The prevalence of type 2 diabetes is significantly increased in the pediatric population,
which is affected by obesity worldwide. The progression from normal glucose tolerance
(NGT) to type 2 diabetes involves intermediate stages of impaired fasting glucose
(IFG) and impaired glucose tolerance (IGT), also known as prediabetes. The pathophysiology
underlying the development of these glucose metabolic alterations is multifactorial;
however an alteration in the balance between insulin sensitivity and insulin secretion
represents the most important player in the development of type 2 diabetes. Obese
children and adolescents affected by IGT and type 2 diabetes are characterized by
severe insulin resistance, which is associated with an increased lipid accumulation
in visceral compartments, liver and muscle tissues and by reduced sensitivity of β-cell
of first and second-phase insulin secretion.
The progression in obese children of insulin resistance to type 2 diabetes has been
shown to be faster than in adults; in addition, type 2 diabetes is already associated
with several metabolic and cardiovascular complications in this age group.
In the present review, we summarize the most recent findings concerning the prevalence
of type 2 diabetes in youth and in particular we explore the pathophysiology of type
2 diabetes and the natural history of this pathology in obese children and adolescents.
Concurrent with the worldwide epidemic increase of childhood obesity, type 2 diabetes
and the two prediabetic conditions, IFG and IGT, are becoming increasingly more common
in obese children and adolescents (1,2). Until 10 years ago, type 2 diabetes accounted
for less than 3% of all cases of new-onset diabetes in adolescents. At present 45%
of cases are attributed to it (3,4).
Type 2 diabetes occurs in youth more often during the second decade of life, coinciding
with the physiological occurrence of pubertal insulin resistance (1). In addition,
most children who develop type 2 diabetes (>75% of cases) have a first- or second-degree
relative affected by this pathology (1).
The pathogenesis of type 2 diabetes is complex, involving the interaction of genetic
and environmental risk factors that strongly contribute to the development of insulin
resistance in the muscle and liver as well as to β-cell failure, the two core pathophysiological
defects in type 2 diabetes (5).
Early onset of type 2 diabetes seems to be associated with an increased risk of morbidity
and mortality during the most productive years of life (4). Microvascular complications
can be present at time of diagnosis with a progression rate that might be higher than
in young people with type 1 diabetes (4). In addition, youths with type 2 diabetes
are also prone to secondary obesity-related complications, including hypertension,
nonalcoholic fatty liver disease, and metabolic syndrome, all of which are associated
with increased cardiovascular risk (4).
Just as in adults, the pattern of development is often preceded by an intermediate
state of impaired glucose tolerance (IGT) (6). This transitional state of IGT in adults
is associated with a high incidence (∼10%) of vascular complications (5) and importantly,
a large number of studies have found that either lifestyle or pharmacological interventions
may reverse it and thus prevent the development of diabetes (7).
Therefore, understanding the pathophysiology and the natural history of type 2 diabetes
in youth is important in order to prevent its development and its related comorbidities
in the pediatric population.
In the present review, we first describe the epidemiology of type 2 diabetes and prediabetic
conditions and, in particular, we explore the current knowledge regarding the pathophysiology
and the natural history of the glucose homeostasis alterations in youth.
EPIDEMIOLOGY
In the last two decades, type 2 diabetes, once thought to be a metabolic disorder
exclusively of adulthood, has become increasingly more frequent in obese adolescents
(3).
Although a very high prevalence of type 2 diabetes has been observed in non-Caucasian
groups (African Americans, Native Americans, Hispanics), type 2 diabetes occurs in
all races (1,8). In the SEARCH study (8), the incidence rate (per 100,000 person-year)
of type 2 diabetes among children and adolescents varies greatly by ethnicity, with
the highest rates observed among youths aged 15–19 years in minority populations.
In particular, the reported incidence rate was 49.4 for Native Americans, 22.7 for
Asian/Pacific Islanders, 19.4 for African Americans, 17 for Hispanics, and 5.6 for
non-Hispanic whites.
Type 2 diabetes in youth is not just an American phenomenon—more cases are being reported
worldwide. For example, in Japan (3) 80% of all new cases of diabetes in children
and adolescents were diagnosed as type 2 diabetes. Likewise, in Taiwan (3) 54.2% of
new cases were diagnosed with type 2 diabetes, with an incidence of 6.5 per 100,000.
In contrast, in the U.K. the minimum incidence of type 2 diabetes in children (<17
years of age) was 0.53 · 100,000−1 · year−1 (9). In Austria, the calculated incidence
of type 2 diabetes in children and adolescents (<15 years of age) was 0.25/100,000
(3). Indeed, many studies from Europe (8) indicate that type 2 diabetes is not as
common as in the U.S. in these populations, accounting for only 1–2% of all diabetes
mellitus cases.
In addition, although some studies (8) support the notion that type 2 diabetes has
a greater prevalence in the high risk ethnic groups, type 2 diabetes accounts for
14.9% of all diabetes cases among non-Hispanic white adolescents (8). Although the
lowest prevalence of type 2 diabetes, observed in Europe, could be attributed to the
differences in obesity rates between U.S. and European youth, the full explanation
for these discrepancies remains unclear (8).
The increased prevalence of type 2 diabetes in the obese pediatric population is paralleled
by an increased prevalence of the prediabetes conditions. In particular, 25% of children
and 21% adolescents with severe degree of obesity, irrespective of ethnicity, were
found to have IGT (10). Similar high prevalence rates in Hispanic obese children and
adolescents were subsequently reported by Goran et al. (11). Surprisingly, very high
prevalence rates of IFG were reported in children from the Studies to Treat or Prevent
Pediatric Type 2 Diabetes (2).
Although previous studies showed a lower prevalence of type 2 diabetes and IGT in
Italian youths (0.5% and 5%, respectively) (12), a recent study conducted in Italy
(13) on a large sample of overweight/obese children and adolescents reported a prevalence
of glucose metabolism alterations of 12.4%. IGT was the most frequent alteration,
accounting for 11.2%, with a higher prevalence in adolescents (14.8%) than in children
(4.1%) (13).
PATHOPHYSIOLOGY OF TYPE 2 DIABETES
The development of alterations in glucose metabolism results from the gradual fall
in β-cell function occurring within a background of insulin resistance. The two principal
components of the blood glucose regulation pathway (5) are insulin secretion and insulin
sensitivity (5).
β-Cell function
Type 2 diabetes is progressive, and one main factor responsible for this is a continued
decline in β-cell function (5). Several studies (5) have demonstrated that diabetes
and prediabetes do not develop until the β-cell fails to compensate appropriately
to the peripheral insulin resistance state. The ability of the β-cell to secrete sufficient
insulin to adequately respond to the peripheral insulin resistance state depends on
multiple factors, including β-cell mass (14) and secretory capacity (14), which are
influenced by genetic (15) and environmental factors (15). In fact, although the progressive
loss of β-cell function could be due to different metabolic derangements (insulin
resistance, lipotoxicity), several studies have suggested that β-cell dysfunction
depends also on a pre-existing and perhaps genetically determined risk, which is crucial
for β-cell dysfunction to occur (5,15).
Cross-sectional studies.
Using state-of-the-art hyperglycemic clamp in conjunction with mathematical modeling
of insulin secretion, we found that obese adolescents with type 2 diabetes have a
marked reduction in both first- and second-phase insulin secretion. Thus at diagnosis,
just as in the adults (5), ∼80% of their β-cell function is reduced or lost (16).
Furthermore, in order to assess whether the defects in β-cell function characterize
all of the various prediabetic conditions seen in obese adolescents, in a cross-sectional
analyses (17) we compared the β-cell function and tissue insulin sensitivity among
subjects with NGT, IFG, IGT, or combined IFG/IGT. The IFG group showed an alteration
in glucose sensitivity of first-phase insulin secretion (Fig. 1), while peripheral
insulin sensitivity was similar between the IFG and the NGT groups. The IGT group
was affected by reduction in glucose sensitivity of first-phase insulin secretion
(Fig. 1) and by a more severe degree of peripheral insulin resistance. Interestingly,
the IFG/IGT group was characterized by a new additional defect in glucose sensitivity
of second-phase insulin secretion (Fig. 1) and by a profound insulin resistance (17).
Figure 1
Glucose sensitivity of first-phase (σ1, dynamic secretion component) and second-phase
(σ2, static secretion component) insulin secretion among NGT, IFG, IGT, and IFG/IGT
obese adolescents. (*P = 0.004 IFG vs. NGT; **P = 0.04 IGT vs. NGT; ***P = 0.0001
IFG/IGT vs. NGT; ♦P = 0.02 IGT vs. NGT).
The relationship between insulin sensitivity and secretion is described by a hyperbolic
function, which implies that a feedback loop governs the interaction between the β-cells
and the peripheral tissue (18). Thus, when insulin sensitivity decreases, insulin
secretion increases for glucose tolerance to remain normal. This equilibrium is quantitatively
described by the “disposition index” (DI), which is the product of insulin sensitivity
and β-cell function and therefore can be considered an index of β-cell function weighted
by insulin sensitivity (18). Studies conducted in adult populations (19) have demonstrated
that the DI is not only a measure for identifying subjects with poor β-cell function
but also a strong predictor for the development of type 2 diabetes. In fact, as we
will further discuss, we have previously demonstrated in a longitudinal study (20)
that obese children who progress to IGT manifest lower DI values than those who do
not experience a worsening of glucose tolerance.
Longitudinal studies.
In order to assess the evolution of the β-cell, we followed longitudinally a group
of obese adolescents with NGT and repeated the serial oral glucose tolerance test
over a period of ∼3 years (20). Of note, we found that those adolescents who progressed
to IGT had a lower β-cell function at baseline than those nonprogressors (Fig. 2A
), as indicated by the glucose β-cell responsitivity (Φd), measured by the oral minimal
model (21). Furthermore, the development of IGT was characterized by progressive decline
in the DI (Fig. 2
B). Thus, those who progressed to IGT had relatively worse β-cell function at baseline,
suggesting that an early defect in β-cell function may underlie the development of
IGT and possibly type 2 diabetes in obese youth (20).
Figure 2
A: Baseline values of the dynamic β-cell responsivity (Φd) in subjects who maintained
NGT (nonprogressors [NP]) and in subjects who developed IGT (progressors [P]) (P =
0.04). B: Changes of the DI values according to changes in glucose tolerance over
the course of approximately 30 months. Subjects who developed IGT (progressors) experienced
a progressive decline of overall β-cell function, as assessed by the DI. OGTT, oral
glucose tolerance test.*P = 0.04.
These data suggest the presence of a preexisting β-cell dysfunction risk in obese
adolescents with NGT. Early identification of markers of β-cell dysfunction in obese
adolescents with NGT might be critical for the prevention of diabetes in youth.
Insulin resistance
Although the pathophysiological mechanism of type 2 diabetes is not completely understood,
it is clear that insulin resistance plays an important role in its development. Evidence
of this comes from cross-sectional and longitudinal studies demonstrating that insulin
resistance occurs 10–20 years before the onset of the disease and that it is the best
predictor of whether or not an individual will later become diabetic (22).
In addition, insulin resistance, by placing an increased demand on the β-cell to hypersecrete
insulin, influences the progressive β-cell failure of type 2 diabetes (5). The precise
mechanism(s) by which insulin resistance leads to β-cell failure remain(s) unknown,
however a possible hypothesis is that the cause of insulin resistance is also directly
responsible for the β-cell failure (i.e., lipotoxicity) (5,14).
Obesity is the most important cause in the development of insulin resistance and it
has been demonstrated that the critical determinant of insulin sensitivity is not
the degree of obesity per se but the distribution of fat partitioning (6). In a previous
study by our group (6), we have demonstrated that obese adolescents with IGT were
more insulin resistant than those with NGT despite the similar degree of adiposity.
The phenotype of subjects with IGT was characterized by increased intramyocellular
lipid content (IMCL) and by increased visceral and decreased subcutaneous fat deposition.
Indeed, IMCL and visceral lipid were positively related to the 2-h plasma glucose
and inversely related to the glucose disposal and nonoxidative glucose metabolism
(6).
The role of IMCL in modulating insulin sensitivity has been well established in both
adults (23) and children (6,24). Petersen et al. (23) showed an increase of IMCL in
offspring of patients with type 2 diabetes and an inverse correlation between insulin
resistance and IMCL. In a previous studies by our group (6,24) we observed an association
between IMCL and insulin resistance in children with prediabetes (6) and a strong
inverse correlation between IMCL and adiponectin (24) in obese children and adolescents.
In addition to an increase in IMCL, there is ample evidence indicating that visceral
fat accumulation is associated with an impaired insulin action in the obese pediatric
population. Although controversy remains regarding the contribution of visceral and
subcutaneous fat to the development of insulin resistance (25), a previous study by
Cruz et al. (26) showed a direct impact of visceral fat accumulation on insulin sensitivity
and secretion, independent of total body adiposity, in obese children with a family
history of type 2 diabetes. Indeed, by stratifying a multiethnic cohort of obese adolescents
into tertiles based on the proportion of visceral fat in the abdomen (visceral/subcutaneous
fat ratio), we observed a significant increase in 2-h glucose and insulin resistance
(homeostasis model assessment) and decrease in insulin sensitivity (Matsuda index)
in obese adolescents with high proportion of visceral fat and relatively low abdominal
subcutaneous fat (25).
These findings suggest that adolescents at risk for developing alterations in glucose
metabolism are not necessarily the most severely obese, but are characterized by an
unfavorable lipid partitioning profile.
Despite the demonstrated relationship between IMCL, visceral fat, and metabolic dysfunction,
the ectopic fat deposition in the liver is emerging as the most important marker of
insulin resistance and glucose dysregulation in adults (27) as well as in obese pediatric
population (28).
Although it remains unclear whether hepatic steatosis is a consequence or a cause
of derangements in insulin sensitivity, the presence of steatosis is an important
marker of multiorgan insulin resistance (29); moreover, insulin resistance is directly
related to percent liver fat (29).
Previously, we reported that rising alanine transaminase levels in obese children
and adolescents were associated with deterioration in insulin sensitivity and glucose
tolerance (30). Furthermore, abnormal alanine transaminase levels were found in children
with type 2 diabetes (31).
In order to understand the potential role of fatty liver in the onset of type 2 diabetes
in obese youth, we have recently assessed whether the severity of hepatic steatosis
affects the presence of glucose metabolism dysregulation in a multiethnic cohort of
obese adolescents (28). Independent of obesity, the severity of fatty liver was associated
with the presence of prediabetes conditions (IGT and IFG/IGT) and hepatic steatosis,
independently, predicted prediabetes in obese adolescents. In addition, paralleling
the severity of hepatic steatosis, there was a significant decrease in insulin sensitivity
and impairment of β-cell function (assessed by using the DI) (Fig. 3) (28).
Figure 3
Liver fat content and impairment of insulin sensitivity and β-cell function in obese
children and adolescents. The whole-body insulin sensitivity index (WBISI) decreased
(P = 0.007) across low (median 0.7%), moderate (median 4.5%), and high (median 28.8%)
liver fat content (%) tertiles. The insulinogenic index (IGI) tended to be higher
(P = 0.05) and the DI tended to be lower (P = 0.05) in the high tertile compared with
the low tertile.
These findings suggest that the intrahepatic fat accumulation is a strong risk factor
for type 2 diabetes, and its early identification is critical to prevent the development
of metabolic complications in youth.
NATURAL HISTORY OF TYPE 2 DIABETES
The transition from prediabetes to type 2 diabetes in adults is usually a gradual
phenomenon that occurs over 5–10 years (32). Therefore, the early presentation of
type 2 diabetes in youth raises the possibility of an accelerated process in pediatric
age compared with adults, thus shortening the transition time between IGT and type
2 diabetes. In fact, an interesting report by Gungor and Arslanian (33) suggested
that despite a relatively robust initial insulin secretion, the deterioration in β-cell
function in youth with type 2 diabetes is more accelerated (∼15% per year) than that
observed in adults.
To study the natural history of IGT in youth, we have longitudinally followed 117
obese children and adolescents (84 with NGT and 33 with IGT) (32). Those with IGT
displayed a mixed picture: 45.5% converted to NGT, 30.3% remained IGT, and 8% progressed
to diabetes. It should be noted that the tempo of progression was remarkably fast—only
21 months. The factors associated with the transition of glucose category were marked
weight gain, profound insulin resistance at baseline, and reduced first-phase insulin
secretion at baseline (32). These data illustrate the importance of variations in
weight gain on changes in glucose tolerance in childhood obesity. The children who
progressed from NGT to IGT had the largest increase in body weight, and the IGT subjects
who converted back to NGT had minimal increases in body weight and a reduction in
BMI Z-score (32), which underlines that cessation of weight gain, and not necessarily
weight loss, may suffice to prevent further deterioration in the glucose tolerance.
The observed rapid progression of the glucose homeostasis alterations in pediatric
age underlines the importance of focusing the attention on the earliest stages of
the disease before the onset of any alterations in glucose tolerance. In addition,
the rapid tempo of the development of type 2 diabetes, which is driven by the rapid
failure of β-cell function, would suggest a rather more aggressive course in the development
of the disease than what is usually seen in adulthood. This would suggest that early
intervention, even before the prediabetic conditions are established, should be implemented
to prevent further decline in β-cell function.
CONCLUSIONS
The growing number of obese children and adolescents affected by type 2 diabetes and
the rapid development of glucose homeostasis dysregulation in this age group explain
why type 2 diabetes is becoming one of the most important public health problems.
Therefore, identifying obese children at risk for type 2 diabetes is of primary importance
in order to interrupt its progression and the diabetes-related cardiovascular complications
in this age group.