Insulin resistance and obesity in childhood

Francesco Chiarelli and Maria Loredana Marcovecchio

Department of Paediatrics, University of Chieti, Via dei Vestini 5, I-66100 Chieti, Italy
(Correspondence should be addressed to F Chiarelli; Email: chiarelli@unich.it)
Abstract
Childhood obesity is a signicant health problem that has reached epidemic proportions around the
world and is associated with several metabolic and cardiovascular complications. Insulin resistance is a
common feature of childhood obesity and is considered to be an important link between adiposity and
the associated risk of type 2 diabetes and cardiovascular disease. Insulin resistance is also a key
component of the metabolic syndrome, and its prevalence in the paediatric population is increasing,
particularly among obese children and adolescents. Several factors are implicated in the pathogenesis
of obesity-related insulin resistance, such as increased free fatty acids and many hormones and
cytokines released by adipose tissue.
Valid and reliable methods are essential to assess the presence and the extent of insulin resistance, the
associated risk factors and the effect of pharmacological and lifestyle interventions. The two most
common tests to assess insulin resistance are the hyperinsulinemic euglycemic clamp and the
frequently sampled i.v. glucose tolerance test utilizing the minimal model. However, both these tests are
not easily accomplished, are time consuming, expensive and invasive. Simpler methods to assess
insulin resistance based on surrogate markers derived from an oral glucose tolerance test or from
fasting insulin and glucose levels have been validated in children and adolescents and widely used.
Given the strong association between obesity, insulin resistance and the development of metabolic
syndrome and cardiovascular disease, prevention and treatment of childhood obesity appear to be
essential to prevent the development of insulin resistance and the associated complications.
European Journal of Endocrinology 159 S67S74
Childhood obesity: dimension of
the problem
Childhood obesity is reaching epidemic proportions and
represents the most important chronic disease in this
age group (1). In the USA 15.8% of children between 6
and 11 years and 16.1% of adolescents have a body
mass index (BMI) in the range of overweight (2). Similar
trends have also been observed in many European
countries, where, based on the latest International Task
Force criteria, overweight and obesity are present in
31.8% of school-aged children (3). Furthermore, the
recent phenomenon of nutritional transition with a
westernization of food, typical of many developing
countries, has caused a signicant rise in obesity even
among populations that were unaware of this problem
until some years ago (4).
Childhood obesity is associated with an increased risk
for several metabolic complications, such as insulin
resistance, glucose intolerance and type 2 diabetes
mellitus (T2DM). In particular, insulin resistance is the
most common metabolic alteration related to obesity
(5), and it represents an important link between obesity
and other metabolic as well as cardiovascular compli-
cations (5) (Fig. 1).
Data from the Bogalusa Heart Study clearly showthat
almost 20% of obese children have adverse levels of at
least one cardiovascular risk factor (hypercholestero-
lemia, hyperinsulinemia, hypertriglyceridema, hyper-
tension) and the presence of multiple risk factors is
strongly associated with early stages of atherosclerosis
(6). As cardiovascular disease is the rst cause of
morbidity and mortality in adulthood, the epidemic of
childhood obesity will cause a real burden for the future
of the society (1).
Obese children are also at risk of developing
psychological problems, orthopaedic and respiratory
disorders and also certain malignancies (7). Further-
more, childhood obesity frequently tracks into adult-
hood (8), thus representing a major contributor to the
adult obesity epidemic and to the increased cardiovas-
cular morbidity and mortality in adult life. All these
data are alarming and underline how obesity is a real
threat for the health of children and adolescents.
This paper was presented at the 5th Ferring International Paediatric
Endocrinology Symposium, Baveno, Italy (2008). Ferring Pharma-
ceuticals has supported the publication of these proceedings.
European Journal of Endocrinology (2008) 159 S67S74 ISSN 0804-4643
q 2008 European Society of Endocrinology DOI: 10.1530/EJE-08-0245
Online version via www.eje-online.org
Obesity-related insulin resistance
Insulin resistance: denition and pathogenesis
Insulin resistance is a state in which a given amount of
insulin produces a subnormal biological response (9,
10). In particular, it is characterized by a decrease in the
ability of insulin to stimulate the use of glucose by
muscles and adipose tissue and to suppress hepatic
glucose production and output (10). Furthermore, it
accounts a resistance to insulin action on protein and
lipid metabolism and on vascular endothelial function
and genes expression (11).
Several defects in the insulin signalling cascade have
been implicated in the pathogenesis of insulin resistance,
such as reduced synthesis or increased degradation of
components of the system, an increased inhibitory serine
phosphorylation of the insulin receptor or the insulin
receptor substrates, the interaction of components of the
systemwithinhibitoryproteins or analterationof theratio
of the different proteins of the signalling cascade (1012).
Insulin resistance is believed to have both genetic and
environmental factors implicated in its aetiology (10,
13). The genetic component seems to be polygenic in
nature, and several genes have been suggested as
potential candidates (10). However, several other
factors can inuence insulin sensitivity, such as obesity,
ethnicity, gender, perinatal factors, puberty, sedentary
lifestyle and diet (13).
The role of fatty acids and adipocytokines
Obesity represents the major risk factor for the
development of insulin resistance in children and
adolescents (14), and insulin resistance/hyperinsuline-
mia is believed to be an important link between obesity
and the associated metabolic abnormalities and cardio-
vascular risk (5). Approximately, 55% of the variance in
insulin sensitivity in children can be explained by total
adiposity, after adjusting for other confounders, such as
age, gender, ethnicity and pubertal stage (14). Obese
children have hyperinsulinemia and peripheral insulin
resistance with an w40% lower insulin-stimulated
glucose metabolism than non-obese children (15). In a
recent population-based study conducted in American
adolescents, insulin resistance was detected in w 50%
obese subjects (16) and adiposity was also conrmed to be
the most important factor affecting insulin sensitivity.
Adipose tissue seems to play a key role in the
pathogenesis of insulin resistance through several
released metabolites, hormones and adipocytokines that
can affect different steps in insulin action (17) (Fig. 1).
Adipocytes produce non-esteried fatty acids, which
inhibit carbohydrate metabolism via substrate compe-
tition and impaired intracellular insulin signalling
(1719). In children, as in adults, several adipocyto-
kines have been related to adiposity indexes as well as
to insulin resistance.
Adiponectin is one of the most common cytokines
produced by adipose tissue, with an important insulin-
sensitizing effect associated with anti-atherogenetic
properties (20, 21). Whereas obesity is generally
associated with an increased release of metabolites by
adipose tissue, levels of adiponectin are inversely related
to adiposity (17). Therefore, reduced levels of this
adipocytokine has been implicated in the pathogenesis
of insulin resistance and metabolic syndrome (17).
Decreased levels of adiponectin have been detected
across tertiles of insulin resistance in children and
adolescents (22), where it is a good predictor of insulin
sensitivity, independently of adiposity (23).
Adipose tissue also produces tumour necrosis
factor-a, an inammatory factor, which can alter
insulin action at different levels in the intracellular
pathway (17). Interleukin-6 (IL-6) is another inam-
matory cytokine released by adipose tissue and its levels
are increased in obesity (17). IL-6 stimulates the hepatic
production of C-reactive protein and this can explain the
state of inammation associated with obesity, and could
mediate, at least partially, obesity-related insulin
resistance (17). Data based mainly on animal studies
also suggest that increased levels of resistin, another
molecule produced by adipose tissue, could impair
insulin sensitivity (17). There are also data showing a
close relationship between leptin levels and insulin
resistance in children (24). Recently, it has also been
shown that serum levels of retinol-binding protein 4
(RBP4) correlate with insulin resistance in subjects with
obesity as well as in those with impaired glucose
tolerance (IGT) or T2DM, therefore suggesting that it
could be useful in assessing insulin resistance and the
associated risk for complications (25). A study
Figure 1 Obesity-mediated insulin resistance and associated
complications.
S68 F Chiarelli and M L Marcovecchio EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
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conducted in normal weight and overweight children
has shown that serum RBP4 is independently related to
obesity as well as to components of the metabolic
syndrome (26).
In obese children, diet composition might be an
additional factor promoting and/or worsening insulin
resistance. Animal and human studies suggest that a
high energy intake as well as a diet rich in fat and
carbohydrates and low in bre could increase the risk of
developing insulin resistance (27).
The role of fat distribution
An altered partitioning of fat between s.c. and visceral or
ectopic sites has been associated with insulin resistance
(5). Visceral fat has a better correlation with insulin
sensitivity than s.c. or total body fat (28), in both obese
adults and children. Based on the portal theory, this
could be related to a higher lipolytic activity of visceral
when compared with s.c. fat, and therefore to a greater
amount of free fatty acids and glycerol carried directly to
the liver (10). Studies conducted in the paediatric
population have shown that in girls the amount of
visceral fat was directly correlated with basal- and
glucose-stimulatedinsulinlevels andinverselycorrelated-
with insulin sensitivity and the rate of glucose uptake
(28). By contrast, no correlation was found between
abdominal s.c. fat and these metabolic indexes (28).
Ectopic deposition of fat in the liver or muscle can also
be responsible for insulin resistance in obese subjects, as
the accumulation of fat in these sites impairs insulin
signalling, with a reduced glucose uptake in the muscle
and a decreased insulin-mediated suppression of hepatic
glucose production (5).
Intramyocellular lipid (IMCL) accumulation has been
shown as a factor related to decreased insulin sensitivity
(29, 30). Obese insulin sensitive children and adoles-
cents present lower levels of visceral fat and IMCL when
compared with obese insulin resistant children (31).
Furthermore, higher IMCL has been reported in obese
children with IGT when compared with normal glucose
tolerance (32), suggesting a pathogenetic role of IMCL
in the development of insulin resistance and IGT.
Accumulation of fat in the liver has also been
associated with insulin resistance, independently of
adiposity (33, 34). Recently, it has also been suggested
that deposits of fat around blood vessels can produce
several cytokines and therefore contribute to the
development of insulin resistance, through a so-called
vasocrine effect (35).
Insulin resistance and associated
complications
Insulin resistance in obesity is strictly related to the
development of hypertension (36, 37), dyslipidemia
(38), IGT (39), hepatic steatosis (40), as well as to the
combination of these factors, also known as metabolic
syndrome (41). Furthermore, insulin resistance is
associated with systemic inammation, endothelial
dysfunction, early atherosclerosis and disordered bri-
nolysis (42) (Fig. 1). It is alarming that these metabolic
and cardiovascular complications are already found in
obese children and adolescents (1). The presence of
these alterations in prepubertal children (36, 40, 43) is
then particularly worrying, as insulin resistance and
related complications might be further exacerbated by
the inuence of puberty, due to the physiological
decrease in insulin sensitivity associated with normal
pubertal development (44).
Obese children with a similar BMI can differ on the
basis of the degree of insulin resistance in the risk for
complications. In fact, those with a more impaired
insulin sensitivity show, for example, a greater risk for
T2DM and cardiovascular disease (45).
It has also been clearly shown that insulin resistance
in childhood can track in adult life (46). A recent study
has shown that insulin resistance at the age of 13 years
predicts insulin resistance at age 19, independently of
BMI, and is also associated with cardiovascular risk in
adulthood (46).
The fundamental role of insulin resistance in human
disease was already recognized in 1988 by Reaven (47)
who emphasized its role in the development of a
grouping of metabolic abnormalities, which he dened
as syndrome X. Later studies strengthened the concept
of insulin resistance as a key component of the
metabolic syndrome, a cluster of IGT, dyslipidemia,
hypertension, hyperinsulinemia, associated with an
increased risk of T2DM and cardiovascular disease
(41). The prevalence of the metabolic syndrome is not
particularly high in the overall paediatric population
(w4%) but it is as high as 3050% among overweight
children and adolescents (22, 48). The presence of
obesity, mainly visceral obesity and reduced insulin
sensitivity are the main mechanisms implicated in the
development of the syndrome. A direct correlation
between the degree of obesity and insulin resistance and
the prevalence of the metabolic syndrome has been
reported already in obese youths (41).
In obese children and adolescents, insulin resistance
is the best predictor for the development of IGT (39) and
T2DM (49). T2DM is a progressive disease with a
gradual increase in insulin resistance associated later
with a decline in insulin secretion with fasting
hyperglycemia. Over the last decade, there has been
an alarming increase of T2DM in youth, concomitant
with the rise of obesity in this age group (49) and in the
USA T2DM now accounts between 8 and 45% of all
cases of diabetes diagnosed among children and
adolescents (49).
Low insulin sensitivity is also a well-known con-
tributor of high blood pressure in children (36, 37, 50).
Whereas in some studies, this has been attributed to the
effect of obesity itself, in others insulin resistance has
Insulin resistance and obesity S69 EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
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emerged as a predictor of blood pressure, independent of
BMI (36, 37, 50). An insulin-mediated effect on the
sympathetic nervous system and on renal sodium
reabsorption are the main mechanisms suggested as
potential links between insulin resistance and increased
blood pressure (5153).
In obese children, insulin resistance is also associated
with an abnormal lipid prole, characterized by
hypertriglyceridemia, hypercholesterolemia, low HDL-
cholesterol, which increase the risk of developing early
atherosclerosis (54).
Increased levels of plasminogen activator inhibitor-1
and brinogen have also been associated with insulin
resistance, and they might contribute to the enhanced
coagulability and the risk of cardiovascular diseases
related to obesity and insulin resistance (17).
In obese children, increased levels of inammatory
markers, such as C-reactive protein and IL-6, have been
shown to progressively increase with insulin resistance
(22), and some of them have been suggested as
additional components of the metabolic syndrome (22).
In obese children, as in adults, evidence exists on an
association between insulin resistance and hepatic
accumulation of fat (40). This has been related to a
reduced effect of insulin action on adipose tissue, with a
consequent lack of suppression of lipolysis and thus an
increased ux of free fatty acids to the liver (55). This
effect, together with an increased hepatic lipogenesis
related to hyperinsulinemia, is responsible for the
accumulation of triglycerides in the hepatocytes and
the development of steatosis (55). Increased levels of
liver enzymes, particularly alanine aminotransferase
(ALT), increase with worsening insulin sensitivity (56).
Based on the association of steatosis and increased ALT
with insulin resistance and IGT in obese adults and
children, steatosis has been suggested as the hepatic
manifestation of the metabolic syndrome (56, 57).
Insulin resistance has also been associated with the
development of polycystic ovary syndrome (PCOS), an
ovulatory dysfunction associated with hyperandrogen-
ism not due to other causes (58). Obese girls with PCOS
have an w 50% lower insulin sensitivity than obese-
matched controls together with a 40% lower rst-phase
insulin secretion (59), and have a signicantly
increased risk of progression to T2DM, if they are left
without intervention. A screening of adolescents with
PCOS demonstrated that 30% had IGT and 4% already
had diabetes (60).
Insulin resistance has also been suggested as a
potential risk factor for the development of respiratory
problems, such as asthma, in severe obese children
and adolescents. In fact, obese children with asthma
have a higher degree of insulin resistance than obese
children without this respiratory problem, and the
state of inammation associated with insulin resistance
has been suggested as a possible mediator of this
relationship (61).
Assessing insulin resistance
Valid and reliable methods are essential to assess the
presence and the extent of insulin resistance, the
associated risk factors and the effect of lifestyle and
pharmacological interventions. Different methods to
assess insulin resistance are currently available and they
include fasting measurements of insulin and glucose, the
OGTT, the insulin tolerance test, the hyperinsulinemic
euglycemic clamp and the frequently sampled i.v. glucose
tolerance test (FSIVGTT) (62).
The two most common tests to measure insulin
sensitivity are the hyperinsulinemic euglycemic clamp
and the FSIVGTT utilizing the minimal model (62). These
methods are accurate and, when labelled glucose tracers
are used, they also allow differentiation between hepatic
and muscular insulin resistance (62). Furthermore, the
use of stable isotopes also permits the assessment of
protein and lipid metabolism together with insulin
sensitivity (62). However, both these tests are difcult to
perform, time consuming, expensive and invasive (62).
Simpler methods basedonsurrogate markers derivedfrom
fasting insulin and glucose or from an OGTT have been
suggested as potential alternatives. These surrogate
measures include: fasting insulin, fasting glucose to
fasting insulin ratio (FGIR), the homeostasis model
assessment of insulin resistance (HOMA-IR), the quan-
titative insulin sensitivity check index (QUICKI). These
indices have been validated and proposed for the purpose
of screening inlarge populations of adults (62). Validation
studies have also been performed in children and
adolescents with normal glucose tolerance, with good
correlation coefcients, when compared with the results
derived from the clamp or FSIVGTT methods (6365). In
childrenand adolescents, the simple use of fasting insulin,
in presence of normoglycemia, could be an estimate of
insulin resistance as good as HOMA-IR, QUICKI or FGIR
(66). However, the validityof these conclusions inchildren
with IGT or T2DM remains to be determined. Further-
more, it is also important to acknowledge that there are
some limitations in the use of these surrogate indexes
related to the variability in insulin measurements across
laboratories, with a consequent difculty in comparing
results obtained in different centres (62). However, these
fasting indexes could be of particular relevance for
screening purposes in populations at high risk of diabetes,
such as obese children and adolescents.
Indexes derived from the OGTT have also been
developed (67). Some of them, such as the whole body
insulin sensitivity index and the insulin sensitivity index
have been validated also in obese children and
adolescents, and a strong correlation between these
two indexes and the euglycemic clamp has been
reported (64). These indexes could have the advantage
over fasting indexes to detect earlier reductions in
insulin sensitivity, mainly related to an impairment of
stimulated insulin to increase peripheral glucose uptake
(64). The OGTT can also offer the advantage of
S70 F Chiarelli and M L Marcovecchio EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
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diagnosing IGT or overt diabetes, and to estimate rst-
phase insulin responses to a glucose challenge, and thus
to evaluate the relationship between insulin secretion
and insulin sensitivity (64). Therefore, the OGTT could
be used as a screening test to assess insulin resistance
mainly in severely obese children or in those with other
risk factors associated with obesity, such as a family
history of T2DM and cardiovascular diseases, who are at
particular risk not only for insulin resistance but also for
impaired -cell function and IGT (39). Recently, insulin
growth factor binding protein-1 (IGFBP-1) has been
suggested as a new potential plasma marker to assess
insulin resistance (68). IGFBP-1 seems to have a good
correlation with FSIVGTT assessment of insulin sensi-
tivity, particularly in children younger than 10 years
(68). However, further studies are required to validate
the utility of this marker.
Prevention of obesity and insulin
resistance
Prevention of obesity and insulin resistance includes
strategies that need to be started early in life, already
during pregnancy and the perinatal period (69). It is
important to strongly recommend breast feeding and
offer guidance for appropriated food choice, caloric
intake and exercise for children (69). The rst step of
prevention must aim towards maintaining normal BMI
(69). A rapid weight gain must be avoided during the
rst years of life as it causes an early adiposity rebound,
which is a well-known risk factor for future persistence
of obesity (70). When obesity is already developed, a
programme of secondary prevention is required, in
order to reverse or at least to avoid progression of
obesity and reduce the risk of co-morbidities (69).
Control of body weight is also particularly important
during adolescence, another important period for the
development of obesity (1). Puberty is a delicate period,
associated with physiological insulin resistance and
hyperinsulinemia. Therefore, the presence of obesity in
this phase, represents an additional stress for the body,
with an increased risk for complications (1).
Preventive strategies need to be further intensied in
presence of other risk factors, such as a family history of
obesity, T2DM or cardiovascular disease, or the presence
of other risk factors for insulin resistance, such as
ethnicity (71).
A recent meta-analysis of studies investigating the
effect of prevention of obesity in children and adoles-
cents has shown that these interventions are often of
limited success (72), thereby suggesting a need of major
efforts in preventing childhood obesity. However, the
same meta-analysis, as well as another systematic
review, have shown that interventions to prevent
obesity are at least associated with improved dietary
habits and physical activity (72, 73).
Treatment of obesity and insulin
resistance
A balanced diet and increased physical activity are
generally the cornerstone of the treatment of obesity
and insulin resistance in children and adolescents.
Decreases in body weight have been associated with a
signicant improvement in insulin sensitivity (74). A
recent study has shown that in obese children, an
8-week exercise training programme increased insulin
sensitivity and was associated with an improvement in
cardiorespiratory tness but was independent of
measurable changes in body composition (75).
In children and adolescents, there is not a wide
experience with weight loss medications or with insulin
sensitizers. Metformin has been shown to improve insulin
sensitivityand BMI innon-diabetic obese adolescents with
fasting hyperinsulinemia and a family history of T2DM
(76). Asimilar efcacyof metformin on insulin sensitivity
and BMI has been found in two other small studies
conducted in obese normoglycemic adolescents (77, 78).
Sibutramine seems to have a good efcacy in reducing
body weight in children and, in some studies, a positive
effect on glucose and lipid metabolism has also been
shown (79). However, this drug has been associated
with an increase in blood pressure and heart rate,
thereby posing limitations for its wide use in the
paediatric population (79).
Orlistat is a weight loss drug, which has been
investigated in children and has been associated with
a signicant weight loss, even though several side effects
have been associated with its use (80); mainly
gastrointestinal disturbances, but also multiple vitamin
deciencies (80). No signicant effects on glucose
metabolism have been reported with this drug (80).
In adults thiazolidinediones have also been shown to
have a good efcacy in improving insulin sensitivity (81);
however, their use in children has not been yet approved,
based on the lack of relevant studies in this age group.
Further controlled trials are required in order to have
a better assessment of the safety and efcacy of drugs to
contrast obesity and insulin resistance in children and
adolescents, and to clarify which group of subjects really
needs pharmacological interventions.
Conclusions
Insulin resistance represents a serious and common
complication of obesity during childhood and adoles-
cence. A timely diagnosis and an appropriated preven-
tion and treatment of obesity and insulin resistance are
required in order to reduce the associated risk of
metabolic and cardiovascular complications. Greater
efforts are therefore required in order to avoid obesity
and the associated insulin resistant status seriously
compromising the health of our children and the future
of our societies.
Insulin resistance and obesity S71 EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
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Disclosure
This paper forms part of a European Journal of Endocrinology
supplement, supportedbyFerringPharmaceuticals. The authors disclose:
no potential conicting relationship withFerring. This article was subject
to rigorous peer review before acceptance and publication.
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Received 26 March 2008
Accepted 17 September 2008
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