Insulin Resistance X Exercise

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© 2001 The International Association for the Study of Obesity. obesity reviews 2, 47–59 47

Insulin resistance and associated metabolicabnormalities in muscle: effects of exercise

extraction of insulin in the liver. Raised FFA levels, like

hyperglycaemia, may also impair b-cell function and inhibit

insulin secretion.

Resistance to insulin-mediated glucose disposal is not

limited to subjects with type 2 diabetes and can be demon-

strated in non-diabetic individuals, especially in obese

subjects. The overall prevalence of obesity and, thus, of

type 2 diabetes is already high and is rising further in

most industrialized societies. Regular physical activity

has proved to be useful in the management of these

diseases.

After a brief review of the determinants of insulin resis-

tance, we will firstly analyse the abnormalities of muscular

carbohydrate (CHO) and lipid metabolisms in insulin resis-

tant subjects and the interaction between these defects. Sec-

ondly, we will emphasize the effects of exercise on these

abnormalities. In the latter part, we will discuss the phys-

iopathological basis for individualized exercise prescription

in insulin resistant individuals, i.e. mainly obese and type

2 diabetic patients.

obesity reviews

Service Central de Physiologie Clinique, Unité

CERAMM (Centre d’Exploration et de

Réadaptation des Anomalies Métaboliques et

Musculaires). CHU Lapeyronie 34295

Montpellier Cedex 5 FRANCE

Received 13 July 2000; revised 12 October

2000; accepted 16 October 2000

Address reprint requests to: Antonia Pérez-

Martin, MD, CERAMM, CHU Lapeyronie,

34 295 MONTPELLIER Cedex 5, FRANCE

E-mail: [email protected]

A. Pérez-Martin, E. Raynaud and J. Mercier

SummarySkeletal muscle is a major site of insulin resistance. In addition to glucose trans-

port, oxidative disposal and storage defects, insulin resistant muscle exhibit many

other metabolic abnormalities. After a brief review of insulin resistance determi-

nants, we will focus on muscular abnormalities in obesity and type 2 diabetes.

Glucose and lipid metabolism defects will be analysed and their interactions dis-

cussed. Exercise can improve many of these muscular abnormalities and the mech-

anisms underlying exercise-induced benefits have been clarified during the past

decades. Therefore, exercise training has proved to be useful in the managementof insulin resistant states, i.e. mainly obesity, especially in its truncal distribution,

and type 2 diabetes. However, exercise prescription remains poorly codified, and

results on glycaemic control are sometimes conflicting. In the last part of this

review, we will emphazise the pathophysiological basis for an individualized exer-

cise prescription in insulin resistant subjects.

Keywords: exercise training, individualized prescription, insulin resistance,

muscular metabolic abnormalities.

obesity reviews (2001) 2, 47–59

Introduction

Insulin resistance denotes the inability of insulin to produce

its usual biologic effects at circulating concentrations that

are effective in normal subjects, i.e. lower plasma glucose

levels through suppression of hepatic glucose production

and stimulation of glucose utilization in muscle and

adipose tissue.

Skeletal muscle is a major site of insulin resistance. Resis-

tance is due mainly to defects at post-receptor sites, and

there is impairment of many steps in insulin action that

leads to glycogen synthesis and oxidative glucose disposal.

Multiple defects in the insulin signalling cascade have been

identified.

Adipocytes may also be insulin-resistant, corresponding

to a failure of basal insulin levels to suppress lipolysis and,

therefore, leading to rising free fatty acids (FFA) concen-

trations. The latter may stimulate triglyceride synthesis and

glucose production in the liver. It also inhibits glucose

uptake and utilization by skeletal muscle and reduces the



Causes and determinants of insulin resistance

Insulin resistance results from variable interactions

between genetic and environmental factors, and its extent

varies considerably among individuals. It is assumed that

insulin resistance may play a key role in the physiopathol-

ogy of type 2 diabetes (Fig. 1).

Genetic causes

Genetic factors are undoubtedly involved, but with the pos-

sible exception of a few pedigrees, a single major gene does

not appear to be responsible. Insulin resistance in obesity

and type 2 diabetes is apparently transmitted as a poly-

genic familial trait, although the genes responsible remain

unknown.

The hereditability of type 2 diabetes is high and studies

in identical twins suggest that 60–90% of the disease sus-

ceptibility could be genetic. The genetic defects have notyet been elucidated. Mutations in the insulin receptor can

cause extreme insulin resistance but are extremely rare and

48 Exercise and muscular insulin resistance A. Pérez-Martin et al. obesity reviews

© 2001 The International Association for the Study of Obesity. obesity reviews 2, 47–59

have been excluded as a significant cause of ‘common’ type

2 diabetes. Several abnormalities have been identified in

various post-binding mechanisms, including reduced activ-

ity of the tyrosine kinase activity of the insulin receptor, the

insulin-sensitive GLUT-4 glucose transporter and of glyco-

gen synthase, but it seems likely that those are a conse-

quence rather than a primary cause of insulin insensitivity.

Some polymorphisms of the genes encoding insulin recep-

tor substrate 1 (IRS-1) (1,2), glycogen synthase (3,4) and

the regulatory subunit of protein phosphatase 1 (5), a key

element in glycogen metabolism, have been associated with

type 2 diabetes. Such defects could theoretically contribute

to the polygenic inheritance of susceptibility to type 2

diabetes, but their aetiological importance is at present

questionable.

Gender influences insulin sensitivity, and skeletal muscle

in men is more insulin resistant than that in equally fit

women (6,7). However, women have a higher proportion

of body fat, and insulin resistance is comparable betweensexes if it is expressed in term of body weight rather than

in muscle mass. Animal studies suggest that a high testos-

Figure 1 Pathophysiology of type 2 diabetes.



terone to oestrogen ratio can induce insulin resistance,

with a shift in muscle-fibre morphology towards an ‘insulin

resistant’ pattern, i.e. predominantly type II fibres.

Environmental causes

Many environmental factors may contribute to insulin

resistance. The sedentary, well-nourished lifestyle is pre-

vailing. The major diabetogenic dietary factor is an energy-

dense diet, especially if combined with inadequate levels of

physical activity.

Furthermore, disturbances in energy balance that lead to

human obesity and metabolic abnormalities that result in

insulin resistance are not completely understood. In addi-

tion of complex genetic determinants, it seems well estab-

lished that the reduced energy expenditure may contribute

to the development of obesity (8). The central deposition

of adipose tissue may also be favoured by overeating,

reduced levels of physical activity, and perhaps by smok-

ing, excessive alcohol consumption and the neuroendocrine

responses (especially increased cortisol secretion) that

results from excessive psychosocial stresses (9). Obesity,

particularly in truncal distribution with increased intra-

abdominal fat mass, is an important determinant of insulin

resistance, especially in skeletal muscle (10,11). Intra-

abdominal adipose tissue is metabolically more active than

in the periphery. Possible reasons for this include the rich

blood supply, dense sympathetic innervation and high

expression levels of b3-adrenoreceptors that mediates lipol-

ysis (12,13). The high rate of triglycerides turnover and of

free fatty acids (FFA) and perhaps, increased expression by

adipocytes and skeletal muscle of tumour necrosis factor

(TNF-a) are involved in the interrelations between central

adiposity and muscular insulin resistance (Fig. 2).

obesity reviews Exercise and muscular insulin resistance A. Pérez-Martin et al. 49


Figure 2 Pathophysiology of insulin

resistance. (FFA: Free Fatty Acids, IL-6:

Interleukin-6, PAI-1: Plasminogen Activator

Inhibitor-1, TNF-a: Tumor Necrosis Factor-

a, vWF: von Willebrand Factor).



In recent years, the possible diabetogenic effects of

malnutrition in utero and during the first year of life have

attracted much interest and controversy. Specific nutri-

tional deficits in early life could predispose to type 2 dia-

betes in middle to late adult life, perhaps by compromizing

the development of the b cells and possibly by inducing

tissue insulin resistance, although both this hypothesis and

its mechanisms are controversial (14,15).

Another already mentioned factor of major importance

is sedentarity and inadequate levels of physical activity.

Insulin sensitivity tends to decline with physical inactivity

while regular physical exercise and fitness increase insulin

sensitivity and can protect against the subsequent develop-

ment of type 2 diabetes (see below). Insulin resistance can

be induced by pregnancy and by certain drugs and perhaps

by cigarette smoking, although the mechanism remains

unclear (16). In type 2 diabetes, chronic hyperglycaemia

per se can also reduce insulin sensitivity (‘glucose toxicity’)

through unknown mechanisms.

Health risks of insulin resistance

The potential implications of insulin resistance are recog-

nized by clinicians ranging from endocrinologists to cardi-

ologists. Indeed, insulin resistance is associated with a

cluster of metabolic and vascular abnormalities called

syndrome X or Reaven’s syndrome (17). These abnormal-

ities include obesity, particulary in a truncal distribution,

glucose intolerance and type 2 diabetes, hypertension, a

specific dyslipidaemia with raised triglyceride concentra-

tion and a high low-density lipoprotein (LDL)/high-density

lipoprotein (HDL) ratio, disturbed fibrinolysis and hyper-

uricaemia. These features are also associated with acceler-

ated atherogenesis and cardiovascular disease, the main

cause of mortality in type 2 diabetes. The positive influence

of exercise on these factors will be discussed later.

There is abundant evidence to implicate obesity as an

important risk factor for type 2 diabetes, although it is not

clear whether obesity itself leads to glucose intolerance

(perhaps in individuals genetically predisposed to insulin

resistance or b-cell failure), or whether a common antecedent

(e.g. insulin resistance) could lead to both obesity and type 2

diabetes. However, it is recognized that skeletal muscle is

largely involved in their respective pathogenesis. Therefore,in this review we focus on muscular metabolic abnormali-

ties, and especially on muscular insulin action defects, and

on exercise-induced effects in insulin resistant individuals.

Muscular metabolic abnormalities in insulinresistant subjects

Glucose metabolism abnormalities

Insulin resistance appears early in individuals with upper

body obesity and becomes more severe when diabetes is



developing (17–19). Skeletal muscle is a typical peripheral

insulin target tissue, responsible for 80–90% of all glucose

uptake in the in vivo insulin stimulated state (20). Thus,

muscular insulin resistance plays a key role in the

pathogenesis of metabolic diseases. Molecular mechanisms

involve interaction among impairments in hormonal sig-

nalling, enzyme and transporter activities, substrate avail-

ability and competition and modulation of blood flow.

Some authors have found a decreased leg muscle blood

flow in basal/rest conditions and a failure of insulin in

capillary recruitment, in obese and type 2 diabetes (21).

A reduction in capillary density has also been described

(22,23). Reduced blood glucose and insulin availability

may contribute to the decrease in total glucose uptake (24).

Muscle fibre morphology has been incriminated in meta-

bolic disorders since, in obese and type 2 diabetes, muscle

contains less oxidative type I fibres and more glycolytic

type II fibres which are less insulin-sensitive than type I

fibres (22,23,25).Insulin signalling defects have been largely involved in

the pathogenesis of insulin resistance. Both insulin recep-

tor and post-receptor events can be altered. In vitro, mus-

cular cells of severe obese subjects exhibit a decrease in

insulin receptor number and in insulin receptor phospho-

rylation capacity. There is also a reduction in insulin

receptor substrate (IRS)-1, in p85 subunit of phosphatidyl

inositol-3 (PI3) Kinase, a decrease of IRS-1 phosphoryla-

tion ability and of the PI3 kinase phosphorylation capac-

ity (26). In type 2 diabetes, similar defects have been

shown, i.e. decrease in insulin receptor, IRS-1 and PI-3

kinase phosphorylations (27,28).Another defect of major importance is the impairment in

glucose transport. In the resting/basal state, Glut 4 trans-

porters, the main muscular glucose transport pathway,

are predominantly located in the cell and translocate to

plasma membrane in response to both insulin (29) and

exercise/contractions (30). Muscular Glut 4 are normally

expressed in individuals with obesity or type 2 diabetes

(31). While their moderate intensity exercise-induced

translocation is maintained (32), the insulin-stimulated

translocation is altered (33,34), leading to a reduced

insulin-stimulated glucose uptake.

In addition, insulin resistance induces an impairment of

glucose utilization. Both glycogen storage and oxidative

glucose utilization are altered in insulin resistant muscle

with several defects identified. In type 2 diabetes, insulin-

stimulated glucose phosphorylation is reduced (27). As the

hexokinase (HK) structure is normal (35), the defect could

be related either to a reduced expression of the HK mRNA

(36), or to a reduced HK activity. The latter could be due

to an altered mitochondrial binding of HK (37) or to a

diminished efficiency in providing ATP to HK (38).

Glycogen synthesis is also reduced, resulting from both

decreased glucose uptake (39) and impaired glycogen syn-



thase (GS) activity. This activity is reduced in type 2

diabetes (40,41,42) and in non-diabetic insulin resistant

subjects (41,43). This defect appears very early in the devel-

opment of obesity and type 2 diabetes (44) and seems to

worsen with disease evolution. In obese individuals,

glucose storage defect is more marked when glucose intol-

erance is developing (43).

The oxidative pathway is also altered. Insulin resistant

muscle displays an increased cytosolic creatine kinase (CK)

activity and glycolytic capacity (phosphofructokinase PFK

activity), leading to an increased capacity for anaerobic

resynthesis of ATP (19). In obese subjects, muscular insulin

resistance strongly correlates to the association of increased

glycolytic and reduced oxidative enzyme activity such as

pyruvate dehydrogenase (PDH) (19). The ratio of glycolytic

to oxidative enzyme activity, and especially the hexokinase

(HK) to citrate synthase (CS) ratio, correlated to insulin sen-

sitivity is a remarkable indicator of oxidative capacities (38).

In type 2 diabetes, the disproportionality between glycolyticand oxidative enzyme activity is even more marked (38).

Independently of fibre type distribution, this disproportion-

ality could contribute to insulin resistance, as an impair-

ment in oxidative phosphorylation pathway or an increased

reliance on cytosolic ATP resynthesis might negatively influ-

ence steps that require ATP stores, such as glycogen forma-

tion or glucose trapping via its phosphorylation (38,45).

Lipid metabolism abnormalities

Insulin resistant subjects may also have an impaired fat oxi-

dation, as evidenced by studies using indirect calorimetry.Fat oxidation and contribution of fat to total energy expen-

diture (at rest and during recovery from exercise) are lower

in formerly obese than in control women (46). After

diet-induced weight reduction, there is a significant fall in

fasting (47) or post-absorptive (48) fat oxidation. However,

the mechanism of reduced fat oxidation capacity remains

incompletely understood. It is generally assumed that at

rest and during low to moderate intensity exercise, plasma-

derived free fatty acids (FFA) are the main source for

fat oxidation, although the contribution of intramuscular

lipids to fat oxidation is not well defined in obese and type

2 diabetic subjects.

Many extra-muscular factors can influence plasma FFA

oxidation: neuro-hormonal modulation of adipose tissue

lipolysis, plasma FFA levels, capillary density, blood flow

and FFA transport capacity across the vessel wall. As vis-

ceral fat tissue is metabolically more active, subjects with

abdominal adipose tissue exhibit a high rate of lipolysis

and have often elevated plasma FFA levels. Plasma FFA

concentrations can also be high in type 2 diabetic individ-

uals (49). However, the muscular availability of plasma fat-

derived fuels is influenced by modifications in both blood

flow and capillarization.

Several mechanisms are involved in the transport of the

FFA across the muscular cell membrane: passive diffusion

or protein-mediated transport. The protein facilitating fatty

acid transmembrane transport are mainly the fatty acid

translocase (FAT), the fatty acid transport protein (FATP)

and the fatty acid binding protein (FABP). In obesity the

importance of the transport systems in fat oxidation

process remains unclear. Kempen and co-workers (50) have

shown that muscular FABP content increases in response

to an hypocaloric diet in obese women, while no change

occurs in fibre type distribution or in activity of enzyme

reflecting the b-oxidation(3-hydroxyacyl-CoA dehydroge-

nase HADH) and mitochondrial density (citrate synthase

concentration).

However, FFA uptake by muscle seems to depend on

both integrity of the transport system and fatty acid con-

centration gradient (51). This gradient, which appears to

be a major determinant in normal subjects, needs a high

rate of cytosolic acyl-coA synthesis (51). However, muscu-lar factors influencing FFA oxidation seems to be mainly

mitochondrial capacity to take up and to oxidize fat and

intracellular mechanisms for regulation of the glucose-fat

balance. In obese and diabetic patients, each of the

processes involved in FFA mobilization and utilization can

be affected.

The FFA translocation across the mitochondrial mem-

brane is mediated by carnitine palmitoyl transferase

(CPT)-1, which is down-regulated by malonyl-CoA (M-

CoA) (52). In obese women, the CPT-1 activity negatively

correlates with visceral adiposity (53). Muscle oxidative

capacity, impaired in insulin resistant states (19,53),depends both on mitochondrial density and on b-oxidation

enzyme activities. Moreover, citrate synthase, a key enzyme

for the entry of glucose and fat-derived acetyl-CoA into the

Krebs cycle is reduced in obese (53).

Thus, several enzymatic steps involved in cellular

processes of lipid oxidation may be altered. A relative

impairment in lipid oxidation could increase the risk for

weight gain (54).

Interaction between CHO and lipidmetabolism abnormalities

In normal subjects, the interactions between glucose and

fat metabolisms, as well as the mechanisms governing shifts

in CHO and fat both at rest and during exercise remain to

be clarified. Thus, the interactions between CHO and fat

metabolism defects are even more intricate. Some models

have been proposed to explain reciprocal changes in fat and

CHO utilization.

The first theory was given by Randle and co-workers in

the 1960s (55,56), with studies on contracting heart and

resting diaphragm muscle. Increasing availability of FFA

for muscle increased both FFA delivery to mitochondria





and rate of b-oxidation, leading to significant rises in

muscle acetyl-CoA and citrate content. Increased acetyl-

CoA could activate PDH kinase that phosphorylates PDH

to its less active form. In addition, citrate could inhibit

allosterically phosphofructokinase (PFK). Decreased PFK

and PDH activities lead to a reduced flux through the gly-

colytic pathway, and to an accumulation of the glycolytic

intermediate Glucose-6-phosphate (G-6-P). The latter

was assumed to inhibit hexokinase (HK) and ultimately

decrease glucose uptake (Fig. 3). Physiologically, the glucose-

fatty acid cycle induced by high FFA levels includes three

periods: during the first 2h of exposure muscular CHO

oxidation decreases; there is a reduction of glucose uptake

after 3–4h and of glycogen storage after 4–6h (57,58). This

delay prevents the apparition of a muscular insulin resis-

tance in normal subject during the post-absorptive state.

However, in obese as well as in type 2 diabetic subjects, the

lasting elevated plasma FFA levels could allow the two

latter stage of the Randle cycle. Thus, the Randle cycle is



an outstanding concept leading to an integrate view of the

relationships between muscular insulin resistance and

abdominal obesity (55,59).

More recent works have clarified the mechanism of

FFA-induced glucose uptake inhibition. In fact, muscle

G-6-P content analysed by Nuclear Magnetic Resonnance

Spectroscopy (NMRS), decreases when FFA availability

increases, while insulin-stimulated GLUT 4 translocation is

impaired (60,61). Increases in FFA availability and, thus,

in fatty acid-CoA (FA-CoA) could lead to increases in the

concentration of diacylglycerol, phosphatidic acid and tri-

acylglycerol and to an activation of one or more phospho-

kinase (PKC) isoforms. PKC phosphorylates and inhibits

both insulin receptor and glycogen synthetase (61,62).

Cytosolic (FA)-CoA concentrations can be increased in

several conditions: (i) when muscles receive excessive

plasma-derived FFA; (ii) when malonyl-CoA (M-CoA)

levels increase and thus impaired long chain fatty acid

(LCFA)-CoA enter into the mitochondria, and (iii) when

Figure 3 Glucose-fatty acids cycle. (FFA:

Free Fatty Acids, F-6-P: Fructose-6-

Phosphate, F1,6-bisP: Fructose-1,6-

bisphosphate, FPase: Fructose

BisPhosphatase, G-6-P: Glucose-6-

Phosphate, G-6-Pase: Glucose-6-

Phosphatase, HK: Hexokinase, PDH: PyruvateDehydrogenase, PFK: Phosphofructokinase).



the muscular triglyceride (mTG) content is increased. The

latter could explain, in part, the well established relation-

ship between mTG content and insulin resistance (19,63).

Another regulatory element for muscle fuel selection

could be the M-CoA and CPT–1 interaction. This hypoth-

esis gained support mainly from studies of rodent muscles

(64,65). M-CoA is produced in the cytoplasm by Acetyl

CoA Carboxylase (ACC) from acetyl-CoA, and is both an

intermediate for the synthesis of FA and an inhibitor of

CPT-1. In skeletal muscle, changes in fuel supply acutely

regulate the M-CoA levels. This regulation could be due to

modifications in cytosol citrate concentration, as citrate is

both an allosteric activator of ACC and a source of acetyl-

CoA. Increases in muscular M-CoA concentrations have

been found in insulin resistant states, including those asso-

ciated with inactivity (52,64). The M-CoA levels could reg-

ulate fat oxidation rate by a reversible inhibition of the

LCFA transport into mitochondria via the CPT-1 complex.

The accumulated LCFA-CoA could incorporate into diacyl-and triglyceride and contribute to the high triglyceride and

diacylglycerol levels observed in many insulin resistant

muscles. It has been demonstrated that glucose-induced

increases in cytosolic citrate restrain the use of fatty acids

as a fuel in heart (66) and in muscle (67). This could

explain that muscular utilization of FFA is decreased in the

post-absorptive state, in hyperglycaemic type 2 diabetics

(68,69) and restored when hyperglycaemia is reduced by

insulin infusion (70). Moreover, increasing insulin concen-

trations decreases plasma FFA oxidation in obese and lean

subjects (71).

All these mechanisms have been demonstrated in restingmuscle. However, the factors influencing substrate depen-

dence and selection in working muscle remain to be dis-

cussed. In rodent skeletal muscle, M-CoA levels decrease

during contractions and could relieve the resting CPT-1

inhibition (72). However, while fat oxidation increases,

M-CoA levels are unchanged in normal human skeletal

muscle, after low to moderate intensity exercise (73) and

during transition from rest to exercise (74). These results

suggest that the regulation of CPT-1 is more complex and

that M-CoA could be a regulator at rest but not during

exercise. The same objections apply to glucose-fatty acid

cycle which has been demonstrated only in resting muscle.

Therefore, there is no evidence it is also operative in

exercising human skeletal muscle. However, increased fat

availability increases fat oxidation and decreases CHO uti-

lization in exercising skeletal muscle (75). By contrast,

increased CHO availability enhances CHO utilization and

reduces lipid oxidation during exercise (76,77).

Effects of exercise

Exercise has deep effects on metabolism in non-diabetic

and in diabetic subjects, and regular physical activity is rec-

ommended for the management of both obesity and type

2 diabetes. Health benefits of regular exercise are now well

established in prevention and in treatment of these diseases.

In addition to its effects on insulin resistance and on body

weight and composition (see below), regular exercise has

many other potential major benefits. Increased cardio-

respiratory and muscle fitness are associated with lower

risks of cardiovascular diseases (78,79). Blood pressure is

strongly improved by moderate intensity training in type

2 diabetes and in obesity (79). Exercise also provides a less

atherogenic lipid profile (79–83). Improvement in many

cardiovascular risk factors has been linked to a decrease in

plasma insulin levels and in insulin resistance. Psychologi-

cal well-being has also been demonstrated (84). In contrast,

the exercise-induced effects on glycaemic control in type 2

diabetic subjects are more discordant. It has been shown

that regular physical activity markedly improves glycaemic

control (78,80,85), while some studies focused on poten-

tial benefits for lipids profile, blood pressure and bodyweight, without significant benefit on glycaemic control

(79).

The effects of exercise on glucose metabolism involve at

least two major mechanisms: body composition changes

and improvement of insulin sensitivity. When combined

with diet, 16 weeks aerobic or resistance training pro-

grammes prevent fat-free mass loss, with similar weight

reduction than diet alone programme, in insulin resistant

subjects (86). Trained groups exhibit lower oral glucose

tolerance tests (OGTT) insulin response, suggesting an

improved insulin action (86). These results confirm previ-

ous studies which demonstrated that endurance trainingimprove insulin sensitivity, independently of weight loss

(87,88). A single bout of exercise is also associated with a

significant improvement of insulin sensitivity (89,90,91).

The main effect of exercise on glucose metabolism in

working muscle is insulin-independent and in a large part

explained by the exercise-induced translocation of the

GLUT 4 transporters. In normal and type 2 diabetic

subjects, a 45–60min cycle exercise at 60–70% VO2max

increases the GLUT 4 content of the muscular plasma

membrane of approximately 70% above resting levels

and increases muscular glucose uptake (32). An insulin-

independent pathway activates the exercise-induced GLUT

4 translocation in working muscle. In normal subjects,

endurance training increases skeletal muscle capillarization

and blood flow (92), muscular GLUT 4 levels, hexokinase

and glycogen synthase activities (93). The latter is markedly

enhanced in post-exercise state and is responsive of the

major part of muscular glucose utilization for several

hours. Therefore, the insulin sensitivity improvement posi-

tively correlates with the exercise-induced muscular glyco-

gen utilization (94), even if this mechanism is associated

with other important determinants (GLUT 4 translocation,

muscle capillarization, hexokinase activity, etc.).





However, the positive metabolic effects of training are

rapidly reversible and 5 days of detraining can significantly

reduce training-induced improvement in insulin action and

in muscular glucose uptake (89,95).

Resistance training also improves insulin sensitivity, in

obese men (86), in post-menopausal women (96) and in

elderly men (97). This effect could be explained by the cor-

responding increase in skeletal muscle mass (98). In older

men, a 16-week resistance training programme improves

the non-oxidative glucose disposal while glucose oxidation

remains unchanged (97). The improved glycogen storage

capacity is associated with an increase in capillary-to-

muscle fibre ratio (99). After resistance training, gly-

caemic control can improve despite no change in VO2max

(98,100).

The effects of exercise training on insulin resistance

could also be explained, at least in part, by weight loss

and associated body composition modifications. Exercise

increases energy expenditure acutely and so favours weightloss, but in practice very few of the overweight population

can maintain the necessary level of exercise on a daily basis.

Therefore, exercise training alone most often fails in sig-

nificant weight reduction and the exercise-induced benefits

appear to be mainly related to the body composition

modifications, i.e. fat-free mass increase and body fat

reduction (101,102). When associated with diet, exercise

programmes favour body fat decrease and prevent diet

alone-induced fat-free decline (86,103). In addition, regular

physical activity is a major factor determining the long-

term success of weight loss programmes and weight main-

tenance (102,104). To summarize, regular physical activitypositively influences glucose metabolism in insulin resistant

states. Moreover, it improves significantly all the factors of

the syndrome X (78–83).

Lipid metabolism also appears to be improved after

training leading to increased oxidative capacity and fatty

acid utilization ability (105,106). In addition, exercise

improves tissue sensitivity to catecholamines, especially

in white adipose tissue, thereby enhancing lipolysis and

providing more FFA to working muscle. However, after

training the main source of FFA during exercise appears

to be increased intramuscular TG breakdown (107).

Thus, the changes in substrate utilization could underlie

the beneficial effects of regular exercise in obesity and type

2 diabetes. In normal weight subjects, physical training

progressively increase lipid oxidation and muscle glycogen

sparing during moderate intensity exercise (108,109). In

obese subjects, at rest, a diet-associated exercise pro-

gramme can prevent fat oxidation decline observed after

diet-alone induced weight loss in some studies (110), but

not all (111). We speculate that these apparently conflict-

ing results may be related to the variability of training pro-

tocols. Low- or moderate-intensity exercises are usually

recommended (112,113). High intensity exercise can also



achieve fat loss and enhance fat oxidation (114). Recently,

Mulla and co-workers (115) have compared lipid mobi-

lization from abdominal subcutaneous adipose tissue

induced by exercise bouts performed at either 40 or 60%

VO2max in normal subjects. Whereas the lipolytic rates

were similar during exercise, independantly from relative

workload, the increase in post-exercise FFA mobilization

was greater after the 60% VO2max exercise bout.

However, in insulin resistant subjects, the optimal intensity

remains controversial. Therefore, while exercise prescrip-

tion needs a clearer codification, regular physical activity

has proved useful in preventing or delaying type 2 diabetes

(116–119). Increasing training levels decreases the inci-

dence of type 2 diabetes (120,121) and the two major pre-

dictive factors for type 2 diabetes are obesity and low

physical levels (122).

Pathophysiological basis for exercise prescriptionin metabolic diseases

Exercise training has some risks, with frequent muscu-

loskeletal injuries and less frequent cardiac events. This

justifies taking proper precautions. An initial medical

examination and an exercising electrocardiogram are wise

precautions.

Exercise programmes should be tailored to the individu-

als’ capabilities, and based upon pathophysiological

characteristics. Indeed, it is not known whether the com-

bination of mode, intensity, duration and frequency of

exercise for optimal decreasing risk factors as insulin resis-

tance, hyperglycaemia, obesity, high blood pressure andblood lipid profile are the same as those which generally

improve fitness. We also need to know more about factors

resulting in long-term compliance to a physically active

lifestyle. Recently, Leermarkers and co-workers overviewed

the behavioural approach of lifestyle modifications in

obesity (123).

Metabolic exercise training-induced effects are some-

times controversial. We speculate that these results could

be related to training protocols themselves, which in fact

do not care about individual metabolic characteristics.

Exercise prescription should include duration, frequency

and intensity of exercising sessions. Optimal frequency and

duration are well established. Exercising duration should

be long enough (45–60min) to avoid glycogenic depletion-

related hypoglycaemic effects and fatty acids mobilization

and use and oxidation (112,113). Recommended frequency

is several times per week (3–5 times per week), as the

benefits on insulin action rapidly reverse (89,95).

Optimal level of exercise intensity remains however, to

be discussed. The most usual recommendations propose

low to moderate intensity exercise (112,113). Very few

studies have focused on benefits of resistance training

(86,100) or high intensity exercise (114). As insulin resis-



tant subjects may exhibit muscle metabolic abnormalities,

an individualized exercise prescription taking into account

these defects could be of interest. Exercise training indi-

vidualization has proved useful in other chronic patholo-

gies (124). Indeed, most of the chronic diseases are

associated with muscular metabolic abnormalities, includ-

ing specific defects and dysfunctions related to physical

inactivity and deconditioning (125). In insulin resistant

states, muscle metabolic abnormalities could be increased

by sedentarity. Sedentarity could also contribute to an

increased fat storage (126) leading to a vicious circle. So,

we may speculate that, in obese and diabetic individuals,

exercise prescription could be based upon a specific ‘meta-

bolic threshold’. This could be achieved by a better under-

standing of muscular defects and of their influence on

muscular fuel selection. With this aim in view, we have

compared substrate oxidation at different exercise intensi-

ties in obese and lean people, using a submaximal test con-

sisting of four 6-min ‘steady-state’ steps. This test providescarbohydrate and fat oxidation rates, according to the non-

protein respiratory exchange ratio technique (127) and cal-

culation of derived quantitative parameters representative

of the balance of substrate utilization during exercise, such

as the crossover point. According to the crossover concept

proposed by Brooks and Mercier (128), the crossover point

of substrate utilization is defined as the power at which

energy from CHO-derived fuels predominates over energy

from lipids, with further increases in power eliciting a rel-

ative increment in CHO utilization and a decrement in lipid

utilization. Preliminary results showed that fat oxidation

rates were lower during exercise and that the crossoverpoint was significantly shifted to lower exercise intensities

in overweight subjects compared to normal weight con-

trols: 34 ± 3.9 vs. 46.1 ± 2.5% of Wmax (129). This could

reflect an alteration of the substrate balance, by the above-

mentioned muscular metabolic disorders underlie. Non-

insulin-treated diabetics patients also seem to exhibit an

impairment in substrate utilization and a shift of their

crossover point to lower exercise intensity. However, this

shift is less marked than in non-diabetic matched obese

subjects (preliminary unpublished data).

These findings are consistent with some recent works:

while total energy expenditure is equal, low-intensity train-

ing (130), or exercise bouts (131) induce a greater fat oxi-

dation in working muscle than high or moderate intensities

do. Accordingly, lifestyle modifications are as efficient as

structured aerobic programmes on short-term weight loss

and more efficient on long-term weight-maintenance (132).

In addition to better individuals complying, similar health

benefits could be due to the low-intensity of lifestyle

activity, which enhances fat oxidation. We think that these

findings should be considered for exercise prescription.

However, the crossover concept has to be compared to

more classical approaches, such as ventilatory threshold,

and we are currently comparing an individualized exercise

prescription (at the crossover point) and a standardized

training programme.

In conclusion, significant metabolic and non-metabolic

exercise-induced benefits have been demonstrated in insulin

resistant states and regular physical activity has proved to

be useful in the management of obesity and type 2 diabetes.

However, optimal intensity remains to be better defined. To

our opinion, exercise prescription should be individualized

and this individualization should consider specific meta-

bolic characteristics.

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Insulin Resistance X Exercise

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