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Metabolic Control of Type 2 Diabetes by Targeting the GLUT4 Glucose


Transporter: Intervention Approaches

Article  in  Current Pharmaceutical Design · March 2016


DOI: 10.2174/1381612822666160307145801

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Current Pharmaceutical Design, 2016, 22, 3034-3049
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no.

Metabolic Control of Type 2 Diabetes by Targeting the GLUT4 Glucose


Transporter: Intervention Approaches
Impact
Factor:
3.45

BENTHAM
SCIENCE

Fahmida Alam1#*, Md. Asiful Islam1#, Md. Ibrahim Khalil1&2 and Siew Hua Gan1*
1
Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia,
16150 Kubang Kerian, Kelantan, Malaysia; 2Department of Biochemistry and Mo-
lecular Biology, Jahangirnagar University, Savar, Dhaka 1342, Bangladesh

Abstract: Type 2 diabetes mellitus (T2DM), the most common form of diabetes, is characterized
by insulin resistance in the hepatic and peripheral tissues. Glucose transporter 4 (GLUT4) plays a
major role in the pathophysiology of T2DM. Its defective expression or translocation to the pe-
ripheral cell plasma membrane in T2DM patients hinders the entrance of glucose into the cell for
energy production. In addition to suitable drugs, an appropriate diet and/or exercise can be im-
plemented to target the increase in GLUT4 expression, GLUT4 concentrations and GLUT4 trans-
location to the cell surface when managing the glucose metabolism of T2DM patients. In this
review, we discussed successful intervention strategies that were individually administered or
coupled with diet and/or exercise and affected the expression and translocation of GLUT4 in T2DM while reducing the excess glucose
load from the blood. Additionally, some potentially good synthetic and natural compounds, which can activate the insulin-independent
GLUT4 signaling pathways for the efficient management of T2DM, are highlighted as possible targets or emerging alternative sources
for future anti-diabetic drug development.

Keywords: Type 2 diabetes mellitus, GLUT4, intervention, exercise, diet, natural compounds.
Current Pharmaceutical Design

INTRODUCTION exercise and drugs or a combination of these interventions can pre-


Diabetes Mellitus (DM) is the world's most prevalent endocrine vent and resolve insulin resistance. These intervention plans can
disorder, with a worldwide prevalence of 382 million people in enhance GLUT4 expression and translocation to the cell membrane
2013 that is projected to reach as high as 592 million by the year and enhance the rate of glucose uptake by the adipose tissues and
2035 [1]. Type 2 diabetes mellitus (T2DM) is a prominent form of skeletal and cardiac muscles of T2DM patients [11-13]. Therefore,
diabetes (90 - 95%) and is characterized by insulin resistance of the GLUT4 can be a potential therapeutic target via the effective inter-
hepatic and peripheral tissues, with an insulin secretory defect in ventions of diet, exercise or natural compounds for better manage-
pancreatic  cells [2]. There are various contributing factors includ- ment strategies in patients with T2DM.
ing physical inactivity, overeating, stress, aging, smoking, obesity, In this review, we discussed and compiled all of the scattered
increased cortisol levels, high blood pressure, abnormal sex hor- data regarding the successful intervention therapies currently avail-
mone secretion, alcohol intake and genetic factors. However, insu- able, either when used singly or when coupled with diet and/or
lin resistance is mainly attributed to obesity and physical inactivity, exercise, which affects the expression and translocation of GLUT4,
both of which precede and predict T2DM [3]. Therefore, T2DM is in managing T2DM patients. Additionally, we discussed some po-
considered as a very serious public health problem with enormous tential alternative synthetic and natural compounds that can be
socioeconomic burden worldwide [4]. emerging sources for future drug development targeting GLUT4 in
Glucose transporters (GLUTs) are a large cluster of membrane T2DM.
proteins that facilitate the transport of glucose through the cellular METABOLIC CONTROL OF GLUCOSE BY GLUT4
plasma membrane. Several GLUTs (such as GLUT 1, 2, 3 and 4)
are present in cells to help maintain low blood glucose levels. How- In normal metabolic conditions, the glucose levels in blood are
ever, GLUT4 is the only transporter responsible for facilitating maintained at normal levels (5–6 mM), even following high load of
glucose transport into the cells in response to insulin, and therefore, carbohydrate ingestion, via tightly regulated cellular mechanisms.
is considered as a vital regulator of entire body glucose homeostasis This further prevents severe dysfunctions, such as hypoglycemia-
[5, 6]. In normal physiology, when insulin binds on the cell surface related unconsciousness and hyperglycemia-related toxicity to the
insulin receptor (IR), GLUT4 translocates from intracellular envi- peripheral tissues [5]. It is well established that the muscle and
ronment to the cell surface, docks and fuses with the membrane to adipose tissues are the main glucose-utilizing centers that contribute
facilitate glucose transport into the cell. However, in T2DM pa- to systemic glucose diminution, even in individuals following a
tients, GLUT4 is not translocated in the adipose tissues, skeletal carbohydrate-rich diet, with the aim of maintaining normal meta-
and cardiac muscles because of insulin resistance. As a conse- bolic homeostasis [14]. Exogenous glucose uptake by the skeletal
quence, the metabolic load of insulin increases in the blood and muscle is regulated by insulin-mediated signaling in the presence of
does not actually enter into the cells as a source of energy [7-10]. a principal GLUT4 (Gene name, SLC2A4) on cell surface mem-
Researchers have shown that an appropriate diet, regular physical brane (Fig. 1). This transporter is highly sensitive to insulin. When
insulin is absent in the basal state, majority of the muscle GLUT4
resides within small intracellular storage vesicles (named GLUT4
*Address correspondence to these authors at the Human Genome Centre, storage vesicles or GSVs) that are excluded from the sarcolemma
School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang and T-tubules [15]. From the plasma membrane, these vesicles
Kerian, Kelantan, Malaysia; E-mails: alam.fahmida@yahoo.com; grasp GLUT4 away through a repulsion mechanism, but in the
shgan@usm.my
# presence of insulin, they undergo rapid exocytosis in a burst-like
These authors contributed equally to this work.
manner [16].

1873-4286/16 $58.00+.00 © 2016 Bentham Science Publishers


Metabolic Control of Type 2 Diabetes by Targeting the GLUT4 Glucose Transporter Current Pharmaceutical Design, 2016, Vol. 22, No. 20 3035

 cell

Pancreas
Capillary

 cell secretes insulin in the


presence of blood glucose Blood

Insulin
Glucose in blood
Increased GLUT gene Improved insulin
expression sensitivity
Blood glucose and insulin
Cycle ergometer training, Aerobic exercise,
approach towards adipose Increased GLUT4 levels in the membrane
Thyroid hormone, Salacia Anthocyanin, Isoflavones,
and muscle tissue
oblonga, Mangiferin Myricetin, Cod Protein,
Insulin Glucose Endurance training (treadmill running),
extracts, Fenugreek seed Creatine, Chromium,
extract, Rosiglitazone, Lipoic acid combined with Short-term high intensity intermittent
Plasma membrane swimming training, Resistance training
Anthocyanin, Tannic acid,
Hesperidin, Naringin, Insulin Receptor along with head-down bed rest, Strength
Creatine, Alpha-lipoic training, Cycle ergometry, Naringenin,
GLUT4 Procyanidins, Alpha-lipoic acid,
acid, Vitamin D,
Chlorogenic acid and P P GLUT4 Pycnogenol, Chromium, Lipoic acid
Ferulic acid storage supplement with exercise, Sulfonylurea
IR vesicle
Cytoplasm
P13K The SNARE ternary complex and
Munc18 helps to dock and fuse the
GLUT4 gene GSV with the plasma membrane Increased glucose uptake
Activate
The exocyst complex, TBC1D4, myosin Glucose intake by Anthocyanin, Cyanidin-3-glucoside,
PKC motors (MYO5 and MYO1C), actin and GLUT4
P Akt/PK P Naringenin, Quercetin, Resveratrol,
Increased GLUT mRNA GLUT4 mRNA small molecular GTPases help in tethering
expression Metformin with exercise, Procyanidins,
Gallic acid, Protocatechuic acid,
Short-term and long-term Epigallocatechin gallate, Alpha-lipoic acid,
Signal GLUT4
swimming training, Acute Sulfonylurea
storage
exercise, Plumbagin vesicle
(Plumbago zeylanica L.
root), Lingonberry, GLUT4 Increased GLUT4 translocation
Rutamarin, Quercetin, storage
Procyanidins vesicle Microtubules, actin and kinesin motors Troglitazone, Irbesartan, Cinnamaldehyde, Corosolic
GLUT4 protein help the GSV to approach towards plasma acid (banaba leaf), Magnolia officinalis, Capparis
membrane moonii (fruits, Salacia oblonga , Mangiferin extracts,
GLUT4
Increased GLUT4 protein level Pongamia pinata (fruits), Mulberry leaf tea,
Anthocyanin, Kaempferitrin, Rutin, Myricetin,
Short-term and long-term swimming Resveratrol, Quercetin, Procyanidins, Gallic acid,
training, Endurance training (treadmill Protocatechuic acid, Epigallocatechin gallate, Cod
walking/running), Acute exercise (cycle Protein, Chromium, Zinc, Vitamin D, Ginger,
ergometer training), High-intensity Resistance training with dietary protein, Creatine
intermittent exercise training, Plumbagin, supplementation combined with an exercise
Anthocyanin, Isoflavones

Fig. (1). Glucose uptake by the GLUT4 glucose transporter via the insulin-dependent signaling pathway.

In muscle and adipose tissues, several cellular mechanisms are isoforms were confirmed in intracellular GLUT4-containing vesi-
initiated for optimal glucose uptake by GLUT4 and glucose utiliza- cles [17]. However, activation of the PI3K-Akt pathway by insulin
tion. When carbohydrates are ingested, they are slowly broken signaling is adequate to activate the exocytosis of GSVs into the
down into smaller components by different digesting enzymes and plasma membrane [16]. Up to 50% of GLUT4 is mobilized from
are finally converted into glucose, which then enters into the blood- the intracellular membrane storage sites into the cell plasma mem-
stream via the capillaries. The pancreatic  cells sense the presence brane by this process [18]. To direct the GSVs towards the plasma
of glucose in the blood and secrete insulin. Glucose sensing occurs membrane, microtubules, actin (found in adipocytes) and insulin-
when blood glucose enters the pancreatic  cell through GLUT2 regulated kinesin motors are important for the delivery of GSVs
glucose transporter which is further metabolized by glucokinase into the cell cortex [19]. The exocyst complex (a tethering appara-
enzyme followed by the generation of adenosine triphosphate tus at the plasma membrane) participates in a meaningful interac-
(ATP). ATP in turn facilitates the interplay of K+ and Ca2+ channels tion by engaging and capturing the GSVs at the cell surface via
leading to the release of insulin via exocytosis into the blood different small GTPases (RAL, ARF6, TC10, Rab8, Rab10, Rab11,
stream. The canonical PI3K (phosphoinositide 3-kinase)-Akt path- Rho and CDC42) [20, 21].
way is activated when insulin engages with its surface receptors on It has been reported that the TBC1D4 (160 kDa protein with
the myocytes and adipocytes) [16]. Several signaling molecules are tether-like features) has the ability to bind to GLUT4 vesicles as
activated in a cascade-like manner. well as the plasma membrane, although the molecular details of
In brief, the binding of insulin with its receptor (a hetero- these interactions have not yet been elucidated [22-24]. Addition-
tetramer with two  and two  subunits) persuades a conforma- ally, myosin motors (MYO5 and MYO1C) were observed on
tional change in the receptor and activates its tyrosine-kinase do- GLUT4 vesicles as well as at the plasma membrane and make link-
main. Upon activation, the receptor recruits and phosphorylates the ages between the GCVs, actin and the plasma membrane [25, 26].
insulin receptor substrate (IRS) family of proteins (IRS-1 and IRS- After tethering, the vesicle docks with the plasma membrane by
2) [17]. The tyrosine-phosphorylated IRS proteins display binding forming a ternary SNARE complex between VAMP2 (v-SNARE)
sites for several effector molecules - such as PI3K. PI3K then tar- on the GSV and syntaxin-4 and SNAP23 (t-SNAREs) on the
gets the serine/threonine kinase Akt /protein kinase B (PKB) and plasma membrane. In the presence of Sec1/Munc18-like (SM) pro-
protein kinase C (PKC) isoforms. In the inner leaflet of the plasma tein, the complex then induces the fusion of GSV lipid bilayer and
membrane, PI3K activates Akt by producing polyphosphoinositi- plasma membrane [27]. Upon fusion, the number of GLUT4
des, which in turns act as the docking site of Akt. This leads to its transporters expressed on the cell surface increases, thus increasing
close proximity to its upstream regulatory kinase, phosphatidyli- the glucose uptake. Thus, GLUT4 is one of the main glucose re-
nositol-dependent kinase-1. Even though the activation mechanism moval mediator from the circulation and is a vital glucose homeo-
of PKC isoforms is unclear, the recruitment of PKC into intracellu- stasis regulator of the entire body.
lar membranes might be involved and indeed, the presence of these
3036 Current Pharmaceutical Design, 2016, Vol. 22, No. 20 Alam et al.

GLUT4: A POSSIBLE TARGET FOR DIABETES MAN- vating AMPK (adenosine monophosphate-dependent protein
AGEMENT kinase) in the white adipose tissue and skeletal muscle. The activa-
Despite the acute regulation of GLUT4 expression by insulin, tion considerably increases the expression of the GLUT4 protein,
the gene expression of GLUT4 can be either hormonally or metab- resulting in enhanced glucose uptake into these tissues via an insu-
olically regulated [28, 29]. Several studies have focused on GLUT4 lin-independent mechanism [42].
expression in insulin-resistant conditions due to its crucial role in In another study, the STZ-treated diabetic rats exhibited lower
regulating glucose transport. In addition to the genetic and envi- GLUT4 expression in heart and skeletal muscle tissues, which was
ronmental factors, an individual’s lifestyle, particularly the inges- significantly improved by ANT (from the black soybean seed coat)
tion of a high-fat diet, can contribute to insulin resistance, causing compared to glibenclamide (anti-diabetic drug), with increased
T2DM and obesity. A high-fat diet can induce impaired glucose translocation of GLUT4 and enhanced uptake of glucose. In addi-
tolerance and a condition resembling T2DM in certain mouse mod- tion, IR phosphorylation is activated by ANT, further suggesting
els [30]. better utilization of glucose by the tissues [43]. Thus, the anti-
Based on the hypothesis that a moderate increase of GLUT4 diabetic effects of ANTs suggest their potential usability as drugs to
expression might correct the impaired glucose tolerance in a tissue- regulate diabetes.
specific manner, an experiment was conducted to observe the ef- A recent study reported that the treatment of insulin-resistant
fects on impaired glucose tolerance. To test this hypothesis, trans- 3T3-L1 cells with a black soybean koji extract [(BSK), high-quality
genic mice with a 14 kb GLUT4 mini-gene (7 kb of 5'-flanking and protein containing fermented product of black soybean, isoflavones
1 kb of 3'-flanking sequence containing all exons and introns of the and ANTs] could ameliorate obesity-associated insulin resistance
GLUT4 gene along with a small foreign DNA tag) were fed a high and increase glucose utilization by upregulating the GLUT4 protein
fat diet. Surprisingly, low-level expression of tissue-specific levels [44]. Therefore, the authors suggested that BSK might be an
GLUT4 mini-gene prevented the glycemic impairments as well as effective source for treating obesity-induced insulin resistance.
hyperglycemia [31]. It is assumed that some defects in the signal However, BSK active compounds need further investigation to
transduction cascade, beginning with insulin binding to its receptor identify the detailed molecular mechanisms of this product.
through the translocation of GLUT4 to cell surface, may be respon- Cyanidin-3-glucoside (C3G), which belongs to the ANT family
sible for insulin resistance in muscle. Nevertheless, it is plausible and is present in black beans, is also an important component that
that GLUT4 was overexpressed despite the defect in the signaling can improve insulin resistance in 3T3-L1 adipocytes via the up-
cascade, which reduces the glucose tolerance. Another study re- regulation of GLUT4 gene expression. However, an additional
ported an opposite result, where the selective overexpression of study on insulin resistance using 3T3-L1 cells and an anti-fat effect
GLUT4 in the adipocytes of transgenic mice [containing an P2 using the diabetic model mice is warranted to verify these findings
(fatty acid binding protein) promoter/enhancer] on a low-fat diet in vivo [45]. C3G (50 mol/L) and its metabolite protocatechuic
failed to improve glucose tolerance [32]. The researchers assumed acid [(PCA), 100 mol/L] also enhance glucose uptake and translo-
that this may be due to insulin resistance in the skeletal muscle and cation of GLUT4 because they exert insulin-like activity via PPAR
liver, where the transgene is not expressed. Other studies using (peroxisome proliferator-activated receptor gamma) activation in
transgenic mice [such as genetically diabetic mice, mice with the 3T3-L1 cells and human omental adipocytes [46]. For the investiga-
insertion of a GLUT4 minigene into the genomic DNA, mice with tion of human adipocyte biology, 3T3-L1 cell line was found to be
an P2 promoter/enhancer ligated to the human GLUT4 gene, and the most suitable model as it showed similar responses to polyphe-
streptozotocin (STZ)-induced diabetic mouse model] have shown nol treatment [46]. Another study using diabetic mice reported that
that the over expression of GLUT4 (1) alleviates insulin resistance C3G ameliorates hyperglycemia and insulin sensitivity by signifi-
by translocating a high level of the GLUT4 protein to the cell sur- cantly up-regulating GLUT4 and down-regulating retinol binding
face, leading to a substantial improvement in glycemic control [33]; protein 4 expression in the white adipose tissue [47]. Therefore,
(2) increases the systemic glucose disposal by increasing the trans- based on the evidence of the good biological activities of C3G and
location of GLUT4 to the plasma membrane [34]; (3) increases PCA, it can be suggested that these polyphenols can be used as
glucose metabolism in all major pathways to maintain metabolic dietary bioactive compounds against the pathological conditions
homeostasis [35]; (4) increases both the basal and insulin- associated with insulin resistance.
stimulated glucose uptake and disposal [36, 37]; and (5) insulin
action improves with reduced basal plasma glucose levels [38]. Kaempferitrin (present in some plant leaves) and rutin (found in
most citrus fruits, berries, including mulberry and cranberries,
From these studies, it is plausible that alterations in GLUT4 buckwheat and asparagus) have been confirmed to affect GLUT4
expression or activity might be a potential target in the treatment of translocation in adipocytes and skeletal muscle cells by stimulating
T2DM (Fig. 1). Therefore, either genetic manipulation or pharma- Akt synthesis and phosphorylation [48, 49]. Another study yielded
cologic intervention directed at increasing the GLUT4 levels at the similar results, where kaempferitrin stimulated GLUT4 transloca-
plasma membrane may be a beneficial therapy for individuals with tion and synthesis in adipocytes through the insulin signaling path-
T2DM because GLUT4 expression can improve glycemic control, way [50]. The dietary intake of myricetin (a natural flavonol from
even in the presence of severe insulin resistance and pancreatic medical plants, vegetables, fruits, berries, red wine and tea) from
defects. foods is approximately 0.98 - 1.10 mg/day [51, 52]. Myricetin has
been shown to improve insulin sensitivity by phosphorylating
THE EFFECT OF INTERVENTIONS ON GLUT4 USING
IR/IRS-1 and PI3K/Akt, which can subsequently affect the translo-
DIETARY COMPOUNDS
cation of GLUT4 in the soleus muscles of fructose chow-fed rats
Polyphenols [53, 54].
Effect of polyphenols on GLUT4 is now being highlighted in Naringenin (a flavonoid normally present in tomatoes and to-
recent articles [39]. Anthocyanins [ANTs (water-soluble plant pig- mato-based products) from a Canna indica plant extract can en-
ments)] are widely available in many dietary items, such as cereals, hance the uptake of glucose and increase the levels of plasma mem-
beans, fruits (blueberries, bilberries, or black currants), vegetables brane GLUT1 and GLUT4 in L8 muscle cells [55]. In addition, the
and red wine. Therefore, large amounts of ANTs from plant-based effects of naringenin on GLUT4 translocation or activity have been
diets are ingested on a daily basis [40, 41]. ANTs from dietary bil- reported in a recent study [56]. Tannic acid (found in green tea,
berry extract (containing 375 g ANT/kg) can ameliorate hypergly- black beans, red beans, fruits, such as apricots, grape, cherries,
cemia and insulin sensitivity in diabetic mice by significantly acti- peaches, berries and dates, and spices, such as cinnamon, cumin,
Metabolic Control of Type 2 Diabetes by Targeting the GLUT4 Glucose Transporter Current Pharmaceutical Design, 2016, Vol. 22, No. 20 3037

oregano and turmeric) is a major component of tannin (polyphenol), concentrations were increased [75]. In humans, a 6-week intake of
which induces GLUT4 by activating the insulin-mediated signaling CrS did not change the GLUT4 mRNA expression in the muscle or
pathway in adipocytes [57, 58]. the total GLUT4 concentration, but muscle glycogen was stimu-
The most common flavonol, quercetin, is present in various lated following creatine ingestion [76]. Due to the discrepancies in
fruits (apples and berries), vegetables, tea, and wine, with the high- these findings, more studies are warranted to provide a clearer pic-
est concentrations found in onion [59]. Quercetin and procyanidins ture on the effects and mechanisms of CrS on GLUT4 expression.
have been reported to possess anti-diabetic properties because they However, based on our current understanding, the molecular
up-regulate the levels of the GLUT4 mRNA and promote the trans- mechanisms of CrS that contribute to the increase in GLUT4 ex-
location of GLUT4 to the cell membrane of adipocytes and skeletal pression are as follows: (a) the expression of the PKB mRNA is
muscle cells [5, 60, 61]. In vitro studies have indicated the roles of assumed to promote GLUT4 translocation to the sarcolemma [77]
quercetin and resveratrol (found in red wine, mulberries, grapes, and (b) the enhancement of the nuclear levels and DNA binding
peanuts, and legumes) in increasing glucose uptake in adipocytes activity of the transcription factors (myocyte enhancer factor 2 iso-
and muscle cells by inducing GLUT4 translocation, mainly via forms) that regulate GLUT4 gene expression in muscle [73]. There-
AMP-activated protein kinase [62, 63]. fore, future studies need to investigate the influence of CrS on the
transcription factors that regulate GLUT4 in the insulin signaling
Hesperidin (present in oranges and mandarins) and naringin pathway for T2DM management.
(present in grapefruit) can increase GLUT4 expression in adipo-
cytes by activating hepatic PPAR, which was in accord with the Alpha-Lipoic Acid
finding of another study, where procyanidins (found in grape seed)
Alpha-lipoic acid (LA) is an antioxidant that is naturally pro-
was observed to increase the amount of insulin-sensitive GLUT4
duced in the body [78]. Very low amounts of LA are found in many
and found to stimulate glucose uptake in adipose tissues [64, 65].
foods, such as asparagus, spinach, broccoli, potatoes, tomatoes,
Gallic acid (which can be found in both green and black teas, as
garden peas, carrots, brussels sprouts, wheat, rice bran and beets.
well as in blueberries) from sea buckthorn leaf extracts promotes
Red meat, particularly organ meat (kidney and liver), has high
glucose uptake in 3T3-L1 adipocytes by inducing the translocation
amounts of LA [79, 80]. Several lines of evidence have highlighted
of GLUT4 in a PI3K-dependent manner, but not through the activa-
the benefits of LA in the prevention and treatment of diabetes.
tion of AMPK [66]. Epigallocatechin gallate (found in apple skin,
plums, onions, carob flour, hazelnuts, and green tea) has also been Oxidative stress has been widely observed in diabetes [81, 82].
suggested to increase glucose uptake and promote translocation of Oxidative stress can impair the insulin-stimulated translocation of
GLUT4 to the plasma membrane in skeletal muscle cells [67, 68]. GLUT4 and activation of PKB in 3T3-L1 adipocytes. LA is re-
ported to confer the ability to maintain the intracellular redox state,
Cod Protein thus providing a partial protection against the impairments induced
Carbohydrates and lipids play some important and promising by oxidative stress [83-85]. In cultured adipocytes, LA treatment
roles in glucose metabolism by modulating insulin action. How- can protect the IR from oxidative damage, without damaging its
ever, the effect of dietary proteins on metabolic homeostasis is not functional integrity [86]. In L6 muscle cells, micromolar concentra-
as well studied. A study conducted on high-fat-fed obese rats con- tions of LA can protect the insulin signaling system from oxidative
firmed that insulin resistance in skeletal muscles can be prevented stress [87].
by feeding the animals with cod protein [69]. Cod protein modu- Evidence suggests that the treatment of diabetic animals and
lates insulin sensitivity by selectively increasing the translocation of humans with LA improves glucose metabolism [88]. In a cell cul-
the GLUT4 transporters to the T-tubules of muscle cells. Addition- ture with L6 GLUT4myc myoblasts, Konrad et al. [89] demon-
ally, cod protein protects the insulin-stimulated PI3-kinase activity strated that LA can increase the GLUT4 concentrations on the
from the deleterious effect of fat ingestion, and subsequently pre- plasma membrane and stimulate glucose uptake in L6 GLUT4-myc
vented insulin resistance. Therefore, the detailed molecular mecha- myotubes, similar to the action of insulin. They suggested that by
nisms of how dietary cod protein improves insulin signaling to PI3- translocating and regulating the intrinsic activity of GLUT4, LA
kinase/Akt needs to be identified so that novel and targeted thera- stimulates glucose uptake by mimicking the action of insulin. Sev-
peutic tools can be developed for insulin resistance. eral studies supported their outcomes and stated the beneficial role
of LA in improving insulin-stimulated glucose uptake in T2DM
Creatine patients.
Creatine is a natural amine that is mainly found in meat and LA increases GLUT4 gene expression as well as its transloca-
fish. It is partly synthesized from plant or animal protein-containing tion from the internal pools to the plasma membrane via T2DM
foods by the pancreas, kidneys and liver in the human body. During insulin signaling pathway [90, 91]. This appears to be mediated via
digestion, creatine is released from the food into the blood stream increases in the kinase activity of the IR, IRS-1, phosphatidylinosi-
and is then transported to the skeletal muscles, brain and testes for tol 3-kinase and PKB, thus suggesting that LA directly influences
absorption [12]. Globally, creatine is one of the most used nutri- the early steps in the insulin signaling pathway [92]. The direct
tional supplements due to its efficacy in improving anaerobic power involvement of LA in reducing hyperglycemic conditions has made
and stimulating protein synthesis, thus enhancing athletes’ fitness LA a unique potential drug for T2DM management.
[70]. A number of studies reported the beneficial roles of creatine
supplements (CrS) for managing T2DM, such as (a) improved glu- Chromium
cose intolerance [71] and (b) improved insulin sensitivity [72]. Chromium (Cr) is found in a variety of foods including whole
These findings spurred the investigations on CrS to delineate its grain, nuts, broccoli, high-bran cereals, egg yolks, meat, green
therapeutic role in diabetes treatment. beans, brewer’s yeast, wine and beer. It is available as a dietary
Several studies have investigated the effects of CrS on GLUT4 supplement in mineral products and various types of multivitamins
expression for T2DM management. It has been demonstrated that 3 [93]. Decreased dietary intake of Cr is associated with many of the
weeks of CrS increases GLUT4 gene expression in the rat skeletal abnormalities (including glucose intolerance, increased body fat
muscles [73], although there were some contradictory outcomes. and elevated total cholesterol) that are related to insulin resistance.
For example, the results from animal studies demonstrated that 5 The presence of Cr in its active form can increase insulin’s sensitiv-
days of CrS treatment failed to alter the muscle GLUT4 content ity, and, thus, it may resolve insulin resistance as well as the associ-
[74], while a 48-hour CrS treatment did not successfully alter ated defects. Therefore, Cr supplements might be beneficial to the
GLUT4 translocation and glucose uptake, although the GLUT4 insulin-resistant T2DM patients who are Cr-deficient due to a poor
3038 Current Pharmaceutical Design, 2016, Vol. 22, No. 20 Alam et al.

diet [94]. Furthermore, the effects of Cr on normal insulin secretion, GLUT4 is impaired in the skeletal muscles due to insulin resistance
which can stimulate the translocation of GLUT4 vesicles to the cell in T2DM. The contractile activity of skeletal muscles during physi-
membrane, have been reported. For example, two different studies cal exercise is a potent therapeutic for T2DM management, as it
conducted on the skeletal muscle of high sucrose diet-fed mice and induces an increase in GLUT4 expression in skeletal muscle, thus
diabetic rats found that supplementation with Cr increased the helping to improve glucose transport capacity and insulin sensitiv-
GLUT4 levels in the membrane [95, 96]. In addition, it has also ity [111]. It is reported that exercise-induced glucose uptake is
been reported that Cr increases GLUT4 membrane translocation in normal (or near normal) in the muscle tissues of T2DM patients
myocardial tissues [97]. [112]. Several studies have suggested that the glucose uptake due to
The mechanism of Cr-mediated GLUT4 translocation to the exercise is mediated by an insulin-independent mechanism [113].
plasma membrane was further investigated using cultured adipo- For example, insulin signaling involves IR phosphorylation, IRS-
cytes [98]. The experiments resulted in an elevation of GLUT4 at 1/2 tyrosine phosphorylation and phosphatidylinositol 3-kinase
the plasma membrane and increased insulin-stimulated glucose activation [114, 115]. However, exercise has no effect on these
transport across the cell membrane. However, in vitro studies sug- activities [114, 116]. Therefore, it is plausible that exercise leads to
gested that Cr regulates GLUT4 translocation independently, with- adaptations that induce glucose transport by activating some mo-
out the involvement of insulin signaling through the IR, IRS-1, lecular signals that could bypass the insulin signaling defects in
PI3K or Akt proteins. Instead, Cr can increase membrane fluidity skeletal muscle. Exercise leads to changes in gene expression,
by decreasing the membrane cholesterol levels [98]. Therefore, the greater blood flow, and increased signaling, as well as changes in
exact mechanisms behind the beneficial effect of Cr on GLUT4 GLUT4 protein exocytosis and endocytosis [117].
have not been elucidated. The effects of exercise on GLUT4 and glucose uptake have
been established in many studies (Table 1). It is thought that acute
Zinc exercise increases the uptake of glucose skeletal muscle by stimu-
Zinc (Zn) is considered as an essential trace element, with mul- lating the translocation of GLUT4 and activating distinct proximal
tiple controlling roles, including insulin synthesis, secretion and signaling mechanisms. However, the detailed mechanisms by which
signaling, as well as glucose transport. In humans, Zn is the second the activated signaling pathways increase glucose uptake and/or
most common trace metal (after iron) found in all tissues and fluids GLUT4 translocation have not been reported.
[99]. The richest zinc food sources include oysters and meat (e.g., AS160 is a Rab GTPase-activating protein and is a substrate for
beef, lamb, veal and pork) [100]. The recommended dietary intake the Akt kinase [118]. AS160 is phosphorylated on multiple phos-
of Zn is 8 mg/day for women or 11 mg/day for men [101]. Nor- pho-Akt-substrate (PAS) sites by the Akt kinase in response to
mally, cellular zinc levels are tightly regulated, and if disturbed, can insulin, which is important for GLUT4 trafficking towards the cell
lead to diabetes mellitus [102]. A severe Zn deficiency can affect surface [118]. Furthermore, defects in insulin action on AS160 may
insulin secretion in the pancreatic islets, which leads to the devel- impair GLUT4 trafficking in T2DM [119]. Based on both human
opment of hyperglycemia [103]. [120, 121] and animal [115] studies, prolonged exercise has been
In 3T3-L1 adipocytes, it has been reported that Zn(opt)2 [bis(1- shown to increase AS160 PAS phosphorylation. In skeletal muscle,
oxy-2-pyridine-thiolato)Zn(II)] stimulates Akt/PKB phosphoryla- combination of 5-Aminoimidazole-4-carboxamide ribonucleotide
tion more strongly and at a faster rate (within 5 min) than insulin- [an analog of adenosine monophosphate (AMP) that is capable of
stimulated Akt/PKB phosphorylation. The activated Akt/PKB help stimulating AMPK activity] with exercise can enhance the AMPK
the translocation of GLUT4 vesicles to the plasma membrane mediated phosphorylation of AS160 (PAS site) [122]. It is reported
within 30 min [7]. Thus, it is concluded that Zn(opt)2 has an insuli- that uptake of glucose facilitated by exercise was inhibited signifi-
nomimetic activity that helps translocating GLUT4 protein from the cantly due to the alterations of the AS160 domain responsible for
cytosol to the plasma membrane by activating the insulin signaling calmodulin-binding, but not the insulin-dependent glucose uptake
cascade through Akt/PKB phosphorylation [104]. Similar results [123]. Therefore, exercise can regulate the phosphorylation and
were obtained with Zn(alx)2 [Zn(II) complex with allixin found in binding of calmodulin to AS160 to promote GLUT4 translocation
garlic] and Zn(tanm)2 [Zn(II)-thioallixin-N-methyl, a Zn(II) com- and glucose uptake.
plex with the allixin-derivative] in another study [105]. These stud- TBC1D1 is a protein that regulates transportation of glucose
ies indicate that the stimulation of GLUT4 translocation is a key provoked by insulin using a PAS-independent approach [124]. Dis-
insulinomimetic function of Zn. Based on its molecular mechanism; tinctive TBC1D1 mutations can regulate glucose uptake differen-
we can propose that Zn would be a beneficial agent in the treatment tially by the stimulation of both insulin and exercise through dis-
of type 2 diabetes. tinct phosphorylation sites [124, 125]. Therefore, TBC1D can serve
as a possible molecular link between the signaling pathways that
Vitamin D converge on GLUT4 translocation and skeletal muscle glucose
Some recent experiments have revealed that vitamin D has the uptake due to exercise.
potential to decrease the blood glucose level by upregulating Protein kinases which are dependent on Ca2+/Calmodulin, serve
GLUT4 in T2DM [106]. In 2015, it was reported that vitamin D as vital constituents of GLUT4 mediated skeletal muscle glucose
increases GLUT4 expression in STZ-induced T2DM Wistar rat uptake in response to exercise. The activation of protein kinase II
adipocytes [107]. GLUT4 translocation was observed in cultured which occurs in response to raised levels of cytosolic Ca2+, can up-
adipocytes (murine 3T3L1 fibroblast cell) [108] as well as in the regulate GLUT4 during muscle contraction [111]. In rats, contrac-
skeletal muscle of STZ-induced T2DM Webster mice [109]. Tamil- tion mediated glucose transportation was reduced after incubating
selvan et al. [110] reported that the anti-diabetic activity of vitamin the skeletal muscle with the Ca2+/Calmodulin inhibitor (KN-93)
D occurs via increasing GLUT4 gene expression in the muscle cells [126].
(L6-myotubes). Therefore, vitamin D is expected to be another
possible emerging therapy to target GLUT4 in T2DM management. Liver kinase B-1 (LKB-1) is the upstream kinase of AMPK (an
element important in cellular metabolism that maintains en-
THE EFFECTS OF EXERCISE INTERVENTIONS ON ergy homeostasis) and directly phosphorylates and activates AMPK
GLUT4 [127]. Nevertheless, the contribution of LKB-1 in glucose uptake as
Glucose uptake in skeletal muscle is generally mediated by a result of exercise is debated. For example, glucose uptake in
insulin via translocation of the GLUT4 glucose transporter to the LKB-1 knockout (KO) mice was reported to be impaired even after
plasma membrane. The insulin-stimulated glucose uptake by exercise by one study [128]; whereas partial inhibition of exercise-
Metabolic Control of Type 2 Diabetes by Targeting the GLUT4 Glucose Transporter Current Pharmaceutical Design, 2016, Vol. 22, No. 20 3039

Table 1. The effect of different exercises on GLUT4 from human and animal studies.

No. of Type of Number of Effect on Year,


Type of Study Age Duration and Intensity Length
Study Exercise Individuals (n) GLUT4 References

Human studies

T2DM patients
T2DM:
(n=9):
53 ± 4 years GLUT4 expression  in
Acute exercise 6 M and 3 F 2012,
both groups immediately
1 (cycle ergome- Case control 60 minutes - [168]
after exercise
try) Control:
Control (n=9): (60% and 66%, p < 0.05).
48 ± 3 years
5 M and 4 F

54.9 - 70.1 Each session with 10 x 60 s 2011,


T2DM patients: GLUT4 protein content 
years cycling bouts (Total 6 [169]
2 HIT - 2 weeks after training [(~369%) (p <
(n=8) sessions), HRmax (90%), 75
0.05)].
min / week

Continuous moderate GLUT4 expression signifi-


Continuous and T2DM: 47 ±
T2DM patients intensity - 3 days/week (60 cantly  in skeletal muscle
high-intensity 2 years
with obesity (n=7) minutes at 55% Wmax); 4 weeks and adipose tissue (36% and 2011,
3 intermittent Case control
Intermittent high-intensity - 20%, p < 0.05) after exer- [170]
training (cycle Control: 54
Control (n=7) 2 days/week (6 x 5 minute cise intervention compared
ergometry) ± 4 years
bouts at 70% Wmax) to baseline.

16 repetitions of the exer- 2008,


Healthy but un- GLUT4, but not GLUT1, 
Cycle exercise 20.9 - 22.6 cise were performed for 6 [171]
4 - trained subjects 16 hours (p < 0.05) after repetitive
training years min at ~90% VO2peak, once
(n=12) sessions of heavy exercise.
per hour

Exercise bouts at ~40 and


80% of the VO2 peak  the
Healthy, physi- 60 min at ~40% VO2 peak GLUT4 mRNA and GLUT4
2006,
cally active but 21.2 - 24.4 (low) or 27 ± 2 min at protein in human skeletal
5 Acute exercise - - [172]
untrained indi- years ~80% muscle to a similar extent,
viduals (n=6) VO2 peak (high) despite the differences in
exercise intensity and
duration.

Obese T2DM T2DM: 42.4 The GLUT4 protein content


Acute bout of exercise (60 Short term
Bicycle er- (n=8): 6 M and 2 F - 46.8 years  in obese T2DM patients 2006,
min at 75% VO2 peak) and exercise (7
6 gometer train- Case control and obese non- and non- (p < 0.05), but not in obese [133]
chronic short term exercise consecutive
ing T2DM (n=7): 6 M T2DM: 43.8 non-T2DM subjects follow-
(1 hour at 75% VO2 peak) days)
and 1 F - 51.6 years ing chronic exercise.

The GLUT4 expression in


skeletal muscle increased
Strenuous Semi-balanced, within hours after exercise; 2005,
Healthy adult [173]
7 treadmill randomized, 3- - 8 hours/day 3 days however, carbohydrate
horses (n=7)
exercise way crossover meals did not enhance
GLUT4 expression in
muscles.

T2DM GLUT4  (40%) in the


Caucasian T2DM Patients: 60 trained muscle of T2DM
patients (n=10) One leg three times per 2004,
Strength train- - 64 years subjects (p < 0.05), but the
8 - and male healthy week (each session total 30 6 weeks [174]
ing and controls: 13% increase in the control
controls subjects min)
59 - 63 years subjects did not achieve
[M (n=7)]
statistical significance.

T2DM (n=6): 4 M GLUT4 protein  by 22 ±


and 2 F T2DM 3 times/week (60% of VO2
10% and 38 ± 8% in the
patients: 41- peak for 20 minutes),
Cycle ergome- diabetic and non-diabetic 2004,
9 Case control 49 years and which increased to 4 8 weeks
ter training Non-T2DM subjects, respectively (p < [163]
controls: 34 times/week (70% of VO2
(n=16): 6 M and 0.05), before and after
- 38 years peak for 45 minutes)
10 F training.
3040 Current Pharmaceutical Design, 2016, Vol. 22, No. 20 Alam et al.

(Table 1) Contd….

No. of Type of Number of Effect on Year,


Type of Study Age Duration and Intensity Length
Study Exercise Individuals (n) GLUT4 References

Control group:
6° head-down tilt at all
times throughout bed rest,
except for showering every
Young subjects other day GLUT4 content in the VL
[M (n=9)] muscle of the control group
Resistance Training group: significantly  after 19 days
training along RCT of bed rest (p < 0.05), 1999,
10 2 groups: control 18 - 26 years Remained at bed rest, 19 days
with head- whereas it significantly  [134]
(n=4) or except during resistance (30
down bed rest during 19 days of bed rest
isometric maximal volun-
resistance training plus isometric training (p <
tary contractions for 3 sec
group (n=5) 0.01) in the training group.
each; leg-press exercise
was used to recruit the
extensor muscles of the
ankle, knee, and hip) train-
ing once in the morning

Cycle ergome- The GLUT4 immunoreac-


ter Healthy subjects 2 hours/day at 65-70% of 1995,
11 - 29 - 33 years 7 – 10 days tivity in muscle  [98% (p <
(n=8): 4 M and 4 F peak O2 uptake [175]
exercise 0.001)] after training.

Sedentary individ- The GLUT4 protein content


Short-term
ual:  [~2.8 ± 0.5-fold (p < 1995,
12 exercise (cycle - ~ 25 years 1 hour/day, Wmax (55%) 7 days
0.05)] in human skeletal [176]
ergometry) [M (n=7)]
muscle.

NIDDM: 56 GLUT4 protein content  (p


NIDDM subjects:
- 60 years; < 0.05) in all groups during
One-legged 7 (M) 1994,
Healthy: 58 training (to 0.43 ± 0.03, [177]
13 ergometer Case control Healthy controls: 8 6 days/week, 30 min/day 9 weeks
- 60 years; 0.40 ± 0.03 and 0.57 ± 0.08
bicycle training (M)
Young: 22 - arbitrary units, respec-
Young subjects: 5 tively).
24 years

The GLUT4 mRNA expres- 1994,


Specific pathogen- sion  2-fold and protein [178]
14 Swimming Case control - 10 min/day 2 days
free rats (F) expression increased 50% in
the epitrochlearis muscle.

Previously seden- Weeks 1 - 3 (30 min 3


Endurance tary middle-aged days/week at 70-80% of
Caucasian men for MHR); weeks 4 - 7 (40 min The GLUT4 protein con-
training (over-
centration  in the skeletal 1993,
ground and/or the exercise group 4 days/week at 70 - 80%
15 Case control 40 - 65 years 14 weeks muscle by 1.8-fold after [179]
treadmill [Case (n = 13)]; MHR); weeks 7 - 14 (45
min 4 days/week at 80-85% exercise in previously
walking and/or Sedentary men
sedentary middle-aged men.
running) without exercise MHR)
[Control (n=7)]

Lean-PX & obese-PX


showed hyperglycemia with
 GLUT4 levels [65% &
Endurance Lean and obese
62%, (p < 0.05)] compared
training (tread- Zucker rats- di- 2 hours/day, 5 days/week, to lean and obese CTLs, 1993,
mill running, vided into sham- 5 weeks old
16 RCT 15% grade, at 1518 15 weeks respectively, whereas the [180]
only obese operated control
m/min (Only obese-PX) obese-PX treated with
pancrea- (CTL) or 90% PX
exercise showed reduced
tomized (PX) groups
hyperglycemia with (2-fold)
 GLUT4 levels compared
to the obese CTL.
Metabolic Control of Type 2 Diabetes by Targeting the GLUT4 Glucose Transporter Current Pharmaceutical Design, 2016, Vol. 22, No. 20 3041

(Table 1) Contd….

No. of Type of Number of Effect on Year,


Type of Study Age Duration and Intensity Length
Study Exercise Individuals (n) GLUT4 References

Animal studies

GLUT4 mRNA (~3-fold) and


protein levels (~2-fold)  in the
10 min/day for 2 days epitrochlearis muscle after
followed by 2 x 3 hour exercise (within 18 h). However,
Two groups of long swimming sessions this exercise-induced result was
Wistar rats (M): 2003,
Swimming RCT separated by a 45 min long completely reversed () in rats
1 exercise group and - 5 days [181]
training rest for 3 days, one group fed a high-carbohydrate diet
sedentary control was fasted and the other (within 42 hour). In contrast, the
group
was fed either increase in the GLUT4 protein
chow or lard ad libitum was still present 66 hours after
exercise in the muscles of rats
fed the carbohydrate-free diet.

Balanced, Healthy adult


randomized, 3- No significant difference was 2003,
Thoroughbred
Running on 3 trials separated by 7 day detected in the muscle GLUT4 [182]
2 way horses (n=6): 4 - 60 min
treadmills intervals protein or mRNA content before
crossover mares and 2 geld-
and after exercise.
fashion study ings

HIT: 8-10 x 20 sec swim-


The GLUT4 content in the
Sprague-Dawley ming bouts with a 10 sec
epitrochlearis muscle was sig-
rats (M) pause
nificantly  by 83 and 91% after
Short-term training in the HIT and LIT
high intensity 3 groups: HIT 3-4 RHT: 5 x17 min swim- groups, respectively, compared 2001,
RCT
3 intermittent (n=16), weeks ming bouts with 3 min of 8 days to the control rats. [183]
swimming RHT (n=15), old rest between bouts
training The GLUT4 content after HIT
LIT (n=8) and
LIT: 6 hours/day in 2 x 3 did not differ from that after
sedentary controls
hour bouts separated by RHT (66% higher in the trained
(n =16)
rats than in the controls).
45 min of rest

SST: 2 x 3 hour/day, 5
days
SST and LST increases the
Specific pathogen- SST (5 GLUT4 mRNA by 48% and
free female Wistar LST: 2 x 3 h/day, 5 days), 60%, respectively; both training
days/wk types increase the GLUT4
SST, LST and rats LST (5 2000,
RCT protein (30%), whereas treadmill
4 treadmill - week) and [184]
run training produces a transient
training Treadmill training: 2 x 10 treadmill
2 groups: exercise increase in the GLUT4 protein
training or seden- min/day run (5 (35%) that is completely re-
tary control groups for 3 days followed by 60 week) versed after the last bout of
min at 30 m/min on a exercise (at 48 hour).

15% incline for 3 weeks

GLUT4 gene expression im-


mediately after exercise and 2000,
Cycle ergome- 20.2 ± 2.6 [185]
5 - 6 F and 4 M - 60 min remained significantly higher
ter training years
than the baseline at 3 hour after
the end of exercise (p <0.05).

Three groups of The GLUT4 content  2-fold in


Wistar rats (F): 1 the epitrochlearis muscle at 16
day of exercise, 2000,
Swimming RCT 1 or 5 hour after 1 day of exercise (p
6 - 6 hours/day [186]
training 5 days of exercise, days <0.05 vs. sedentary rats), with
and the sedentary no further increase noted after 5
controls days of exercise.
3042 Current Pharmaceutical Design, 2016, Vol. 22, No. 20 Alam et al.

(Table 1) Contd….

No. of Type of Number of Effect on Year,


Type of Study Age Duration and Intensity Length
Study Exercise Individuals (n) GLUT4 References

Functional M (n=4) and F


electrical (n=1) with motor-
1999,
stimulation complete SCI (3 - 31 - 50 [187]
7 - 30 minutes, 3 days/ week 8 weeks GLUT4  [72% (p < 0.05)]
(FES) Ieg cycle 25 years post- years
ergometer injury involving
training levels C5 - T8)

The GLUT4 protein con-


Progressive Two groups of
10 min/day for 2 days, then 6 centration  (~2-fold) in 1999,
Wistar rats: exer- 7 weeks
8 swimming Case control hours with 2 x 3 bouts/day for - triceps muscle of the exer- [188]
cise and control old
program 2 days cised group compared to the
groups
control group.

First day: 1 hour followed by


Two groups of
a 2 hour bout
Wistar rats [M]: Total GLUT4 levels 
Swimming 1998,
9 RCT sedentary group & - 4 days (30%) in swimming training
training [189]
swimming training vs. sedentary rats
group
Last 3 days: 2 x 3 h/day

The GLUT4 levels were


Specific-pathogen- higher (90%) in triceps
free Wistar rats (F) muscle of the trained (5
days) animals compared to
the controls, whereas, the 1998,
Swimming RCT 6 weeks 6 hours/day 5 days or 5
10 3 groups: seden- increase in the GLUT4 [190]
training tary control, 5-day old weeks
protein levels was com-
trained & 5-day pletely reversed after the
trained/40-h de- last exercise bout (within 40
trained hour) after both 5 days and
5 weeks of training.

Sprague-Dawley
rats [M (n=180)] In the trained rats, the
with initial body GLUT4 protein  (85%) in
weights of 80–90 g 2 hours/day in 4 x 30 min the epitrochlearis muscle at
Swimming 4 weeks 1997,
11 RCT bouts separated by 5 min of 5 days 18 hour after training, and
training old [191]
2 groups: seden- rest remained ~50% higher than
tary group & the control group at 42 hour
swimming training after training.
group

In the epitrochlearis muscle,


the cell surface GLUT4
Specific pathogen- 1997,
expression  48% in the [192]
12 Swimming Case control free male Wistar - 2 times, 3 hours/day 5 days
insulin-stimulated group
rats
and  40% in the hypoxia-
stimulated group.

18 meters/min (15% grade), 5 Exercise training of obese


Endurance Lean (Fa/-) and days/week for gradually rats for 18 or 30 weeks  the
training (tread- obese (fa/fa) 36 weeks increasing durations during 18 or 30 GLUT4 levels by 1.7 and 1990,
13 RCT
mill running) Zucker rats (M) old the first 2 weeks and at 20 weeks 2.3-fold, respectively, [193]
meters/min for 1.5 hours/day compared to the sedentary
thereafter obese rats.
T2DM = Type 2 diabetes mellitus, Wmax = Peak power output, M = Male, F = Female, HRmax = Maximal heart rate, MHR = Maximum heart rate, VL = Vastus lateralis, SCI = Spinal
cord injury, SST = Short-term swim training, LST = Long-term swim training, HIT = High-intensity intermittent exercise training, RHT = Relatively high-intensity intermittent pro-
longed exercise training, LIT = Low-intensity prolonged exercise training, RCT = Randomized controlled trial,  = Increase,  = Decrease

stimulated glucose transport was reported by another study in LKB- stimulation. On the other hand, chronic exercise improves skeletal
1 knockout mice [129]. muscle insulin sensitivity in T2DM patients by specifically restor-
Therefore, acute exercise activates the alternative signaling ing the mitochondrial function in skeletal muscle and by increasing
pathway in skeletal muscle and bypasses the insulin signaling de- the expression of the GLUT4 protein [130].
fects, causing enhancement of glucose uptake without insulin
Metabolic Control of Type 2 Diabetes by Targeting the GLUT4 Glucose Transporter Current Pharmaceutical Design, 2016, Vol. 22, No. 20 3043

However, the effects of exercise can be reversed within 18-24 In the skeletal muscle of L6 rat, Girón et al. [145] suggested
hours of the activity. For example, it is reported that the discon- that the Salacia oblonga and mangiferin extracts may exert their
tinuation of exercise for one week is sufficient to reduce the anti-diabetic effects through enhancing the expression and translo-
GLUT4 levels in the heart and in adipocytes [131]. Therefore, de- cation of GLUT4 via the 5' AMPK and PPAR pathways. Khan et
training can affect the translocation of GLUT4 to the insulin- al. [146] successfully identified at least four compounds (1, 5, 6 and
sensitive cell surface. Consequently, the GLUT4 levels return to the 7) from Kigelia pinnata that stimulated significant translocation
baseline levels. activity of GLUT4 in the skeletal muscle cell surface, without af-
To obtain the proper therapeutic effects of exercise, it is neces- fecting cell viability. Jaiswal et al. [147] identified that Karanjin
sary to know the total amount, duration, intensity and length of the (obtained from Pongamia pinata fruits) improved the GLUT4
exercise session to be conducted. Although several opinions exist translocating activity toward the cell surface of L6 myotubes
regarding the essential quantity of exercise for the improvement of through the AMPK pathway stimulation. In L6 myotubes, chloro-
metabolism, however, the recommended amount of exercise for genic and ferulic acids exerted higher glucose uptake by increased
T2DM individuals is a moderate intensity exercise ( 210 min) or GLUT4 expression via PI3-K independent and dependent path-
high-intensity exercise ( 125 min) per week [132]. In addition, ways, respectively [148].
both resistance and aerobic exercise can be followed in combina- In 2014, an in vivo investigation on Fenugreek seed extract
tion. In each week, it is suggestible to perform exercise for mini- confirmed that it may be a potent inducer of GLUT4 expression, as
mum 3 days. If possible, exercise performing with moderate and it has been found to improve T2DM in STZ-induced T2DM male
high-intensity can also be adopted in combination [132]. However, Sprague-Dawley rats compared to the control group [149]. Mul-
in every occasion, it is recommended that exercise programs are berry (Morusalba L.) leaf tea, which is a popular drink in Asian
planned and delivered by qualified and trained personnel, particu- nations, has been reported to have anti-diabetic effects by stimulat-
larly for T2DM patients. ing GLUT4 translocation and glucose uptake in the adipocytes of
Despite optimistic outputs of experiments conducted on the STZ-induced Sprague-Dawley diabetic male rats [150]. Recently,
effect of exercise on GLUT4, many researchers stated some limita- Lingonberry (Vccinium vitisidaea L.) in diabetic mice model in-
tions of their studies including limited number of experimental duced by diet, reported to exhibit anti-diabetic activities in skeletal
subjects [133] and statistical limitation due to the small number of muscle via enhanced expression of GLUT4 [151]. In an in vitro
controls [134]. study Rani et al. [152] observed that Ginger (Zingiber officinale)
has the potential to express or transport GLUT4 receptors from
POTENTIAL SYNTHETIC AND ALTERNATIVE NATURAL internal vesicles. Rutamarin, a natural compound, was identified as
COMPOUNDS IN THE REGULATION OF GLUT4 the inducer of GLUT4 expression. Eventually, GLUT4 transloca-
A number of alternative synthetic and natural compounds were tion capability of rutamarin was also confirmed to maintain glucose
shown to significantly affect the metabolic regulation of glucose via homeostasis in diet-induced obese mice through the PI3K-Akt/PKB
GLUT4 translocation. For example, Troglitazone, an insulin- pathways [153]. A recent study (2015) revealed that Kaempferol (a
sensitizing synthetic compound was reported to fuel the uptake of natural flavonoid) is another potential compound to restore GLUT4
glucose through activating the translocation of GLUT4 in L6 myo- activity in T2DM obese mice [154].
tubes [135]. Rosiglitazone (insulin sensitizer) exerts its anti-diabetic The successful natural compounds could be evaluated further
effect by increasing GLUT4 expression [136]. In cell surface, Irbe- for their effects on GLUT4 in combination with popular anti-
sartan (an angiotensin II type 1 receptor inhibitor) induced GLUT4 diabetic drugs. If they could produce synergistic effect on GLUT4,
translocation lead to significant increase in glucose transportation in potential ant-diabetic drugs from the useful chemical component of
L6-GLUT4-myc myoblasts as well as in male Zucker rats (geneti- those natural compounds can be developed in future targeting
cally obese) [137]. The thyroid hormone (T3) induces GLUT4 gene GLUT4. To be noted, although many bioactive compounds present
expression in male Sprague-Dawley rats [138] and is believed to be in natural products are therapeutically useful, investigations into the
useful when used in combination with other treatments (for exam- chemical components from a natural remedy is often challenging
ple, combination with -blockers) for T2DM. [155].
In an in vivo study using male Wistar rats, Cinnamaldehyde THE EFFECTS OF COMBINED INTERVENTIONS ON
(isolated from the stem bark of Cinnamomum zeylanicum) in- GLUT4
creased the translocation of GLUT4. It also induced glucose trans-
port across the membranes of skeletal muscle in diabetic rats com- Many researchers have shown that, occasionally, the combined
pared to the untreated diabetic rats [139]. In another in vivo study, interventions of diet, exercise or drugs in T2DM patients can sig-
Plumbagin, which is isolated from Plumbago zeylanica L. root, was nificantly improve the glucose uptake compared to individual inter-
confirmed to enhance the expression of the GLUT4 mRNA and ventions, due to increased insulin activity and GLUT4 expression
protein in STZ-induced diabetic rats (male albino Wistar rats) and translocation. For example, a study revealed that exercise can
[140]. It was also concluded that glucose homeostasis was likely improve the expression of IRS-1 (65% - 90%) and significantly
maintained by enhancing GLUT4 translocation. decrease the fasting blood glucose level (p < 0.05) of patients
treated with metformin and/or sulfonylurea [156]. It is plausible
In another study, Miura et al., [141] demonstrated that corosolic that the glucose uptake is mediated by the increased expression or
acid, which is isolated from banaba leaf, exerts its hypoglycemic translocation of GLUT4 [133].
activity by increasing GLUT4 translocation in the total muscle
membrane of male KK-Ay mice, which have genetically induced Another study confirmed that a combination of diet (high fiber,
T2DM. In a recent study, translocation of GLUT4 was facilitated low-fat) and daily aerobic exercise ameliorates insulin sensitivity,
by Magnolia officinalis in 3T3-L1 adipocytes as well as C2C12 likely by increasing the patients’ GLUT4 concentrations [157].
myotubes by activating the signaling pathways related to insulin When a combined intervention of diet (lipoic acid) and exercise
[142]. Pycnogenol [a procyanidin (a natural flavonoids) enriched was applied, an in vivo study reported increased levels of GLUT4,
extract of Pinus maritima bark] also had found to increase the rela- with glucose lowering effects (26 - 32%), and a significant im-
tive abundance of GLUT4 in fully differentiated 3T3-L1 adipocytes provement in insulin sensitivity (29 - 30%) in Zucker rats compared
[143]. Additionally, the fruits of Capparis moonii were found to to the sedentary controls [158]. Furthermore, a study on nine post-
increase the mRNA expression of GLUT4, causing increased glu- menopausal Greek women with T2DM (seven were treated with
cose uptake in L6 cells [144]. sulfonylurea and two were under dietary control) showed a signifi-
cant improvement (p < 0.001) of glucose uptake and insulin action
3044 Current Pharmaceutical Design, 2016, Vol. 22, No. 20 Alam et al.

[159], which were believed to be mediated by GLUT4, after a 16- CONFLICT OF INTEREST
week exercise program [160]. In addition, an in vivo study by Smith The authors confirm that this article content has no conflict of
et al., [161] found that a combined intervention with metformin and interest.
exercise can significantly improve insulin-stimulated glucose trans-
port via GLUT4 in female Zucker diabetic fatty rats, further con- ACKNOWLEDGEMENTS
firming that a combined intervention is superior to individual inter- We would like to acknowledge Universiti Sains Malaysia
ventions. (USM) for Research University (RU) grant (1001/PPSP/812115).
It has been reported that resistance training in combination with We would also like to acknowledge USM Global Fellowship (2014/
a moderately high amount of dietary proteins can enhance the de- 2015) and USM Vice-Chancellor Award (2015/2016) awarded to
velopment of insulin signaling proteins in older persons (61 ± 1 Fahmida Alam and Md. Asiful Islam, respectively, to pursue their
year) [162]. It is plausible that this phenomenon is the consequence PhD.
of enhanced GLUT translocation [12, 163]. A double-blind, ran-
domly assigned trial (12 weeks) conducted in 2011 [12] revealed REFERENCES
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Received: January 28, 2016 Accepted: March 4, 2016

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