Question:
What is the pathophysiology of type 2 diabetes in
children and adolescents?
Answer:
Type 2 diabetes is a complex metabolic disorder of heterogeneous
etiology with social, behavioral, and environmental risk factors
unmasking the effects of genetic susceptibility [7]. There is a
strong hereditary (likely multigenic) component to the disease,
with the role of genetic determinants illustrated when
differences in the prevalence of type 2 diabetes in various
racial groups are considered. The recent increases observed in
diabetes prevalence have occurred too quickly to be the result
of increased gene frequency and altered genetic pool,
emphasizing the importance of environmental factors.
Glucose homeostasis depends on the balance between insulin
secretion by the pancreatic beta-cells and insulin action. For
hyperglycemia to develop, insulin resistance alone is not
sufficient and inadequate beta-cell insulin secretion is
necessary. There has been considerable debate about whether
insulin resistance or insulin hyposecretion is the primary
defect in type 2 diabetes in adults. The constellation of
clinical characteristics in children with type 2 diabetes
suggests that the initial abnormality is impaired insulin
action, compounded later with beta-cell failure.
It is well recognized that resistance to insulin-stimulated
glucose uptake is a characteristic finding in patients with type
2 diabetes and impaired glucose tolerance. Cross-sectional and
longitudinal studies in populations at high risk for developing
type 2 diabetes demonstrate that hyperinsulinemia and insulin
resistance are present in the prediabetic normoglycemic state.
The evolution from normal to impaired glucose tolerance is
associated with a worsening of insulin resistance. In patients
with type 2 diabetes, impaired insulin action and insulin
secretory failure are both present. The failure of the beta-cell
to continue to hypersecrete insulin underlies the transition
from insulin resistance (with compensatory hyperinsulinemia and
normoglycemia) to clinical diabetes (with overt fasting
hyperglycemia and increased hepatic glucose production).
It has been proposed that hyperglycemia may worsen both insulin
resistance and insulin secretory abnormalities, thus enhancing
the transition from impaired glucose tolerance to diabetes or
aggravating the diabetes. This way, hyperglycemia may beget more
hyperglycemia—a concept called glucose toxicity. Glucose
toxicity–induced abnormalities of insulin secretion and action
can be ameliorated by correction of hyperglycemia.
Puberty appears to play a major role in the development of type
2 diabetes in children. During puberty, there is increased
resistance to the action of insulin, resulting in
hyperinsulinemia [8]. It has been known for many years that
insulin responses during an OGTT increase significantly from the
toddler ages to adolescence. After puberty, basal and stimulated
insulin responses decline. Hyperinsulinemic-euglycemic clamp
studies demonstrate that insulin-mediated glucose disposal is on
average 30% lower in adolescents between Tanner stages II and IV
compared with prepubertal children in Tanner stage I and
compared with young adults. In the presence of normal pancreatic
beta-cell function, puberty-related insulin resistance is
compensated by increased insulin secretion.
Both growth hormone and sex steroids have been considered as
candidates for causing insulin resistance during puberty. The
fact that sex steroids remain elevated after puberty while
insulin resistance decreases makes sex steroids an unlikely
cause of insulin resistance. Conversely, mean growth hormone
levels increase transiently during puberty coincidental with the
decrease in insulin action. In addition, administering growth
hormone to non–growth hormone–deficient adolescents is
associated with deterioration in insulin action, while
testosterone administration has no such effect. Thus, increased
growth hormone secretion is most likely responsible for the
insulin resistance during puberty, and both growth hormone
secretion and insulin resistance decline with completion of
puberty.
Given this information, it is not surprising that the peak age
at presentation of type 2 diabetes in children coincides with
the usual age of mid-puberty. In an individual who has a genetic
predisposition for insulin resistance, compounded with
environmental risk exposure, the additional burden of insulin
resistance during puberty may tip the balance from a state of
compensated hyperinsulinemia with normal glucose tolerance to
inadequate insulin secretion and glucose intolerance that
continues beyond puberty.
The adverse effect of obesity on glucose metabolism is evident
early in childhood. In healthy white children, total adiposity
accounts for ~55% of the variance in insulin sensitivity. Obese
children are hyperinsulinemic and have ~40% lower insulin-
stimulated glucose metabolism compared with nonobese children.
Moreover, the amount of visceral fat in obese adolescents is
directly correlated with basal and glucose-stimulated
hyperinsulinemia and inversely correlated with insulin
sensitivity. In African-American children, as BMI increases,
insulin-stimulated glucose metabolism decreases and fasting
insulin levels increase. Furthermore, in these children, the
inverse relationship between insulin sensitivity and abdominal
fat is stronger for visceral than for subcutaneous fat. In a 7-
year longitudinal study of African-American and white young
adults 18 years and older, the strongest predictor for increases
in both insulin and glucose concentrations was an increase in
BMI.
Data about hyperandrogenism and type 2 diabetes are limited in
the pediatric age-group. In adults, however, women with PCOS are
at increased risk of type 2 diabetes because they have profound
insulin resistance, independent of obesity, and they have
abnormalities in beta-cell function. In women with PCOS, 31%
have impaired glucose tolerance and 7.5–16% have type 2 diabetes
[9]. Adolescents with PCOS have evidence of skeletal muscle
insulin resistance with ~40% reduction in insulin-stimulated
glucose disposal, compared with body composition–matched
nonhyperandrogenic control subjects. Those adolescents with PCOS
who have impaired glucose tolerance have ~50% decrement in first-
phase insulin secretion.
Racial differences in insulin sensitivity are also evident in
childhood. African-American 7- to 11-year-old children have
significantly higher insulin levels than age-matched white
children. The Bogalusa Heart Study evaluated plasma glucose and
insulin levels during an OGTT in 377 children aged 5–17 years
from a biracial community. After adjusting for weight, age,
ponderal index, and pubertal stage, African-Americans showed
higher insulin responses than their white counterparts,
suggesting compensated insulin resistance. In other studies
using clamp experiments, insulin sensitivity was 30% lower in
African-American adolescents compared with white adolescents.
These data suggest that minority children may have a genetic
predisposition to insulin resistance, which, in the presence of
environmental modulators, could increase their risk of type 2
diabetes and result in disease expression during physiologic
(puberty) or pathologic (obesity) states of insulin resistance.
