolino 2004; Myers et al. 2012;
Chimienti 2013; Jeong and Eide 2013). When the
concentration of zinc in the intestine is high, the ZIP4
transporter undergoes endocytosis or it is degraded by
ubiquitination. Likewise, zinc ions suffer from metal-
lothioneins action and/or are sequestrated by
microvesicles (zincosomes) to avoid toxicity (Jeong
and Eide 2013; Silvestri et al. 2016). In addition, other
transporters from this family such as ZIP8 and ZIP14
also were found at the plasma membrane of beta cells
(Huang 2014).
Among the transporters from SLC30 family
(ZNTs), ZnT5 is the most abundant in pancreatic beta
cells, and it is expressed in the endoplasmic reticulum
and in the Golgi apparatus (Kambe et al. 2014). On the
other hand, ZnT7 participates in the transportation of
cytoplasmic zinc to the Golgi complex, where this
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Biometals
mineral will be stored or incorporated in newly
synthesized proteins (Huang et al. 2010). ZnT8 has a
particular expression profile, being almost exclusively
restricted to the pancreatic islets, suggesting an
essential role in the accumulation of zinc in the
insulin granules as well as in the regulation of insulin
secretion (Chimienti et al. 2004, 2006). During the
course of DM2, zinc levels and the proteins implicated
in its storage are crucial for beta cells protection from
cellular death, since the depletion of this mineral can
induce cells to undergo apoptosis and generate oxida-
tive stress, exacerbating this condition (Seve et al.
2002).
The hypozincemia observed in individuals with
DM2 can be partially explained by reduced gastroin-
testinal absorption of this mineral (Al-Maroof and Al-
Sharbatti 2006; Masood et al. 2009; Khan et al. 2015).
According to Al-Maroof and Al-Sharbatti (2006),
DM2 is associated with the average decrease of
12.56 lg/dL in serum zinc concentration.
The serum concentration was the most used mea-
sure of zinc nutritional status in the selected studies.
Since this indicator reflects the alteration in the current
dietetic ingestion, the evaluation of the individuals
food consumption is important. In Al-Maroof and Al-
Sharbattis study (2006), differences among the aver-
ages of zinc ingestion in both DM2 and control groups
were not found.
However, contrary to that, Lima et al. (2011) found
more dietetic ingestion of zinc in diabetic individuals
when compared to the control group. Marreiro et al.
(2007) observed that the ingestion of zinc in diabetic
women was under the recommendation of the Dietary
Reference Intakes (IOM 2001), which did not happen
in diabetic men, since they had an inferior dietetic
ingestion of zinc.
Although it reflected in low zinc levels in diabetic
individuals, dietetic ingestion doesnt seem to be a
determining factor of zinc imbalance, given that lack
of glycemic control can bring alterations in the
compartmentalization of this mineral in tissues (Lima
et al. 2011). However, it is emphasized that the dietetic
source is also a predictive factor of zinc absorption
because food high in phytates, iron, and casein can
reduce this minerals absorption (Lonnerdal 2000;
Marreiro et al. 2007; Sun et al. 2009).
Another factor that influences the status of body
zinc is hyperzincuria (Parham et al. 2008; Masood
et al. 2009). The hyperglycemia state interferes in the
Biometals
active transportation of zinc back to renal cells,
leading to a loss of this mineral in the urine (Chausmer
1998). This loss was observed by Nsonwu et al.
(2006); Marreiro et al. (2007); Xu et al. (2013), in
which they found high urinary excretion of zinc in
diabetic patients. Authors also showed that the longer
the duration of DM2, the lower the serum concentra-
tion of zinc and the higher the urinary excretion of this
mineral, indicating the loss of compensatory capacity
over the natural course of the disease (Nsonwu et al.
2006; Luo et al. 2015).
On the other hand, high plasma and erythrocyte
zinc levels were found by Lima et al. (2011) in patients
with DM2 when compared to the healthy individuals
(control group), which can be explained by the short
time from diagnosis (4 years). According to Jansen
et al. (2009), the concentration of zinc depends on
DM2 diagnosis time, being high in the initial period of
the disease, when it is starting to spread, and gradually
decreasing afterwards. The initial elevation of zinc
concentration can be related to this minerals active
participation in the battle against oxidative stress
(Shan et al. 2014).
The influence of the sex over the body concen-
trations of zinc is contradictory. Nsonwu et al.
(2006) observed that, compared to men, women
presented higher serum concentration and lower
urinary excretion of zinc. However, Al-Maroof and
Al- Sharbatti (2006) observed that diabetic women
presented lower serum concentrations of zinc by
comparison with men. The seminal loss of this
mineral in men does not seem to be predictor of a
low serum concentration of zinc, demonstrating that
the body status of zinc is controlled in a multifac-
torial fashion (Nsonwu et al. 2006).
Interestingly, age was negatively correlated to
the serum concentration of zinc (Luo et al. 2015)
and to the excretion of this mineral (Nsonwu et al.
2006). Ageing is accompanied by physiological
alterations, different food necessities, emergence of
chronic disorders and consequent use of medica-
tions, not to mention the increase in oligoelements
excretion and changes in the bioavailability of
minerals (Ekmecioglu 2001; Savarino et al. 2001;
Vanquero 2002). However, these findings seem to
be divergent from other studies that could not find
significant differences in zinc concentrations corre-
sponding to age (Masood et al. 2009; Saharia and
Goswami 2013).
Nutritional state implicating zinc and glycemic
control
Zinc is an essential micronutrient in insulin produc-
tion, regulating synthesis mechanisms, storage, secre-
tion, and hormone transportation in a manner such that
its deficiency can decrease the response of the receptor
to this hormone (Salgueiro et al. 2001; Viktornova
et al. 2009). Generally, zinc roles are grouped in: (1)
structural, assisting in the shape maintenance and
spatial disposition of proteins and enzymes; (2)
enzymatic, contributing to the catalytic activities of
some enzymes and of the blood acidbase balance; (3)
regulator, acting in the activity of neurons and
memory (Chasapis et al. 2012).
Considering that insulin resistance is one of the
main points when it comes to the persistence of
chronic hyperglycemia in DM2 patients, the main-
tenance of the adequate nutritional state for zinc
seems to be fundamental (Doddigarla et al. 2015).
It has been suggested that this mineral is involved
in the signal transduction of the insulin receptor,
contributing to better glycemic control (Yoshiwaka
et al. 2004; Haase and Maret 2005). Therefore,
zinc presents an insulin-mimetic effect (Basuki
et al. 2007; Nakayama et al. 2008; Naito et al.
2011).
The concentration of serum zinc appeared nega-
tively correlated to the HbA1c percentage (Saharia
and Goswami 2013; Doddigarla et al. 2015; Luo et al.
2015). Still, authors found a negative correlation
between the concentrations of serum zinc and fasting
glucose (Al-Maroof and Al-Sharbatti 2006; Saharia
and Goswami 2013; Badran et al. 2016). Yerlikaya
et al. (2013), performed with diabetic obese women,
corroborated previous findings that demonstrated that
women with a deficient nutritional state of zinc had
higher levels of glucose accompanied by higher
HOMA-IR (homeostatic model assessment) and C
peptide values.
Oh and Yoon (2008) showed that body levels of
zinc within the normal range can increase the produc-
tion and liberation of insulin, as indicated by the
increase of C peptide after an adequate daily supply of
zinc. C peptide is an indicator of pancreas secretory
capacity, since it is released for circulation in quan-
tities that match insulin (Gross et al. 2002). Despite the
evidence of participation in glycemic control, authors
such as Marreiro et al. (2007); Masood et al. (2009);
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Basaki et al. (2012) didnt find any correlation
between glycemic control variables and body zinc
concentrations.
The maintenance of glycemic control is essential to
stop the progression of diabetes. Luo et al. (2015)
corroborated this statement by showing increased
diabetic microvascular complications (DR, DPN, and
DN) in individuals with low serum zinc levels. Xu
et al. (2013) as well as Luo et al. (2015) observed
worse nutritional state of zinc in patients with DM2
with complications when compared to the patients
with DM2 but without complications. In addition,
Khan et al. (2015) found an inverse relationship
between zinc concentrations and proteinuria markers
in DM2 with this complication.
Supplementation of zinc and glycemic control
Studies have shown that the supplementation of zinc in
patients with DM2 improves glycemic control (Al-
Maroof and Al-Sharbatti 2006; Parham et al. 2008; Oh
and Yoon 2008; Jayawardena et al. 2012), therefore
confirming that zinc has a promising role in the control
of this disease.
Zinc supplementation was capable of increasing the
plasma concentrations of zinc as well as promoting
significant decrease in the percentage of glycated
hemoglobin in DM2 patients. This was verified by
Parham et al. (2008) supplementing with 30 mg of
elemental zinc and Oh and Yoon (2008) when they
supplemented 50 mg of zinc gluconate, both for three
months.
Oh and Yoon (2008) identified a better answer to
the supplementation of individuals with DM2 that
presented with lower plasma zinc concentrations, with
positive changes in fasting glucose, insulin, and C
peptide. It is also pointed out that the participants with
high Hb1Ac percentage (C7.5%) presented with
significantly decreased glycemic control markers
(fasting glucose and %Hb1Ac). Zinc supplementation
was capable of increasing glycemic control, observed
by at least one parameter, regardless of the disease
duration (longer or shorter than 4 years).
These results showed the benefits of zinc supple-
mentation in glycemic control, similar to the one
demonstrated in two meta-analyses, which pointed to
zinc supplementation as the reason why fasting glucose,
postprandial glycemia, and glycated hemoglobin levels
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Biometals
decreased in individuals with diabetes (Jayawardena
et al. 2012; Ranasinghe et al. 2015).
The decrease of the glycated hemoglobin values in
individuals with DM2 allows us to point with more
accuracy to the role of zinc in glycemic control. This is
the most sensitive and reliable glucidic marker to
control the disease, reflecting the variation of plasma
glucose levels during the three months prior to dosage.
Considering that erythrocytes have a half-life of
120 days, the 90 days of zinc supplementation in
these studies was enough to alter this marker (Koga
and Kasayama 2010). Besides the direct benefits in
glycemic control, zinc supplementation can help in the
control of diabetes progression, as is highlighted in the
study presented by Parham et al. (2008) where they
verify the decrease of microalbuminuria in individuals
with DM2 after intervention with zinc.
Conclusion
This review combines previous evidence of the effect
of zinc on glycemic metabolism. The results presented
show the participation of zinc in controlling circulat-
ing glucose concentration through maintenance of
insulin homeostasis. Therefore, adequate dietetic
ingestion and/or zinc supplementation are essential
in the control of DM2. It is possible to notice the
necessity of studies that evaluate the effect of dietetic
interventions compared to the supplementation of this
mineral in individuals affected by the disease, in order
to establish the adequate ingestion values. It is also
necessity to establish safe and effective supplementa-
tion doses of zinc.
Acknowledgements The authors thank the research funding
from CNPq (Conselho Nacional para o Desenvolvimento
Cientfico e Tecnologico, Proc. n 455117/2014-4) related to
the theme of this review.
Compliance with ethical standards
Conflict of interest The authors declare that they have no
conflict of interest.
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