Exercise Causes Muscle GLUT4 Translocation in an Insulin-Independent Manner
Giovanni Messina1,4 Filomena Palmieri1, Vincenzo Monda1, Antonietta Messina1, Carmine Dalia1, Andrea Viggiano2, Domenico Tafuri3, Antonietta Messina1, Fiorenzo Moscatelli4,5, Anna Valenzano4, Giuseppe Cibelli4, Sergio Chieffi1 and Marcellino Monda1*
1Department of Experimental Medicine, Section of Human Physiology and Clinical Dietetic Service, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy
2Faculty of Medicine, University of Salerno, Salerno, Italy
3Department of Motor Sciences and Wellness, University of Naples "Parthenope", Naples, Italy
4Department of Clinical and Experimental Medicine University of Foggia, Foggia, Italy
5Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, Rome, Italy
- *Corresponding Author:
- Marcellino Monda
Department of Experimental Medicine
Section of Human Physiology and Clinical Dietetic Service
Second University of Naples, Via Costantinopoli 16
80138 Naples, Italy
Tel. +39 +81 566 5804
Fax +39 +81 5665844
E-mail: [email protected]
Received date: May 14, 2015, Accepted date: July 27, 2015 Published date: August 3, 2015
Citation: Messina G, Palmieri F, Monda V, Messina A, Dalia C et al. (2015) Exercise Causes Muscle GLUT4 Translocation in an Insulin-Independent Manner. Biol Med (Aligarh) S3:007. doi:10.4172/0974-8369.1000S3007
Copyright: © 2015 Monda M. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Glucose uptake in skeletal muscle is dependent on the translocation of GLUT4 glucose transporters to the plasma membrane. The most important stimulators of glucose transport in skeletal muscle are insulin and exercise. Glucose uptake in skeletal muscle during exercise induces acceleration of many processes compared to the resting state. The scientific literature does not underline the role played by muscle contraction to increase glucose uptake with insulin-independent mechanisms. Search on Pub Med (May 05, 2015) using the key words "contraction and glucose uptake and muscle" gives 717 reports, while a search using the key words "insulin and glucose uptake and muscle" cites 5676 publications. The present paper describes the role of exercise in the muscle glucose uptake. Contraction of muscle induces GLUT4 translocation in the absence of insulin. There are different intracellular "pools" of GLUT4, one stimulated by insulin and another one stimulated by exercise. The roles exerted by AMPK, AICAR, calcium, NO, glycogen and hypoxia in the glucose uptake during exercise are emphasized. The effects of these phenomena on human wellness are reported
Glucose; GLUT4; Muscle; Exercise
The population statistics of most countries of the world are
indicating that industrialization and computerization have been
associated with an increase in sedentary behavior and more recently
with a significant shift from healthy weight to overweight. In general,
this change in the overweight/obesity prevalence is attributed by
health professionals to suboptimal diet and physical activity practices.
The beneficial effects of physical exercise on the decreased insulin
sensitivity caused by detrimental lifestyle have been demonstrated by
experimental evidences. In epidemiological studies, disease prevention
has been considered at three levels: primary (avoiding the occurrence
of disease), secondary (early detection and reversal), and tertiary
(prevention or delay of complications) [1-5]. The major purpose of
physical exercise for primary prevention and treatment of lifestylerelated
diseases is to improve insulin sensitivity [6-9]. It is known that,
during physical exercise, glucose uptake by the working muscles rises 7
to 20 times over the basal level, depending on the intensity of the work
performed. However, intense exercise provokes the release of
insulin-counter regulatory hormones such as glucagon and
catecholamines, which ultimately counter-balance insulin
action[11-16]. Continued physical training improves the reduced
peripheral tissue sensitivity to insulin in impaired glucose tolerance
and Type II diabetes, along with regularization of abnormal lipid
metabolism. Furthermore, combination of salt intake restriction and physical training ameliorates hypertension. In practical terms, before
diabetic patients undertake any program of physical exercise, various
medical examinations are needed to determine whether they have
good glycemic control and are without progressive complications.
Because the effect of exercise that is manifested in improved insulin
sensitivity decreases within 3 days after exercise and is no longer
apparent after 1 week, a continued program is needed.
Muscle glucose uptake  can be separated into three sequential
steps, i.e. delivery of glucose from the blood to the muscle, transport
across the sarcolemma by a GLUT, and irreversible phosphorylation to
glucose-6-phosphate by an HK isozyme. Each of these steps can serve
as a barrier to MGU and, thus, are important in regulating glucose
influx. During resting conditions, the transport step exerts the most
control in regulating MGU, as GLUT1 (1–4) or GLUT4 [18,19]
overexpression augments basal MGU. Previous work suggests that
normal GLUT4 content is sufficient for increases in MGU during
exercise, because GLUT4 overexpression alone does not further
increase exercise-stimulated MGU . Instead of glucose transport,
glucose phosphorylation is a primary limitation of exercise-stimulated
MGU [21,22]. Heterozygous GLUT4 knock-out mice serve as a useful
tool for examining the impact of reductions in glucose transport
capacity on MGU[23-26].
Insulin stimulation and physical exercise are the most
physiologically relevant stimulators of glucose transport in skeletal
muscle [27,28] and interestingly in patients with Type 2 diabetes, insulin- but not contraction-stimulated glucose transport is impaired
Both insulin and exercise/muscle contraction increase skeletal
muscle glucose uptake by translocation of glucose transporters from
an intracellular location to the plasma membrane and t-tubules.
GLUT4 is the predominant glucose transporter isoform expressed in
skeletal muscle. Early studies have demonstrated that there are distinct
proximal signaling mechanisms responsible for the stimulation of
GLUT4 translocation and glucose transport by insulin and exercise.
Insulin signaling involves the rapid phosphorylation of the insulin
receptor, insulin receptor substrate-1/2 (IRS-1/2) on tyrosine residues,
and the activation of phosphatidylinositol 3-kinase (PI3-K)[30,31]. In
contrast, exercise and muscle contraction have no effect on insulin
receptor and IRS-1 phosphorylation or on PI3-K activity, and
muscle-specific knockout of the insulin receptor does not impair
contraction-stimulated glucose transport [33,34]. Clearly, these data
demonstrate that the initiating signals that lead to GLUT4
translocation by insulin and exercise in skeletal muscle are distinct.
Stimulation of insulin secretion by glucose involves the enhanced
synthesis of ATP by mitochondria  and closure of ATP-sensitive K
+ channels . Subsequent depolarization of the plasma membrane
 then opens voltage-sensitive (L-type) Ca2+ channels  causing
insulin containing vesicles to fuse at the plasma membrane. The
mechanisms that link changes in glucose concentration to the
regulation of Β-cell genes are less well understood[40,41]. Recently, we
have demonstrated that AMP-activated protein kinase (AMPK) is
involved in the regulation of gene expression by glucose in this cell
type. AMPK is a multisubstrate, heterotrimeric serine/threonine
protein kinase, consisting of a catalytic α-subunit and non-catalytic β-
and γ-subunits .
Regular physical activity leads to a number of adaptations in skeletal
muscle that allow the muscle to more efficiently utilize substrates for
ATP production and thus become more resistant to fatigue. The three
major adaptations to exercise training are: 1) muscle fiber type
transformations as defined by the expression of specific contractile
proteins (myosin heavy chain isoforms), 2) increases in mitochondrial
activity and content, and 3) increases in GLUT4 protein expression.
Adaptations, which might underlie the increased insulin sensitivity
in trained individuals, include increases in levels of the glucose
transporter protein GLUT-4 and in muscle glycogen synthase activity,
a decrease in the serum triglyceride concentration and, possibly, an
increase in the muscle capillary network.
In post absorptive humans, there are 100g of glycogen in the liver
and 400g of glycogen in muscle. Carbohydrate oxidation by the
working muscle can go up by 10-fold with exercise, and yet after 1 h,
blood glucose is maintained at 4g. Blood glucose is preserved at the
expense of liver and muscle glycogen. Liver glycogen breakdown
protects blood glucose as the glucose moieties that comprise it are
released into the blood. Muscle glycogen breakdown impedes the
removal of glucose from the blood by increasing glucose 6-phosphate
(G6P), which inhibits the hexokinase (HK) reaction, and by providing
a source of fuel that diminishes the need for blood glucose. The
amount of glucose in the blood can still be constant after 2 h of
exercise in well-nourished subjects. Blood glucose is protected by liver
gluconeogenesis after glycogen stores become critically low. Only after
extremely prolonged exercise does blood glucose fall to concentrations
that result in hypoglycemia severe enough to cause
Glucagon is the primary controller of hepatic glucose production in
the sedentary state . Exercise is a robust challenge of the processes
involved because of the high rates of glucose production necessary to
maintain blood glucose. Glucagon secretion from the pancreatic α
cell increases during exercise, whereas insulin secretion from the
pancreatic β cell declines. The decline in insulin secretion potentiates
the actions of glucagon [46–48]. Studies in animals [49–51] and
humans [46,52] demonstrate that the increase in glucagon is the
primary stimulator of hepatic glucose production during exercise. The
powerful effect of glucagon on hepatic glucose production was
recently demonstrated by Berglund et al. . This study showed that
increasing glucagon in sedentary mice to levels similar to those seen
during exercise causes a marked discharge of hepatic energy stores so
that the adenosine monophosphate (AMP) to adenosine triphosphate
(ATP) ratio is increased. This increase in the AMP: ATP ratio, through
allosteric mechanisms, facilitates the glucagon-induced breakdown of
glycogen and the oxidation of fat in the liver [51,54].
The translocation of GLUT4 from an intracellular vesicle to the
plasma membrane and T tubules is a major mechanism through which
both insulin and exercise increase skeletal muscle glucose transport.
Contractile activity can stimulate GLUT4 translocation in the absence
of insulin, and some studies suggest there are different intracellular
"pools" of GLUT4, one stimulated by insulin and one stimulated by
exercise . These findings have provided the basis for our
understanding of the glucose transport system with exercise in skeletal
Systematic review of literature indicates that regular participation in
moderately intense physical activity is associated with a substantially
lower risk of type 2 diabetes. The association was partly independent
of BMI, suggesting that moderate-intensity physical activity can
reduce the risk of type 2 diabetes even in those who do not achieve
weight loss [56–58]. Findings from several prospective studies [59–62]
indicate that 30 min or more of daily moderate-intensity activity, as
recommended in multiple guidelines [63,64] can substantially reduce
the risk of type 2 diabetes as compared with being sedentary.
Moderately intense activity as defined in guidelines (3.0–6.0 MET h)
includes walking at brisk pace but not walking at an easy or casual
pace  and walking at brisk pace also seems preferable for the
prevention of type 2 diabetes [61,66–70]. Further studies are needed to
define more specifically what combinations of duration and pace are
optimal for reducing the risk of type 2 diabetes. However, given that
only a low percentage adults in the industrialized countries currently
meet the general physical activity recommendations, efforts to prevent
type 2 diabetes should strongly emphasize the benefit of moderately
intense physical activities and encourage wider participation in these
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