abnormalities accompanied by multiple risk factors listed in figure 1.
In the fully established diabetic picture, the common pathophysiology
involves decreased glucose uptake, decreased beta cell function and an increased
hepatic glucose production [33–36]. Glucotoxicity caused by undetected, prolonged
hyperglycemia and lipotoxicity interfere with residual insulin action
further, may therefore compound the picture and may also hamper therapeutic
success with oral antidiabetic agents. To date metformin is the only oral drug
approved for diabetes therapy in pediatrics in the United States [30].
Obesity, especially visceral fat accumulation, appears to be a major risk
factor for T2DM [3, 5, 20, 21]. Obesity is now the most common nutritional
disease of children in the US, 25% are already obese or are at risk of becoming
obese [37, 38]. In Japanese children, the increasing evidence of T2DM appears
to parallel the increasing prevalence of obesity from 1975–95 [22]. Consumption
of sugared soft drinks nearly doubled in the last 15 years in the US [28, 39,
40]. In addition, an increasingly sedentary lifestyle, number of hours of television
and intake of saturated fats all contribute to the rise in T2DM. The epidemic
of T2DM in minority children has to be viewed with the knowledge in
mind that African-American children have a higher degree of insulin resistance
and have at baseline higher insulin levels than Caucasian children [41, 42].
This genetic predisposition based on race is further compounded by the
positive family history of T2DM. Among our population up to 65% of patients
had a first-degree relative with T2DM [8].
Puberty itself is associated with physiologic insulin resistance. As elegant
studies by Arslanian and coworkers have shown, the physiologically increased
growth hormone secretion during normal puberty is probably responsible for
the transient insulin resistance that evolves during puberty. This would also
explain at least in part why the peak age of T2DM is in mid-puberty [43].
T2DM as Part of the Metabolic Syndrome
T2DM is part of a larger complex called metabolic syndrome, insulin
resistance (IR) syndrome or syndrome X. This syndrome has many components
and clearly the most dangerous long-term risk is that of coronary, cerebral and
peripheral vascular diseases [44]. The definition of IR or metabolic syndrome
by the WHO (1998) or the NCEP Adult Treatment Panel III (2001) is given in
table 2 [45, 46]. Recently, the ADA has lowered the upper normal level of fasting
glucose to 100 mg/dl (table 3) [47].
Abnormalities associated with IR are:
Glucose intolerance (IGT) or manifest DM
Dyslipidemia
Hemodynamic changes: BP, sympathetic tone, sodium retention
Hemostasis: PAI-1, fibrinogen
Endothelial dysfunction: mononuclear cell adhesion, endothelial dependent
vasodilatation
Reproductive: PCOS or ovarian hyperandrogenism
Defined by its most specific physiologic manifestation, i.e. insulin resistance,
is actually impedance to the ability of insulin to promote the uptake of
glucose into the skeletal muscle and its conversion into glucagon [48]. Insulin
resistance is, however, a much more generalized condition, e.g. the ability of
insulin to promote increased muscle blood flow through the activation of
endothelial nitric oxide synthase is blunted in insulin resistant subjects parallel
to the decrease of glucose transport into muscle [48].
The gold standard for the clinical assessment of this stage was and is the
insulin clamp. This elegant but cumbersome insulin clamp test is impractical
outside of research settings [49, 50].
Other clinically useful methods are [44, 51]:
1) HOMA IR (homeostasis model assessed; fasting insulin/fasting glucose
22.5). This test takes advantage of the fact that in no diabetic
insulin resistant subjects, normoglycemia is modulated through increased
insulin secretion.
2) FSIVGTT (frequently sampled i.v. GTT).
3) OGTT.
4) G/I ratio.
5) ‘Quicki’ test.
It should be noted that the definition of IR in non-diabetic subjects is
arbitary. If is defined as the bottom 10% of HOMA values (M value, higher
M more sensitive) in lean, non-diabetic individuals, then 26% of obese individuals
are insulin resistant [52]. IR is considerably higher in morbidly obese
subjects. A patient may, for example, have an abnormal M value but still have
a normal GTT. Only a minority will have an impaired GTT. Impaired glucose
tolerance is then accompanied not just by IR but also by deficiencies in insulin
secretion. In impaired glucose tolerance there is always also beta-cell insufficiency.
Defective insulin signaling in the beta-cell itself can result in beta-cell
failure and when coupled with obesity in clinical diabetes [53].
The rate progression of IGT to T2DM ranges from 2–14% per year depending
on additional risk factors such as ethnicity, obesity, etc. The rate of progression
in children is not known. The majority of individuals who exhibit IGT do
not go on to develop clinical diabetes. The primary determinant of progression
to these more clinically significant states is rather a further decline in insulin
secretion than worsening IR [54]. Any feature or condition associated with
IR/hyperinsulinism should alert the physician to screen youths at risk for IGT
and/or T2DM. The ADA consensus conference recommends for screening purposes
the use of obesity as a major criterion with two additional minor criteria
(e.g. family history, high-risk minority population or features of syndrome X).
The suggested age for screening is age 10 or earlier if onset of puberty precedes
this age. It remains to be determined whether a fasting plasma glucose or a
2-hour oral GTT is a better screening tool. It is already clear that children as
young as 6 years of age can present with T2DM and furthermore it is becoming
evident that fasting plasma glucose level screening may miss children at risk [20].
Prevention and Treatment
Two central principles regarding the management of T2DM need to be
emphasized [28]:
1. Frank DM is a late metabolic decomposition. The increased risk of cardiovascular
complications begins early in the disease process (hypertension,
hyperalbuminuria). The importance of a healthy diet and a physically
active lifestyle should be emphasized for all overweight children.
2. Because T2DM is caused by relative insulin deficiency in the setting of
insulin resistance, optimal therapy requires obviously measures to decrease
insulin resistance.
Weight Loss
The cornerstone of therapy for T2DM is weight loss. A multidisciplinary
approach involving dietary modification, increased physical activity, decreased
sedentary time and behavior therapy offer the best chances for successful
intervention [55–58].
Diet
In addition to lower calories, a low-carbohydrate, high-fat diet is recommended.
Polyunsaturated fat from vegetable and marine sources decreases risk.
Habitual consumption of low glycemic index foods may also lower risk of
T2DM and improve metabolic control once it has developed. A low glycemic
index diet may also facilitate weight loss, though this possibility has not yet
been examined in long term clinical trials [28].
Physical Activity
Increased physical activity increases insulin sensitivity and glucose tolerance.
Sedentary activities such as television have been shown to increase the risk for
obesity [28].
Medical Therapy (Table 4)
The goal of therapy for adolescents with T2DM should be to maintain
glucose levels as normal as possible in order to avoid the micro- and macrovascular
complications [8]. The ADA recommends maintaining a fasting glucose
level of 80–120 mg/dl, bedtime blood sugar, 100–140 mg/dl and a HgbA1c
less than 7% [59]. In our population, initial therapy consisted of Metformin
500 mg b.i.d. Insulin was used if the patient presented in DKA, with ketosis or
if good glycemic control was not achieved with diet and maximal doses of oral
medications (metformin 1,000 mg twice daily after meals). Insulin was used as
the only form of initial therapy in those patients in whom a diagnosis of T1DM
instead of T2DM was initially suspected. In the follow-up, as glycemic control
improved and HgbA1c fell, insulin was tapered and discontinued first, followed
by metformin. If blood sugars remain persistently elevated above normal or
the HgbA1c level increased further, with diet and exercise, metformin was
re-initiated at does up to 2,000 mg/day [18].
Metformin does not only have insulin sensitizing effects, but also has been
described to have an anorectic effect and the ability to decrease fatty acid
oxidation with a reduction in plasma triglyceride and low-density lipoprotein
cholesterol levels [60, 61].
Metformin has also been used in the treatment of impaired glucose tolerance
in obese adolescents in a research study [62]. Side effects such as gastrointestinal
complaints, nausea and diarrhea occur in the beginning of treatment
in up to 40% of patients but are usually mild and self-limited. Patients with
T2DM are obese and may have steatohepatitis at the outset. In our experience
metformin does not cause fatty liver. Very rarely lactic acidosis has been
observed. Baseline assessment of CO2, creatinine levels and liver function tests
are recommended. Metformin is contraindicated in pregnancy, hepatic, renal or
respiratory disease or when radiographic contrast agents are used. Metformin
does not cause hypoglycemia and it may cause welcome weight loss. In our
patients on metformin alone there was a mean reduction of BMI of 9 2%.
Other drugs that increase insulin sensitivity are a glucosidase inhibitors.
Agents that increase insulin levels such as sulfonylureas and meglitinides
may lead to further weight gain and also hypoglycemia. They are currently not
recommended in T2DM in children and adolescents. Thiazolidinediones are not
currently approved for use in children.
Patients requiring insulin often experience further weight gain, the dose
required is usually less than 0.4 U/kg/day, much less than in T1DM. By 3 years
after diagnosis 83% of our patients were able to maintain a HgbA1c of less than
7% without insulin [18].
A recent survey of members of the Lawson Wilkins Pediatric Endocrine
Society (LWPES) in North America revealed that approximately 48% of youth
with T2DM were treated with insulin (typically twice a day) and 44% with oral
hyopyglycemic agents. Among the latter 71% received metformin which is
clearly the first-line drug for T2DM, 46% received sulfonylurea, 9% thiazolidinediones
and 4% meglinitide [63]. A therapeutic decision tree for treatment
of T2DM is suggested in figure 2. Please note that sulfonylureas may further
increase weight and should therefore not be used as first-line drugs.
T2DM and obesity in youths are a worldwide phenomenon. We need to
recognize not just the tip of the iceberg, manifest T2DM, but we need to focus
on the larger issues of IR and metabolic syndrome in children and adolescents.
‘Prediabetes’ is being increasingly found in obese youth. It is characterized by
severe insulin resistance and altered myocellular and abdominal fat partitioning
[63, 65]. Babies from SGA (small for gestational age) are at increased risk for
insulin resistance, particularly when there is early postnatal catch-up growth
[66]. As the clinical epidemiology of childhood diabetes is changing rapidly he
major task for pediatricians remains and is prevention [67].
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