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Molecular mechanisms involved in physical exercise and factors that may influence them. particularities in patients with type 2 diabetes mellitus

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Phisical activity, regularly performed, give us a lot of health benefit, especially in preventing cardiovascular disease, diabetes mellitus (DM) and obesity. Physical exercise, defined as a controlled, progressive, supervised, requires muscular activity, involving energy consumption through metabolic and thermoregulatory processes. It can be classified as aerobic and anaerobic, according to the metabolic processes that take place. The metabolic equivalent (MET) represents the body’s energy consumption during rest and it is used for quantifying fhisical activity (for example, a MET value of 3 would require 3 times the energy that is consumed at rest). Muscle contraction has two different phases: the isometric one (usually during the first part of the contraction) and the isotonic one. This article presents the interrelation of phisical activity with with the complexity of metabolic patwais, bringing the arguments for the necessity of performing regular and controlled phisical activity.
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No. 1 Tabaci Street, Postal Code 200642, Craiova, Romania, Phone: +40-251 502418,
Fax: +40-251 502246,, corresponding author e-mail: mmota53@yahoo.com
MOLECULAR MECHANISMS INVOLVED IN PHYSICAL EXERCISE
AND FACTORS THAT MAY INFLUENCE THEM. PARTICULARITIES
IN PATIENTS WITH TYPE 2 DIABETES MELLITUS
Isabela Popa 1, Diana Protasiewicz 2, Cristina Muntean 3,
Simona Georgiana Popa 1, Maria Mota 1,
1 University of Medicine and Pharmacy Craiova, Clinic of Diabetes Nutrition and
Metabolic Diseases
2 Clinical Emergency County Hospital Craiova, Clinic of Diabetes Nutrition and
Metabolic Diseases
3 Clinical Hospital of Neuropsychiatry Department of Neurology
received:
November 10, 2011
accepted:
March 09, 2012
available online:
May 31, 2012
Abstract
Phisical activity, regularly performed, give us a lot of health benefit, especially in
preventing cardiovascular disease, diabetes mellitus (DM) and obesity. Physical
exercise, defined as a controlled, progressive, supervised, requires muscular activity,
involving energy consumption through metabolic and thermoregulatory processes. It
can be classified as aerobic and anaerobic, according to the metabolic processes
that take place. The metabolic equivalent (MET) represents the body’s energy
consumption during rest and it is used for quantifying fhisical activity (for example,
a MET value of 3 would require 3 times the energy that is consumed at rest). Muscle
contraction has two different phases: the isometric one (usually during the first part
of the contraction) and the isotonic one. This article presents the interrelation of
phisical activity with with the complexity of metabolic patwais, bringing the
arguments for the necessity of performing regular and controlled phisical activity.
key words: phisical activity, type 2 diabetes mellitus, metabolic pathwais
Introduction
Physical activity (PA) regularly performed
is seen as a healthy lifestyle component.
Recently its importance has been underlined
by studies that have shown the link between
constantly and regularly performed PA and the
overall health benefit, especially in preventing
cardiovascular disease (CD), diabetes mellitus
(DM) and obesity.
Definition of terms
The notion of physical exercise (PE) is
defined as a controlled, progressive,
supervised PA. This action requires muscular
activity, involving energy consumption
through metabolic and thermoregulatory
© 2012 ILEX PUBLISHING HOUSE, Bucharest, Roumania
http://www.jrdiabet.ro
Rom J Diabetes Nutr Metab Dis. 19(2):189-200
doi: 10.2478/v10255-012-0023-3
190 Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 19 / no. 2 / 2012
processes [1]. PE can be classified as follows:
aerobic PE and anaerobic PE according to the
metabolic processes that take place.
Aerobic PE consists of rhythmic, repeated
and continuous movements of the same
muscle groups for a minimum of 10 minutes
(brisk walking, jogging, swimming, cycling).
Anaerobic PE is characterized by short,
intense periods of muscle activity (sprinting,
swimming vigorously for short periods,
isometric PE-lifting, pushing, pulling
weights). Anaerobic PE is accompanied by an
increase in blood pressure and heart rate due
to sympathetic nervous system stimulation,
with secondary catecholamine hypersecretion.
Muscular fitness refers to muscular
strength and muscular endurance [5].
Resistance PE: PA that uses muscular
strength to lift a weight [5].
The metabolic equivalent (MET)
represents the body’s energy consumption
during rest and it is used for quantifying PA
(for example, a MET value of 3 would require
3 times the energy that is consumed at rest)
[5]. Muscle contraction has two different
phases: the isometric one (usually during the
first part of the contraction) and the isotonic
one.
Isometric contraction increases muscle
tension, although the length remains constant.
It is a characteristic of postural muscles. It
doesn’t produce mechanical work but instead
produces heat. The joints angle also does not
change. For example, when a person pushes a
wall or tries to lift a very heavy object, the
muscles are involved in isometric contraction.
The tension developed in the muscles during
these types of contractions is higher than the
one obtained during isotonic contractions.
Isotonic contraction, considered to be a
dynamic contraction, causes the muscle to
change its length while the tension remains
constant. It is a characteristic of the skeletal
muscles. Isotonic contraction produces
mechanical work and movement.
Elements of anatomy and physiology
of the skeletal muscle fiber [2]
There are two types of muscle fibers: type
I slow twitch fibres and type II rapid
twitch fibres.
Type I muscle fibres or slow twitch-
oxidative fibres have the following
characteristics:
small amount of glycogen;
large amount of myoglobin (red fibres)
and mitochondria ;
small calibre;
extensive network of capillaries providing
an important oxygen supply;
preferentially use of aerobic reactions;
resistant to fatigue;
increased lipoprotein lipase (LPL) activity;
they slowly develope muscle strength and
maintain it for a long period, being used
for intense PA.
They are found in the postural muscles:
psoas, soleus muscle.
Type II muscle fibres differentiate in two
subtypes:
1. Type IIb or slow twitch fibres have the
following features:
increased amount of glycogen;
decresed amount of myoglobin and
mytochondria;
limited aerobic metabolism;
glycogenolysis and glycolysis are
important metabolic processes;
large calibre;
increased sensitivity to fatigue due to
ATP synthesis mainly through
glycolysis with an increased
Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 19 / no. 2 / 2012 191
production of lactic acid followed by
low pH and downregulation of this
macroergic compound;
decreased lipoprotein lipase (LPL)
activity;
activated in sprint and resistance PE.
2. Type IIa fibres are a combination of
type I and type IIb fibres, sharing their
functional characteristics.
Fast twitch fibres may rapidly produce an
increased force of contraction. They are found
in muscles of the lower and upper extremities,
which are responsible for high intense
movements of short duration. The percentage
of the fibres varies: the triceps muscle has
32.6 % type I fibres, while the soleus muscle
has 87.7% type I fibres.
“Fuels“ utilization
Skeletal muscles use different "fuels" to
generate adenosine triphosphate (ATP), each
with a unique and special role in the
mechanism of contraction. ATP is a
macroergic compound responsible for energy
transfer and not for energy storing [4].
Aerobic and anaerobic glycolysis lead to ATP
generation.
All skeletal muscles contain mitochondria
that are capable of fatty acids (FA) and ketone
bodies oxidation (beta-hydroxybutyric acid,
acetoacetic acid). They are also able to
completely oxidize the carbon skeleton of
alanine, aspartate, glutamate, valine, leucine
and isoleucine. ATP level allosterically
inhibits or activates energy producing
reactions such as oxidation or hydrolysis [2,
4]. Creatine phosphate (CP), also known to
be an important macroergic compound, is an
immediate source of high energy which can be
used to replenish ATP from adenosine
diphosphate (ADP). CP plays a particularly
important role in muscles during PE [2].
Creatine synthesis begins in the kidneys and is
completed in the liver. In the kidney, glycine
combines with arginine to form guanidine
acetate. This product is next methylated in the
liver by S-adenosyl methionine forming
creatine (Figure 1). Hence creatine is provided
to the skeletal muscles, heart and brain. Under
creatine phosphokinase action and in the
presence of ATP, CP is synthesized
(Figure 2). CP is a stable product which
during a non-enzymatic reaction is converted
to creatinine, which in turn is excreted by the
kidney (Figure 3).
For up to 40 minutes of mild PE, glucose
is obtained initially during muscle
glycogenolysis and next during hepatic
glycogenolysis. During PE, muscle glycogen
phosphorylase is activated by increased levels
of adenosine monophosphate (AMP), an
allosteric activator of this enzyme and also by
phosphorylation, which is stimulated by Ca2+
release during contraction. Glycogen
phosphorylase converts glycogen to glucose-
6-phosphate (G-6-P) in the muscles, while
phosphofructokinase-1 (PFK-1) converts G-6-
P to pyruvic acid. Next, there are two
possibilities: the first one consists in
conversion of the pyruvic acid to acetyl-CoA
(that will enter the Krebs cycle) due to
pyruvate dehydrogenase intervention and the
second one is represented by lactic acid
synthesis from pyruvate under lactic
dehydrogenase action. Both pathways
generate ATP.
In the liver, glycogen is transformed to
glucose-1-phosphate (G-1-P), which in turn is
converted to G-6-P. Under the action of
glucose-6-phosphatase, an enzyme found in
192 Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 19 / no. 2 / 2012
the liver and kidney, lacking in the muscles, G-6-P is converted to glucose [4].
Figure 1. Sinthesys of creatine, creatine phosphate and creatinine (2, modified).
CPK- creatine phosphokinase.
After 40 to 240 minute from the PE onset,
there is an increased release of
catecholamines, glucagon, cortisol, and STH,
thus leading to adipose tissue lipolysis
activation and production of triglycerides
(TG). TG are formed by combining 3 fatty
Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 19 / no. 2 / 2012 193
acids (palmitic, oleic and stearic acids) with
glycerol phosphate. They travel bound to
albumin to various tissues. One of these
tissues is the muscular tissue where they are
exposed to β oxidation in the mytochondria
resulting:
acetyl CoA that will enter the Krebs cycle;
ketone bodies (in the liver) that will be
converted to acetyl CoA in the muscles,
entering also the Krebs cycle.
Figure 2. The most important reactions of intermediary metabolism (3, modified).
194 Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 19 / no. 2 / 2012
The liver produces glucose during hepatic
glycogenolysis and gluconeogenesis which
uses as substrates: lactic acid, glucogenic
amino acids, glycerol, citric cycle
intermediates (oxaloacetate, α-ketoglutarate,
succinyl-CoA and fumarate) [4].
The liver is the only organ capable of
amino acids (AA) synthesis and degradation
through all the possible pathways. During AA
degradation, the carbon skeleton may be
reduced to:
CO2;
Subtrates for gluconeogenesis;
Ketone bodies or their precursors
(acetoacetat and acetyl-CoA).
There are ketogenic AA (if the carbon
skeleton is finally reduced to acetoacetate and
acetyl CoA), glucogenic AA (if the carbon
skeleton is degraded to a glucose precursor)
and also ketogenic-glucogenic AA [2].
“Fuels” utilization during rest
The level of fuel used at rest by the
muscular tissue depends on the serum levels
of glucose, AA and FA. Glucose has several
metabolic functions: it represents the primary
source of energy for the human body;
converted to glycogen it represents a form of
energy storage; glucose precursors may give
rise to different substrates for other metabolic
pathways:
Glycerol and acetyl CoA: used for
synthetising FA, TG, cholesterol;
Pentoses: used for nucleotides and acids
synthesis;
NADPH: used in reductive biosynthesis;
The carbon skeleton: necessary for AA
biosynthesis [5].
There are three mechanisms of glucose
uptake: simple diffusion, facilitated diffusion,
active transport. In case of simple diffusion,
the transport rate for glucose correlates with
the its concentration gradient. As for glucose
entering the cell through passive transport it is
possible only with the help of a class of
glucose transporters (GLUT) and it doesn’t
require energy. Glucose active transport is
realized against its concentration gradient and
it consumes energy (ATP). Sodium glucose
transporters (SGLT) are an important class of
glucose transporters. They act through a
sodium-glucose cotransport and are found in
the intestinal mucosa, in the kidney and
choroid plexus. They are tissue-specific [5].
GLUT family has 13 members. GLUT 1,
GLUT 4, GLUT 11, GLUT 12 [8, 9, 10, 11]
are found in the muscles. GLUT 4 is insulin-
sensitive and its action depends on the PE.
These transporters are stored in intracellular
vesicles. Insulin binding to its receptor
activates the vesicles containing GLUT 4
transporters. Furthermore the vesicles fuse
with the membrane increasing the number of
GLUT4 transporters expressed at the cell
surface and finally increasing glucose uptake
[6, 11]. During some studies carried out in
2009, it was found that insulin causes GLUT
12 translocation to the cell surface [8].
SGLT family is represented in the
muscular tissue by 3 transporters: SGLT 1,
SGLT 2, SGLT 3 [5].
During rest FA are the main energetic
sources for the muscle fibres.
There is a balance maintained by the level
of citrate between oxidation of glucose and
FA. If the muscle cell has sufficient energy
resources, citrate leaves the mitochondria and
activates acetyl CoA carboxylase 2 (ACC-2),
which mediates the synthesis of malonyl CoA.
This will inhibit carnitine palmitoyl
transferase I (CPT-1), thereby adjusting the
FA oxidation rate by blocking their entry into
Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 19 / no. 2 / 2012 195
the mitochondria. Muscles also contain
malonyl-CoA decarboxylase that catalyzes the
conversion of malonyl-CoA to acetyl-CoA
and CO2 [2]. Branched-chain AA give 20 %
energy during rest. Their oxidation generates
ATP and synthesizes glutamine. Under
conditions of acidosis, there is an increased
demand for glutamine, necessary for
transferring ammonia to the kidney and
tamponating urine as ammonium during
protons excretion.
“Fuel” utilization during exercise
The usage rate of ATP in skeletal muscles
during PE is about 100 times more intense
than the rate used at rest. ATP and CP would
be quickly exhausted if they were not
continuously regenerate. ATP comes from
aerobic/anaerobic glycolysis and oxidative
phosphorylation. Anaerobic glycolysis is an
important source of ATP in the following
three situations:
during onset of PE, when the blood flow
with high oxygen supply increases
allowing aerobic processes to take place;
in muscles with fast twitch contracting
fibres, with a high reserve of glycogen;
during intense PE, when the demand for
ATP exceeds the aerobic capacity of
tissue.
Anaerobic glycolysis at the onset of PE
ATP at rest is provided to the muscular
tissue through aerobic reactions. Once the PE
starts the energy required increases. ATP
reserves in the muscles are sufficient to
support FE only for 1-2 seconds and the
amount of CP for 9 seconds (considering they
would not be continuously regenerated). More
than 1 minute is required for the muscle blood
supply to increase significantly during
contraction secondary to vasodilatation. That
is why glycogen conversion to lactic acid will
be the main source of ATP until the glucose
and FA oxidation increase.
Anaerobic glycolysis in type IIb
muscle fibres (fast twitch fibres)
These muscles contract quickly and
vigorously only for short periods of time,
being used to lift weights. At this point,
glycolytic capacity is increased by the
presence of specific enzymes.
The tissues rely on the endogenous
reserves of glycogen and CP to produce
energy. Glycogen is catabolized to glucose-1-
phosphate, which is converted to glucose-6-
phosphate and finally lactic acid is obtained.
Glucose-6-phosphate resulted from
glycogenolysis, inhibits hexokinase II, thereby
permitting to a small amount of circulatind
glucose to be used for ATP synthesis,
preventing hypoglycemia.
It is confirmed that an increase in
hexokinase II gene transcription during PE,
could explain the persistence of insulin action
after PA stops and also the adaptation which
occurs through practice [5].
During PE, glycogenolysis and glycolysis
are both activated, as AMP alloesterically
upregulates phosphofructokinase-1 (PFK-1)
and glycogen phosphorylase b (Figure 3).
AMP is an ideal activator since its
concentrations are kept low by adenylate
kinase activity (2ADP → ATP + AMP). Thus,
whenever ATP levels are low, AMP
concentration proportionally increases.
Increased AMP stimulates AMP-kinase
activation (signaling pathway involved in
stimulation of transcription and protein
synthesis), which in turn causes translocation
of GLUT4 to the cell surface and increases
196 Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 19 / no. 2 / 2012
insulin-independent transmembrane glucose transport.
Figure 3. Activation of muscle glycogenolysis and glycolysis by AMP (2, modified). PFK- 1
phosphofructokinase- 1, MC muscle contraction, AK adenylate kinase.
The anaerobic glycolysis, considered a
primitive mechanism for obtaining energy [4],
generates 3 molecules of ATP, compared to
32-34 molecules of ATP provided during
Krebs cycle. Rapid contractile fibers have a
high concentration of glycolytic enzymes thus
compensating for this energetic difference.
The usage rate of G-6-P is 12 times faster than
in type I fibers. Muscle wasting during PE
occurs by lowering the pH to about 6.4.
Depletion of glycogen reserve occurs in less
than two minutes of anaerobic exercise.
Muscle glycogen degradation is not
influenced by glucagon as there are no
specific receptors at this level. Glycogen
synthesis is inhibited during the PE, but can be
activated at rest after ingestion of high
amounts of carbohydrates.
Unlike the liver isoform of glycogen
phosphorylase, the muscle isoform contains an
AMP allosteric site. When AMP binds to this
site the enzyme is activated although it is not
phosphorylated. As PE begins myosin ATPase
hydrolysis the existing ATP to ADP. AMP
begins to accumulate and glycogen
degradation is stimulated. The glycogen
phosphorylase b activation is stimulated
additionaly by Ca2+ release from sarcoplasmic
reticulum once muscle contraction starts [2].
During vigorous PE, the catecholamines
stimulate adenylate cyclase in muscle cells by
activating AMP-dependent protein kinase. The
protein kinase A phosphorylates and activates
the glycogen phosphoryl kinase, so that a
continuous activation of glycogen
phosphorylase can be possible.
Anaerobic glycolysis during vigorous
exercise
Once PE starts, electron transport chain,
Krebs cycle and FA oxidation are activated by
an increased level of ADP associated with a
decreased level of ATP. Pyruvate
dehydrogenase remains active in a non-
phosphorylated form as long as NADH can be
reoxidised in the electron transport chain and
acetyl CoA can enter the Krebs cycle.
Although mitochondrial metabolism is
working at full capacity, additional ATP is
needed when AMP begins to accumulate
during intense PE. The increased level of
AMP activates PFK-1 and glycogenolysis,
thus providing the necessary ATP through
anaerobic glycolysis [2].
Pyruvic acid resulted from anaerobic
glycolysis, crosses mitochondrial membrane
through active transport. At this level, under
the pyruvate dehydrogenase action, it is
Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 19 / no. 2 / 2012 197
converted to acetyl-CoA, further being
oxidised in the Krebs cycle [4].
The lactate released during PE can be
used by muscle at rest and also by heart (a
muscle rich in mitochondria and with an
increased oxidative activity). In this type of
muscle the NADH / NAD + ratio is lower than
the one during FE.
Figure 4. Stimulation of glycogenolysis in muscle by epinephrine (2, modified).
Figure 5. The Cori Cycle (3, modified).
The reaction catalyzed by lactate
dehydrogenase will lead to pyruvate synthesis.
Hence, pyruvate is converted to acetyl CoA
which will enter the Krebs cycle producing
energy through oxidative phosphorylation.
Another possibility is that lactate, as an end
product of the anaerobic glycolysis, to re-enter
the Cori cycle (Figure 5) in the liver, where it
is converted to glucose so that the body
recovers a large amount of energy [4]. Mild or
moderate PE is possible for a longer period of
time than vigorous PE, due to aerobic
degradation of glucose and FA, which
produces more energy than anaerobic
reactions, and also due to lactic acid
production at a slower rate compared to
anaerobic metabolism. Thus, the lactate
production decreases if the energy is obtained
198 Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 19 / no. 2 / 2012
mainly through the aerobic metabolism of
glucose and AG.
Particularities in patients
with type 2 DM
Progression of DM may associate skeletal
muscle atrophy, weakness, reduced neural
activity and skeletal muscle hypoperfusion.
Skeletal muscle atrophy in patients with type 2
DM is mediated by an ubiquitin proteasome
system [12].
Diabetic neuropathy affects both the
motor and the sensory nerves, with hypoxia
and hyperglycemia being the main causes.
Hypoxia is the result of reduction in capillary
density on one hand and of the vascular
luminal diameter on the other. Decreased
muscle contractility can be explained by
several phenomena: altered neuromuscular
junction, altered muscle architecture, modified
contractile properties, defective excitation-
contraction coupling [12].
Obesity and type 2 DM are associated
with increased levels of FA and TG, with
reduced muscle oxidative capacity of the FA,
leading to TG accumulation in the muscle
[12].
Figure 6. The TCA Cycle at patients with type 2 diabetes mellitus (2, modified).
Lipid accumulation in the muscle and
liver is responsible for:
poor insulin signaling;
enzymatic equipment malfunction;
insulin resistance development.
An accelerated FA oxidation leads to an
increased amount of mitochondrial acetyl
CoA, inhibition of pyruvate dehydrogenase
activity and high level of cellular citrate, that
inhibit phosphofructokinase resulting in
decreased glycolysis with G-6-P upregulation
and intracellular hexokinase II
downregulation. Hexokinase II inhibition
causes accumulation of glucose and reduced
glucose uptake.
The insulin resistance induced by lipid
accumulation decreases muscle glycogen
synthesis due to reduction in insulin receptor
Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 19 / no. 2 / 2012 199
signaling and glucose transport. The increased
level of products resulted from FA metabolism
activates serine/threonine kinases responsible
for phosphorylation of the insulin receptor
substrate 1 (IRS-1) and insulin receptor
substrate 2 (IRS-2), thereby altering insulin
signaling through phosphatidyl-inositol-3-
kinase (PI3K) pathway and glucose transport.
Insulin-dependent stimulation of PI3K is
altered in patients with type 2 DM.
Figure 7. Insulin receptor signaling (a).
The insulin receptor- protein kinase B signaling pathway (b) (2- modified).
Ins insulin; IRS insulin receptor substrate; PDK 1 Phosphoinositide-dependent protein kinase 1;
PKB protein kinase B.
People with type 2 DM have normal
levels of GLUT 4 in skeletal muscles,
although insulin-dependent glucose uptake is
defective. Glucose uptake and GLUT 4
translocation that depend on the PE are
normal. Moderate PE is associated with 10
times increase in lipid oxidation due to rised
energy costs and increased FA availability.
Accelerated lipolysis in adipose tissue and
reduced TG re-esterification occur under the
action of catecholamines and insulin. It was
also found the TG are an important source of
energy in the muscle [5]. In patients with type
2 DM and obesity, FA metabolism is reduced
during PE while intramuscular TG utilization
is increased [5].
Characterstically, these patients have
altered glycogen storage. Numerous studies
have shown a 60% decrease in glycogen
synthesis caused by alterations of glucose
transport and hexokinase II activity and not by
the compromised glycogen synthase action
[12].
Insulin-independent glucose disposal is
sustained by the lack of IRS-1and IRS-2 or
PI3K phosphorylation in response to muscle
200 Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 19 / no. 2 / 2012
contraction, explaining thus the increased
glucose use as a response to the PE in patients
with type 2 DM and IR [5]. Increased insulin
action in response to PE is explained by the
following mechanisms: increased blood flow
with increased capillary surface and insulin
bioavailability and also postreceptor signal
transduction upregulation [5].
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