Zinc transporters and insulin resistance: therapeutic implications for type 2 diabetes and metabolic disease
Norouzi et al. Journal of Biomedical Science
Zinc transporters and insulin resistance: therapeutic implications for type 2 diabetes and metabolic disease
Shaghayegh Norouzi 0
John Adulcikas 0
Sukhwinder Singh Sohal 0
Stephen Myers 0
0 Faculty of Health, School of Health Sciences, University of Tasmania , Newnham Campus, Launceston, TAS 7250 , Australia
Background: Zinc is a metal ion that is essential for growth and development, immunity, and metabolism, and therefore vital for life. Recent studies have highlighted zinc's dynamic role as an insulin mimetic and a cellular second messenger that controls many processes associated with insulin signaling and other downstream pathways that are amendable to glycemic control. Main body: Mechanisms that contribute to the decompartmentalization of zinc and dysfunctional zinc transporter mechanisms, including zinc signaling are associated with metabolic disease, including type 2 diabetes. The actions of the proteins involved in the uptake, storage, compartmentalization and distribution of zinc in cells is under intense investigation. Of these, emerging research has highlighted a role for several zinc transporters in the initiation of zinc signaling events in cells that lead to metabolic processes associated with maintaining insulin sensitivity and thus glycemic homeostasis. Conclusion: This raises the possibility that zinc transporters could provide novel utility to be targeted experimentally and in a clinical setting to treat patients with insulin resistance and thus introduce a new class of drug target with utility for diabetes pharmacotherapy.
Zinc ions; Skeletal muscle; Cell signaling; Glycemic control
Insulin resistance (IR) is a common pathophysiological
condition in which patients present with reduced insulin
sensitivity and thus glucose intolerance, particularly in
liver, adipose tissue and skeletal muscle [
]. This has
significant implications for the patient, as they are unable
to obtain to process the required energy from glucose to
maintain cellular metabolic processes. IR is of major global
concern as it is well-established as underpinning many
chronic health conditions including type 2 diabetes mellitus
(T2DM), obesity, cardiovascular disease polycystic ovary
syndrome (PCOS), liver cirrhosis [
hypertension, and stroke [
]. Moreover, given that IR
usually precedes the development of T2DM and
contributes to the progressive nature of this challenging and
devastating disease, understanding the molecular mechanisms
that lead to IR will help facilitate the development of
novel therapeutic strategies to prevent or lessen disease
progression. However, despite extensive ongoing research
into IR, its molecular mechanism(s) of action remains
Recently, research on metabolic processes associated
with IR and T2DM has revealed an exciting role for the
biochemical and physiological role of zinc and the proteins
that transport zinc in cells in diseases associated with
abnormal cellular signaling [
]. Accordingly, zinc and the
proteins that transport this metal ion have emerged as
potential therapeutic targets for disease states associated
with dysfunctional metabolism. For example, zinc in the
diet and zinc transporter proteins that influence/regulate
zinc metabolism are implicated in metabolic homeostasis in
peripheral tissues (e.g. skeletal muscle and liver) that
respond to insulin [
Zinc is ubiquitous in physiological systems, albeit, within
tightly controlled parameters, and therefore suggests that
atypical levels are likely to have significant biological and
clinical effects on disease processes. Knowing how zinc
transporter proteins and the storage of zinc in cells are
involved in metabolic processes implicated in IR for example,
may present opportunities to develop novel drugs targeting
these transporters to prevent or treat IR and T2DM disease
Type 2 diabetes mellitus
Type 2 diabetes mellitus (T2DM) is devastating disorder
characterised by hyperinsulinemia, hyperglycaemia,
compromised energy metabolism and expenditure, and the
progression of chronic illness and disease. T2DM is high
complex involving both genetic predisposition and
environmental factors. A major factor involved in a person’s
susceptibility to T2DM can be linked through family
history of diabetes. For example, Pacific Islander peoples
are a unique population with especially high rates of T2DM
]. The environment also plays a major role in the
development of IR and T2DM with inactivity and poor
nutritional status being two key factors [
Development of T2DM
The development of T2DM is preceded by IR, a disorder
associated with hyperinsulinemia, glucose intolerance
and dysfunctional energy metabolism [
]. A leading
concern for people with IR is the progressive failure of
pancreatic β-cell function (a major determinant of T2DM
progression) and thus, compromised insulin secretion
]. T2DM occurs primarily due to pancreatic β-cell
failure, including disruption of β-cell function and mass [
Elevated blood glucose causes the pancreatic β-cells to
produce more insulin resulting in hyperinsulinemia. Thus,
pancreatic β-cells amplify insulin synthesis as well as insulin
secretion pathways to overcome IR through an adaptive
response called β-cell compensation [
]. Consequently, the
failure of β-cells occurs in response to elevated insulin
levels and thus elevated blood glucose which results in
insulin insufficiency and overt diabetes. Accordingly, T2DM
patients with loss of β-cell function will cease to live a
normal life and will endure life-long pharmacological
intervention, often with episodes of illness from unfavourable
side-effects associated with the anti-diabetic treatments.
Therefore, prevention strategies that take advantage of this
“window of opportunity” (before β-cell failure) to prevent
or lessen disease progression would have an enormous
impact on the health and wellbeing of our communities.
Current drug treatments for T2DM
There are a range of medicines available to manage and
treat IR and T2DM, however, side effects of these drugs
have always been a foremost challenge in relation to the
goal of pharmacotherapy [
] (Table 1). Yet, treatments
for IR have not advanced significantly in the last few
decades because of the inadequate knowledge about the
pleiotropic effects that these drugs have on specific
molecular targets [
]. Therefore, finding strategies to
increase the efficacy and safety of therapeutic treatment for
IR and T2DM is highly critical. In this context, research
over the last decade has suggested a role for zinc in the
treatment of T2DM [
]. For example, lowered zinc
concentrations have been identified in some patients
with T2DM [
] and zinc supplementation appears to
improve the effectiveness of oral hypoglycaemic agents,
decreasing blood glucose, triglycerides and inflammation
in some patients [
]. However, many of these kinds of
studies are not consistent in their findings and adds
further complications in determining a role for zinc in these
processes. Thus, it will be important to look at the role of
zinc transporters and how they transport zinc within a
cellular context during disease progression.
Zinc is an essential trace element that is found in all
parts of the body including the fluids and secretions,
tissues and organs. Zinc is one of the most abundant
trace metals (next to iron) in the human body,
containing approximately 2–4 g [
]. The concentration
of zinc in tissues is highest in the prostate
(approximately 200 μg/ml), followed by the pancreas
(approximately 40 μg/ml) and then muscle (approximately
50 μg/ml). In human plasma, there is approximately
14–16 μM of total zinc that is distributed to cells and
subcellular organelles [
]. In multicellular organisms,
almost all zinc is intracellular with the nucleus
harbouring approximately 30–40%, the cytoplasm,
organelles and specialised vesicles approximately 50%, and
the cell membrane has about 10% [
]. Under normal
cellular conditions there is no free zinc and therefore,
the compartmentalization and distribution of cellular
zinc is highly important and tightly controlled so that
zinc homeostasis is maintained with an appropriate
cellular concentration and physiological range. This is
achieved by a family of zinc transporter proteins and
Metallothioneins and zinc transporters
Two families of zinc transporter proteins and zinc buffering
proteins play a critical role in the influx, efflux, buffering
and compartmentalization of zinc. These are the zinc
transporters (ZnT proteins and Zrt/Irt-like ZIP proteins),
and the intracellular zinc-binding metallothionein (MT)
proteins . MT proteins are a group of soluble low
molecular weight metal binding proteins that buffer
and translocate zinc within the cytosol [
]. The ZIP
and ZnT1 zinc transporters belong to a family of
transmembrane proteins that control zinc movement and
thus zinc concentrations in cells. The ZnT family
members (ZnT1–10) are involved in depleting cytosolic zinc by
moving this metal ion into intracellular organelles or from
the extracellular space while the ZIP family members
increase cytosolic zinc by transporting this metal ion from
outside the cell or from intracellular organelles (Fig. 1).
ZIP transporter family
The original member of the ZIP family of zinc transporters
was identified in Saccharomyces cerevisiae (designated
ZRT1) based on an amino acid sequence similarity to
that of Irt1p, an Fe(II) regulated transporter from
Arabidopsis thaliana [
]. Consistent with the
proposed role of ZRT1 in zinc uptake, zinc uptake was
increased when this transporter was overexpressed in
yeast cells. Similarly, a mutation that disrupted the
function of ZRT1 led to reduced levels of zinc uptake and poor
cellular growth in the mutant yeast strain .
The ZIP family of zinc transporters have a predicted
eight transmembrane domain (TMD) structure and this
is orientated with the N- and C-terminal facing the
extracytosolic region. Many of these members have a predicted
long histidine-rich loop region (HXn, n = 3–5) situated
between TMD 3 and TMD 4 that is suggested to serve as
a zinc-binding site (Fig. 2) [
]. In mammals, there are
at least fourteen ZIP transporters that have critical roles in
the transport of zinc into cytoplasm from extracellular
sources and intracellular storage compartments such as
the Golgi apparatus and endoplasmic reticulum, when the
cytosolic zinc is depleted. The ZIP transporters are
regulated by intracellular and extracellular zinc concentrations,
and hormones and cytokines. They are also expressed in
several tissues and cell types and their proteins are
localized to specific subcellular compartments and have been
extensively reviewed elsewhere .
ZnT transporter family
The ZnT zinc transporters are a large family that include
members with similar structural homology to bacteria,
fungi, nematodes, insects, plants and mammals [
family is predicted to have six transmembrane domains
(TMDs) with a histidine-rich loop region between TMD 4
and TMD 5 (Fig. 2). The original mammalian ZnT was
identified from a rodent cDNA library and was shown
experimentally to confer resistance to zinc toxicity in baby
hamster kidney cell lines [
]. Since the discovery of
ZnT1, nine other members have been identified
(designated SLC30A1–10). ZnTs are implicated in the transport
of zinc into subcellular organelles and from the cytosol
through the plasma membrane into the extracellular space
]. Like the ZIPs, the ZnTs are regulated by intracellular
and extracellular zinc, hormones, and cytokines and are
extensively reviewed elsewhere [
Zinc, zinc transporters and cellular signaling: A prelude to
cell signaling and insulin resistance
Changes in zinc compartmentalization and availability in
cells is typically detected and regulated by the intrinsic
control of zinc transporter proteins. The cellular
homeostasis of zinc is highly complex and there are several highly
significant reviews on these processes [
12, 15, 16, 27–30
Accordingly, this section of the review aims to delineate the
mechanisms by which zinc, and zinc transporters
contribute to cell signaling and how these processes might provide
insights into the molecular mechanisms implicated in
disease processes such as insulin resistance and type
Zinc mimics the action of several molecules implicated
in cellular metabolism including hormones, growth factors,
and cytokines, and given the large number of mammalian
zinc transporters that regulate zinc homeostasis, it is not
surprising that this metal ion has been highlighted as a
leading signaling molecule like calcium. Two modes of
zinc signaling have been described. These are 1) early
zinc signaling (EZS) and, 2) late zinc signaling (LZS).
EZS, is a process that is independent of gene
transcription and results in rapid changes in intracellular levels
of zinc that occurs in minutes (the ‘zinc wave’ response)
through the triggered release of zinc from subcellular
organelles into the cytosol [
]. This phenomenon was
first shown in studies in mast cells where an extracellular
stimulation of these cells with the high affinity IgE
resulted in a rapid increase in intracellular zinc from the
endoplasmic reticulum within minutes [
]. LZS can
also be triggered by extracellular stimuli but involves
transcriptional-dependent changes in genes and thus
proteins that are involved in zinc homeostasis such as
storage proteins or transporters [
]. The importance
of these two mechanisms of EZS and LZS highlight the
diverse roles that this metal ion plays in processes that
require rapid signals (such as metabolism) and more
longterm functions such as cell differentiation and cell growth.
The defining role of zinc as a signaling molecule was
shown in early studies in rat adipocytes where zinc could
stimulate lipogenesis, independent, and additive to that
of insulin [
]. Similarly, in rat adipocytes, zinc activated
cAMP phosphodiesterase and the mobilization of glucose
transporters to the plasma membrane, independent of
insulin receptor kinase activity [
]. Since these studies
implicating zinc as a signaling molecule, there is
increasing evidence suggesting zinc acts in extracellular signal
], second messenger activity [
kinase activity [
], protein phosphorylation [
transcription factor regulation [
]. These studies clearly
highlight the role of zinc in signaling processes that are
also associated with insulin-mediated metabolism.
The mechanisms of the insulin-mimetic action of zinc
have been delineated in several studies however it is still
unclear how these processes occur. One well-established
mechanism of zinc action on cellular signaling events
occurs through the inhibition of protein tyrosine
phosphatase 1B (PTP1B). PTP1B functions as a negative regulator of
insulin and leptin signaling transduction pathways [
Thus, the inhibition of PTP1B by zinc ions can prolong the
insulin signal through the insulin receptor. Similarly, the
ability of zinc to modulate glucose transport, glycogen
synthesis, lipogenesis, to inhibit gluconeogenesis and lipolysis,
and to regulate key elements of the insulin signaling
] suggests that this metal ion could provide
therapeutic insight or utility in the management and/or
treatment of insulin resistance. This is an interesting
notion in a clinical context since patients that are insulin
resistance have a “blunted” response to insulin and
subsequent downstream cellular signaling responses. Therefore,
the activation of cellular insulin signaling cascade that is
critical to achieve glycemic control might involve zinc.
However, the question remains as to whether zinc
independently activates critical molecules involved in cellular
signaling in the absence of insulin or whether zinc requires
insulin for these processes.
Zinc transporters, cellular signaling and insulin resistance
Given the well-established role of zinc transporters in
mediating the critical control of zinc homeostasis in
cells, it will be important to further delineate their
function in cell signaling events in the context of metabolic
control. Currently, information is limited to what role the
zinc transporters might play in cell signaling events in the
context of insulin resistance. Therefore, extrapolation of
studies from other cellular systems or disease states that
have identified zinc transporters and thus zinc flux in
facilitating cell signaling events might prove useful.
Studies accessing the role of zinc transporters in cellular
signaling found that the zinc transporters ZnT5 and ZnT7
are responsible for loading zinc to alkaline phosphatases
(ALPs) in the biosynthetic-secretory pathway in chicken B
lymphocyte-derived cells [
]. These authors noted that
mutant cells lacking both ZnTs resulted in a marked loss
in ALP activity and this activity could be restored by
overexpressing both ZnT5 and ZnT7. Similarly, the
cooperative activity of ZnT1, ZnT4 and metallothioneins are
required for the full activation of alkaline ALP in the
early-secretory pathway [
]. Accordingly, the above
studies demonstrate that ALP can be activated by the ZnT
family of zinc transporters and therefore aid in the control
of numerous cellular events.
In other studies, ZnT1 can regulate Raf-1 enzymatic
activity in Xenopus oocytes and cultured mammalian cells
]. Raf-1 plays a critical role in signal transduction in
eukaryote cells where it phosphorylates and activates
MEK1, a protein threonine and tyrosine kinase that
activates the MAPK family members ERK1 and ERK2 [
ZnT1 was shown to bind to the amino end of the Raf-1
protein and promote kinase activation. Moreover,
increasing the concentration of intracellular zinc inhibited
Ras-mediated signaling through zinc blocking the
ability of ZnT1 to bind Raf-1 [
] suggesting that Raf-1
activity requires functional ZnT1.
Of the ZIP transporters, ZIP14 is important in G-protein
coupled receptor (GPCR)-mediated signaling through the
maintenance of intracellular cAMP levels via suppression
of phosphodiesterase activity [
]. In these studies, fasting
gluconeogenesis is impaired in the livers of ZIP14 knockout
mice which was attributable to changes in GPCR signaling
processes. Similarly, in ZIP14 knock-out mouse
chondrocytes, parathyroid hormone-related peptide
(PTHrP)mediated c-fos activity was significantly reduced. PTHrP
stimulates the phosphorylation of cAMP response
elementbinding protein (CREB) which in turn induces the
transcription of c-fos [
Studies in MCF breast cancer cell lines have identified
that ZIP7 is essential in the redistribution of zinc from
intracellular stores to the cytoplasm and subsequent
zincinduced inhibition of phosphatases [
]. Moreover, ZIP7
knock-down in these cells prevented the zinc-induced
activation of epidermal growth factor receptor (EGFR),
insulinlike growth factor-1 receptor (IGF-1R), and protein kinase
B (AKT); key molecules implicated in cellular metabolism.
In fact, ZIP7 has been coined the “gatekeeper” of cytosolic
release from the endoplasmic reticulum (ER) and Golgi
]. ZIP7 is phosphorylated by CK2 in MCF-7
cells and this activation leads to the “gated” release of zinc
from the ER and the subsequent activation of multiple
downstream signaling pathways including AKT and
extracellular signal-regulated kinases 1and 2 (ERK1/2) [
ZIP7 is essential for the proliferation of intestinal
epithelial cells and mice lacking this transporter in intestinal
epithelium have massive apoptosis of transit-amplifying cells
due to increased endoplasmic reticulum stress (ER) [
Similarly, studies identified that the phosphorylation of
ZIP7 was increased in cardiomyocytes under
hyperglycemia conditions and was implicated in driving ER
]. Given that ZIP7 facilitates the release of
zinc from the ER [
] and ablation of ZIP7 in
mesenchymal stem cells led to the accumulation of zinc in
the ER and subsequent ER dysfunction [
], it is
plausible that ZIP7 could also be implicated in ER stress in
type 2 diabetes. Undeniably, ER stress and the
dysregulation of ER function in pancreatic beta cells are central
in the pathogenesis of diabetes [
Previously we have identified a role for ZIP7 in glycemic
control in skeletal muscle [
]. Skeletal muscle acts as a
major reservoir for zinc containing approximately 60% of
total whole-body zinc [
]. Knock-down of ZIP7 in C2C12
mouse skeletal muscle cells led to a significant reduction in
several genes and proteins involved in glucose metabolism
including the insulin receptor (Ir), insulin receptor
substrates 1 and 2 (Irs1 and Irs2), the phosphorylation of Akt,
glucose transporter Glut4, and glycogen branching enzyme
]. These data suggest that ZIP7 controls glucose
metabolism via the phosphorylation of Akt and Glut4
mobilization (Fig. 3). It is not clear if reduced ZIP7 and thus
reduced zinc levels leads to changes associated with the
phosphorylation status of the insulin receptor substrates
directly, or if reduced ZIP7 leads to inhibition of insulin
receptor signaling via binding of PTP-1B. Studies have
identified that the ZIPs play a major role in regulating
cytosolic zinc homeostasis and insulin secretion [
]. In these
studies, it was suggested that the zinc transporters ZIP6
and ZIP7 may have a role in insulin secretion in pancreatic
beta cells via alterations in cytosolic and/or subcellular
organelle-specific zinc pools. The down regulation of these
transporters via knock-down studies led to a significant
reduction in glucose-stimulated zinc uptake and oxidative
stress in mouse islet cells [
]. These authors speculate that
reduced expression of ZIP6 and ZIP7 may disrupt zinc
homeostasis and thus produce defects in insulin secretion
and beta cell viability that could potentially lead to the
development of diabetes.
Recent studies have shown a relationship with ZIP13 and
beige adipocyte biogenesis and thermogenesis [
primary white preadipocytes isolated from white fat from
ZIP13 null mice, there was a slight increase in common
white fat genes but a significant increase in the gene
expression of brown-fat specific genes and suggests that this
transporter is implicated the inhibition of beige fat differentiation
]. Moreover, these authors demonstrated that
ubiquinated C/EBP-β was decreased in ZIP13 null mice. C/EBP is
a major regulator of adipogenesis through the activation of
genes essential for mitotic clonal expansion and thus,
terminal adipocyte differentiation [
]. Accordingly, these
studies suggest that ZIP13 deletion promotes beige adipocyte
production and is associated with increased exergy
expenditure, reduced diet-induced obesity and insulin resistance.
ZIP14 has been identified as a critical route for
nontransferrin bound iron (NTBI) uptake into liver and
pancreatic acinar cells and is essential for the development of
liver iron overload in hemochromatosis [
]. Diabetes is
frequently associated with hemochromatosis and patients
with type 2 diabetes present with high ferritin levels which
correlate with diabetic retinopathy [
]. Similarly, ZIP14
knock-out mice have enlarged pancreatic islets, low
grade inflammation, and subsequent hyperinsulinemia
and increased body fat which are characteristic of type
2 diabetes [
Do the zinc transporters and zinc signaling play a role
in insulin resistance and the progression of type 2
Zinc plays a major role in many aspects of cell
signaling events in several physiological and
pathophysiological processes. While it is well established that at
least one zinc transporter (ZnT8) is critical for the
compartmentalization, structure and secretion of
insulin in beta cells of the pancreas [
], there is little
information about the other family members in this
context. Nonetheless, given the important role that
zinc transporters play in delivering bioactive zinc to
extracellular, cytosolic and subcellular milieu, and the
action of this metal ion on cell signaling events, it is
highly tempting to speculate that aberrant storage and
release of zinc will result in unfavorable processes
associated with insulin signaling and glycemic control.
ZnT8 and type 2 diabetes
Zinc is critical for the physiological role of insulin in the
form of storage in the secretory granules of the pancreas
as an inactive zinc-insulin hexamer [
]. When the
zinc-insulin hexamer is released into the blood circulation,
a change in pH drives the dissociation of the complex into
a bioactive monomer of insulin . The zinc transporter
that initializes zinc movement into insulin granules of the
pancreatic β-cells is ZnT8. In fact, this transporter is
almost exclusively localized in pancreatic β-cells and it is
critical for the synthesis, storage and action of insulin [
Genome-wide association studies (GWAS) have
discovered that a nonsynonymous single nucleotide
polymorphism (SNP) in ZnT8 (rs13266634) encodes a C → T base
substitution resulting in a change in the coded protein
(p.Arg325Trp) and the production of two protein variants
R and W of which the C allele (R variant) is associated with
susceptibility to type 2 diabetes [
]. The frequency of the
diabetes risk R allele is 91.5%, 71.7% and 56.7% in Africans,
Europeans, and Asians, respectively [
]. Moreover, the
corresponding at-risk R325 variant had reduced zinc
transporter activity compared to the W325 ZnT8 in pancreatic
beta-cell lines. Therefore, carriers of the R325 variant may
have compromised packaging of insulin in pancreatic
betacell granules [
]. In studies of 846 European individuals,
each of whom had a parent with type 2 diabetes, it was
demonstrated that homozygous carriers of the major C
risk-allele variant had compromised pancreatic β-cell
insulin secretion following an intravenous glucose load [
was suggested by these authors that the function and/or
production of ZnT8 in carriers of the C risk allele is
reduced and therefore likely to contribute to compromised
pancreatic beta-cell function.
Although GWAS studies have been successful in
identifying variant ZnT8 alleles, it does not necessarily imply
that the risk allele has a direct pathophysiological effect
on beta-cell insulin secretion. A Meta-Analysis of Glucose
and Insulin-related traits Consortium (MAGIC) was
recently formed to conduct large-scale meta-analyses of
genome-wide data for continuous diabetes-related traits
in non-diabetics [
]. Meta-analyses were performed on
approximately 2.5 M directly genotyped or imputed
SNPs from twenty-one GWAS that were informative
for fasting glucose (FG), fasting insulin (FI) and,
pancreatic beta-cell function (HOMA-B) and insulin
resistance (HOMA-IR) in non-diabetic participants [
was identified that the risk allele for ZnT8 was
associated with higher FG levels and an increase in two-hour
glucose response in non-diabetics. Although these studies
identified several genetic glycemic risk loci for type 2
diabetes, including ZnT8, not all loci are associated with
pathological levels of glucose and type 2 diabetes risk.
More recent studies that sequenced approximately
150,000 individuals across five ancestry groups reported
twelve rare protein-truncating mutations in ZnT8 which
together explain a 65% reduced risk of developing type 2
]. It was found that a nonsense variant
encoding (c.412C → T, p.Arg138*) heterozygosity yielded a
53% reduction in type 2 diabetes risk. Similarly,
heterozygosity for the variant encoding p.Lys34Serfs*50 which
is predicted to cause a frameshift and loss of all six
ZnT8 transmembrane domains was associated with an
80% reduction in type 2 diabetes risk.
Recently, studies aimed to delineate the effect of dietary
factor interactions with ZnT8 polymorphism (rs13266634)
and the risk of developing metabolic syndrome found a
significant interaction among omega-3 fatty acid consumption
and ZnT8 in the context of metabolic syndrome,
dyslipidemia, and abdominal obesity [
]. Participants with the CC
genotype benefited more from the consumption of
omega3 fatty acids than carriers of the CT + TT genotypes.
Carriers of the CC genotype had reduced risk of developing
these disease states with increased consumption of
omega3 fatty acids. Moreover, the risk of abdominal obesity in the
CT + TT genotype groups increased significantly with salty
snack consumption but not in the CC homozygote carriers.
Studies to investigate the role of ZnT8 and glucose
homeostasis has been established with ZnT8 null mouse
models with global deletion of ZnT8 or pancreatic
betacell specific ZnT8 deletion [
]. Most models resulted in
impaired or unaltered glucose tolerance, however in
ZnT8-depleted beta cells insulin granule abnormalities
were observed, and this was concomitant with a loss of
zinc release from secretory granules [
ZnT8specific deletion in beta cells resulted in reduced
peripheral insulin concentrations despite an unexpected increase
in insulin secretion from isolated ZnT8-depleted islets
]. These authors suggest that secreted insulin from the
pancreas in the ZnT8 knock-out mouse suppresses
hepatic insulin clearance and dysregulation of this process
could play a role in the pathogenesis of type 2 diabetes. A
recent study [
] revealed ZnT8 deletion in mouse
betacells resulted in a significant impairment in zinc release,
normal or increased insulin secretion and subsequent
impairment in glucose tolerance. Moreover, transgenic mice
that overexpressed ZnT8 in beta cells showed a significant
improvement in zinc release, lower levels of insulin
secretion and improved glucose tolerance [
Given the pancreatic tissue-specificity of ZnT8 there is
potential for this transporter to be amendable to therapy
in the treatment of diabetes. However, targeting ZnT8 in
the treatment of diabetes could prove to be highly
complex. Although results from ZnT8 null mice suggest that
increasing ZnT8 could improve insulin secretion and
glycemic control, loss of function mutations in ZnT8
suggest a protective role for this transporter in type 2
diabetes. While ZnT8 plays a critical role in insulin
physiology, and over the last decade or so this
transporter has been given much attention for its role in
diabetes, other zinc transporters have not had the same
focused attention until recently. Apart from the many
studies on zinc signaling in cells and the insulin-mimetic
action of zinc, it is unclear which zinc transporters are
involved in initiating these signaling processes. Clues
from studies on the role of ZIP7 as the “gate-keeper” of
zinc release from the Golgi apparatus [
subsequent ZIP7-mediated cell signaling events in skeletal
] no doubt place this transporter in an
important position for further studies. Identifying how the
zinc transporters are implicated in zinc signaling events
that are amendable to insulin signaling processes in
insulin resistance may help elucidate novel therapeutic
options for the treatment of early diabetic symptoms and
thus the long-term management of this disorder and
associated type 2 diabetes.
Zinc is an essential metal ion that is ubiquitous in many
metabolic and physiological processes. The emerging
role of zinc as an insulin mimetic in maintaining
cellular function suggests that atypical levels, and aberrant
compartmentalization, transport and storage of zinc
will have biological effects that could be amendable to
clinical intervention. Although current understandings
on the role of zinc transporters in insulin resistance is
not available, and this knowledge is only just emerging
in type 2 diabetes, it is clear from studies on ZnT8 that
this family of transporters has utility for the development
of novel diabetic therapies. While ZnT8 plays a significant
role in insulin biology and therefore represents an
attractive target for diabetes therapy, the other members of the
zinc transporter family in diabetes are less defined.
However, we can speculate from the information presented in
this review that the other transporters are involved in
processes that facilitate insulin signaling and glycemic control
and therefore could offer exciting new targets that are
amendable to therapeutic intervention in the treatment of
diseases associated with insulin resistance and type 2
1For brevity, the terms ZIP and ZnT
will be used
Clifford Craig Medical Research Trust Grant, Launceston, Australia.
Availability of data and materials
SM and SN both contributed equally to the writing, literature research, figure
design, preparation, and editing of this article. JA contributed to the review
and editing of the article and the creation of the figures. SS contributed to
the editing and review of the article. All authors read and approved the final
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