Association between type two diabetes and non-alcoholic fatty liver disease in youth.
ABSTRACT In the last three decades prevalence of insulin related diseases has been growing worldwide with epidemic obesity, type 2 diabetes mellitus and non alcoholic fatty liver disease. In children such epidemics are particularly worrisome, since metabolic abnormalities track to the adulthood with significant implications for the health care system. Epidemiological studies support a close association between type 2 diabetes and fatty liver disease. We review the most recent epidemiological data on prevalence of both diseases in youth and their association.
- [Show abstract] [Hide abstract]
ABSTRACT: Adiposity is a key risk factor for NAFLD. Few studies have examined prospective associations of infant and childhood adiposity with subsequent NAFLD risk. We examined associations of weight-for-height trajectories from birth to age 10 with liver outcomes in adolescence, and assessed the extent to which associations are mediated through fat mass at the time of outcome assessment. Individual trajectories of weight and height were estimated for participants in the Avon Longitudinal Study of Parents and Children using random-effects linear-spline models. Associations of birthweight (adjusted for birth length) and weight change (adjusted for length/height change) from 0-3 months, 3 months-1y, 1-3y, 3-7y and 7-10y with ultrasound scan (USS) determined liver fat and stiffness, and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) at mean age 17.8y were assessed with linear and logistic regressions. Mediation by concurrent fat mass was assessed with adjustment for fat mass at mean age 17.8y. Birth weight was positively associated with liver stiffness and negatively with ALT and AST. Weight change from birth to 1y was not associated with outcomes. Weight change from 1-3, 3-7 and 7-10y was consistently positively associated with USS and blood-based liver outcomes. Adjusting for fat mass at mean age 17.8y attenuated associations toward the null, suggesting associations are largely mediated by concurrent body fatness. Greater rates of weight-for-height change between 1 and 10y are consistently associated with adverse liver outcomes in adolescence. These associations are largely mediated through concurrent fatness.Journal of Hepatology 04/2014; · 9.86 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) affects about 30% of the general population in the United States and includes a spectrum of disease that includes simple steatosis, non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis. Significant insight has been gained into our understanding of the pathogenesis of NALFD; however the key metabolic aberrations underlying lipid accumulation in hepatocytes and the progression of NAFLD remain to be elucidated. Accumulating and emerging evidence indicate that hepatic mitochondria play a critical role in the development and pathogenesis of steatosis and NAFLD. Here, we review studies that document a link between the pathogenesis of NAFLD and hepatic mitochondrial dysfunction with particular focus on new insights into the role of impaired fatty acid oxidation, the transcription factor peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and sirtuins in development and progression of NAFLD.International Journal of Molecular Sciences 05/2014; 15(5):8713-42. · 2.46 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Background and study aims Nonalcoholic fatty liver disease (NAFLD) is an emerging problem in children and adolescents worldwide. This study was done to investigate the prevalence of NAFLD in children and adolescents as well as to determine the associated risk factors of fatty liver and to explore the ability of some obesity indices to predict and consequently be used as a screening method of fatty liver disease at certain cutoff points in schoolchildren. Patients and methods A cross-sectional, nested case–control study was carried out. Cases and controls were randomly selected from outpatient schoolchildren aged 6–18 years attending the radiology clinic at Sporting Health Insurance Paediatric Hospital in Alexandria. They were subjected to ultrasonic examination as well as complete anthropometric and laboratory measurements including fasting plasma glucose (FPG) level, fasting insulin, alanine aminotransferase (ALT) level, and lipid profile. Results Fatty liver was prevalent in schoolchildren (15.8%) and increased significantly with age (p = 0.004). Positive family history of diabetes mellitus (DM), hypertension (HTN), obesity, and liver disease were all statistically significant risk factors for fatty liver. Waist circumference (WC), body mass index (BMI) and its Z-score were significantly sensitive predictors. BMI was considered the best predictor of paediatric NAFLD at a cutoff = 22.9. NAFLD was significantly associated with high triglycerides (TGs), low high-density lipoprotein cholesterol (HDL), homoeostatic model assessment (HOMA) percentile, and the number of metabolic syndrome (MS) components. Conclusion Paediatric NAFLD is a substantial problem in schoolchildren and has a close relationship with obesity, dyslipidaemia, insulin resistance (IR), and consequently MS. BMI and WC can be used as useful predictors and screening tools for NAFLD in schoolchildren.Arab Journal of Gastroenterology 06/2014;
Annals of Hepatology 8(1) 2009: S44-S50
Annals of Hepatology 2009; 8(1): Supplement: S44-S50
Association between type two diabetes and
non-alcoholic fatty liver disease in youth
Anna Alisi;1 Melania Manco;2 Nadia Panera;1 Valerio Nobili1
Bambino Gesù Paediatric Hospital and Research Institute;
Type two diabetes mellitus (T2DM), metabolic syndrome (MetS),
non-alcoholic fatty liver disease (NAFLD), nonalcoholic
steatohepatitis (NASH), impaired fasting glucose (IFG), impaired
glucose tolerance (IGT), National Health and Nutrition
Examination Survey (NHANES), alanine aminotransferases
(ALT), aspartate aminotransferase (AST), free fatty acid (FFA),
Address for correspondence:
Anna Alisi, PHD
Unit of Hepatology
Bambino Gesù Hospital and Research Institute
Piazza San Onofrio 4
00165 Rome; Italy
Phone: +39-06-68592650; Fax: +39-06-68592904;
Manuscript received and accepted: 23 December 2008
In the last three decades prevalence of insulin related
diseases has been growing worldwide with epidemic
obesity, type 2 diabetes mellitus and non alcoholic fatty
liver disease. In children such epidemics are particu-
larly worrisome, since metabolic abnormalities track
to the adulthood with significant implications for the
health care system. Epidemiological studies support a
close association between type 2 diabetes and fatty liver
disease. We review the most recent epidemiological
data on prevalence of both diseases in youth and their
Key words: Aminotransferases, glucose, insulin resis-
tance, non alcoholic steatohepatitis, obesity.
Estimates from population- and hospital-based studies
indicate that the number of children and adolescents with
type two diabetes mellitus (T2DM) has been increasing
in the last decades.1 This is likely to occur since the num-
ber of adolescents and young adults affected by insulin
resistance-associated morbidities is increasing.2 In fact,
T2DM is characterized by the simultaneous occurrence
of both insulin-resistance and relative insulin-deficien-
cy.3 During puberty, insulin resistance represents a phys-
iological condition aimed to favor growth. Obesity may
exacerbate this condition. It has been shown that up to
one in third obese adolescents with insulin resistance
will keep this condition until the adulthood, whilst the
remaining two will recover normal insulin sensitivity as
it happens for all the normal weight adolescents.4 Sub-
jects with severe insulin resistance which persists over
the puberty are candidate to develop type 2 diabetes mel-
litus, when their beta cell activity fails to compensate for
increased and long term insulin resistance.5
T2DM in youth is usually not an isolated condition,
but it is often accompanied by other metabolic abnor-
malities which represent cardiovascular risk factors and
cluster together in the metabolic syndrome (MetS),6 i.e.
obesity, dyslipidemia, hypertension and low-grade in-
flammation.2,7 Recent evidence suggests a close associa-
tion also between T2DM and two other condition of in-
sulin resistance, namely the polycystic ovary syndrome
and the non-alcoholic fatty liver disease (NAFLD).8,9
NAFLD has a broad spectrum of manifestations, rang-
ing from simple steatosis to its inflammatory representa-
tion of nonalcoholic steatohepatitis (NASH). The bound-
aries between NAFLD and NASH are defined only by liv-
er biopsy and prediction is difficult using any single or
combined clinical or laboratory test.10 A small proportion
of patients with NAFLD progresses to cirrhosis, hepato-
cellular carcinoma and liver failure.11,12
Pediatric NAFLD is becoming the leading cause for re-
ferral to liver clinics especially in overweigh/obese chil-
dren from Western country.13 The occurrence of NAFLD in
these children who are already at cardiovascular risk, is
particularly worrisome, since the disease appears to be a
per se independent cardiovascular risk.9 Patients with
NAFLD seem also prone to develop more frequently an
impairment of the carbohydrate metabolism varying from
a condition of pre-diabetes to overt T2DM. In our series of
children and adolescents with biopsy proven NAFLD, we
observed a prevalence of pre-diabetes and diabetes as high
as 10-12%,14,15 and, in most of them the impaired glucose
metabolism will likely track to the adulthood.
The meaning of this association remains unclear. The
question is whether NAFLD is per sè a determinant of di-
A Alisi et al. NAFLD and T2DM
abetes or its effect is mediated by more severe obesity
and insulin resistance.
In the present review, we will try to verify the occur-
rence of this association in youth by resuming the most
recent epidemiological data on prevalence/incidence of
both diseases, thus highlighting their common trends;
and considering pathogenetic mechanisms which may
underlie both. The epidemic of T2DM and NAFLD will
bear fruit in forthcoming decades, putting further stress
on the healthcare system and, probably, leading to in-
creased morbidity and a shorter lifespan for future gener-
Epidemiology of T2DM
Prediabetes and T2DM are serious adverse conse-
quences of obesity and pediatric metabolic syndrome,
more likely to manifest in adolescence and early adult-
hood than clinical atherosclerotic diseases.16
The American Diabetes Association defines diabetes
as occurring if one of three criteria are present: 1) a casual
plasma glucose of > 200 mg/dL in some one with symp-
toms of diabetes; fasting plasma glucose of ≥ 126 mg/
dL; 3) 2 hr plasma glucose of ≥ 200 as part of an oral
glucose tolerance test.17 The dose of glucose used as load
is of 1.75 g/kg to a maximum of 75 g, although the pre-
cise pediatric dose is not well validated.18 Impaired fast-
ing glucose (IFG) or impaired glucose tolerance (IGT)
Most data on the epidemiology of diabetes comes
from national surveys. However, they provide data on in-
cidence and prevalence of the disease based on the num-
ber of cases referred by physicians or self reported by pa-
tients. For instance, the Search for diabetes in Youth is a
6-center observational study conducting population-
based ascertainment of physician diagnosed diabetes in
youth.20 The National Health and Nutrition Examination
Survey (NHANES) is a stratified, multistage probability
sample of the civilian non-institutionalized US popula-
tion and diagnosis of diabetes was self reported. To esti-
mate prevalence and incidence of diabetes, the adoles-
cents of the NHANES study (N = 4,370, age 12-19 years)
were simply asked about having or not the disease. Then,
they underwent measurement of fasting glucose. Subjects
without self reported diabetes but presenting with IFG (N
= 1,496) were considered diabetic as well.21 In a longitu-
dinal study, performed in the United Kingdom to evalu-
ate the incidence of T2DM in subjects < 17 years of age,
the estimate of cases was based on active monthly report-
ing of cases by consultant pediatricians, as described
above.22 Therefore, the major limit of this survey studies
is related to the fact that they do not estimate the rate of
prediabetes assessed by the impaired glucose tolerance,
which is, on the contrary the most frequent form of im-
pairment in the carbohydrate metabolism in the youth.
Therefore, large surveys such as the SEARCH and the
NHANES are likely to see just the top of the iceberg, and
to severely underestimate a more common phenomenon.
On the other hand, surveys offer the opportunity to evalu-
ate the effect of several factors, mainly age, sex and races.
Both prevalence and incidence of T2DM vary among
races, with the highest prevalence and incidence in mi-
norities.20-22 The SEARCH found that overall prevalence
ranged from 6% in non Hispanic white youth to 76% in
American Indians; incidence from 17 in Hispanic to 49.9
in American-Indian per x 100,000-1 x year-1 in 15-19 year
olds. In the same range of age, incidence for non-Hispan-
ic white was 5.6.20 Data from NHANES found an inci-
dence of 8.1 x 100,000-1 in 10–14-year-olds and 11.8 x
100,000-1 in 15–19-year-olds in 2002–2003. The esti-
mated incidence of T2DM in the Bostonian Youth varies
from 0.79 x 1000-1 in children ≤ 9 years of age to 1.74 x
1000-1 in adolescents (age 10-19 years).23 In the UK
study, a total of 168 confirmed cases of non-type 1 diabe-
tes were reported, resulting in a national incidence of 1.3
x 100,000-1 x year-1. Of these, 40% were diagnosed with
type 2 diabetes giving a minimum incidence of 0.53 x
100,000-1 x year-1.22 In New Zeeland, a 6 year study,
which included 1,095.074 children of ≤ 14 years old es-
timated incidence of impaired glucose tolerance (IGT)
was 0.72 x100000-1 x year-1 in subjects of ≤ 14 years
and 2.27 x100000-1 in those of 10-14 years. Type 2 DM
had a rate of 0.84 x 100,000-1 x year-1.24 In Chinese
youth, a nationally representative cross-sectional survey
enrolling 44 880 children aged 7–17.9 years, showed an
incidence of diseases, varying from 0.2 in subjects 7-12
year old to 0.4 in 12-18 year olds.25
To obtain data on rates of IGT we have to look to small
size studies, often performed in high risk populations, i.e.
including obese individuals with co-morbidities and/or fa-
miliar history of diabetes. We resume in Table 1 the most
significant among those conducted and published in the
last 5 years, and using the oral glucose tolerance test to di-
agnose diabetes.26-36 Of note, even in samples of individu-
als with severe obesity and familiarity for diabetes and car-
diovascular disease, European rates were not as high as
those in US studies. In Europe, T2DM remains a rarity, ac-
counting only for 1% to 2% of all cases of diabetes melli-
tus. Although, differences in obesity rates between US and
European youth are likely contributors, the full explana-
tion for this discrepancies remains uncertain.
Epidemiology of NAFLD
The real prevalence of NAFLD/NASH remains un-
known in the general population because prospective
studies lack and the information available in a given
population strictly depend on the diagnostic criteria
used.37 NAFLD, as estimated on the basis of ultrasonogra-
phy and increased levels of liver enzymes, seems to be
very common, occurring in persons of all ages and ethnic
Annals of Hepatology 8(1) 2009: S44-S50
Population-based studies suggest that, as in the
adults, its prevalence has been increasing over the past
three decades also in children and adolescents, and that
the disease represents a worldwide problem with case se-
ries described in North and South America, Europe, Aus-
tralia and Asia.13,37 These studies indicate that prevalence
increases with age, ranging from 0.7% for ages 2 to 4 up
to 17.3% for ages 15 to 19 years, but these rates are likely
to be underestimated and all these reports do not dis-
criminate between simple steatosis, necro-inflammation
The most prominent risk factor for fatty liver is obesi-
ty and the disease is most common in males adoles-
cents.39-41 In a recent study on 909 Korean obese children
(boys 613, girls 296) the prevalence of NAFLD, mea-
sured as surrogate of alanine aminotransferases (ALT),
was 33.4% in boys, and 19.6% in girls respectively.42
Race, ethnicity and degree of obesity significantly pre-
dicted the presence of fatty liver, with Hispanics having
the highest and African Americans the lowest figure.43
One study with 181 consecutive asymptomatic obese
children demonstrated that 8% had an elevated ALT sug-
gestive of NAFLD, but the prevalence decreased in black
As shown in table II, studies on prevalence of NAFLD
in overweigh/obese children report values ranging from
8% to 80% (USA), depending upon the methods used for
the diagnosis.45-50 Unfortunately, most studies have been
limited to the use of indirect measures such as elevated
serum (ALT) and ultrasound to predict histological out-
come,51 but up to a 20% of young patients have normal
values of liver enzyme at the time of biopsy, despite hav-
ing histological proven NASH and/or fibrosis.52 Data
Table II. Data of prevalence of NAFLD/NASH in obese children from
19.6%° and 33.4%^
§Number of overweight/obese children included in the study.
* Percentage of presumed NASH.
° Girls ^ Boys
Table I. Prevalence/incidence of type 2 diabetes mellitus in youth.
Country Study and populationPrevalence/incidence% Ref.
N = 427 obese/overweight subjects, Age 10.7 ± 3.5
N = 214 obese and normal weight subjects, Age 8-10
N = 520 obese/overweight subjects, Age 8.9-20.4
N = 102 with Metabolic syndrome, Age 7-18
N = 721 school-leaving boys, mean age 15.5 ± 0.7
N = 250 obese/overweight subjects, Age not provided
N = 234 obese/overweight subjects, Age 5-22
N = 514 obese/overweight subjects, Age 13.6-14
N = 105 obese and normal weight subjects, Age 10-18
N = 196 obese subjects, Age 7-18
N = 169 obese subjects, Age 7-18
IGT: 7%, T2DM: 1.6%26
IGT : 6.5%, T2DM 0.5%27
IGT: 5.2%, T2DM: 1.5%28
IGT: 36%, T2DM: 6%
IFG 0.41%, T2DM 0.83% (lean individuals)
‡IGT, T2DM 2.5% (obese/overweight)
‡IGT 13.6%, T2DM 1.2% 31
IGT, T2DM: 13.5% 32
IGT 5.4%, T2DM 0.5%33
IGT 18%, T2DM 3%
Prepubertal IGT 19%, T2DM 2%
Pubertal IGT 27.5%, T2DM 4.3%
We included exclusively data from studies published in the list five years and using standard glucose tolerance test to assess impaired glucose tolerance (IGT) and type 2 diabetes
mellitus according to the ADA criteria. In few studies diagnosis was made according to the WHO criteria. (‡). Some articles were not accessible through the website, therefore the
abstract alone was available.
A Alisi et al. NAFLD and T2DM
from NHANES in 2450 adolescents found elevated ALT
in 6% of overweight and 10% of obese subjects.53 Simi-
larly, the 1998 Korean National Health and Nutrition Ex-
amination Survey found a prevalence of elevated ALT as
high as 3.2%.54 In a sample of Mexican obese/overweight
children from an elementary school, elevated ALT were
observed in 42% of subjects.55
Based on ultrasonography evidence of fatty liver,
NAFLD was diagnosed in 2.6% of Japanese children and
occurrence of disease correlated significantly with indices
of obesity such as the body mass index;56 42% of 375, and
44% of 268 morbidly obese Italian children had hepatic
steatosis;57,58 among 123 obese Chinese children, 99 sub-
jects showed abnormal hepatic sonograms and 54 were di-
agnosed as NASH.59 Some studies combine data from ul-
trasonography and elevated ALT; for instance a study
demonstrating that 52.4% of obese Turkish children had
fatty liver by ultrasonography and 13.8% had high ALT
levels.60 According to an Italian survey in 195 obese chil-
dren, 55% had liver steatosis by ultrasonography, 20%
had elevated ALT and AST levels, and 15% had both.61
Type 2 diabetes: pathogenetic mechanisms
T2DM is caused by a combination of increased insu-
lin resistance and decreased insulin secretion. Peripheral
insulin-resistance is tightly coupled with obesity in chil-
dren and seems to be the major driving force of deterio-
rating glucose metabolism, and is also associated with
lipid partitioning in specific compartments (i.e., viscera,
muscle and liver). On the other hand, the reduction of in-
sulin secretion is probably a secondary event evolving
Insulin resistance is an impairment of the physiologic
effects of insulin on glucose.63 Normal glycemic control
requires the pancreatic β-cell sensing of glucose concen-
tration, synthesis and release of insulin, binding of insu-
lin to receptors with a consequent activation of several
signaling proteins. The activation of multiple signaling
cascade causes increased glucose uptake by muscles, fat,
and liver and decreased glucose production by the liv-
er.64 These molecular mechanisms are all altered in
T2DM, causing insulin resistance in muscle tissue, de-
creased pancreatic insulin secretion, and increased hepat-
ic glucose output.65
In children and adolescents with T2DM, defects of
glucose metabolism are characterized by a decline in the
first phase sensitivity of the β-cell coupled with the de-
cline of both first and second phase sensitivity.66 The dy-
namics of the impaired glucose metabolism in childhood
seem to be faster than in adults, representing a limited
window of opportunity for successful preventive inter-
vention. Early identification of children with altered glu-
cose metabolism is important in order to quantify public
health needs and to allocate resources for appropriate
The risk factors for developing type 2 diabetes in
youth include a genetic predisposition and certain envi-
ronmental characteristics.67 The majority of diabetes in
both adults and children is polygenic.68 Thus, the family
history of diabetes represents the most important risk fac-
tor of developing T2DM with respect to the general pop-
Ethnicity is another important factor predisposing to
T2DM development. The increased incidence of T2DM
in youth of color was identified first in the Pima Indians
of the southwest. Children of Pima Indian were found to
have high rates of morbid obesity and from 1980 the re-
search has focused on this group as well as other ethnic
and racial groups with high rates of diabetes.70 Low birth-
weight, maternal diabetes and the intrauterine environ-
ment also are important areas to consider in risk for the
development of T2DM in youth.71 Puberty coupled with
insulin resistance provides a strong basis for the develop-
ment of pre-diabetes and T2DM in youth with over-
weight or frank obesity.72
The changing environment during the past several de-
cades provided a further contribution of the dramatic in-
crease in T2DM in youth. There has been a movement to-
ward a positive energy balance due to diet intake, de-
creased physical activity and increased sedentary activity.
Fast food consumption and portion sizes have increased
from 30 years ago, leading to caloric intake in excess of
metabolic need, and youth are the major consumers of fast
food meals. Moreover, youth are increasingly inactive, re-
ducing their physical activity and using sedentary screen
activities, such as television viewing and playing video
games, for an average of 5.5 hours daily.67
All these evidence demonstrate that development of
T2DM in youth is complex and requires astute health
care providers who understand the pathophysiology, pa-
tient history, family history, and genetic predisposition,
coupled with environmental factors, to manage each
youth at the appropriate intervention level.
NAFLD: pathogenetic mechanisms
The pathogenesis of NAFLD is not yet completely un-
derstood, however a currently favored hypothesis is that
«two hits» are required for a subject to develop the dis-
ease.73 A first hit that provokes steatosis (i.e. fat accumu-
lation in liver and/or insulin resistance) and predisposes
the liver to a second hit which leads to necro-inflamma-
tion and fibrosis. This second hit includes the alteration
of several signaling pathways regulating oxidative stress,
mitochondrial dysfunctions and production of pro-in-
flammatory and pro-fibrotic cytokines and their signal-
ing. Recent advances demonstrate that fatty liver and its
progressive development in NASH is a more complex
phenomenon which originates by multiple hits.74,75 In
fact, the subsequent development of fibrosis requires
probably the coexistence of multiple factors, including
Annals of Hepatology 8(1) 2009: S44-S50
ESTE DOCUMENTO ES ELABORADO POR MEDI-
served a prevalence of IGT as high as 9% and T2DM of
2%. The degree of insulin resistance was not correlated
with liver histology in terms of grade of steatosis, inflam-
mation or fibrosis. Subjects with IGT/T2DM did differ
from normo-tolerant individuals neither in anthropomet-
rics or liver histology. Conversely the prevalence of
overt MetS was higher in subjects presenting with fibro-
sis and/or NASH.14 The limited number of subjects with
impaired carbohydrate metabolism did not allow exclud-
ing that visceral adiposity (i.e. through reduced levels of
adiponectin or increased pro-inflammatory adipocytok-
ines) mediates both derangements in liver histology and
host (genes) and environmental factors as well as those
related to lifestyles and behaviors.76,77
All today theories consider insulin resistance as an
important driving force, which promotes lipolysis of pe-
ripheral adipose tissue which, in turn, increases free fatty
acid (FFA) influx into the liver.78 Hyperinsulinemia and
hyperglycemia promote de novo lipogenesis and inhibit
simultaneously FFA oxidation.79 Fatty deposition at the
liver side is also favored by defective incorporation of
triglyceride into apolipoprotein carrier proteins and lipid
Fatty loaded hepatocytes are susceptible of additional
insults, which may lead to hepatocyte injury, inflamma-
tion, and fibrosis. Also the role of oxidative stress is well
documented in NASH., There is accumulating evidence
that oxidative stress and mitochondrial dysfunction play
a key role in the physiopathology of NAFLD/NASH
whatever its initial cause.81 Moreover, there is a close in-
teraction between development of mitochondrial dys-
function, insulin resistance and cytokines in many liver
diseases.82 Conversely, many forms of oxidative stress
lead to antioxidant depletion, which then further en-
hances oxidative stress and cytokine-mediated hepatox-
icity.83 In addition, although the exact mechanisms pro-
moting progressive liver injury are not well defined, also
substrates derived from adipose tissue such as FFA, tumor
necrosis factor alpha, leptin, and adiponectin have been
Taken together, all discussed evidences highlight the
complicated network of interactions existing among the
several molecules and signaling pathways which contrib-
ute do development of NAFLD/NASH. Thus, today it is
impossible to distinguish between causes or effects dur-
ing NAFLD/NASH development and progression.
More than a clinical association
The NHANES found NAFLD to be more prevalent in
obese race minorities, with T2DM, hypertension and hy-
perlipidemia.86 These associations have led to the hy-
pothesis that NAFLD may precede the onset of type 2 di-
abetes in some individuals. But, why should NAFLD as-
sociate with diabetes? The links between the two
diseases reflect processes related to insulin action or re-
sistance which may be mediated through the location
and function of fat, excess total body fatness or hepatic
fat. Otherwise, the risk for new onset diabetes may be me-
diated by components of the MetS which occur very fre-
quently in NAFLD.
NAFLD, as estimated by elevated ALT levels, and pre-
diabetes or T2DM were found to be associated indepen-
dently of confounders, including obesity in adults.87 The
West of Scotland Coronary Prevention Study, consistent-
ly with a number of other studies, found that compared
with men with values for baseline ALT in the bottom
quartile (< 17 U/L), those with levels in the top quartile
(> 29 U/L) had an adjusted odds ratio of 2.04 (95% CI
1.16–3.58) for incident diabetes.88 In the British Hearth
Regional Study, the risk of type 2 diabetes increased sig-
nificantly with increasing levels of ALT and gamma-
glutamil-transpeptidase (GGT), even after adjustment for
a range of confounders, again including BMI (top vs bot-
tom quartile, ALT: RR 2.72, 95% CI 1.47–5.02; GGT:
RR 3.68, 95% CI 1.68–8.04) or with further additional
adjustment for insulin resistance.89
Data on the association between T2DM and NAFLD
in paediatric settings are poor, but nevertheless very
strong. In the San Diego series of biopsy proven NAFLD,
6 out of 43 children had type 2 diabetes mellitus
(14%).49,90 In our series of 120 babies,14 all subjects un-
derwent oral glucose tolerance test and diagnosis of im-
paired glucose tolerance or T2DM was done according to
the criteria of the American diabetes Association. We ob-
Also in youth, T2DM and NAFLD seem to be signifi-
cantly associated. The meaning and the causative rela-
tion of this finding is still unclear. It is likely that the in-
sulin resistant phenotype, charactering non alcoholic fat-
ty liver disease, contributes to anticipate significantly
the onset of type 2 diabetes from mature adulthood to
youth. This observation may translate into the worrisome
anticipation of all cardiovascular abnormalities linked to
T2DM. In addiction, NAFLD may represent an indepen-
dent risk factor which augments further the total cardio-
vascular risk. Therefore, both NAFLD and T2DM em-
body a growing healthcare burden which will boost
health related costs in the next future.
1.Shaw J. Epidemiology of childhood type 2 diabetes and obesity.
Pediatr Diabetes 2007; 8 (Suppl 9): 7-15.
De Ferranti SD, Osganian SK. Epidemiology of paediatric meta-
bolic syndrome and type 2 diabetes mellitus. Diab Vasc Dis Res
2007; 4: 285-96.
Matyka KA. Type 2 diabetes in childhood: epidemiological and
clinical aspects. Br Med Bull 2008; 86: 59-75.
A Alisi et al. NAFLD and T2DM
4. Eckel RE. Insulin resistance; an adaptation for weight mainte-
nance. Lancet 1992; 340: 1542-3.
Burcelin R, Knauf C, Cani PD. Pancreatic alpha-cell dysfunction
in diabetes. Diabetes Metab 2008; 34 (Suppl 2): S49-55.
Morrison JA, Ford ES, Steinberger J. The pediatric metabolic
syndrome. Minerva Med 2008; 99: 269-87.
Newfield RS, Dewan AK, Jain S. Dyslipidemia in children with
type 2 diabetes vs. obesity. Pediatr Diabetes 2008; 9: 115-21.
Franks S. Polycystic ovary syndrome in adolescents. Int J Obes
(Lond) 2008; 32: 1035-41.
Targher G, Bertolini L, Padovani R, Rodella S, Tessari R, Zenari
L, Day C, et al. Prevalence of nonalcoholic fatty liver disease and
its association with cardiovascular disease among type 2 diabetic
patients. Diabetes Care 2007; 30: 1212-8.
10. Preiss D, Sattar N. Non-alcoholic fatty liver disease: an overview
of prevalence, diagnosis, pathogenesis and treatment consider-
ations. Clin Sci (Lond) 2008; 115: 141-50.
11. Yeh MM, Brunt EM. Pathology of nonalcoholic fatty liver dis-
ease. Am J Clin Pathol 2007; 128: 837-47.
12. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from ste-
atosis to cirrhosis. Hepatology 2006; 43 (2 Suppl 1): S99-S112.
13. Barshop NJ, Sirlin CB, Schwimmer JB, Lavine JE. Review article:
epidemiology, pathogenesis and potential treatments of paediat-
ric non-alcoholic fatty liver disease. Aliment Pharmacol Ther
2008; 28: 13-24.
14. Manco M, Marcellini M, Devito R, Comparcola D, Sartorelli MR,
Nobili V. Metabolic syndrome and liver histology in paediatric
non-alcoholic steatohepatitis. Int J Obes (Lond) 2008; 32: 381-7.
15. Manco M, Bedogni G, Marcellini M, Devito R, Ciampalini P,
Sartorelli MR, Comparcola D, et al. Waist circumference corre-
lates with liver fibrosis in children with non-alcoholic
steatohepatitis. Gut 2008; 57: 1283-7.
16. Jones TF. Type 2 diabetes in children: a growing epidemic. Ky
Nurse 2007; 55: 7-8.
17. American Diabetes Association. Type 2 diabetes in children
and adolescents (Consensus Statement). Diabetes Care 2000;
18. Alberti G, Zimmet P, Shaw J, Bloomgarden Z, Kaufman F, Silink
M. Type 2 diabetes in the young: the evolving epidemic: the
international diabetes federation consensus workshop. Diabetes
Care 2004; 27: 1798-811.
19. Cali AM, Caprio S. Prediabetes and type 2 diabetes in youth: an
emerging epidemic disease? Curr Opin Endocrinol Diabetes Obes
2008; 15: 123-7.
20. SEARCH for Diabetes in Youth Study Group, Liese AD,
D’Agostino RB Jr, Hamman RF, Kilgo PD, Lawrence JM, Liu
LL, Loots B et al. The burden of diabetes mellitus among US
youth: prevalence estimates from the SEARCH for Diabetes in
Youth Study. Pediatrics 2006;118:1510-8.
21. Duncan GE. Prevalence of diabetes and impaired fasting glucose
levels among US adolescents: National Health and Nutrition Ex-
amination Survey, 1999-2002. Arch Pediatr Adolesc Med 2006;
22. Haines L, Wan KC, Lynn R, Barrett TG, Shield JP. Rising inci-
dence of type 2 diabetes in children in the U.K. Diabetes Care
2007; 30: 1097-101.
23. Writing Group for the SEARCH for Diabetes in Youth Study
Group, Dabelea D, Bell RA, D’Agostino RB Jr, Imperatore G,
Johansen JM, Linder B, Liu LL, et al. Incidence of diabetes in
youth in the United States. JAMA 2007; 27:2716-24. Erratum in:
JAMA 2007 8; 298: 627.
24. Campbell-Stokes PL, Taylor BJ. New Zealand Children’s Diabe-
tes Working Group. Prospective incidence study of diabetes mel-
litus in New Zealand children aged 0 to 14 years. Diabetologia
2005; 48: 2442-3.
25. Li Y, Yang X, Zhai F, Piao J, Zhao W, Zhang J, Ma G. Childhood
obesity and its health consequence in China. Obes Rev 2008; 9
(Suppl 1): 82-6.
26. Mazza CS, Ozuna B, Krochik AG, Araujo MB. Prevalence of
type 2 diabetes mellitus and impaired glucose tolerance in obese
Argentinean children and adolescents. J Pediatr Endocrinol Metab
2005; 18: 491-8.
27. Holst-Schumacher I, Nuñez-Rivas H, Monge-Rojas R, Barrantes-
Santamaría M. Insulin resistance and impaired glucose tolerance
in overweight and obese Costa Rican schoolchildren. Food Nutr
Bull 2008; 29: 123-31.
28. Wabitsch M, Hauner H, Hertrampf M, Muche R, Hay B, Mayer
H, Kratzer W, et al. Type II diabetes mellitus and impaired glu-
cose regulation in Caucasian children and adolescents with obe-
sity living in Germany. Int J Obes Relat Metab Disord 2004; 28:
29. Wiegand S, Dannemann A, Krude H, Grüters A. Impaired glu-
cose tolerance and type 2 diabetes mellitus: a new field for pedi-
atrics in Europe. Int J Obes (Lond) 2005; 29 (Suppl 2): S136-42.
30. Herder C, Schmitz-Beuting C, Rathmann W, Haastert B, Schmitz-
Beuting J, Schäfer M, Scherbaum WA, et al. Prevalence of im-
paired glucose regulation in German school-leaving students. Int
J Obes (Lond) 2007; 3: 1086-8.
31. Felszeghy E, Juhasz E, Kaposzta R, Ilyes I. Alterations of
glucoregulation in childhood obesity—association with insulin
resistance and hyperinsulinemia. J Pediatr Endocrinol Metab
2008; 2: 847-53.
32. Shalitin S, Abrahami M, Lilos P, Phillip M. Insulin resistance and
impaired glucose tolerance in obese children and adolescents
referred to a tertiary-care center in Israel. Int J Obes (Lond)
2005; 2: 571-8.
33. Invitti C, Gilardini L, Pontiggia B, Morabito F, Mazzilli G, Viberti
G. Period prevalence of abnormal glucose tolerance and cardio-
vascular risk factors among obese children attending an obesity
centre in Italy. Nutr Metab Cardiovasc Dis 2006; 16: 256-62.
34. Babaoðlu K, Hatun S, Arslanoðlu I, Iþgüven P, Baþ F, Ercan O,
Darendeliler F, et al. Evaluation of glucose intolerance in adoles-
cents relative to adults with type 2 diabetes mellitus. J Pediatr
Endocrinol Metab 2006; 19: 1319-26.
35. Atabek ME, Pirgon O, Kurtoglu S. Assessment of abnormal glu-
cose homeostasis and insulin resistance in Turkish obese children
and adolescents. Diabetes Obes Metab 2007; 9: 304-10.
36. Atabek ME, Pirgon O, Kurtoglu S. Prevalence of metabolic syn-
drome in obese Turkish children and adolescents. Diabetes Res
Clin Pract 2006; 72: 315-21.
37. Angulo P. GI epidemiology: nonalcoholic fatty liver disease.
Aliment Pharmacol Ther 2007; 25: 883-9.
38. Saadeh S, Younossi ZM, Remer EM, et al. The utility of radio-
logical imaging in nonalcoholic fatty liver disease. Gastroenter-
ology 2002; 123: 745-50.
39. Dunn W, Schwimmer JB. The obesity epidemic and nonalco-
holic fatty liver disease in children. Curr Gastroenterol Rep 2008;
40. Chan DF, Li AM, Chu WC, Chan MH, Wong EM, Liu EK, Chan
IH, et al. Hepatic steatosis in obese Chinese children. Int J Obes
Relat Metab Disord 2004; 28: 1257-63.
41. Franzese A, Vajro P, Argenziano A, Puzziello A, Iannucci MP,
Saviano MC, Brunetti F, et al. Liver involvement in obese chil-
dren. Ultrasonography and liver enzyme levels at diagnosis and
during follow-up in an Italian population. Dig Dis Sci 1997; 42:
42. Yoo J, Lee S, Kim K, Yoo S, Sung E, Yim J. Relationship be-
tween insulin resistance and serum alanine aminotransferase as a
surrogate of NAFLD (nonalcoholic fatty liver disease) in obese
Korean children. Diabetes Res Clin Pract 2008; 81: 321-6.
43. Schwimmer JB, McGreal N, Deutsch R, Finegold MJ, Lavine JE.
Influence of gender, race, and ethnicity on suspected fatty liver
in obese adolescents. Pediatrics 2005; 115: e561-5.
44. Louthan MV, Theriot JA, Zimmerman E, Stutts JT, McClain CJ.
Decreased prevalence of nonalcoholic fatty liver disease in black
obese children. J Pediatr Gastroenderol Nutr 2005; 41: 426-9.
45. Kinugasa A, Tsunamoto K, Furukawa N, Sawada T, Kusunoki T,
Shimida N. Fatty liver and its fibrous changes found in simple
obesity of children. J Pediatr Gastroenterol Nutr 1984; 3: 408–
Annals of Hepatology 8(1) 2009: S44-S50
46. Kawasaki T, Hashimoto N, Kikuchi T, Takahashi H, Uchiyama
M. The relationship between fatty liver and hyperinsulinemia in
obese Japanese children. J Pediatr Gastroenterol Nutr 1997; 24:
47. Tazawa Y, Noguchi H, Nishinomiya F, Takada G. Serum alanine
aminotransferases activity in obese children. Acta Paediatr 1997;
48. Zou CC, Liang L, Hong F, Fu JF, Zhao ZY. Serum adiponectin,
resistin levels and non-alcoholic fatty liver disease in obese chil-
dren. Endocr J 2005; 52: 519-24.
49. Schwimmer BJ, Deutsch R, Kahen T, Lavine EJ, Stanley C, Behling
C. Prevalence of fatty liver in children and adolescents. Pediat-
rics 2006; 118: 1388-93.
50. Papandreou D, Rousso I, Mavromichalis I. Update on non-alco-
holic fatty liver disease in children. Clin Nutr 2007; 26: 409.
51. Patton HM, Sirlin C, Behling C, Middleton M, Schwimmer JB,
Lavine JE. Pediatric nonalcoholic fatty liver disease: a critical
appraisal of current data and implications for future research. J
Pediatr Gastroenterol Nutr 2006; 43: 413.
52. Manco M, Alisi A, Nobili V. Risk of severe liver disease in
NAFLD with normal ALT levels. A pediatric report. Hepatology
2008; in press.
53. Strauss RS, Barlow SE, Dietz WH. Prevalence of abnormal serum
aminotransferase values in overweight and obese adolescents. J
Pediatr 2000; 136: 727-33.
54. Park HS, Han JH, Choi KM, Kim SM. Relation between elevated
serum alanine aminotransferase and metabolic syndrome in Ko-
rean adolescents. Am J Clin Nutr 2005; 82: 1046-51.
55. Flores-Calderon J, Gomez-Diaz RA, Rodriguez-Gomez G, Moran-
Villota S. Frequency of increased aminotransferases levels and
associated metabolic abnormalities in obese and overweight chil-
dren of an elementary school in Mexico City. Ann Hepatol 2005;
56. Tominaga K, Kurata JH, Chen YK, Fujimoto E, Miyagawa S,
Abe I, Kusano Y. Prevalence of fatty liver in Japanese children
and relationship to obesity. An epidemiological ultrasonographic
survey. Dig Dis Sci 1995; 40: 2002-9.
57. Guzzaloni G, Grugni G, Minocci A, Moro D, Morabito F. Liver
steatosis in juvenile obesity: correlations with lipid profile, he-
patic biochemical parameters and glycemic and insulinemic re-
sponses to an oral glucose tolerance test. Int J Obes Relat Metab
Disord 2000; 24: 772-6.
58. Sartorio A, Del Col A, Agosti F, Mazzilli G, Bellentani S, Tiribelli
C, Bedogni G. Predictors of non-alcoholic fatty liver disease in
obese children. Eur J Clin Nutr 2007; 61: 877-83.
59. Fu JF, Liang L, Wang CL, Hong F, Dong GP, Li Y. Nonalco-
holic steatohepatitis in obese children: the prevalence and pos-
sible mechanism. Zhejiang Da Xue Xue Bao Yi Xue Ban 2006;
60. Tuba F. Eminoðlu1, Orhun M. Çamurdan2, Suna Ö. Oktar3, Aysun
Bideci2, Buket DalgiÇ4 Factors related to non-alcoholic fatty liver
disease in obese children. The Turkish Journal of Gastroenterol-
ogy 2008; 19: 85-91.
61. Bergomi A, Lughetti L, Corciulo N. Italian multicenter study on
liver damage in pediatric obesity. Int J Obes Relat Metab Disord
1998; 22: S22.
62. Weiss R, Caprio S. Development of type 2 diabetes in children
and adolescents. Minerva Med 2006; 97: 263-9.
63. Pattaranit R, van den Berg HA, Spanswick D. The development
of insulin resistance in Type 2 diabetes: insights from knockout
studies. Sci Prog 2008; 91: 285-316.
64. Schmitz-Peiffer C, Biden TJ. Protein kinase C function in muscle,
liver, and beta-cells and its therapeutic implications for type 2
diabetes. Diabetes 2008; 57: 1774-83.
65. White MF. IRS proteins and the common path to diabetes. Am J
Physiol Endocrinol Metab 2002; 283: E413-22.
66. Weiss R, Gillis D. Patho-physiology and dynamics of altered
glucose metabolism in obese children and adolescents. Int J
Pediatr Obes 2008; 3 (Suppl 1): 15-20.
67. Berry D, Urban A, Grey M. Understanding the development and
prevention of type 2 diabetes in youth (part 1). J Pediatr Health
Care 2006; 20: 3-10.
68. Silverstein JH, Rosenbloom AL. Type 2 diabetes in children. Urr
Diab Rep 2001; 1: 19-27.
69. Gill-Carey O, Hattersley AT. Genetics and type 2 diabetes in
youth. Pediatr Diabetes 2007; 8 (Suppl 9): 42-7.
70. Pavkov ME, Hanson RL, Knowler WC, Bennett PH, Krakoff J,
Nelson RG. Changing patterns of type 2 diabetes incidence among
Pima Indians. Diabetes Care 2007; 30: 1758-63.
71. Sugihara S, Sasaki N, Amemiya S, Kohno H, Tanaka T, Matsuura
N. Analysis of weight at birth and at diagnosis of childhood-
onset type 2 diabetes mellitus in Japan. Pediatr Diabetes 2008;
72. Jasik CB, Lustig RH. Adolescent obesity and puberty: the «per-
fect storm». Ann N Y Acad Sci 2008; 1135: 265-79.
73. Day CP, James OFW. Steatohepatitis: A tale of two «hits»? Gas-
troenterology 1998; 14: 842-5.
74. Day CP. NASH-related liver failure: one hit too many? Am J
Gastroenterol 2002; 7: 1872-4.
75. Charlton M. Noninvasive indices of fibrosis in NAFLD: starting
to think about a three hit (at least) phenomenon. Am J Gastroenterol
2007; 102: 409-11.
76. Day CP. Genes or environment to determine alcoholic liver disease
and non-alcoholic fatty liver disease. Liver Int 2006; 26: 1021-28.
77. Marra F, Gastaldelli A, Svegliati Baroni G, Tell G, Tiribelli C.
Molecular basis and mechanisms of progression of non-alco-
holic steatohepatitis. Trends Mol Med 2008; 14: 72-81.
78. Saito T, Misawa K, Kawata S. Fatty liver and non-alcoholic
steatohepatitis. Intern Med 2007; 46: 101-13.
79. Ahima RS. Insulin resistance: cause or consequence of nonalco-
holic steatohepatitis? Gastroenterology 2007; 132: 444-6.
80. Charlton M, Sreekumar R, Rasmussen D, Lindor K, Nair KS.
Apolipoprotein synthesis in nonalcoholic steatohepatitis.
Hepatology 2002; 35: 898-904.
81. Begriche K, Igoudjil A, Pessayre D, Fromenty B. Mitochondrial
dysfunction in NASH: causes, consequences and possible means
to prevent it. Mitochondrion 2006; 6: 1-28
82. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos
MJ, Sterling RK, Luketic VA, et al. Nonalcoholic steatohepatitis:
association of insulin resistance and mitochondrial abnormali-
ties. Gastroenterology 2001; 120: 1183-92.
83. Begriche K, Igoudjil A, Pessayre D, Fromenty B. Mitochondrial
dysfunction in NASH: causes, consequences and possible means
to prevent it. Mitochondrion 2006; 6: 1-28.
84. Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk
SF, Rydzewski R, Burgart LJ, et al. Free fatty acids promote
hepatic lipotoxicity by stimulating TNF-alpha expression via a
lysosomal pathway. Hepatology 2004; 40: 185-94.
85. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J.
Beyond insulin resistance in NASH: TNF-alpha or adiponectin?
Hepatology 2004; 40: 46-5.
86. Ong JP, Pitts A, Younossi ZM. Increased overall mortality and
liver-related mortality in non-alcoholic fatty liver disease. J
Hepatol 2008; 49: 608-12.
87. Schindhelm RK, Diamant M, Dekker JM, Tushuizen ME, Teerlink
T, Heine RJ. Alanine aminotransferase as a marker of non-alco-
holic fatty liver disease in relation to type 2 diabetes mellitus and
cardiovascular disease. Diabetes Metab Res Rev 2006; 22: 437-43.
88. Sattar N, Scherbakova O, Ford I, O’Reilly DS, Stanley A, Forrest
E, Macfarlane PW, et al. Elevated alanine aminotransferase pre-
dicts new-onset type 2 diabetes independently of classical risk
factors, metabolic syndrome, and C-reactive protein in the west of
Scotland coronary prevention study. Diabetes 2004; 53: 2855-60.
89. Wannamethee SG, Shaper AG, Lennon L, Whincup PH. Hepatic
enzymes, the metabolic syndrome, and the risk of type 2 diabetes
in older men. Diabetes Care 2005; 28: 2913-8.
90. Schwimmer JR, Deutsch R, Rauch JB, Behling C, Newbury R,
Lavine JE. Obesity, insulin resistance, and other clinicopatho-
logical correlates of pediatric nonalcoholic fatty liver disease. J
Pediatr 2003; 143: 500-5.