Introduction
Diabetes mellitus (DM) is a chronic disease related
to metabolic disorders. Diabetes mellitus type 2 (T2DM) is the most common type
with biomarkers of hyperglycemia, insulin resistance, and low adiponectin
levels (Abdella & Mojiminiyi, 2018; Federation,
2019; Jiffri & Al-Dahr, n.d.).
The global prevalence of DM in 2019 was 463 million for ages 20 to 79 years
where the DM management can be done with nutritional diet therapy. Nutritional
diet therapy plays a very important role in the treatment of DM patients,
especially in DM patients who are resistant to conventional treatment. That's
because nutritional therapy can reduce the risk of diabetic retinopathy,
structure of the retina, and maintaining normal function (Robles-Rivera et al., 2020).
However, ineffective DM treatment therapy can lead to the development of DM can
cause complications. Management solutions for T2DM related to nutritional diet
therapy need to be developed to obtain the optimal T2DM management so that
other disease complications do not occur (Organization, 2018).
Several studies found that the abnormal zinc levels
can be risk factors for DM (Jiang et al., 2004; Xu et al., 2013).
Zinc supplementation in the treatment of DM has been carried out but has given
controversial results concerning blood sugar levels. This study aims to review
the effect of zinc supplementation on blood sugar levels and insulin resistance
in the treatment of DM.
Research
Method
This study
uses the literature review method. The article search strategy was carried out using
national international journal articles that were searched through Google
Scholar. Articles were searched with the keywords �Zn supplementation�,
�insulin resistance�, �blood glucose�, and �diabetes mellitus�. The search
obtained as many as 1,640 articles.
Figure 1
Search Scheme Of
Articles
Articles were screened with inclusion criteria, namely articles
published in the last 10 years (2011�2021), free access, free of charge, using
English, and types of research. Screening results obtained 40 articles. There
were 11 articles that matched the research topic containing the results of Zn
supplementation on insulin resistance and blood glucose levels.
Discussion
Zinc aids in the use of glucose and
fat and is required as a cofactor for the function of intracellular enzymes
involved in the metabolism of protein, lipids, and glucose (Siddiqui et al., 2014).
The Recommended Dietary Allowance (RDA) for zinc for ages 19 and over is 11
mg/day for men and 8 mg/day for women. Zinc can be obtained from food or
supplements. Foods that contain zinc include red meat, poultry, nuts, certain
types of seafood (such as oysters, crab, and lobster), whole grains, cereals,
and dairy products. Supplements that contain zinc include zinc sulfate, zinc
acetate, and zinc gluconate with different zinc content for each supplement (Khan, 2021).
The normal range of Zn in
serum/plasma is 84-159 𝜇g / dL. One of the levels of
Zn in the breath that is not within normal limits is related to disease, one of
which is DM. The antigenic nature of Zn affects insulin binding to the
hepatocyte membrane and deficiency can increase insulin resistance and hyperglycemia
(Siddiqui et al., 2014).
Serum levels of Zn in T2DM patients
are lower than in non-diabetic individuals because impaired endogenous
intestinal reabsorption and increased excretion of zinc into the intestine
during digestion can lead to low serum Zn levels (Sharifah et al., 2018; Siddiqui et al., 2014).
Zn is very complex, with no clear causal relationship. Zinc has a role in the
storage, secretion and synthesis of insulin, as well as the integrity of the hexameric conformation of insulin. This role may regulate the
occurrence of intracellular insulin receptors that affect the ability to
support normal pancreatic reactions and glucose tolerance to glucose load. It
affects the protection of β cell damage and has an antiviral effect (Sharifah et al., 2018).
Zinc stimulates the oligomerization
of higher molecular weight forms of adiponectin by modulating the formation of
disulfide bonds. There is a positive correlation between serum Zn and
adiponectin levels. Zinc-α 2-glycoprotein (ZAG) functions in adipose
tissue. Downward or upward ZAG expression is governed by negative or positive
stimuli. In adipose tissue, ZAG inhibits the activity of FAS and Acetyl-CoA
carboxylase 1 (ACC1), thereby causing a decrease in fatty acid synthesis. Lower
levels of free fatty acids together with increased expression of
Zinc-a2-glycoprotein (ZAG)-induced adiponectin can significantly reduce insulin
resistance (Olechnowicz et al., 2018).
The cause of decreased serum Zn
levels in DM is an increase in urine output. Hyperglycemia impairs active
transport back to tubular cells. Other causes can interfere with the metabolism
of zinc metalloenzymes and abnormal binding of Zn to tissue proteins, leading
to hyperzincuria. Zinc has been found to increase the
effectiveness of insulin in-vitro and hence, Zn deficiency can worsen insulin
resistance in T2DM. Antioxidant enzymes such as oxide dismutase, catalase, and
peroxidase require Zn. Insulin, stored as a hexamer containing two Zn ions in
pancreatic β cells and released into the portal venous system during
β cell de-granulation (Afkhami-Ardekani et al., 2015).
Zn supplementation has many
beneficial effects on DM in animal and human (Table 1). A study giving a single
injection of alloxan and ZnCl2 in mice resulted in a significantly reduced
alloxan-induced increase in blood glucose concentrations at 24, 48, and 72
hours post-treatment with ZnCl2 (Ranasinghe et al., 2015).
Study review showed that the effect of zinc supplementation in diabetic
patients indicated that supplementation Zinc has a beneficial effect on
glycemic control (Jayawardena et al., 2012). Zinc plays an
important role in β cell function, glucose homeostasis, insulin action,
and the pathogenesis of diabetes and its complications (Ranasinghe et al., 2015).
Zn supplementation caused significant
reductions in FBG and HbA1c in humans and rat with DM. In rats, DM model rat
were prepared by induced streptozotocin (STZ), a decrease in sugar levels
occurred with 5 mg/kg zinc sulfate supplementation for 30 days and even a
decrease in glucose levels was seen 24 hours after 5 mg/kg ZnCl2 and 100 mg/kg
alloxan supplementation (Ranasinghe et al., 2015; Ryadinency et al., 2018).
Similar results were reported with supplementation with 10 mg/kg zinc sulphate (Ryadinency et al., 2018),
10 mg/kg ZnONP (Afify et al., 2019), and 150 mg/kg
curcumin�Zn complex in the on-Rats DM model.
In human
researches (Table 1), a decrease in HbA1c levels occurred after supplementation
of 100 mg/day zinc sulfate for 8 (Afkhami-Ardekani et al., 2015), and 50 mg/day
zinc sulphate for 8 weeks (Jayawardena et al., 2012). Significant
reduction in FBG levels occurred after supplementation with 20 mg/day Zinc
gluconate for 12 months (Ranasinghe et al., 2015)
nd 30 mg/day zinc gluconate for 3 months (Naghizadeh et al., 2018).
(Naghizadeh et al., 2018)
reported that HbA1c was not significantly decreased with supplementation of 30
mg/day zinc gluconate for 3 months in patients with non-proliferative diabetic
retinopathy. (Seet et al., 2011)
reported that supplementation with 240 mg/day Zn gluconate in T2DM does not
affect FBG and insulin.
Zn supplementation
affects the regulation of blood glucose levels which can be explained by
various molecular mechanisms. The mimetic and hypoglycemic properties of
insulin via the Zn (II) complex have been studied in in-vivo and in-vitro
research. Protein tyrosine phosphatase 1B (PTP 1B), the main regulator of the
phosphorylation state of insulin receptors, targets Zn ions. Zinc can play a
role in increasing peripheral insulin sensitivity because it can increase
glucose transport stimulated by insulin. Zinc has an important functional role
in β cell physiology. Zinc supplementation also reduces the HbA1c value (Jayawardena et al., 2012).
Zn
supplementation not only affects blood sugar levels but also insulin
resistance. Several studies reported a significant reduction in insulin
resistance based on the homeostasis model assessment (HOMA) index after Zn
supplementation in DM patients (Ranasinge, Roshanravan, Naghizadeh).
Different result reported by (Soheilykhah et al., 2012)
that Zn significantly increased adiponectin levels, but not significantly
decreased insulin levels and insulin resistance.
Increased circulating
insulin and adiposity decrease the expression of zinc-alpha2-glycoprotein (ZAG)
gene in adipose tissue. ZAG mRNA and insulin resistance parameters such as
plasma insulin and the homeostasis model of insulin resistance were negatively
associated (Chen et al., 1998). However, ZAG and
adiponectin mRNA were positively related, and ZAG increased adiponectin
production by human gluconeogenesis and increased glucose adipocytes. (Chen et al., 1998)
evaluated the effect of Zn supplementation on insulin and plasma glucose levels
in obese and lean control mice. As a result, zinc supplementation reduced
fasting plasma glucose in obese mice by 51% and in lean mice by 25%.
Conclusion
Zinc
deficiency played role in the pathogenesis of DM. Zinc supplementation reduced
blood sugar levels and insulin resistance in DM. These results were even obtained
from various types of Zn supplements. The implication of these results is that
zinc supplements can be useful as an alternative nutritional therapy for DM
patients who are able to reduce blood sugar levels and insulin resistance.
However, some
irrelevant results are possible due to differences in characteristics subject,
doses, and periods of zinc supplementation. The various mechanisms involved
have not been fully elucidated with certainty that may affect the outcome on
blood glucose levels and insulin resistance. Research related to variations in
dosage and duration of zinc supplementation as well as patient characteristics
need to be studied in further research to find out the effectiveness of
supplementation. Human studies are still few and there are not many studies on
the factors that influence therapeutic effectiveness as well as the proper
dosage and period of nutritional therapy, so further research is needed.
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