Although type 1 diabetes continues to remain the most common form of childhood diabetes in most of the countries including India, the prevalence of type 2 diabetes is increasing worldwide. This increase is attributed to the modern sedentary lifestyle causing a phenotype of insulin resistance in genetically predisposed individuals. The differentiation between type 1 and type 2 diabetes can be done in most of the cases but may be difficult in obese adolescents with relatively acute presentation. The demonstration of various antibodies is helpful in such circumstances. The earlier age of onset puts patients at risk of earlier age of complications. The management is very challenging as lifestyle modification by the patient and the family is the mainstay of the management. Emphasis should be done on primary prevention with a focus on healthier lifestyles among children.

1. Type 2 Diabetes in Children and Adolescents

2. Review Article
TYPE 2 DIABETES IN CHILDREN AND ADOLESCENTS
Ganesh Jevalikar and Ambrish Mithal
Apollo Centre for Obesity, Diabetes and Endoerinology (ACODE),
Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India.
Correspondence to: Dr Ambrish Mithal, Senior Consultant, Apollo Centre for Obesity, Diabetes and
Endoerinology (ACODE), Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India.
Although type 1 diabetes continues to remain the most common form of childhood diabetes in most of the
countries including India, the prevalence of type 2 diabetes is increasing worldwide. This increase is
attributed to the modern sedentary lifestyle causing a phenotype of insulin resistance in genetically
predisposed individuals. The differentiation between type 1 and type 2 diabetes can be done in most of the
cases but may be difficult in obese adolescents with relatively acute presentation. The demonstration of
various antibodies is helpful in such circumstances. The earlier age of onset puts patients at risk of earlier
age of complications. The management is very challenging as lifestyle modification by the patient and the
family is the mainstay of the management. Emphasis should be done on primary prevention with a focus on
healthier lifestyles among children.
Key words: Type 2 diabetes, Children, Adolescents
INTRODUCTION
Type 2 diabetes mellitus is a heterogeneous disorder
characterized by relative lack of insulin secretion in the face
of insulin resistance. Progressive decline in the insulin
secretory capacity and intercurrent illnesses may lead to a
state of insulin dependency hence the previously used term
‘Non Insulin Dependent Diabetes Mellitus’ (NIDDM) is no
more in use. While type 1 diabetes still remains the most
common form of childhood diabetes in most of the
countries including India, increasing prevalence of type 2
diabetes in children is being reported worldwide and is
closely associated with increase in childhood obesity.
Management of type 2 diabetes is a new challenge for the
healthcare system because of parallel risk of metabolic
syndrome and coronary artery disease. The extensive
lifestyle modification which is the mainstay of management
makes it more difficult to manage.
EPIDEMIOLOGY
There has been a sharp increase in cases of type 2
diabetes amongst children and adolescents in the past two
decades. This was predominantly seen in the AfricanAmerican and Mexican Hispanic American population.
These high risk ethnic groups constitute nearly 70-75% of
the cases of pediatric type 2 diabetes in United States [1].
Among 15- to 19-year-old North American Indians,
prevalence of type 2 diabetes per 1000 was 50.9 for Pima
Indians, 4.5 for all US American Indians, and 2.3 for
Canadian Cree and Ojibway Indians in Manitoba. From
357
1967-1976 to 1987-1996, prevalence increased 6-fold for
Pima Indian adolescents. Among African Americans and
whites aged 10 to 19 years in Ohio, type 2 diabetes
accounted for 33% of all cases of diabetes [2]. In the search
for diabetes in youth study from United States the
proportion of T2DM ranged from 6% of new cases of
diabetes (0.19 cases per 1000 youth for non-Hispanic
white youth) to 76% (1.74 cases per 1000 youth for
American Indian youth) [3]. The increasing prevalence of
type 2 diabetes and obesity has also been reported from
other countries. In Japan 80% of new cases of childhood
diabetes were of type 2 diabetes [4].
Population based studies from India on the prevalence
of type 2 diabetes in children are lacking. In a recently
reported multicentric study from India, MEDI (Multicenter
survey of early onset Diabetes in India) 6% of the 603
patients younger than 20 years were of type 2 diabetes [5].
Another report from north India showed 8 % cases
amongst 160 predominantly middle socio-economic group
patients with onset less than 18 years [6]. Mohan et al
reported 26.7 % cases due to type 2 diabetes amongst 434
cases with age of onset less than 16 years [7].
In most of the studies BMI, waist circumference,
family history of diabetes and sedentary lifestyle are
significantly associated with risk of diabetes.
The Asian Indian phenotype is well known to be
associated with central adiposity and insulin resistance[8].
The high incidence of maternal malnutrition and low birth
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3. Review Article
weight coupled with sedentary lifestyle and easy
availability of calorie dense food makes Indian children
more susceptible to obesity, diabetes and other components
of metabolic syndrome.
ETIO-PATHOGENESIS
The Thrifty genotype hypothesis [9]
This is an adaptation to adverse nutritional conditions in
an effort to conserve energy and survive periods of
starvation. It is associated with insulin resistance as one of
the mechanism. With the modern lifestyle and easy
availability of high calorie food, the same genotype confers
risk of visceral adiposity, insulin resistance and metabolic
syndrome.
Role of in-utero and childhood nutrition
Maternal malnutrition causes adverse in utero nutrition
to the fetus and low birth weight. This is associated with
insulin resistance and limited capacity to secrete insulin.
Birth weight has a U shaped relation with the risk of type 2
diabetes. Both low and high birth weights are associated
with glucose intolerance later in life. In a recent study
published by Brufani, et al, obese children who were born
SGA failed to adequately compensate for their reduced
insulin sensitivity manifesting deficit in early insulin
response and reduced glucose disposal in comparison to
children born AGA and LGA [10].
Overfeeding of SGA babies with high calorie feeds puts
them at risk for diabetes. Exclusive breast feeding protects
against obesity and diabetes.
Role of gestational diabetes
Gestational diabetes is associated with high amniotic
fluid insulin levels. The children of mothers with
gestational diabetes have been shown to be having
significantly high BMI Z-scores and insulin resistance
indices [11] which might put them at risk of diabetes.
Role of obesity, diet and physical inactivity
In a recent study from Mysore, India, 8.5% prevalence
of overweight and 3.4% prevalence of obesity was reported
[12]. Higher prevalence of overweight (15.3%) was
reported amongst children from high socioeconomic status
in Delhi [13]. The prevalence of obesity is likely to
increase further due to the lifestyle changes.
Obesity, especially the visceral fat deposition is
associated with insulin resistance mediated by various
adipokines and compensatory increase in insulin secretion.
The risk increases with increasing BMI [14].
Apollo Medicine, Vol. 6, No. 4, December 2009
The South Asian diets have been reported to be having
low intake of MUFA, omega-3 PUFA and fibre, and high
intake of fats, saturated fats, carbohydrates and trans-fatty
acids. These factors are associated with insulin resistance,
hyperinsulinemia and dyslipidemia [15].
Physical inactivity resulting from decreased outdoor
play, increased television viewing, internet surfing, video
games etc is one of the major risk factor for obesity.
Role of puberty
In majority of the reports, the most common age of
presentation of type 2 diabetes is peri-pubertal. Puberty is
associated with increased activity of growth hormone- IGF
axis leading to a state of insulin resistance. This is
compensated by insulin hyper secretion in normal children.
Failure to compensate for the physiological resistance
results in impaired glucose tolerance and diabetes.
Genetic predisposition [16]
Type 2 diabetes is a polygenic trait. Its familial
occurrence and high risk ethnic groups points to a genetic
background of the condition. However genetic mechanisms
alone can not explain the increase in prevalence which is
more likely to be due to the lifestyle changes. Linkage
analysis and genome wide association scans (GWAS) have
identified certain candidate genes and polymorphisms that
are significantly associated with risk of type 2 diabetes. The
gene encoding the transcription factor 7-like 2 (TCF7L2) is
the locus that confers the strongest effect on type 2 diabetes
risk yet found. Polymorphisms in some genes like PPARG
encoding peroxisome proliferator-activated receptor 2,
KCNJ11 gene encoding Kir 6.2 subunit of the KATP
channel, Hepatocyte Nuclear Factor 1 and others like
HHEX, SCL30A8, CDKAL1, IGF2BP2 and CDKN2A/B
have been significantly associated with the disease risk
whereas in some of the genes like HNF 1A, HNF 4A etc
suggestive evidence not quite reaching genome wide
statistical significance has been identified. All these
susceptibility genes have not been adequately studied in
children.
Current 2 diabetes risk variants may explain as little as
5-10% of the genetic basis of type 2 diabetes.
CLINICAL FEATURES
Type 2 diabetes may be incidentally detected on
screening of the high risk population or it may present with
osmotic symptoms of polyuria, polydipsia. Type 2 diabetes
is almost exclusively seen in overweight or obese children
and is very commonly associated with family history of
type 2 diabetes in first or second degree relatives. In many
of the reported series the most common age of presentation
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4. Review Article
is around puberty, and there is a female preponderance.
Physical examination may show signs of insulin resistance
such as acanthosis nigricans. However with increasing
prevalence of obesity, even patients with type 1 diabetes
also may be obese. Acute clinical presentation and diabetic
ketoacidosis at presentation are more common but not
exclusive to type 1 diabetes and can be seen in type 2
diabetes due to beta cell dysfunction from glucotoxicity.
The hyperglycemic hyperosmolar state is almost exclusive
to type 2 diabetes. In patients with T2DM, both plasma
insulin and C-peptide concentrations are usually high,
reflecting underlying insulin resistance. Chronic
hyperglycemia, however, can cause transient insulin
deficiency (glucose toxicity) with a low initial plasma
insulin concentration, despite insulin resistance. Insulin
and C-peptide levels therefore may be low in the presence
of acute metabolic deterioration at the time of presentation.
Patients with type 1 diabetes can have detectable insulin
and C-peptide secretion due to some retained
cell
function. Because of this overlap, measurement of insulin
secretory capacity with insulin and C-peptide may
contribute to the assessment (especially when elevated) but
is not by itself diagnostic.
Islet cell autoantibodies (ICAs), insulin autoantibodies
(IAA), glutamic acid decarboxylase (GAD), and tyrosine
phosphatase (ICA-512 or islet antigen-2) employed
individually or in combination may be helpful in
differentiation of type 1 and type 2 diabetes. Autoantibodies
are more commonly found in patients with type 1 diabetes,
although the titer decreases with the increasing duration of
the disease. However, as many as 10-20% cases may lack
evidence of autoimmunity at diagnosis. Conversely, 1520% of patients with clinical diagnosis of type 2 diabetes
may show antibody positivity (termed as Latent Auto
immune Diabetes of Adults by some). In these individuals
insulin secretion goes down fast and they become insulin
dependant at an earlier stage.
SCREENING
The American Diabetes Association consensus
statement in 2000 recommends that overweight (defined as
BMI >85th percentile for age and sex, weight for height
>85th percentile, or weight >120% of ideal [50th
percentile] for height) youths with any two of the risk
factors listed below be screened. Testing should be done
every 2 years starting at age 10 years or at the onset of
puberty if it occurs at a younger age. Testing may be
considered in other high-risk patients who display any of
the following characteristics.
•
Have a family history of type 2 diabetes in first- and
second-degree relatives;
•
Belong to a certain race/ethnic group (Native
Americans, African-Americans, Hispanic Americans,
Asians/South Pacific Islanders);
•
Have signs of insulin resistance or conditions
associated with insulin resistance (acanthosis
nigricans, hypertension, dyslipidemia, polycystic
ovary syndrome) [17].
As Indians are considered a high risk group, the Indian
Academy of Pediatrics (IAP) recommends testing children
who are overweight by national standards and have any one
of either family history or signs of insulin resistance.
Furthermore, it is recommended that clinical judgment be
used to test for diabetes in high-risk patients who do not
meet these criteria (for example in a morbidly obese patient
without any other risk factor). Screening should be done
irrespective of obesity in a predisposing condition like
Turner, Klinefelter, Prader Willi or Cushing syndrome [18].
DIAGNOSIS [17]
American Diabetes Association Criteria for the
diagnosis of diabetes
• Symptoms of diabetes plus casual plasma glucose
concentration 200 mg/dL (11.1 mmol/l). Casual is defined
as any time of day without regard to time since last meal.
The classic symptoms of diabetes include polyuria,
polydipsia, and unexplained weight loss.
OR
• FPG 126 mg/dL (7.0 mmol/l). Fasting is defined as
no caloric intake for at least 8 h.
OR
• 2-h PG 200 mg/dL (11.1 mmol/l) during an OGTT.
The test should be performed as described by the World
Health Organization, using a glucose load containing the
equivalent of 1.75 g/kg up to 75-g anhydrous glucose
dissolved in water.
In the absence of unequivocal hyperglycemia with
acute metabolic decompensation, these criteria should be
confirmed by repeat testing on a different day. The third
measure (OGTT) is not recommended for routine clinical
use.
Chronic complications and co-morbidities [19]
Patients with type 2 diabetes have higher rate of
complications and co-morbidities like hypertension,
microalbuminuria, retinopathy, dyslipidemia etc at
diagnosis. The rate of progression of these complications is
faster compared to later onset of the disease.
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5. Review Article
Poor adherence to treatment is very common amongst
adolescents and is associated with higher A1Cs, higher
body mass index, mean arterial pressure and abnormal lipid
profile. Hypertension has been reported in 10-32% cases at
diagnosis. Microalbuminuria has been reported in 14-22%
cases at diagnosis. The progression to overt nephropathy is
faster in comparison to type 1 diabetes and is associated
with poor glycaemic control and hypertension.
Retinopathy, neuropathy, non-alcoholic steatohepatitis and
neuropsychiatric abnormalities have also been reported.
Dyslipidemia are more common in type 2 diabetes in
comparison to type 1 diabetes. Patients with type 2 diabetes
in the search for diabetes in the youth had
hypercholesterolemia (33%), hypertriglyceridemia (29%),
high LDL (24%) and low HDL (44%). These abnormalities
reflect reduction of insulin effect [20].
Treatment of type 2 diabetes is a therapeutic challenge
because it requires extensive dietary and lifestyle
modifications not just by the patient but by the entire family.
This, as against the pharmacologic treatment is the
mainstay of the management.
Care of type 2 diabetes requires teamwork of patient,
family, pediatric endocrinologist, diabetes nurse, dietician,
counselor, clinical psychologist, foot care specialist and
social worker. Close collaboration with adult endocrinologist is needed especially for transition into adulthood.
Goals of the treatment are [22]
Primary prevention of type 2 diabetes involves
interventions to prevent the development of obesity in
children who are not overweight. This include
Optimizing the fetal environment in pregnancy by
maintaining maternal nutrition and proper antenatal
care.
•
Encouraging healthy eating habits amongst children.
Avoiding westernization of diet and encouraging
traditional Indian diet.
To eliminate symptoms of hyperglycemia.
To promote achievement of healthy body weight and
normal growth.
•
To maintain near- normoglycemia (Fasting glucose
<126 mg%), and HbA1C <7%.
•
To achieve a healthy diet and physical exercise
schedule.
•
To treat co-morbidities to prevent long term metabolic
and cardiovascular risk.
Promotion of exclusive breast feeding.
•
•
•
PREVENTION
•
MANAGEMENT
•
Encouraging physical activity and avoiding sedentary
activities like television viewing.
The preventive measures should be implemented at
family, school, community and national levels and should
involve commitment and active participation on the part of
media and politicians.
The schools should provide healthy meals, incorporate
healthy lifestyle training into curriculum, create
opportunities for physical activity and do regular
anthropometric assessment.
The entire family should practice healthy eating habits,
have rules regarding television viewing and encourage
physical activity like walking or cycling. Parents should act
as a role model for children.
Secondary prevention includes early diagnosis by
screening of the high risk children as discussed above and
encouraging weight loss and lifestyle changes in these
cases. Studies have proven that these interventions may
delay the progression from impaired glucose tolerance to
diabetes by several years [21].
Apollo Medicine, Vol. 6, No. 4, December 2009
DIET
Patient should be referred to an experienced dietician/
nutritionist and diet plan should be individualized
depending on culture and resources of the family. A simple
starting intervention should be to eliminate frequent
consumption of sugar containing drinks, juices, sweetened
tea etc. The portion size should be controlled. Between
meal snacking should be avoided. The diet should contain
low total and saturated fats and high fiber. Prolonged
fasting should be avoided. Meals should be taken on
schedule, in one place, with no other activity (television,
studying, reading, playing etc.).
Eating disorders are very common in patients with type
2 diabetes and should be considered during evaluation.
PHYSICAL ACTIVITY
In general, children and adolescents should be
encouraged to be physically active for at least 60 minutes
per day. The activity should be age appropriate and should
be enjoyable to the child. Even mild degrees of weight loss
can cause significant benefit in glycaemic control. Time
spent in sedentary activities (e.g., television viewing)
should be minimized, and other barriers to physical activity
should be identiûed and addressed.
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6. Review Article
albuminuria, creatinine), retinopathy, neuropathy, nonalcoholic steatohepatitis (liver enzymes) should be done at
diagnosis and annually thereafter.
PHARMACOLOGIC MANAGEMENT
Metformin
Metformin is a biguanide and acts by reducing hepatic
glucose output and improving insulin sensitivity. It causes
mild weight loss in overweight children. It is the only drug
universally approved for use in children and has minimal
side effects. It was shown to be effective in doses upto 1000
mg twice daily in 82 subjects treated up to 16 weeks [23].
Side effects are mainly GI and include anorexia, abdominal
discomfort, nausea and diarrhea. These can be minimized
by taking the drug with the food or by using sustained
release formulations. The starting dose should be low and
slowly escalated over 1-3 weeks. Lactic acidosis is very
rare.
Metformin is contraindicated in renal or hepatic
impairment, cardio respiratory insufficiency or use of
radio-contrast material. It should not be given in diabetic
ketoacidosis.
Sulfonylureas
In a randomized single blind comparative study,
glimepride was as effective as metformin in terms of
glycaemic control without an increase in incidence of
hypoglycemia. However, it caused a significant weight gain
compared to metformin [24]. Other drugs have not been
studied well in children.
Other hypoglycemic agents
Other drugs used in adults include thiazolidinediones
(rosiglitazone, pioglitazone), meglitinides, glucosidase
inhibitors (acarbose, miglitol), amylin, DPP-IV inhibitors
(sitagliptin) and incretin mimetics (exenatide) have not
been approved for use below 18 years.
Insulin
Insulin may be the initial therapy for patients presenting
with ketosis, ketoacidosis, dehydration, hyperosmolar state
or during decompensation. It also can be given at diagnosis
when differentiation between type 1 and type 2 diabetes is
unclear.
Addition of basal insulin at an earlier stage in
combination with oral hypoglycemics has been shown to
improve glycaemic control.
With decreasing cell function eventually all patients
may require insulin for day to day management, when oral
medications fail.
Treatment of comorbidities
Complication screening for nephropathy (micro-
Hypertension
Blood pressure should be checked during each visit and
should be maintained below the 90th centile for age, sex
and height. High BP readings should be confirmed by
taking additional readings. Mild hypertension can be
initially managed with lifestyle and diet changes. If it does
not respond to these interventions, the first line of
pharmacological treatment is angiotensin-converting
enzyme inhibitors
Dyslipidemias
Fasting lipid levels should be obtained after initial
glycaemic control and annually thereafter. LDL should be
maintained below 100 mg/dL. Dyslipidemia should be
managed initially with diet and lifestyle changes and
glycaemic control. If lipids remain elevated after 6 months
of above, then statins can be started in children older than
10 years.
TREATMENT RECOMMENDATIONS [22]
Asymptomatic patients with type 2 diabetes may be
initially managed with diet and exercise. Fasting and
postprandial glucose should be monitored frequently in a
week. Failure to maintain HbA1C < 7 % and glucose
readings below 130 mg/dL fasting and below 180 mg/dL
post meal after 3-6 month trial of diet and exercise is an
indication to start metformin.
Symptomatic patients without ketosis can be started on
metformin and lifestyle modification. Blood glucose
readings should be maintained as above and target HbA1C
should be below 7%. Poor compliance is the most common
reason for poor control and must be addressed before
adding other treatment. Add on therapy with
sulphonylureas or insulin can be considered if there is no
control with adequate doses of metformin. Failure of single
or multiple oral hypoglycemics is indication to start insulin.
Patients with high blood glucose at diagnosis (>250 mg/
dL), HbA1C more than 9 % or ketosis at onset may be
started on insulin. Metformin may be added later and
insulin can be withdrawn gradually.
SUMMARY
Modern lifestyle and improved socioeconomic status
has contributed to increased prevalence of type 2 diabetes
in at younger age particularly in genetically prone
individuals. It is a disease of the family, demanding
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7. Review Article
extensive lifestyle changes not just by the patient but by the
entire family. The differentiation between type 1 and type 2
diabetes is difficult in obese children with acute
presentation. Therapeutic options are mainly metformin
and insulin, with majority of the other drugs not being
approved for use in children. The earlier onset also means
longer duration of hyperglycemia and occurrence of
complications at an earlier age. Primary prevention and
screening of high risk individuals is far more cost effective
and must be emphasized.
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