Sie sind auf Seite 1von 20

2/24/2019 https://reference.medscape.

com/article/925700-print

reference.medscape.com

Pediatric Type 2 Diabetes


Mellitus
Updated: Feb 28, 2017
Author: Alba E Morales Pozzo, MD; Chief Editor: Sasigarn A Bowden, MD

Overview

Practice Essentials
Although type 2 diabetes is widely diagnosed in adults, its frequency has markedly increased in the pediatric age group
since the end of the 20th century. Most pediatric patients with type 2 diabetes belong to minority communities. A simplified
scheme for the etiology of type 2 diabetes mellitus is shown in the image below.

Simplified scheme for the pathophysiology of type 2 diabetes mellitus.

Signs and symptoms


Distinguishing between type 1 and type 2 diabetes at diagnosis is important. Typical characteristics of type 2 diabetes
include the following:

Slow and insidious onset

Most common in overweight or obese patients from a minority group (Native Americans, blacks, and Pacific
Islanders)

Signs of insulin resistance

Strong family history of type 2 diabetes: Familial lifestyle risk factors leading to obesity may be present, as may a
family history of cardiovascular disease or metabolic syndrome

Physical findings may include the following:

Obesity (strongly associated with type 2 in children and adolescents)

Acanthosis nigricans

https://reference.medscape.com/article/925700-print 1/20
2/24/2019 https://reference.medscape.com/article/925700-print

Polycystic ovary syndrome

Hypertension

Retinopathy

See Clinical Presentation for more detail.

Diagnosis

Testing for type 2 diabetes should be considered when a patient is overweight and has any 2 of the following[1] :

Family history of type 2 diabetes in first-degree or second-degree relative

Minority race or ethnicity (eg, American Indian, black, Hispanic, Asian or Pacific Islander)

Signs of insulin resistance or conditions associated with insulin resistance (eg, acanthosis nigricans, hypertension
dyslipidemia, PCOS)

Recommendations for screening are as follows:

Initial screening may begin at age 10 years or at onset of puberty if puberty occurs at a young age

Screening should be performed every 2 years

A fasting plasma glucose test is the preferred screening study; if clinical suspicion is high but fasting blood glucose is
normal (< 100 mg/dL), an oral glucose tolerance test should be considered

Glucose values may be interpreted as follows:

A random plasma glucose concentration of 200 mg/dL or greater in association with polyuria, polydipsia, or
unexplained weight loss is diagnostic of diabetes[2]

In an asymptomatic patient, a fasting plasma glucose value of 126 mg/dL or greater or a 2-hour plasma glucose
value of 200 mg/dL or greater during an oral glucose tolerance test is also diagnostic of diabetes[2]

Other laboratory results that usually suggest type 2 diabetes are as follows:

Elevated fasting C-peptide level

Elevated fasting insulin level

Absence of autoimmune markers (glutamic acid decarboxylase [GAD] and islet cell antibodies)[2]

Testing for albuminuria can be done by means of 1 of the following 3 methods:

Measurement of the albumin-creatinine ratio in a random spot collection

A 24-hour collection for albumin and creatinine determinations, which allows simultaneous measurement of
creatinine clearance

Timed (eg, 4-hour or overnight) collection

Fasting lipid profiles should be obtained after stable glycemia is achieved and every 2 years thereafter if normal. Optimal
values for children with type 2 diabetes are as follows[3] :

Triglycerides < 150 mg/dL

Low-density lipoprotein (LDL) < 100 mg/dL

High-density lipoprotein (HDL) >35 mg/dL

See Workup for more detail.

Management

The goal of therapy is to achieve and maintain euglycemia and near-normal hemoglobin A1c (HbA1c) levels (< 7%). More
specifically, glycemic and nonglycemic goals may include the following[4] :

Fasting glycemia of less than 126 mg/dL

Resolution of polyuria, nocturia, and polydipsia

https://reference.medscape.com/article/925700-print 2/20
2/24/2019 https://reference.medscape.com/article/925700-print

Healthy body weight

Maintenance of cardioprotective levels of lipids and blood pressure (LDL level < 100 mg/dL, triglyceride < 150 mg/dL,
HDL level >35 mg/dL; blood pressure < 95th percentile for age, sex, and height)

Participation of the whole family as a unit

Treatments for pediatric type 2 diabetes include the following:

Diabetes education and lifestyle changes (diet, exercise, weight control)

Pharmacologic therapy with metformin, insulin, a sulfonylurea, or another hypoglycemic agent

Lipid-lowering agents and blood pressure medications to achieve cardioprotection, if necessary

To protect these patients from future cardiovascular disease, treatment should emphasize the following:

Improvement of glycemia, dyslipidemia, and hypertension

Weight management

Prevention of short- and long-term complications

Blood glucose monitoring 2-3 times daily (more often when insulin treatment is being adjusted)

Evaluation every 3 months at the diabetes clinic (more often, as necessary, when treatment is being adjusted)

HbA1c values should be monitored at each quarterly visit. HbA1c testing has the following advantages over glucose
measurement:

It captures long-term glucose exposure

It has less biologic variability

It does not require fasting or timed samples

It is currently used to guide management decisions

Additional monitoring should be performed as follows:

Microalbuminuria and fasting lipid profile (annually)

Dilated eye examination (annually)

Blood pressure evaluation and careful neurologic examination (at each clinic visit)

See Treatment and Medication for more detail.

Background
In the past, type 2 diabetes mellitus was very rare in pediatric patients. However, coinciding with the increasing prevalence
of obesity among American children, the incidence of type 2 diabetes in children and adolescents has markedly increased,
to the extent that it now accounts for as many as one third of all new cases of diabetes diagnosed in adolescents. This trend
is particularly pronounced in minority racial and ethnic groups. (See Epidemiology.)[5]

Complications

Although the natural history of type 2 diabetes mellitus in children is not well studied, the experience accumulated over
years of treating adults may help to minimize the occurrence of complications in children. (See Prognosis and Clinical.)

Acute complications of type 2 diabetes include hyperglycemia, diabetic ketoacidosis, hyperglycemic-hyperosmolar state,[6]
and hypoglycemia. Complications from insulin resistance include hypertension, dyslipidemia, and polycystic ovarian
syndrome (PCOS).[7]

As many as 4% of patients with type 2 diabetes initially present in a hyperglycemic-hyperosmolar coma, which can lead to
cerebral edema and death if not promptly recognized and treated.[6]

Long-term complications of type 2 diabetes mellitus include the following:

https://reference.medscape.com/article/925700-print 3/20
2/24/2019 https://reference.medscape.com/article/925700-print

Nephropathy

Neuropathy

Retinopathy

Coronary artery disease

A retrospective study found that adults diagnosed with type 2 diabetes before age 45 years have a much higher risk of
cardiovascular disease relative to age-matched control subjects. The investigators concluded that early onset type 2
diabetes appears to be a more aggressive disease from a cardiovascular standpoint. (See Prognosis, Clinical, and
Treatment.)[8]

Etiology
In individuals without diabetes, approximately 50% of their total daily insulin is secreted during basal periods to suppress
lipolysis, proteolysis, and glycogenolysis. In response to a meal, rapid insulin secretion (also called first-phase insulin
secretion) ensues. This secretion facilitates the peripheral use of the prandial nutrient load, suppresses hepatic glucose
production, and limits postprandial elevations in glucose levels. The second phase of insulin secretion follows and is
sustained until normoglycemia is restored. A simplified scheme for the etiology of type 2 diabetes mellitus is shown in the
image below.

Simplified scheme for the pathophysiology of type 2 diabetes mellitus.

Type 2 diabetes spans a continuum from impaired glucose tolerance and impaired fasting glucose to frank diabetes that
results from progressive deterioration of insulin secretion and action. Although the first phase of insulin response is
markedly reduced early in the course of the disease, ongoing disorganized basal insulin secretion associated with
deterioration of peripheral insulin action occurs during the progression from normal to impaired glucose tolerance to frank
diabetes.[9]

In parallel, as a result of decreased insulin sensitivity in the liver, endogenous glucose output increase adds to the already
hyperglycemic milieu, worsening peripheral insulin resistance and beta cell function. Failure of the beta cell to keep up with
the peripheral insulin resistance is the basis for the progression from impaired glucose tolerance to overt clinical type 2
diabetes. Longitudinal studies have demonstrated that during the transition between normal glucose tolerance to diabetes,
31% of a person's insulin-mediated glucose disposal capacity, as well as 78% of his or her acute insulin response, is lost.

The UK Prospective Diabetes Study found that beta cell function was 50% of normal at the time of diagnosis of type 2
diabetes in adults.[10] A case study of the progression of diabetes in an adolescent female found an almost 15% decline in
beta cell function per year over the 6-year duration of diabetes, with no substantial changes in insulin sensitivity.[11] Further
prospective studies in young persons with type 2 diabetes are needed in order to clarify the mechanism of disease in this
population.

Risk factors

The major risk factors for type 2 diabetes in young persons are as follows:[12]

https://reference.medscape.com/article/925700-print 4/20
2/24/2019 https://reference.medscape.com/article/925700-print

Obesity and inactivity, which are important contributors to insulin resistance

Native American, black, Hispanic, Asian, or Pacific Islander descent

Family history of type 2 diabetes in first- and second-degree relatives

Age of 12-16 years, the mean age range of onset of type 2 diabetes in youths - These ages coincide with the relative
insulin resistance that occurs during pubertal development

Low birth weight and high birth weight[13]

Maternal gestational diabetes or type 2 diabetes[14, 15]

Not breastfed during infancy[16]

In a retrospective cohort study of more than 43,000 individuals, study participants who were prescribed antipsychotics were
significantly more likely to develop type 2 diabetes within the first year of use compared with matched controls who were not
prescribed these medications. The risk increased with higher medication doses and remained elevated for up to 1 year after
the medications were discontinued. The association between antipsychotic use and type 2 diabetes remained highly
significant when only participants younger than 18 years were assessed.

The study included 28,858 first-time users of antipsychotic medications and 14,429 matched control individuals who had
recently initiated use of a psychotropic other than an antipsychotic, all from the Tennessee Medicaid program. All
participants were 6 to 24 years of age. Antipsychotics used included risperidone, quetiapine, aripiprazole, and olanzapine.
Medications used by the control group included mood stabilizers such as lithium, as well as antidepressants,
psychostimulants, α-agonists, and benzodiazepines.

A total of 106 study subjects receiving antipsychotics were diagnosed and treated for type 2 diabetes (mean age, 16.7
years; 63% girls), translating into 18.9 cases per 10,000 person-years. Antipsychotic users had a 3-fold increased risk of
developing type 2 diabetes by the end of the study compared with the group of nonusers. This risk was significant within the
first year of follow-up.[17, 18]

Epidemiology
Occurrence in the United States

Although type 2 diabetes is widely diagnosed in adults, its frequency has markedly increased in the pediatric age group
since the end of the 20th century. Depending on the population studied, type 2 diabetes now represents 8-45% of all new
cases of diabetes reported among children and adolescents.[19] Most pediatric patients with type 2 diabetes belong to
minority communities.

The SEARCH for Diabetes in Youth Study (a US multicenter, observational study conducting population-based
ascertainment of cases of diabetes mellitus in individuals over age 20 y) found that the incidence of type 2 diabetes was
highest among American Indians aged 15-19 years (49.4 cases per 100,000 person-years). Second and third highest
incidence belonged to Asian-Pacific Islanders and blacks, aged 15-19 years, with 22.7 cases per 100,000 person-years and
19.4 cases per 100,000 person-years, respectively.[20]

International occurrence

An increased prevalence of type 2 diabetes has also been recognized in countries other than the United States, including
Japan, where the incidence of type 2 diabetes in school children after 1981 was found to be strongly related to an increasing
prevalence of obesity.[21] Studies among the Indian, British, Chinese, Taiwanese, Libyan, Bangladeshi, Australian, and
Maori populations also have shown increasing incidence of youth-onset type 2 diabetes.[22, 23, 24, 25, 26, 27, 28, 29]

Race-, sex-, and age-related demographics

Type 2 diabetes primarily affects minority populations.[20] From 1967-1976 to 1987-1996, the prevalence of type 2 diabetes
increased 6-fold in Pima Indian adolescents and appeared for the first time in children and adolescents younger than age 15
years.[30] Similar increases in prevalence were observed among Japanese, Asian-American, and black children. In several
clinics across the United States, pediatric patients with a diagnosis of type 2 diabetes were from minority ethnic groups
(black, Asian, and Hispanic groups).

The prevalence of type 2 diabetes in the pediatric population is higher among girls than boys, just as the prevalence is
higher among adult females than it is in adult males.[12]

https://reference.medscape.com/article/925700-print 5/20
2/24/2019 https://reference.medscape.com/article/925700-print

The mean age range of onset of type 2 diabetes is 12-16 years; this period coincides with puberty, when a physiologic state
of insulin resistance develops. In this physiologic state, type 2 diabetes develops only if inadequate beta cell function is
associated with other risk factors (eg, obesity).[31]

A white paper by the FAIR Health organization that analyzed private claims from more than 21 billion 0- to 22-year-olds
found that claim lines with a diagnosis of type 2 diabetes increased 109% between 2011 and 2015. The study also found
that although obesity was diagnosed more frequently in females, type 2 diabetes were more frequently diagnosed in males,
however, further study is warranted to analyze this association between prevalence of pediatric type 2 diabetes and gender
as other studies have found conflicting results.[32, 33]

According to data from the SEARCH for Diabetes in Youth study, the overall prevalence of type 2 diabetes among American
youths aged 10-19 years rose by 35% between 2001 and 2009 (from 0.34 per 1000 to 0.46 per 1000). Study data were
obtained from 38 counties in five states, as well as American Indian reservations in Arizona and New Mexico, and included
young people from several different racial-ethnic backgrounds.

The greatest increase in the prevalence of type 2 diabetes from 2001 to 2009 was observed in Hispanic youths (from 0.45
per 1000 to 0.79 per 1000), followed by blacks (from 0.95 per 1000 to 1.06 per 1000), and whites (from 0.14 per 1000 to
0.17 per 1000).[34] There were no significant changes in prevalence for either American Indians or Asian Pacific Islanders.

Prognosis
After 30 years of postpubertal diabetes, 44.4% of people with type 2 diabetes and 20.2% of people with type 1 diabetes
develop diabetic nephropathy. Overall, the incidence of nephropathy has declined among patients with type 1 diabetes since
the end of the 20th century; however, it has not for persons with type 2 diabetes.

So far, no population-based follow-up study has been conducted to determine the long-term prognosis of type 2 diabetes
among children and adolescents. Mortality rates and standardized mortality ratios in type 2 diabetes are likely higher than
those in type 1 diabetes, given that the major cause of death in type 1 diabetes is end-stage renal disease.

Morbidity and mortality/ Complications


Overall, morbidity and mortality associated with type 2 diabetes are related to short-term and long-term complications. A
longitudinal, population-based study conducted from 1965-2002 in the Arizona Pima Indian population found that youth-
onset type 2 diabetes is associated with substantially increased incidence of end-stage renal disease and mortality in middle
age.[35]

In a comparative study among Japanese youths with type 1 and type 2 diabetes, the cumulative incidence of nephropathy
among patients with type 2 diabetes was higher than it was in those with type 1 diabetes. Nephropathy also appeared
earlier in type 2 diabetes than it did in type 1 diabetes.[36]

The SEARCH for Diabetes in Youth Study found that American youth with type 2 diabetes have a higher prevalence of
elevated albumin-to-creatinine ratio (ACR) than do young persons with type 1 diabetes. The study also found that high blood
pressure, hyperglycemia, and high triglyceride concentrations are associated with elevated ACR, independent of the type of
diabetes.[37] Albuminuria is a risk factor for renal failure in pediatric type 2 diabetics. Youth with type 2 diabetes are at a
fourfold increased risk of renal failure compared to pediatric patients with type 1 diabetes.[38]

Among the Pima Indians of Arizona, the risk of retinopathy is lower in patients with youth-onset type 2 diabetes than in those
with adult-onset diabetes.[39]

The TODAY study was a recent multicenter clinical trial comparing treatment options in a large cohort of youth with recently
diagnosed type 2 diabetes.[40] The trial showed that high rates of complications and comorbidities (hypertension,
hyperlipidemia, retinopathy, and microalbuminuria) were already present in during the first few months of diagnosis and the
rate of progression of these conditions increased progressively throughout the trial period. In fact, the common
complications of type 2 diabetes seen in adults are also found in youth with type 2 diabetes but appear to progress on an
accelerated timeline. Consequently, preventive measures, aggressive screening and a high index of suspicion are therefore
required in order to curb these negative outcomes that could significantly burden this population during their third and fourth
decades of life.[41, 42]

Patient Education
Education is an essential component of the treatment plan in type 2 diabetes; it is a continuing process involving the child,
family, and all members of the diabetes team. The following strategies may be used:
https://reference.medscape.com/article/925700-print 6/20
2/24/2019 https://reference.medscape.com/article/925700-print

Appropriate teaching of survival skills at diagnosis

Explanation and discussion about the possible causes of type 2 diabetes

Discussion about the need for blood glucose monitoring and the importance of compliance with the drug regimen

Practical skills training includes the following:

Insulin injections (if insulin is part of the treatment plan)

Blood and/or urine testing for ketone bodies

Hypoglycemia recognition and treatment

Emergency telephone contact procedure

Psychosocial adjustment to the diagnosis

Importance of regular follow-up

Basic dietary advice

Diabetes education is an ongoing process and should address the following issues:

Formal education during clinic visits or during diabetes classes

Educational holidays and camps

Support groups

Complications - Use times of crisis or acute complications as opportunities to reinforce the importance of some
aspects of self ̶ diabetes management that may have been neglected

Educate the patient about the potential side effects of oral hypoglycemic agents (eg, the presence of ketonuria or of any
condition predisposing to the accumulation of lactate in patients on metformin).

With regard to the patient’s sexual health, provide advice about contraception, genital hygiene, sexually transmitted
diseases, and fungal infections. In pregnant patients with type 2 diabetes, emphasize the importance of good glycemic
control before and during pregnancy and discuss the effect of maternal diabetes on the fetus.

Presentation

History
At the time of diagnosis, determining whether a patient has type 1 or type 2 diabetes is important, because patients with
type 1 diabetes are totally dependent on exogenous insulin administration for survival, whereas patients with type 2 diabetes
do not necessarily require exogenous insulin to survive.[2]

Because of the increasing prevalence of obesity in the pediatric population, the percentage of immune-mediated diabetes in
overweight or obese patients is increasing, rendering the distinction between type 1 and type 2 diabetes difficult at times.
Blood glucose monitoring is required regardless of the type of diabetes, and treatment with insulin should be started when
indicated.[2]

The onset of type 2 diabetes is usually slow and insidious; it most often occurs in overweight or obese patients from a
minority group (Native Americans, blacks, and Pacific Islanders). Patients with type 2 diabetes often have signs of insulin
resistance, such as hypertension, PCOS,[43] or acanthosis nigricans.

A strong family history of type 2 diabetes is usually reported among affected youth. The families of adolescents with type 2
diabetes often have lifestyle risk factors leading to obesity.[44] In addition, children with type 2 diabetes are more likely to
report a family history of cardiovascular disease and/or metabolic syndrome.

Type 1 diabetes occurs in people of all races; its onset is typically acute and severe. Patients with type 1 diabetes are often
lean and do not show manifestations of insulin resistance.

https://reference.medscape.com/article/925700-print 7/20
2/24/2019 https://reference.medscape.com/article/925700-print

Physical Examination
Obesity is strongly associated with type 2 diabetes in children and adolescents. Eighty-five percent of children with type 2
diabetes are either overweight or obese (defined as at or above the 85th percentile of the sex-specific body mass index
[BMI] for age-based growth charts).[30]

Acanthosis nigricans, a marker of insulin resistance, is a velvety, hyperpigmented thickening of the skin; it is frequently seen
on the nape of the neck and in intertriginous areas; it is found in as many as 90% of children with type 2 diabetes.[30]

PCOS is a reproductive disorder commonly seen in young women with acanthosis nigricans. It is characterized by
hyperandrogenism and chronic anovulation. The role of insulin resistance in the etiology of PCOS has been extensively
studied, and medications that decrease insulin resistance and/or hyperinsulinemia in women with this syndrome often
attenuate the hyperandrogenism and metabolic abnormalities.

Hypertension may occur in children with type 2 diabetes. The risk of macrovascular and microvascular diabetic
complications is positively associated with elevated systolic blood pressure.

Ophthalmologic examination should be performed at or shortly after diagnosis to detect incipient retinopathy.

DDx

Diagnostic Considerations
Conditions to consider in the differential diagnosis of type 2 diabetes include the following:

Atypical diabetes mellitus (ADM)

Maturity-onset diabetes of the young (MODY)

Diabetes secondary to mutations in mitochondrial deoxyribonucleic acid (DNA)

Genetic defects of the beta cell

Genetic defects in insulin action

Diseases of the exocrine pancreas

Endocrinopathies

Drug- or chemical-induced diabetes

Differential Diagnoses
Diabetic Ketoacidosis

Type 1 Diabetes Mellitus

Workup

Workup

Approach Considerations
According to criteria established by the American Diabetes Association, testing for type 2 diabetes should be considered
when a patient is overweight (eg, body mass index [BMI] at the 85th percentile for age and sex, weight at the 85th
percentile, weight 120% of ideal for height) and any 2 of the following factors exist[1] :

Family history of type 2 diabetes in first-degree or second-degree relative

Minority race or ethnicity (eg, American Indian, black, Hispanic, Asian or Pacific Islander)

https://reference.medscape.com/article/925700-print 8/20
2/24/2019 https://reference.medscape.com/article/925700-print

Signs of insulin resistance or conditions associated with insulin resistance (eg, acanthosis nigricans, hypertension
dyslipidemia, PCOS)

Recommendations for screening are as follows:

Initial screening may begin at age 10 years or at onset of puberty if puberty occurs at a young age

Screening should be performed every 2 years.

A fasting plasma glucose test is the preferred screening study

In children who do not meet the criteria described above but in whom diabetes is highly suspected, clinical judgment should
be applied. If clinical suspicion for diabetes is high but a fasting blood glucose level is normal (< 100 mg/dL), an oral glucose
tolerance test should be considered as a more sensitive screening tool.

Because the onset of type 2 diabetes frequently precedes the diagnosis by several years, testing for end-organ effects of
the disease is important. In addition, perform dilated eye examination for retinopathy shortly after diagnosis and yearly
thereafter.

Plasma Glucose and Other Tests


A random plasma glucose concentration of 200 mg/dL or greater in association with polyuria, polydipsia, or unexplained
weight loss is diagnostic of diabetes.[2]

In an asymptomatic patient, a fasting (ie, no caloric intake for at least 8 h) plasma glucose value of 126 mg/dL or greater or
a 2-hour plasma glucose value of 200 mg/dL or greater during an oral glucose tolerance test is also diagnostic of diabetes.
[2]

Fasting C-peptide and insulin levels are usually elevated in type 2 diabetes. Autoimmune markers (glutamic acid
decarboxylase [GAD] and islet cell antibodies) are usually negative in type 2 diabetes but are frequently present in type 1
diabetes.[2]

Evaluation for Diabetic Nephropathy


Microalbuminuria is said to be present if urinary albumin excretion is 30 mg/24 h (equivalent to 20 µg/min with a timed
specimen or 30 mg of albumin per gram creatinine with a random sample; see Urinalysis). Testing for albuminuria can be
performed using 1 of 3 methods, as follows:

Measurement of the ACR in a random spot collection

A 24–hour collection for albumin and creatinine determinations, which allows for simultaneous measurement of
creatinine clearance

Timed (eg, 4-h or overnight) collection

Evaluation for Dyslipidemia


Obtain fasting lipid profile after stable glycemia has been achieved and every 2 years thereafter if normal. Optimal lipid
levels for children with type 2 diabetes are as follows[3] :

Triglycerides optimal level - Less than 150 mg/dL

Low-density lipoprotein (LDL) optimal level - Less than 100 mg/dL

High-density lipoprotein (HDL) optimal level - More than 35 mg/dL

https://reference.medscape.com/article/925700-print 9/20
2/24/2019 https://reference.medscape.com/article/925700-print

Treatment

Approach Considerations
Ideally, management of diabetes should involve a pediatric endocrinologist, a diabetes nurse educator, a nutritionist, and a
behavioral specialist.

In January 2013, the American Academy of Pediatrics (AAP) issued clinical practice guidelines on the management of type
2 diabetes in children and adolescents. The guidelines recommend insulin treatment in all patients who present with ketosis
or extremely high blood glucose levels because it may not be clear initially whether these patients have type 2 or type 1
diabetes. Once a diagnosis of type 2 diabetes is confirmed, lifestyle modification and metformin treatment should be
initiated.[45, 46]

The goal of therapy is to achieve and maintain euglycemia, as well as near-normal hemoglobin A1c (HbA1c) levels (≤7%).
Patients who are not ill at diagnosis can be treated initially with lifestyle changes (eg, diet, exercise, weight control).
However, because few patients can maintain euglycemia with lifestyle changes alone, most children and adolescents
require medication.[2]

Hemoglobin A1c (HbA1c) levels should be measured every 3 months and treatment adjusted if goals for both HbA1c and
blood glucose are not met. Fingerstick self-glucose monitoring is recommended for all patients receiving insulin or
sulfonylureas, those starting or changing therapy, and those who have not met treatment goals or who have intercurrent
illness.[45, 46]

Insulin therapy is indicated in symptomatic patients with persistent hyperglycemia, the presence of an HbA1c of more than
9%, or ketoacidosis. After blood glucose levels are normalized, efforts to taper insulin with progressive substitution of an oral
agent are undertaken.

Glycemic and nonglycemic goals should be clearly stated and may include the following[4] :

Fasting glycemia of less than 126 mg/dL

Resolution of polyuria, nocturia, and polydipsia

Healthy body weight

Maintenance of cardioprotective levels of lipids and blood pressure - Ie, LDL level of less than 100 mg/dL, triglyceride
level of less than 150 mg/dL, HDL level of greater than 35 mg/dL, blood pressure of less than the 95th percentile for
age, sex, and height

Participation of the whole family as a unit

Unless an acute complication (eg, recurrent hypoglycemia, persistent ketosis, hyperglycemic hyperosmolar state) occurs or
there is poor patient compliance with treatment, type 2 diabetes is usually managed in an outpatient setting.

Recognize that, in patients with PCOS who are receiving metformin, possible resumption of normal ovulation and menstrual
cycles increases the risk of pregnancy. Transfer care to an obstetrician when pregnancy is established.

Diet

Referral to a nutritionist with experience in pediatric diabetes is necessary. Dietary recommendations should be culturally
appropriate, sensitive to family resources, and provided to all caregivers, especially those in charge of cooking the family's
meals.

The entire family should be encouraged to adopt healthier lifestyle habits such as participation in daily exercise and
decreasing the intake of high-calorie, high-fat foods.[2]

Activity
A study by Loimaala et al study showed that long-term endurance and strength training resulted in improved metabolic
control of type 2 diabetes compared with standard treatment. However, significant cardiovascular risk reduction and conduit
arterial elasticity did not improve.[47]

Prevention

Because type 2 diabetes in children and adolescents is strongly associated with obesity and sedentary lifestyle, any
intervention designed to increase physical activity and improve dietary habits should be encouraged.[48]

https://reference.medscape.com/article/925700-print 10/20
2/24/2019 https://reference.medscape.com/article/925700-print

Pharmacologic Therapy
Pharmacologic therapy is indicated when the disease is not well controlled with diet and exercise. Metformin should be the
first oral agent used in children and teenagers with an HbA1c level of less than 9%. If metformin is unsuccessful as
monotherapy, the addition of insulin, a sulfonylurea, or another hypoglycemic agent may be appropriate.[2]

Lipid-lowering agents, such as 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), and


blood pressure medications (ideally, angiotensin-converting enzyme [ACE] inhibitors) should be used if lifestyle
modifications are insufficient in achieving cardioprotective levels of lipids and blood pressure. For example, statins may be
needed to treat hyperlipidemia patients with type 2 diabetes if their fasting LDL ̶ level goals are not met after 3-6 months of
lifestyle modification.[49, 3] ACE inhibitors are the agents of choice to treat hypertension and microalbuminuria.[50]

Proposed Management Algorithm


Diabetes education is indicated, including lifestyle changes to achieve healthy weight goals. First-line therapy is metformin
at 1000-2000 mg/d. Goals include a fasting glucose level goal of less than 126 mg/dL and/or an HbA1c level of less than
7%.[4] If goals in step 1 are achieved, continue therapy.

If goals in step 1 not achieved after 3 months (fasting glucose level >126 mg/dL or HbA1c level >7%), add 0.4-0.6 U/kg of
24-hour insulin at bedtime (Glargine or Levemir). If combination therapy is adequate, continue therapy. If combination
therapy is inadequate after 3 months, intensify insulin therapy until the fasting plasma glucose level is less than 126 mg/dL
and the HbA1c level is less than 7%.

Stroke Prevention
In 2010, the American Heart Association-American Stroke Association released updated guidelines for the primary
prevention of stroke. Specific recommendations for patients with diabetes are incorporated in these.[51]

Hypertension

Regular blood pressure screening, lifestyle modification, and drug therapy are recommended. A lower risk of stroke and
cardiovascular events are seen when systolic blood pressure levels are less than 140 mm Hg and diastolic blood pressure
is less than 90 mm Hg. In patients who have hypertension with diabetes or renal disease, the blood pressure goal is less
than 130/80 mm Hg.

Diabetes

Blood pressure control is recommended in type 1 and 2 diabetes. Hypertensives agents that are useful in the diabetic
population include ACE inhibitors and angiotensin receptor blockers (ARBs). Treating adults with diabetes with statin
therapy, especially patients with other risk factors, is recommended, and monotherapy with fibrates may also be considered
to lower stroke risk. Taking aspirin is reasonable in patients who are at high cardiovascular disease risk; however, the
benefit of taking aspirin in diabetic patients for the reduction of stroke risk has not been fully demonstrated.

Dyslipidemia

Treating patients with statins is recommended in patients with coronary heart disease or certain high-risk conditions, for the
primary prevention of ischemic stroke. In addition to statin therapy, therapeutic lifestyle changes and LDL-cholesterol goals
are recommended. Niacin may be used in patients with low HDL cholesterol or elevated lipoprotein (a), but its efficacy in
preventing ischemic stroke is not established.

Fibric-acid derivatives, niacin, bile acid sequestrants, and ezetimibe may be useful in patients who have not achieved target
LDL levels with statin therapy or who cannot tolerate statins. However, their effectiveness in reducing the risk of stroke has
not been established.

Diet

A diet that is low in sodium and high in potassium is recommended to reduce blood pressure. Diets that promote the
consumption of fruits, vegetables, and low-fat dairy products, such as the DASH (Dietary Approaches to Stop

https://reference.medscape.com/article/925700-print 11/20
2/24/2019 https://reference.medscape.com/article/925700-print

Hypertension)-style diet, help to lower blood pressure and may lower risk of stroke.

Physical activity

Increasing physical activity is associated with a reduction in the risk of stroke. The goal is to engage in at least 30 minutes of
moderate intensity activity on a daily basis.

Long-Term Monitoring
Prevention and treatment of hyperlipidemia and hypertension in individuals with type 2 diabetes are necessary in order to
protect these patients from future cardiovascular disease. (The risk for vascular complications and cardiovascular mortality
in patients with diabetes mellitus is increased by poor glucose control.) Treatment of type 2 diabetes should target the
improvement of glycemia, dyslipidemia, and hypertension, as well as weight management and the prevention of short- and
long-term complications.[4] Blood sugar monitoring should be performed 2-3 times daily, and more often than this when
insulin treatment is being adjusted.

The patient should be seen every 3 months at the diabetes clinic, and more often, as necessary, when treatment is being
adjusted.

Hemoglobin monitoring

HbA1c values should be monitored at each quarterly visit. An international expert committee composed of appointed
representatives of the American Diabetes Association, the European Association for the Study of Diabetes, and others,
recommended HbA1c assay for the diagnosis of diabetes mellitus in nonpregnant adults.[52] The committee’s
recommendation to diagnose diabetes is an HbA1c level of 6.5% or higher, with confirmation from repeat testing (unless
clinical symptoms are present and the glucose level is >200 mg/dL). Glucose measurement should remain the choice for
diagnosing pregnant women or should be used if HbA1c assay is unavailable. The committee listed the following
advantages of HbA1c testing over glucose measurement:

Captures long-term glucose exposure

Has less biologic variability

Does not require fasting or timed samples

Is currently used to guide management decisions

Additional concerns

Additional monitoring should be performed as follows:

Microalbuminuria and fasting lipid profile - Should be checked yearly

Dilated eye examination - Should be done annually

Blood pressure evaluation and careful neurologic - Should be performed at each clinic visit

Weight loss, increased physical activity, and better food choices should be encouraged because they improve fasting lipid
profile. Growth assessment is important.

Medication

Medication Summary
In general, the treatment of type 2 diabetes in children follows the same rationale as does treatment for the disease in
adults. The safety and efficacy of oral hypoglycemic therapy in children and adolescents with type 2 diabetes have not been
established; however, physicians have prescribed drugs typically used in adults to treat children and adolescents. Among all
of the drugs currently in use to treat type 2 diabetes in adults, the US Food and Drug Administration (FDA) has approved
only metformin and insulin degludec for use in children with type 2 DM.

https://reference.medscape.com/article/925700-print 12/20
2/24/2019 https://reference.medscape.com/article/925700-print

Biguanides

Class Summary
These agents reduce hepatic glucose production; they also increase peripheral insulin sensitivity. Metformin rarely induces
hypoglycemia. Because of its anorexigenic effects, many treated children maintain or lose weight. Since metformin can lead
to ovulatory cycles and resumption of regular menses in patients with PCOS, appropriate counseling should be provided to
sexually active adolescents.

Kooy et al found improved body weight, glycemic control, and insulin requirements when metformin was added to insulin in
type 2 diabetes mellitus. No improvement of an aggregate of microvascular and macrovascular morbidity and mortality was
observed; however, risk reduction of macrovascular disease was evident after a follow-up period of 4.3 years. Because of
these sustained beneficial effects, the policy to continue metformin treatment after the introduction of insulin in type 2
diabetes mellitus should be followed unless contraindicated.[53]

Metformin (Glucophage, Glumetza, Riomet, Fortamet)


Metformin use frequently results in weight loss and mild improvement of all aspects of the lipid profile. It cannot be used in
renal or hepatic insufficiency or decompensated congestive heart failure requiring pharmacologic therapy (due to an
increased risk for lactic acidosis).

Metformin can be used as monotherapy or with sulfonylureas, glitazones, or insulin. It reduces hepatic glucose output, may
decrease intestinal absorption of glucose, and may increase glucose uptake in peripheral tissues. It is a major drug used in
obese patients with type 2 diabetes.

Because of adverse gastrointestinal (GI) effects from metformin, titrate the drug slowly and have patients take the
medication during (rather than before) meals. Many patients tolerate metformin best if it is administered in the middle or at
the end of the meal. The drug is available in immediate-release (IR) or extended-release (ER) form. Only the IR form has
been approved for children.

Sulfonylureas

Class Summary
These agents promote insulin release from the pancreas.

Chlorpropamide
Chlorpropamide may increase insulin secretion from pancreatic beta cells.

Glipizide (Glucotrol, Glucotrol XL)


Glipizide is a second-generation sulfonylurea that stimulates the release of insulin from pancreatic beta cells.

Glyburide (DiaBeta, Glynase, PresTab)


Glyburide is a second-generation sulfonylurea. It may be started at a high dose in patients with severe hyperglycemia and in
those with symptoms, if home glucose monitoring and close follow-up can be arranged.

Tolbutamide
Tolbutamide increases insulin secretion from pancreatic beta cells.

https://reference.medscape.com/article/925700-print 13/20
2/24/2019 https://reference.medscape.com/article/925700-print

Meglitinides

Class Summary
These agents promote short-term insulin secretion from the pancreas and are designed to be taken immediately before
meals.

Repaglinide (Prandin)
Stimulates insulin release from pancreatic beta cells.

Nateglinide (Starlix)
Nateglinide is an amino acid derivative that stimulates insulin secretion from the pancreas (within 20 minutes of oral
administration), which, in turn, reduces blood glucose levels. The drug's action depends on functional beta cells in
pancreatic islets. Nateglinide interacts with the adenosine triphosphate (ATP) ̶ sensitive potassium channel on pancreatic
beta cells.

Alpha-glucosidase inhibitors

Class Summary
These agents lower postprandial glucose by slowing glucose absorption and delaying the hydrolysis of ingested complex
carbohydrates and disaccharide. They must be taken immediately before meals.

Acarbose (Precose)
Acarbose delays the hydrolysis of ingested complex carbohydrates and disaccharides and the absorption of glucose. It
inhibits the metabolism of sucrose to glucose and fructose.

Miglitol (Glyset)
Miglitol delays glucose absorption in the small intestine and lowers postprandial hyperglycemia.

Thiazolinediones (glitazones)

Class Summary
The first of this class, troglitazone, was removed from the US market due to fatal hepatic necrosis. Rosiglitazone is an
antidiabetic agent (thiazolidinedione derivative) that improves glycemic control by enhancing insulin sensitivity. The drug is a
potent, highly selective agonist for the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Activation of
PPAR-gamma receptors regulates insulin-responsive gene transcription involved in glucose production, transport, and use,
thereby reducing blood glucose concentrations and reducing hyperinsulinemia. Potent PPAR-gamma agonists have been
shown to increase the incidence of edema.[54, 55]

A meta-analysis reported an increased risk of myocardial infarction and heart-related death in patients treated with
rosiglitazone. The report prompted the FDA to issue an alert on May 21, 2007, to patients and healthcare professionals,
enjoining patients to discuss the issue with their physician in order to make individualized decisions regarding their care. A
large-scale phase IV trial specifically designed to study cardiovascular outcomes of rosiglitazone is under way. Whether this
warning also applies to the other thiazolidinediones (eg, pioglitazone) is unknown.

https://reference.medscape.com/article/925700-print 14/20
2/24/2019 https://reference.medscape.com/article/925700-print

As of September 2010, the FDA was requiring a restricted access program to be developed for rosiglitazone under a risk
evaluation and mitigation strategy (REMS). Patients currently taking rosiglitazone and benefiting from the drug will be able
to continue if they choose to do so. Rosiglitazone will only be available to new patients if they are unable to achieve glucose
control on other medications and are unable to take pioglitazone, the only other thiazolidinedione.

Results from the RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for
Type 2 Diabetes) trial indicated that the use of rosiglitazone for type 2 diabetes mellitus increases the risk of heart failure. In
the study, cardiovascular outcomes were assessed after adding rosiglitazone to metformin or sulfonylurea regimens for type
2 diabetes mellitus.[56] The study was a multicenter, open-label trial that included 4447 patients with mean HbA1c of 7.9%.
Follow-up of the 2 combinations took place over 5-7 years.

No difference was observed between the 2 groups for cardiovascular death, myocardial infarction, and stroke; 61 patients
who received rosiglitazone experienced heart failure that caused either hospital admission or death compared with 29
patients in the active control group.

Noncardiovascular adverse effects in the study included increased upper and distal lower limb fracture rates, particularly in
women. At 5 years, mean HbA1c was lower in the rosiglitazone group compared with the active control group. In addition to
finding that the use of rosiglitazone for type 2 diabetes mellitus increases the risk of heart failure, the study found that the
drug increases the risk for select fractures, particularly in women.

For more information, see the FDA’s Safety Alert on Avandia. The online meta-analysis is titled " Effect of Rosiglitazone on
the Risk of Myocardial Infarction and Death from Cardiovascular Causes. " Additionally, responses to the controversy can be
viewed at the Heartwire news (theheart.org from WebMD) including the following articles:

- " Rosiglitazone increases MI and CV death in meta-analysis. "

- " The rosiglitazone aftermath: Legitimate concerns or hype? "

- " RECORD interim analysis of rosiglitazone safety: No clear-cut answers. "

Rosiglitazone (Avandia)
Rosiglitazone is available only via a restricted access program. It is an insulin sensitizer with a major effect in the stimulation
of glucose uptake in skeletal muscle and adipose tissue. It lowers plasma insulin levels and is used to treat type 2 diabetes
associated with insulin resistance.

Pioglitazone (Actos)
Pioglitazone improves target cell response to insulin without increasing insulin secretion from the pancreas. It decreases
hepatic glucose output and increases insulin-dependent glucose use in skeletal muscle and, possibly, in liver and adipose
tissue.

Glucagon-like Peptide-1 (GlP-1) Receptor Agonists

Class Summary
Exenatide enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated
glucagon secretion, and slows gastric emptying.

Exenatide (Byetta)
Exenatide is an incretin mimetic agent that mimics glucose-dependent insulin secretion and several other antihyperglycemic
actions of incretins. It improves glycemic control in patients with type 2 diabetes mellitus by enhancing glucose-dependent
insulin secretion by pancreatic beta cells. It also suppresses inappropriately elevated glucagon secretion and slows gastric
emptying. The drug's 39–amino acid sequence partially overlaps that of the human incretin, glucagonlike peptide-1.
Exenatide is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes who are taking
metformin or a sulfonylurea but who have not achieved glycemic control.

Liraglutide (Victoza)
Liraglutide is an incretin mimetic agent that elicits glucagonlike peptide-1 (GLP-1) receptor agonist activity. It activates the
GLP-1 receptor by stimulating G-protein in pancreatic beta cells. Liraglutide increases intracellular cyclic adenosine
https://reference.medscape.com/article/925700-print 15/20
2/24/2019 https://reference.medscape.com/article/925700-print

monophosphate (AMP), leading to insulin release in the presence of elevated glucose concentrations. It is indicated as an
adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. The drug has not been studied in
combination with insulin.

Amylin analogue

Class Summary
This agent is a synthetic analogue of human amylin, a naturally occurring hormone made in pancreatic beta cells. It slows
gastric emptying, suppresses postprandial glucagon secretion, and regulates food intake through centrally mediated
appetite modulation. It is indicated to treat type 1 and type 2 diabetes in combination with insulin. This agent is administered
before mealtime for patients who have not achieved desired glucose control despite optimal insulin therapy. It helps to
achieve lower blood glucose levels after meals, less fluctuation of blood glucose levels during the day, and improvement of
long-term control of glucose levels (ie, HbA1C levels), compared with insulin alone. Less insulin use and a reduction in body
weight are also observed.

Pramlintide (Symlin)
Pramlintide is a synthetic analogue of human amylin, a naturally occurring hormone made in pancreatic beta cells. It slows
gastric emptying, suppresses postprandial glucagon secretion, and regulates food intake through centrally mediated
appetite modulation. The drug is indicated to treat type 1 and type 2 diabetes in combination with insulin. It is administered
before mealtime for patients who have not achieved desired glucose control despite optimal insulin therapy. Pramlintide
helps to achieve lower blood glucose levels after meals, less fluctuation of blood glucose levels during the day, and
improvement of long-term control of glucose levels (ie, HbA1C levels), compared with insulin alone. Less insulin use and a
reduction in body weight are also observed.

Dipeptidyl peptidase IV (DPP-4) inhibitors

Class Summary
These agents block the action of DDP-4, which is known to degrade incretin. DDP-4 inhibitors have not yet gained FDA
approval for use in children.

Linagliptin (Tradjenta)
Linagliptin increases and prolongs incretin hormone activity, which is inactivated by the DPP-4 enzyme. It is indicated, along
with diet and exercise, for adults with type 2 diabetes mellitus, to lower blood sugar. Linagliptin may be used as
monotherapy or in combination with other common antidiabetic medications, including metformin, sulfonylurea, and
pioglitazone. It has not been studied in combination with insulin.

Sitagliptin (Januvia)
Sitagliptin blocks the enzyme DPP-4, which is known to degrade incretin hormones. It increases concentrations of active
intact incretin hormones (GLP-1, GIP). The hormones stimulate insulin release in response to increased blood glucose
levels following meals. This action enhances glycemic control. Sitagliptin is indicated for type 2 diabetes as monotherapy or
is combined with metformin or with a PPAR-gamma agonist (eg, thiazolidinediones).

Saxagliptin (Onglyza)
Saxagliptin blocks DPP-4, which is known to degrade incretin hormones, increasing concentrations of active intact incretin
hormones (GLP-1 and GIP). The hormones stimulate insulin release in response to increased blood glucose levels following
meals. This action enhances glycemic control. Saxagliptin is indicated as an adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes.

https://reference.medscape.com/article/925700-print 16/20
2/24/2019 https://reference.medscape.com/article/925700-print

Antidiabetics, Insulins

Class Summary
Insulin acts via specific membrane-bound receptors on target tissues to regulate metabolism of carbohydrate, protein, and
fats. Target organs for insulin include the liver, skeletal muscle, and adipose tissue.

Insulin degludec (Tresiba)


Ultra-long-acting insulin that is the only insulin product approved by the FDA to improve glycemic control in pediatric patients
aged ≥1 y with type 2 DM. It usually takes 3-4 days for insulin degludec to reach steady state, peak plasma time is 9 h and
the duration of action is at least 42 h. It is highly protein bound, and following SC administration, the protein-binding provides
a depot effect.

Insulin degludec is produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae
followed by chemical modification. Insulin degludec differs from human insulin in that the amino acid threonine in position
B30 has been omitted and a side-chain consisting of glutamic acid and a C16 fatty acid has been attached.

Contributor Information and Disclosures

Author

Alba E Morales Pozzo, MD Associate Professor, Department of Pediatrics, Division of Endocrinology and Diabetes,
Kentucky Children's Hospital, University of Kentucky Healthcare

Alba E Morales Pozzo, MD is a member of the following medical societies: American Academy of Pediatrics, American
Diabetes Association, American Medical Association, American Telemedicine Association, Arkansas Foundation for Medical
Care, Arkansas Medical Society, Endocrine Society, Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-
in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) Professor and Chair, First Department of Pediatrics,
Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care,
University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American
Academy of Pediatrics, American College of Physicians, American Pediatric Society, American Society for Clinical
Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric
Research, American College of Endocrinology

Disclosure: Nothing to disclose.

Chief Editor

Sasigarn A Bowden, MD Associate Professor of Pediatrics, Section of Pediatric Endocrinology, Metabolism and Diabetes,
Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Associate Fellowship
Program Director, Division of Endocrinology, Nationwide Children’s Hospital; Affiliate Faculty/Principal Investigator, Center
for Clinical Translational Research, Research Institute at Nationwide Children’s Hospital

Sasigarn A Bowden, MD is a member of the following medical societies: American Society for Bone and Mineral Research,
Central Ohio Pediatric Society, Endocrine Society, International Society for Pediatric and Adolescent Diabetes, Pediatric
Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

https://reference.medscape.com/article/925700-print 17/20
2/24/2019 https://reference.medscape.com/article/925700-print

Arlan L Rosenbloom, MD Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida College of
Medicine; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology

Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics, American
College of Epidemiology, American Pediatric Society, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric
Research, Florida Chapter of The American Academy of Pediatrics, Florida Pediatric Society, International Society for
Pediatric and Adolescent Diabetes

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Jean-Claude
DesMangles, MD,to the development and writing of the source article.

References

1. [Guideline] Diagnosis and classification of diabetes mellitus. Diabetes Care. 2004 Jan. 27 Suppl 1:S5-S10. [Medline].

2. American Diabetes Association. Type 2 diabetes in children and adolescents. Diabetes Care. 2000 Mar. 23(3):381-9. [Medline].

3. Management of dyslipidemia in children and adolescents with diabetes. Diabetes Care. 2003 Jul. 26(7):2194-7. [Medline].

4. Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update
including new drugs and 2-drug combinations. Ann Intern Med. 2011 May 3. 154(9):602-13. [Medline].

5. 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 Jul. 27(7):1798-811. [Medline].

6. Morales AE, Rosenbloom AL. Death caused by hyperglycemic hyperosmolar state at the onset of type 2 diabetes. J Pediatr.
2004 Feb. 144(2):270-3. [Medline].

7. Ten S, Maclaren N. Insulin resistance syndrome in children. J Clin Endocrinol Metab. 2004 Jun. 89(6):2526-39. [Medline].

8. Hillier TA, Pedula KL. Complications in young adults with early-onset type 2 diabetes: losing the relative protection of youth.
Diabetes Care. 2003 Nov. 26(11):2999-3005. [Medline].

9. Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the
pathogenesis of type 2 diabetes mellitus. J Clin Invest. 1999 Sep. 104(6):787-94. [Medline].

10. Matthews DR, Cull CA, Stratton IM, Holman RR, Turner RC. UKPDS 26: Sulphonylurea failure in non-insulin-dependent diabetic
patients over six years. UK Prospective Diabetes Study (UKPDS) Group. Diabet Med. 1998 Apr. 15(4):297-303. [Medline].

11. Gungor N, Arslanian S. Progressive beta cell failure in type 2 diabetes mellitus of youth. J Pediatr. 2004 May. 144(5):656-9.
[Medline].

12. Rosenbloom AL, Joe JR, Young RS, Winter WE. Emerging epidemic of type 2 diabetes in youth. Diabetes Care. 1999 Feb.
22(2):345-54. [Medline].

13. Wei JN, Sung FC, Li CY, et al. Low birth weight and high birth weight infants are both at an increased risk to have type 2
diabetes among schoolchildren in taiwan. Diabetes Care. 2003 Feb. 26(2):343-8. [Medline].

14. Silverman BL, Metzger BE, Cho NH, Loeb CA. Impaired glucose tolerance in adolescent offspring of diabetic mothers.
Relationship to fetal hyperinsulinism. Diabetes Care. May 1995. 18(5):611-7. [Medline].

15. Young TK, Martens PJ, Taback SP, et al. Type 2 diabetes mellitus in children: prenatal and early infancy risk factors among
native canadians. Arch Pediatr Adolesc Med. 2002 Jul. 156(7):651-5. [Medline].

16. Mayer-Davis EJ, Dabelea D, Lamichhane AP, D'Agostino RB Jr, Liese AD, Thomas J. Breast-feeding and type 2 diabetes in the
youth of three ethnic groups: the SEARCh for diabetes in youth case-control study. Diabetes Care. 2008 Mar. 31(3):470-5.
[Medline].

17. Brauser D. More Proof Antipsychotics Boost Kids' Diabetes Risk. Medscape Medical News. Available at
http://www.medscape.com/viewarticle/809942. Accessed: August 27, 2013.

18. Bobo WV, Cooper WO, Stein CM, Olfson M, Graham D, Daugherty J, et al. Antipsychotics and the Risk of Type 2 Diabetes
Mellitus in Children and Youth. JAMA Psychiatry. 2013 Aug 21. [Medline].

19. Type 2 diabetes in children and adolescents. American Diabetes Association. Pediatrics. 2000 Mar. 105(3 Pt 1):671-80.
[Medline].

20. Dabelea D, Bell RA, D'Agostino RB Jr, et al. Incidence of diabetes in youth in the United States. JAMA. 2007 Jun 27.
297(24):2716-24. [Medline].

21. Urakami T, Kubota S, Nitadori Y, Harada K, Owada M, Kitagawa T. Annual incidence and clinical characteristics of type 2
diabetes in children as detected by urine glucose screening in the Tokyo metropolitan area. Diabetes Care. 2005 Aug.
https://reference.medscape.com/article/925700-print 18/20
2/24/2019 https://reference.medscape.com/article/925700-print
28(8):1876-81. [Medline].

22. Ehtisham S, Hattersley AT, Dunger DB, Barrett TG,. First UK survey of paediatric type 2 diabetes and MODY. Arch Dis Child.
2004 Jun. 89(6):526-9. [Medline].

23. Kadiki OA, Reddy MR, Marzouk AA. Incidence of insulin-dependent diabetes (IDDM) and non-insulin-dependent diabetes
(NIDDM) (0-34 years at onset) in Benghazi, Libya. Diabetes Res Clin Pract. 1996 May. 32(3):165-73. [Medline].

24. Chan JC, Cheung CK, Swaminathan R, Nicholls MG, Cockram CS. Obesity, albuminuria and hypertension among Hong Kong
Chinese with non-insulin-dependent diabetes mellitus (NIDDM). Postgrad Med J. 1993 Mar. 69(809):204-10. [Medline]. [Full
Text].

25. Ramachandran A, Snehalatha C, Satyavani K, Sivasankari S, Vijay V. Type 2 diabetes in Asian-Indian urban children. Diabetes
Care. 2003 Apr. 26(4):1022-5. [Medline].

26. Sayeed MA, Hussain MZ, Banu A, Rumi MA, Azad Khan AK. Prevalence of diabetes in a suburban population of Bangladesh.
Diabetes Res Clin Pract. 1997 Jan. 34(3):149-55. [Medline].

27. Braun B, Zimmermann MB, Kretchmer N, Spargo RM, Smith RM, Gracey M. Risk factors for diabetes and cardiovascular
disease in young Australian aborigines. A 5-year follow-up study. Diabetes Care. 1996 May. 19(5):472-9. [Medline].

28. McGrath NM, Parker GN, Dawson P. Early presentation of type 2 diabetes mellitus in young New Zealand Maori. Diabetes Res
Clin Pract. 1999 Mar. 43(3):205-9. [Medline].

29. Eppens MC, Craig ME, Jones TW, Silink M, Ong S, Ping YJ. Type 2 diabetes in youth from the Western Pacific region:
glycaemic control, diabetes care and complications. Curr Med Res Opin. 2006 May. 22(5):1013-20. [Medline].

30. Fagot-Campagna A, Pettitt DJ, Engelgau MM, et al. Type 2 diabetes among North American children and adolescents: an
epidemiologic review and a public health perspective. J Pediatr. May 2000. 136(5):664-72. [Medline].

31. Grinstein G, Muzumdar R, Aponte L, et al. Presentation and 5-year follow-up of type 2 diabetes mellitus in African-American and
Caribbean-Hispanic adolescents. Horm Res. 2003. 60(3):121-6. [Medline].

32. Obesity and Type 2 Diabetes as Documented In Private Claims Data. A FAIR Health White Paper. FAIR Health, Inc.; January
2017. 1-16.

33. Phillips D. Diabetes, Obesity-Linked Disorders Double in Kids. Medscape Medical News. Available at
http://www.medscape.com/viewarticle/874716#vp_1. January 20, 2017; Accessed: January 31, 2017.

34. Dabelea D, Mayer-Davis EJ, Saydah S, Imperatore G, Linder B, Divers J, et al. Prevalence of type 1 and type 2 diabetes among
children and adolescents from 2001 to 2009. JAMA. 2014 May 7. 311(17):1778-86. [Medline].

35. Pavkov ME, Bennett PH, Knowler WC, Krakoff J, Sievers ML, Nelson RG. Effect of youth-onset type 2 diabetes mellitus on
incidence of end-stage renal disease and mortality in young and middle-aged Pima Indians. JAMA. 2006 Jul 26. 296(4):421-6.
[Medline].

36. Yokoyama H, Okudaira M, Otani T, et al. Higher incidence of diabetic nephropathy in type 2 than in type 1 diabetes in early-
onset diabetes in Japan. Kidney Int. 2000 Jul. 58(1):302-11. [Medline].

37. Maahs DM, Snively BM, Bell RA, Dolan L, Hirsch I, Imperatore G. Higher prevalence of elevated albumin excretion in youth with
type 2 than type 1 diabetes: the SEARCH for Diabetes in Youth study. Diabetes Care. 2007 Oct. 30(10):2593-8. [Medline].

38. Dart AB, Sellers EA, Martens PJ, Rigatto C, Brownell MD, Dean HJ. High Burden of Kidney Disease in Youth-Onset Type 2
Diabetes. Diabetes Care. 2012 Mar 19. [Medline].

39. Krakoff J, Lindsay RS, Looker HC, et al. Incidence of retinopathy and nephropathy in youth-onset compared with adult-onset
type 2 diabetes. Diabetes Care. 2003 Jan. 26(1):76-81. [Medline].

40. Zeitler P, Epstein L, Grey M, Hirst K, KaufmanF, Tamborlane W, et al. Treatment options for type 2 diabetes in adolescents and
youth: a study of the comparative efficacy of metformin alone or in combination with rosiglitazone or lifestyle intervention in
adolescents with type 2 diabetes. Pediatric Diabetes. 2007. 8(2):74-87. [Medline].

41. Tryggestad JB, Willi SM. Complications and comorbidities of T2DM in adolescents: findings from the TODAY clinical trial. J
Diabetes Complications. 2015 Mar. 29(2):307-12. [Medline].

42. Solis- Herrera C, Triplitt CL. Nephropathy in Youth and Young Adults with Type 2 Diabetes. Curr Diab Rep. 2014. 14:456-y.
[Medline].

43. Palmert MR, Gordon CM, Kartashov AI, et al. Screening for abnormal glucose tolerance in adolescents with polycystic ovary
syndrome. J Clin Endocrinol Metab. 2002 Mar. 87(3):1017-23. [Medline].

44. Pinhas-Hamiel O, Standiford D, Hamiel D, et al. The type 2 family: a setting for development and treatment of adolescent type 2
diabetes mellitus. Arch Pediatr Adolesc Med. 1999 Oct. 153(10):1063-7. [Medline].

45. Tucker ME. New guidelines address type 2 diabetes in youth. Medscape Medical News. Jan 28, 2013. Available at
http://www.medscape.com/viewarticle/778330. Accessed: Feb 5, 2013.

https://reference.medscape.com/article/925700-print 19/20
2/24/2019 https://reference.medscape.com/article/925700-print
46. Copeland KC, Silverstein J, Moore KR, Prazar GE, Raymer T, et al. Management of Newly Diagnosed Type 2 Diabetes Mellitus
(T2DM) in Children and Adolescents. Pediatrics. 2013 Feb. 131(2):364-82. [Medline].

47. Loimaala A, Groundstroem K, Rinne M, Nenonen A, Huhtala H, Parkkari J, et al. Effect of long-term endurance and strength
training on metabolic control and arterial elasticity in patients with type 2 diabetes mellitus. Am J Cardiol. 2009 Apr 1.
103(7):972-7. [Medline].

48. McGavock J, Sellers E, Dean H. Physical activity for the prevention and management of youth-onset type 2 diabetes mellitus:
focus on cardiovascular complications. Diab Vasc Dis Res. 2007 Dec. 4(4):305-10. [Medline].

49. Kavey RE, Allada V, Daniels SR, Hayman LL, McCrindle BW, Newburger JW, et al. Cardiovascular risk reduction in high-risk
pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention
Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and
Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary
Working Group on Quality of Care and Outcomes Research: endorsed by the American Aca... Circulation. 2006 Dec 12.
114(24):2710-38. [Medline].

50. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics.
2004 Aug. 114(2 Suppl 4th Report):555-76. [Medline].

51. [Guideline] Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, Chaturvedi S, et al. Guidelines for the primary prevention
of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke.
2011 Feb. 42(2):517-84. [Medline].

52. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care. 2009 Jul.
32(7):1327-34. [Medline]. [Full Text].

53. Kooy A, de Jager J, Lehert P, Bets D, Wulffelé MG, Donker AJ, et al. Long-term effects of metformin on metabolism and
microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med. 2009 Mar 23. 169(6):616-
25. [Medline].

54. Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Jones NP, et al. Rosiglitazone evaluated for cardiovascular
outcomes--an interim analysis. N Engl J Med. 2007 Jul 5. 357(1):28-38. [Medline].

55. McAfee AT, Koro C, Landon J, Ziyadeh N, Walker AM. Coronary heart disease outcomes in patients receiving antidiabetic
agents. Pharmacoepidemiol Drug Saf. 2007 Jul. 16(7):711-25. [Medline].

56. Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, et al. Rosiglitazone evaluated for cardiovascular
outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet.
2009 Jun 20. 373(9681):2125-35. [Medline].

57. Waknine Y. Diabetes rates rocket in US tweens and teens. Medscape Medical News. May 6, 2014. [Full Text].

58. US Food and Drug Administration. Early Communication About Safety of Lantus (insulin Glargine). [Full Text].

59. Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R, et al. Comparative effectiveness and safety of
medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. 2011 May 3.
154(9):602-13. [Medline].

60. Jaiswal M, Lauer A, Martin CL, Bell RA, Divers J, Dabelea D, et al. Peripheral Neuropathy in Adolescents and Young Adults
With Type 1 and Type 2 Diabetes From the SEARCH for Diabetes in Youth Follow-up Cohort: A pilot study. Diabetes Care. 2013
Dec. 36(12):3903-8. [Medline]. [Full Text].

61. Tucker M. Peripheral Neuropathy Common in Youth With Type 2 Diabetes. Medscape Medical News. Available at
http://www.medscape.com/viewarticle/815107. Accessed: December 3, 2013.

https://reference.medscape.com/article/925700-print 20/20