Anda di halaman 1dari 12


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 supplementation and 12 reporting observational stud-
zinc in several metabolic processes, such as the ies. The main findings of these studies consisted of low
glucidic metabolism. The present systematic review body contents of zinc and high excretion of zinc in
aims to discuss zincs participation in the glycemic urine. Hyperglycemia was one of the mechanisms that
control of type 2 diabetes mellitus (DM2) patients. In caused these alterations owing to its interference in
order to accomplish that, a systematic search was zinc reabsorption via renal cells. Another evidence
performed in the Pubmed database using the following was the negative correlation between the glycated
indexed and theme-related descriptors: zinc AND hemoglobin percentage (%HbA1c) and the plasma
type 2 diabetes mellitus, AND MeSH terms related zinc levels. Additionally, it has been observed that
to glycemic control combined with the boolean zinc supplementation in DM2 patients has improved
operator OR. In total, 1078 articles were retrieved glycemic control, since the %HbA1c significantly
from the research, of which 15 articles of original reduced in these individuals. This present review
studies conducted with DM2 patients were included, shows the positive effect of adequate zinc levels on
with three being about the effect of mineral glycemic control, whether it is through dietetic
ingestion or supplementation, since its role in insulin
homeostasis is clear.
G. B. de Carvalho
Graduation in Nutrition, Department of Nutrition, Federal
University of Sergipe, Sao Cristovao, Sergipe, Brazil Keywords Zinc  Glycemic control  Diabetes 
P. N. Brandao-Lima
Health Sciences Post-graduation Program, Department of
Medicine, Federal University of Sergipe, Aracaju,
Sergipe, Brazil Introduction

C. S. C. Maia Zinc widely participates in physiological processes,

Department of Nutrition, State University of Ceara, such as glucidic metabolism (Chimienti 2013; Badran
Fortaleza, Ceara, Brazil
et al. 2016). Highly present in beta cells of the
K. B. F. Barbosa  L. V. Pires (&) pancreas (Lemaire et al. 2009), its participation in
Department of Nutrition, Federal University of Sergipe, glucidic metabolism occurs during the synthesis,
Avenida Marechal Rondon, S/N Jardim Rosa Elze, storage, crystallization, and secretion of insulin (Cap-
Sao Cristovao, Sergipe 49100-000, Brazil
e-mail:; dor et al. 2013; Shan et al. 2014; Maruthur et al. 2015). In addition, zinc is involved in the phosphorylation of


insulin receptors and regulation of signaling by Selecting studies and evaluation

tyrosine-phosphatase (Wijesekara et al. 2009; Shan
et al. 2014). The observational, casecontrol, and supplementation
Zincs deficiency can lead to an increase in studies, performed in humans, which presented data
circulating glucose due to beta cells malfunctioning related to the nutritional state of zinc (Serum, Plasma, or
and resistance to insulin, which makes it easier for Erythrocyte) and glycemic control (Fasting Glucose,
type 2 diabetes mellitus (DM2) to happen (Kazi et al. Postprandial Glucose, %HbA1c, Serum Insulin, or C
2008; Saharia and Goswami 2013). On the other hand, Peptide) were considered eligible. There was no restric-
the disease can alter this minerals body homeostasis tion regarding the language used in the publications.
(Saharia and Goswami 2013). In vitro studies in animals and review studies were
Individuals with DM2 can present with low excluded, as well as articles that did not present an
erythrocyte and plasma zinc body concentrations, abstract or those published only in an abstract format.
combined with hyperzincuria and intestinal malab- The reading of the titles and abstracts was accom-
sorption (Jasen et al. 2012; Sinha and Sen 2014). A plished independently by two reviewers. Selected
few studies showed that the daily supplementation of articles met the eligibility criteria described above.
zinc is capable of improving fasting glucose, serum The controversial cases were discussed and rated by a
insulin and glycated hemoglobin of individuals with third reviewer. Then, the pre-selected articles were
DM2 (Oh and Yoon 2008; Parham et al. 2008). In entirely read by two reviewers and those which did not
addition to a better glycemic control, zinc can reduce answer this primary question were excluded. After the
the emergence of microvascular complications selection of the eligible articles, an evaluation of their
through the reduction of reactive oxygen species references lists to include important articles concern-
caused by the action of superoxide dismutase, an ing this topic was performed.
enzyme that depends on zinc in its catalytic center The Kappa coefficient was calculated to measure
(Basaki et al. 2012). In this regard, this review the inter rater reliability in each selection stage. The
proposes to discuss the participation of zinc in the present review was elaborated according to the
glycemic control mechanisms of patients with DM2. guidelines proposed by the PRISMA method (Pre-
ferred Reporting Items for Systematic Reviews and
Meta-analysis). The articles selection stages are
Materials and methods outlined in Fig. 1.

Literature review or Search strategy Analysis

This research consists of a systematic review, aiming Descriptive statistics using the present data in the
to discuss the main effects of zinc status in the glucidic articles was carried out in order to characterize the
control of patients with DM2. The Pubmed database individuals participating in the study. The agreement
was used to search for studies published from January rate among the evaluators was determined by the Kappa
2006 to March 2016. coefficient, according to Landis and Kochs (1977)
The search strategy included indexed English terms classification, considering \01 interval, being
from Health Sciences Descriptors (DeCS) and Med- \0 = No agreement, 00.19 = Poor agreement,
ical Subject Headings (MeSH), as its informed as 0.200.39 = Fair agreement, 0.400.59 = Moderate
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 executed by using R statistics software (3.2.3 version).
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 Based on the eligibility criteria, out of 618 articles
hyperglycemia. found on the search, 33 were selected for full reading


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


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

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

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

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
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
Plasma zinc

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

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

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)
53.86 5.82 years(women)
DR Diabetic retinopathy, DPN Diabetic peripheral neuropathy, DN Diabetic nephropathy


of diabetes mellitus (Viktornova et al. 2009; Badran mineral will be stored or incorporated in newly
et al. 2016), just as this mineral homeostasis can be synthesized proteins (Huang et al. 2010). ZnT8 has a
affected by the presence of the disease (Basaki et al. particular expression profile, being almost exclusively
2012) and actively participates in the synthesis process restricted to the pancreatic islets, suggesting an
and insulin storage (Salgueiro et al. 2001; Viktornova essential role in the accumulation of zinc in the
et al. 2009). The results from several studies per- insulin granules as well as in the regulation of insulin
formed worldwide are examples of this; individuals secretion (Chimienti et al. 2004, 2006). During the
with DM2 presented lower serum concentrations of course of DM2, zinc levels and the proteins implicated
zinc, which is associated with alterations in this in its storage are crucial for beta cells protection from
minerals biodisponibility in this population (Masood cellular death, since the depletion of this mineral can
et al. 2009; Basaki et al. 2012; Saharia and Goswami induce cells to undergo apoptosis and generate oxida-
2013; Xu et al. 2013; Doddigarla et al. 2015; Badran tive stress, exacerbating this condition (Seve et al.
et al. 2016). 2002).
In regular conditions, only 30% of dietetic zinc is The hypozincemia observed in individuals with
absorbed by the intestine, from where it is distributed DM2 can be partially explained by reduced gastroin-
to the skeletal muscle, bones, liver, pancreas, and other testinal absorption of this mineral (Al-Maroof and Al-
organs (Kambe et al. 2014). The SLC30 (ZnTs) Sharbatti 2006; Masood et al. 2009; Khan et al. 2015).
proteins are responsible for excluding and pushing According to Al-Maroof and Al-Sharbatti (2006),
zinc out of the cytoplasm or the cellular compart- DM2 is associated with the average decrease of
ments, while SLC39 proteins (ZIPs) are responsible 12.56 lg/dL in serum zinc concentration.
for the influx of this mineral to the cytoplasm. Both The serum concentration was the most used mea-
transport proteins alongside metallothioneins control sure of zinc nutritional status in the selected studies.
intra- and extra-cellular zinc distribution, allowing the Since this indicator reflects the alteration in the current
maintenance of basal zinc levels (Fukada et al. 2011; dietetic ingestion, the evaluation of the individuals
Jeong and Eide 2013; Kambe et al. 2014). food consumption is important. In Al-Maroof and Al-
Among the SLC29 family transporters (ZIPs), ZIP4 Sharbattis study (2006), differences among the aver-
stands out. It is expressed at the plasma membrane of ages of zinc ingestion in both DM2 and control groups
pancreatic beta cells, allowing the capture of zinc were not found.
through the cell (Dufner-Beattie et al. 2003). During However, contrary to that, Lima et al. (2011) found
the low dietetic supply of zinc, the absorption of zinc is more dietetic ingestion of zinc in diabetic individuals
mainly performed by ZIP4, which carries the intestinal when compared to the control group. Marreiro et al.
lumen mineral to the intracellular compartments (2007) observed that the ingestion of zinc in diabetic
(Mafra and Cozzolino 2004; Myers et al. 2012; women was under the recommendation of the Dietary
Chimienti 2013; Jeong and Eide 2013). When the Reference Intakes (IOM 2001), which did not happen
concentration of zinc in the intestine is high, the ZIP4 in diabetic men, since they had an inferior dietetic
transporter undergoes endocytosis or it is degraded by ingestion of zinc.
ubiquitination. Likewise, zinc ions suffer from metal- Although it reflected in low zinc levels in diabetic
lothioneins action and/or are sequestrated by individuals, dietetic ingestion doesnt seem to be a
microvesicles (zincosomes) to avoid toxicity (Jeong determining factor of zinc imbalance, given that lack
and Eide 2013; Silvestri et al. 2016). In addition, other of glycemic control can bring alterations in the
transporters from this family such as ZIP8 and ZIP14 compartmentalization of this mineral in tissues (Lima
also were found at the plasma membrane of beta cells et al. 2011). However, it is emphasized that the dietetic
(Huang 2014). source is also a predictive factor of zinc absorption
Among the transporters from SLC30 family because food high in phytates, iron, and casein can
(ZNTs), ZnT5 is the most abundant in pancreatic beta reduce this minerals absorption (Lonnerdal 2000;
cells, and it is expressed in the endoplasmic reticulum Marreiro et al. 2007; Sun et al. 2009).
and in the Golgi apparatus (Kambe et al. 2014). On the Another factor that influences the status of body
other hand, ZnT7 participates in the transportation of zinc is hyperzincuria (Parham et al. 2008; Masood
cytoplasmic zinc to the Golgi complex, where this et al. 2009). The hyperglycemia state interferes in the


active transportation of zinc back to renal cells, Nutritional state implicating zinc and glycemic
leading to a loss of this mineral in the urine (Chausmer control
1998). This loss was observed by Nsonwu et al.
(2006); Marreiro et al. (2007); Xu et al. (2013), in Zinc is an essential micronutrient in insulin produc-
which they found high urinary excretion of zinc in tion, regulating synthesis mechanisms, storage, secre-
diabetic patients. Authors also showed that the longer tion, and hormone transportation in a manner such that
the duration of DM2, the lower the serum concentra- its deficiency can decrease the response of the receptor
tion of zinc and the higher the urinary excretion of this to this hormone (Salgueiro et al. 2001; Viktornova
mineral, indicating the loss of compensatory capacity et al. 2009). Generally, zinc roles are grouped in: (1)
over the natural course of the disease (Nsonwu et al. structural, assisting in the shape maintenance and
2006; Luo et al. 2015). spatial disposition of proteins and enzymes; (2)
On the other hand, high plasma and erythrocyte enzymatic, contributing to the catalytic activities of
zinc levels were found by Lima et al. (2011) in patients some enzymes and of the blood acidbase balance; (3)
with DM2 when compared to the healthy individuals regulator, acting in the activity of neurons and
(control group), which can be explained by the short memory (Chasapis et al. 2012).
time from diagnosis (4 years). According to Jansen Considering that insulin resistance is one of the
et al. (2009), the concentration of zinc depends on main points when it comes to the persistence of
DM2 diagnosis time, being high in the initial period of chronic hyperglycemia in DM2 patients, the main-
the disease, when it is starting to spread, and gradually tenance of the adequate nutritional state for zinc
decreasing afterwards. The initial elevation of zinc seems to be fundamental (Doddigarla et al. 2015).
concentration can be related to this minerals active It has been suggested that this mineral is involved
participation in the battle against oxidative stress in the signal transduction of the insulin receptor,
(Shan et al. 2014). contributing to better glycemic control (Yoshiwaka
The influence of the sex over the body concen- et al. 2004; Haase and Maret 2005). Therefore,
trations of zinc is contradictory. Nsonwu et al. zinc presents an insulin-mimetic effect (Basuki
(2006) observed that, compared to men, women et al. 2007; Nakayama et al. 2008; Naito et al.
presented higher serum concentration and lower 2011).
urinary excretion of zinc. However, Al-Maroof and The concentration of serum zinc appeared nega-
Al- Sharbatti (2006) observed that diabetic women tively correlated to the HbA1c percentage (Saharia
presented lower serum concentrations of zinc by and Goswami 2013; Doddigarla et al. 2015; Luo et al.
comparison with men. The seminal loss of this 2015). Still, authors found a negative correlation
mineral in men does not seem to be predictor of a between the concentrations of serum zinc and fasting
low serum concentration of zinc, demonstrating that glucose (Al-Maroof and Al-Sharbatti 2006; Saharia
the body status of zinc is controlled in a multifac- and Goswami 2013; Badran et al. 2016). Yerlikaya
torial fashion (Nsonwu et al. 2006). et al. (2013), performed with diabetic obese women,
Interestingly, age was negatively correlated to corroborated previous findings that demonstrated that
the serum concentration of zinc (Luo et al. 2015) women with a deficient nutritional state of zinc had
and to the excretion of this mineral (Nsonwu et al. higher levels of glucose accompanied by higher
2006). Ageing is accompanied by physiological HOMA-IR (homeostatic model assessment) and C
alterations, different food necessities, emergence of peptide values.
chronic disorders and consequent use of medica- Oh and Yoon (2008) showed that body levels of
tions, not to mention the increase in oligoelements zinc within the normal range can increase the produc-
excretion and changes in the bioavailability of tion and liberation of insulin, as indicated by the
minerals (Ekmecioglu 2001; Savarino et al. 2001; increase of C peptide after an adequate daily supply of
Vanquero 2002). However, these findings seem to zinc. C peptide is an indicator of pancreas secretory
be divergent from other studies that could not find capacity, since it is released for circulation in quan-
significant differences in zinc concentrations corre- tities that match insulin (Gross et al. 2002). Despite the
sponding to age (Masood et al. 2009; Saharia and evidence of participation in glycemic control, authors
Goswami 2013). such as Marreiro et al. (2007); Masood et al. (2009);


Basaki et al. (2012) didnt find any correlation decreased in individuals with diabetes (Jayawardena
between glycemic control variables and body zinc et al. 2012; Ranasinghe et al. 2015).
concentrations. The decrease of the glycated hemoglobin values in
The maintenance of glycemic control is essential to individuals with DM2 allows us to point with more
stop the progression of diabetes. Luo et al. (2015) accuracy to the role of zinc in glycemic control. This is
corroborated this statement by showing increased the most sensitive and reliable glucidic marker to
diabetic microvascular complications (DR, DPN, and control the disease, reflecting the variation of plasma
DN) in individuals with low serum zinc levels. Xu glucose levels during the three months prior to dosage.
et al. (2013) as well as Luo et al. (2015) observed Considering that erythrocytes have a half-life of
worse nutritional state of zinc in patients with DM2 120 days, the 90 days of zinc supplementation in
with complications when compared to the patients these studies was enough to alter this marker (Koga
with DM2 but without complications. In addition, and Kasayama 2010). Besides the direct benefits in
Khan et al. (2015) found an inverse relationship glycemic control, zinc supplementation can help in the
between zinc concentrations and proteinuria markers control of diabetes progression, as is highlighted in the
in DM2 with this complication. study presented by Parham et al. (2008) where they
verify the decrease of microalbuminuria in individuals
Supplementation of zinc and glycemic control with DM2 after intervention with zinc.

Studies have shown that the supplementation of zinc in

patients with DM2 improves glycemic control (Al- Conclusion
Maroof and Al-Sharbatti 2006; Parham et al. 2008; Oh
and Yoon 2008; Jayawardena et al. 2012), therefore This review combines previous evidence of the effect
confirming that zinc has a promising role in the control of zinc on glycemic metabolism. The results presented
of this disease. show the participation of zinc in controlling circulat-
Zinc supplementation was capable of increasing the ing glucose concentration through maintenance of
plasma concentrations of zinc as well as promoting insulin homeostasis. Therefore, adequate dietetic
significant decrease in the percentage of glycated ingestion and/or zinc supplementation are essential
hemoglobin in DM2 patients. This was verified by in the control of DM2. It is possible to notice the
Parham et al. (2008) supplementing with 30 mg of necessity of studies that evaluate the effect of dietetic
elemental zinc and Oh and Yoon (2008) when they interventions compared to the supplementation of this
supplemented 50 mg of zinc gluconate, both for three mineral in individuals affected by the disease, in order
months. to establish the adequate ingestion values. It is also
Oh and Yoon (2008) identified a better answer to necessity to establish safe and effective supplementa-
the supplementation of individuals with DM2 that tion doses of zinc.
presented with lower plasma zinc concentrations, with
positive changes in fasting glucose, insulin, and C Acknowledgements The authors thank the research funding
from CNPq (Conselho Nacional para o Desenvolvimento
peptide. It is also pointed out that the participants with Cientfico e Tecnologico, Proc. n 455117/2014-4) related to
high Hb1Ac percentage (C7.5%) presented with the theme of this review.
significantly decreased glycemic control markers
(fasting glucose and %Hb1Ac). Zinc supplementation Compliance with ethical standards
was capable of increasing glycemic control, observed
Conflict of interest The authors declare that they have no
by at least one parameter, regardless of the disease conflict of interest.
duration (longer or shorter than 4 years).
These results showed the benefits of zinc supple-
mentation in glycemic control, similar to the one References
demonstrated in two meta-analyses, which pointed to
zinc supplementation as the reason why fasting glucose, Al-Maroof RA, Al-Sharbatti SS (2006) Serum zinc levels in
postprandial glycemia, and glycated hemoglobin levels diabetic patients and effect of zinc supplementation on


glycemic control of type 2 diabetics. Saudi Med J Huang L (2014) Zinc and its transporters, pancreatic b-cells, and
27:344350 insulin metabolism. Vitam Horm. doi:10.1016/B978-0-12-
Badran M, Morsy R, Soliman H, Elnimr T (2016) Assessment of 800174-5.00014-4
trace elements levels in patients with type 2 diabetes using Huang L, Yan M, Kirschke CP (2010) Over-expression of ZnT7
multivariate statistical analysis. J Trace Elem Med Biol increases insulin synthesis and secretion in pancreatic beta-
33:114119. doi:10.1016/j.jtemb.2015.10.006 cells by promoting insulin gene transcription. Exp Cell
Basaki M, Saeb M, Nazifi S, Shamsaei HA (2012) Zinc, copper, Res. doi:10.1016/j.yexcr.2010.06.017
iron, and chromium concentrations in young patients with Institute of Medicine (US) Panel on Micronutrients (2001)
type 2 diabetes mellitus. Biol Trace Elem Res Dietary reference intakes for Vitamin A, Vitamin K,
148:161164. doi:10.1007/s12011-012-9360-6 arsenic, boron, chromium, copper, iodine, iron, man-
Basuki W, Hiromura M, Sakurai H (2007) Insulinomimetic Zn ganese, molybdenum, nickel, silicon, vanadium, and zinc.
complex (Zn(opt)2) enhances insulin signaling pathway in National Academy Press, Washington
3 T3-L1 adipocytes. J Inorg Biochem 101:692699. doi:10. Jansen J, Karges W, Rink L (2009) Zinc and diabetes-clinical
1016/j.jinorgbio.2006.12.015 links and molecular mechanisms. J Nutr Biochem
Capdor J, Foster M, Petocz P, Samman S (2013) Zinc and gly- 20:399417. doi:10.1016/j.jnutbio.2009.01.009
cemic control: a meta-analysis of randomised placebo Jasen J, Rosenkranz E, Overbeck S, Warmuth S, Mocchegiani E,
controlled supplementation trials in humans. J Trace Elem Giacconi R, Weiskirchen R, Karges W, Rink L (2012)
Med Biol 27:137142. doi:10.1016/j.jtemb.2012.08.001 Disturbed zinc homeostasis in diabetic patients by in vitro
Chasapis CT, Loutsidou AC, Spiliopoulou CA, Stefanidou ME and in vivo analysis of insulinomimetic activity of zinc.
(2012) Zinc and human health: an update. Arch Toxicol J Nutr Biochem 23:14581466. doi:10.1016/j.jnutbio.
86:521534. doi:10.1007/s00204-011-0775-1 2011.09.008
Chausmer AB (1998) Zinc, insulin and diabetes. J Am Coll Nutr Jayawardena R, Ranasinghe P, Galappatthy P, Malkanthi
17:109115. doi:10.1080/07315724.1998.1071873 RLDK, Constantine GR, Katulanda P (2012) Effects of
Chimienti F (2013) Zinc, pancreatic islet cell function and zinc supplementation on diabetes mellitus: a systematic
diabetes: new insights into an old story. Nutr Res Rev review and meta-analysis. Diabetol Metab Syndr 4:111.
26:111. doi:10.1017/S0954422412000212 doi:10.1186/1758-5996-4-13
Chimienti F, Devergnas S, Favier A (2004) Identification and Jeong J, Eide DJ (2013) The SLC39 family of zinc transporters.
cloning of a B-cell-specific zinc transporter, ZnT-8, Mol Aspects Med 34:612619. doi:10.1016/j.mam.2012.
localized into insulin secretory granules. Diabetes 05.011
53:23302337. doi:10.2337/diabetes.53.9.2330 Kambe T, Hashimoto A, Fujimoto S (2014) Current under-
Chimienti F, Devergnas S, Pattou F, Schuit F, Garcia-Cuenca R, standing of ZIP and ZnT zinc transporters in human health
Vandewalle B, Kerr-Conte J, Van Lommel L, Grunwald D, and diseases. Cell Mol Life Sci 71:32813295. doi:10.
Favier A, Seve M (2006) In vivo expression and functional 1007/s00018-014-1617-0
characterization of the zinc transporter ZnT8 in glucose- Kazi TG, Afridi HI, Kazi N, Jamali NK, Arain MB, Jalbani N,
induced insulin secretion. J Cell Sci 119:41994206. Kandhro GA (2008) Copper, chromium, manganese, iron,
doi:10.1242/jcs.03164 nickel, and zinc levels in biological samples of diabetes
Doddigarla Z, Parwez I, Ahmad J (2015) Correlation of serum mellitus patients. Biol Trace Elem Res 122:118. doi:10.
chromium, zinc, magnesium and SOD levels with HbA1c 1007/s12011-007-8062-y
in type 2 diabetes: a cross sectional analysis. Diabetes Khan FA, Jameil NAI, Arjumand S, Khan MF, Tabassum H,
Metab Syndr 10:126129. doi:10.1016/j.dsx.2015.10.008 Alenzi N, Hijazy S, Alenzi S, Subaie S, Fatima S (2015)
Dufner-Beattie J, Wang F, Kuo YM, Gitschier J, Eide D, Comparative study of serum copper, iron, magnesium and
Andrews GK (2003) The acrodermatitis enteropathica gene zinc in type 2 diabetes-associated proteinuria. Biol
ZIP4 encodes a tissue-specific, zinc-regulated zinc trans- Trace Elem Res 168:321329. doi:10.1007/s12011-015-
porter in mice. J Biol Chem 278:3347433481. doi:10. 0379-3
1074/jbc.M305000200 Koga M, Kasayama S (2010) Clinical impact of glycated
Ekmecioglu C (2001) The role of trace elements for the health of albumin as another glycemic control marker. Endocr J
elderly individuals. Nahrung 45:309316. doi:10.1002/ 57:751762. doi:10.1507/endocrj.K10E-138
1521-3803(20011001)45:5\309:AID-FOOD309[3.0. Landis JR, Koch GG (1977) The measurement of observer
CO;2-0 agreement for categorical data. Biometrics 33:159174.
Fukada T, Yamasaki S, Nishida K, Murakami M, Hirano T doi:10.2307/2529310
(2011) Zinc homeostasis and signaling in health and dis- Lemaire K, Ravier MA, Schraenen A, Creemers JW, Van de
eases. J Biol Inorg Chem 16:11231134. doi:10.1007/ Plas R, Granvik M, Van Lommel L, Waelkens E, Chimienti
s00775-011-0797-4 F, Rutter GA, Gilon P, int Veld PA, Schuit FC (2009)
Gross JL, Silveiro SP, Camargo JL, Reichelt AJ, Azevedo MJ Insulin crystallization depends on zinc transporter ZnT8
(2002) Diabetes Melito: diagnostico, Classificacao e Ava- expression, but is not required for normal glucose home-
liacao do Controle Glicemico. Arq Bras Endocrinol Metab ostasis in mice. Proc Natl Acad Sci USA
46:1626. doi:10.1590/S0004-27302002000100004 106:1487214877. doi:10.1073/pnas.0906587106
Haase H, Maret W (2005) Fluctuations of cellular, available zinc Lima VBS, Sampaio FA, Bezerra DLC, Moita Neto JM, Mar-
modulate insulin signaling via inhibition of protein tyr- reiro DN (2011) Parameters of glycemic control and their
osine phosphatases. J Trace Elem Med Biol 19:3742. relationship with zinc concentrations in blood and with
doi:10.1016/j.jtemb.2005.02.004 superoxide dismutase enzyme activity in type 2 diabetes


patients. Arq Bras Endocrinol Metabol 55:701707. Salgueiro MJ, Krebs N, Zubillaga MB, Weil R, Postaire E,
doi:10.1590/S0004-27302011000900006 Lysionek A, Caro RA, De Paoli T, Hager A, Boccio J
Lonnerdal BO (2000) Dietary factors influencing zinc absorp- (2001) Zinc and diabetes mellitus: is there a need of zinc
tion. J Nutr 130:13781383 supplementation in diabetes mellitus patients? Biol Trace
Luo YY, Zhao J, Han XY, Zhou XH, Wu J, Ji LN (2015) Elem Res 81:215228. doi:10.1385/BTER:81:3:21
Relationship between serum zinc level and microvascular Savarino L, Granchi D, Ciapetti G, Cenni E, Ravaglia G, Forti P,
complications in patients with type 2 diabetes. Chin Med J Maroli F, Mathiolio R (2001) Serum concentrations of zinc
128:32763282. doi:10.4103/0366-6999.171357 and selenium in elderly people; result in healthy nonage-
Mafra D, Cozzolino SMF (2004) Importancia do zinco na narians/centenarians. Exp Gerontol 36:327339. doi:10.
nutricao humana. Rev. Nutr 17:7987. doi:10.1590/S1415- 1016/S0531-5565(00)00218-7
52732004000100009 Seve M, Chimienti F, Favier A (2002) Role of intracellular zinc
Marreiro DN, Martins MPSC, Sousa SSR, Torres VIS, Pires LV, in programmed cells death. Pathol Biol 50:212221
Nogueira NN, Lima JMC, Monte SJH (2007) Urinary Shan Z, Bao W, Zhang Y, Rong Y, Wang X, Jin Y, Song Y, Yao
excretion of zinc and metabolic control of patients with P, Sun C, Hu FB, Liu L (2014) Interactions between zinc
diabetes type 2. Biol Trace Elem Res 120:4250. doi:10. transporter-8 gene (SLC30A8) and plasma zinc concen-
1007/s12011-007-8000-z trations for impaired glucose regulation and type 2 dia-
Maruthur NM, Clark JM, Fu M, Linda KWH, Shuldiner AR betes. Diabetes 63:17961803. doi:10.2337/db13-0606
(2015) Effect of zinc supplementation on insulin secretion: Silvestri S, Orlando P, Bruge F, Falcioni G, Tiano L (2016)
interaction between zinc and SLC30A8 genotype in old Effect of different metals on oxidative state and mito-
order amish. Diabetologia 58:295303. doi:10.1007/ chondrial membrane potential in trout erythrocytes. Eco-
s00125-014-3419-1 toxicol Environ Saf 134:280285. doi:10.1016/j.ecoenv.
Masood N, Baloch GHm Ghori RA, Memon IA, Memon MA, 2016.07.040
Memon MS (2009) Serum zinc and magnesium in type-2 Sinha S, Sen S (2014) Status of zinc and magnesium levels in
diabetic patients. J Coll Physicians Surg Pak 19:483486 type 2 diabetes mellitus and its relationship with glycemic
Myers SA, Nield A, Myers M (2012) Zinc transporters, mech- status. Int J Diabetes Dev Ctries 34:220223. doi:10.1007/
anisms of action and therapeutic utility: implications for s13410-014-0196-9
type 2 diabetes mellitus. J Nutr Metabol. doi:10.1155/ Sun Q, van Dam RM, Willet WC, Hu FB (2009) Prospective
2012/173712 study of zinc intake and risk of type 2 diabetes in women.
Naito Y, Yoshikawa Y, Yasui H (2011) Cellular mechanism of Diabetes Care 31:629634. doi:10.2337/dc08-1913
zinchinokitiol complexes in diabetes mellitus. Bull Chem Vanquero MP (2002) Magnesium and trace elements in the
Soc Jpn 84:298305. doi:10.1246/bcsj.20100262 elderly; intake, status and recommendations. J Nutr Health
Nakayama A, Hiromura M, Adachi Y, Sakurai H (2008) Ageing 6:147153
Molecular mechanism of antidiabetic zinc-allixin com- Viktornova A, Toserova E, Krizko M, Durackova Z (2009)
plexes: regulations of glucose utilization and lipid meta- Altered metabolism of copper, zinc, and magnesium is
bolism. J Biol Inorg Chem 13:675684. doi:10.1007/ associated with increased levels of glycated hemoglobin in
s00775-008-0352-0 patients with diabetes mellitus. Metabolism 58:14771482.
Nsonwu AC, Usoro CAO, Etukudo MH, Usoro IN (2006) doi:10.1016/j.metabol.2009.04.035
Influence of Age, gender and duration of diabetes on serum Wijesekara N, Chimienti F, Wheeler MB (2009) Zinc, a regu-
and urine levels of zinc, magnesium, and chromium in type lator of islet function and glucose homeostasis. Diabetes
2 diabetics in Calabar, Nigeria. Turk J Biochem 1:107114 Obes Metabol 11:202214. doi:10.1111/j.1463-1326.2009.
Oh HM, Yoon JS (2008) Glycemic control of type 2 diabetic 01110.x
patients after short-term zinc supplementation. Nutr Res Xu J, Zhou Q, Liu G, Tan Y, Cai L (2013) Analysis of serum and
Pract 2:283288 urinal copper and zinc in Chinese Northeast population
Parham M, Amini M, Aminorroaya A, Heidarian E (2008) with the prediabetes or diabetes with and without compli-
Effect of zinc supplementation on microalbuminuria in cations. Oxid Med Cell Longev 2013:111. doi:10.1155/
patients with type 2 diabetes: a double blind, randomized, 2013/635214
placebo-controlled, cross-over trial. Rev Diabetic Stud Yerlikaya FH, Toker A, Aribas A (2013) Serum trace elements
5:102109. doi:10.1900/RDS.2008.5.102 in obese women with or without diabetes. Indian J Med Res
Ranasinghe P, Pigera S, Galappatthy P, Katulanda P, Constan- 137:339345
tine GR (2015) Zinc and diabetes mellitus: understanding Yoshiwaka Y, Ueda E, Kojima Y, Sakurai H (2004) The action
molecular mechanisms and clinical implications. DARU J mechanism of zinc(II) complexes with insulinomimetic
Pharm Sci 17:2344. doi:10.1186/s40199-015-0127-4 activity in rat adipocytes. Life Sci 76:741751. doi:10.
Saharia GK, Goswami RK (2013) Evaluation of serum zinc 1016/j.lfs.2004.02.006
status and glycated hemoglobin of type 2 diabetes mellitus
patients in a tertiary care hospital of Assam. J Lab Physi-
cians 5:3033. doi:10.4103/0974-2727.115923