AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Until recently, type 2 diabetes mellitus was almost exclusively a disease of adults. 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 point that it accounts for as many as one third of all the new cases of diabetes diagnosed in adolescents. This trend is particularly pronounced in minority racial and ethnic groups.

Pathophysiology

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 utilization 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.

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

In parallel, as a result of decreased insulin sensitivity in the liver, endogenous glucose output increase adds to the already hyperglycemic milieu, worsening both 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. A longitudinal study demonstrated that, during the transition between normal glucose tolerance to diabetes, 31% of the person's insulin-mediated glucose disposal capacity is lost, whereas 78% of the acute insulin response is also lost during the same period.

Frequency

United States

Although type 2 diabetes is widely diagnosed in adults, its frequency has increased markedly in the pediatric age group during the past decade. Type 2 diabetes represents 8-45% of all new cases of diabetes reported among children and adolescents. Most pediatric patients in whom type 2 diabetes is diagnosed belong to minority communities.

International

An increased prevalence of type 2 diabetes has also been recognized in countries other than the United States, including Japan, where the incidence has doubled during the past 2 decades. In the Chinese, Taiwanese, and indigenous people of Australia, a trend for type 2 diabetes to occur at younger ages than before has also been recognized.

Mortality/Morbidity

Overall, morbidity and mortality associated with type 2 diabetes are related to short- and long-term complications.

• According to a follow-up study of Pima Indians in whom type 2 diabetes was diagnosed before the age of 20 years, the incidence of nephropathy was not significantly different from that in patients with adult-onset diabetes. This result indicated a high risk of end-stage renal disease in the third and fourth decades of life.
• In a comparative study among youths with type 1 and type 2 diabetes, the cumulative incidence of nephropathy was higher than it was in those with type 1 diabetes. Nephropathy also appeared earlier in type 2 than in type 1 diabetes.
• The risk of retinopathy is lower in patients with youth-onset type 2 diabetes than in those with adult-onset diabetes.

Race

Type 2 diabetes primarily affects minority populations.

• 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 15 years.
• Similar increases in prevalence were observed among Japanese, Asian-American, and African-American children. In several clinics across the United States, pediatric patients with a diagnosis of type 2 diabetes were from minority ethnic groups (African-American, Asian, and Hispanic groups).

Sex

The prevalence of type 2 diabetes in the pediatric population is higher among girls than boys, just as it is higher among women than men.

Age

The mean age 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).

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

At the time of diagnosis, determine whether a patient has type 1 or type 2 diabetes 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.

• 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 diagnoses difficult at times. Blood glucose monitoring is required regardless of the type of diabetes, and treatment with insulin should be started when indicated.
• The onset of type 2 diabetes is usually slow and insidious; it most often occurs in overweight or obese patients from a minority group.
• • Patients with type 2 diabetes often have signs of insulin resistance, such as hypertension or acanthosis nigricans.
  • A strong family history for the disease is usually reported among affected youth. The families of adolescents with type 2 diabetes also often have lifestyle risk factors leading to obesity.
  • Children with diabetes type 2 are more likely to report a family history of cardiovascular disease.
  • Autoimmune markers are usually negative.
• 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.
  • Autoimmunity is present in diabetes type 1.

Physical

• 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).
• 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.
• Polycystic ovarian syndrome (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.

Causes

The major risk factors for type 2 diabetes in youths are the following:

• Obesity and inactivity, which are important contributors to insulin resistance
• Native American, Hispanic, Asian, and Pacific Islander descent
• Family history of type 2 diabetes
• Age of 12-16 years, the mean age at the onset of type 2 diabetes in youths (This age coincides with relative insulin resistance that occurs during pubertal development.)
• Low birth weight

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Atypical diabetes mellitus (ADM)
Maturity-onset diabetes of the young (MODY)
Diabetes secondary to mutations in mitochondrial DNA
Genetic defects of the beta-cell
Genetic defects in insulin action
Diseases of the exocrine pancreas
Endocrinopathies
Drug- or chemical-induced diabetes

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• A random plasma glucose concentration of 200 mg/dL or greater in association with polyuria, polydipsia, or unexplained weight loss is diagnostic of diabetes.
• 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 are also diagnostic of diabetes.
• Fasting C-peptide and insulin levels are usually elevated in type 2 diabetes.
• Autoantibody results are usually negative.
• Because the onset of type 2 diabetes frequently precedes the diagnosis by several years, it is important to test for end-organ effects of the disease.
• • Evaluation for diabetic nephropathy: Testing for albuminuria can be performed by using 1 of 3 methods. 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). The methods are as follows:
    
    
    1. Measurement of the albumin-to-creatinine ratio in a random spot collection
    2. A 24–hour collection for albumin and creatinine determinations, which allow for simultaneous measurement of creatinine clearance
    3. Timed (eg, 4-h or overnight) collection
  • Evaluation for dyslipidemia
  • • Hypertriglyceridemia
    • Elevated very-low-density lipoproteins (VLDL) levels
    • Elevated low-density lipoprotein (LDL) cholesterol levels
    • Elevated lipoprotein(a) levels
    • Decreased high-density lipoprotein (HDL) cholesterol levels
  • Evaluation for retinopathy

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The goal of therapy is to achieve and maintain euglycemia as well as near-normal hemoglobin A_1c (HbA_1c) levels (£7%).

• Patients who are not ill at diagnosis can be treated initially with lifestyle changes (eg, diet, exercise, weight control).
• Because only a few patients can maintain euglycemia with only lifestyle changes, most children and adolescents require medication.
• Insulin therapy is indicated in symptomatic patients with persistent hyperglycemia or with ketoacidosis. After blood glucose levels are controlled, efforts to taper insulin with progressive substitution with an oral agent are undertaken.
• 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. If metformin is unsuccessful as monotherapy, the addition of insulin, a sulfonylurea, or another hypoglycemic agent may be appropriate.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

In general, the treatment of type 2 diabetes in children follows the same rationale as that for treatment 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 the drugs currently in use to treat type 2 diabetes in adults, the US Food and Drug Administration has approved only metformin and insulin for use in children.

Drug Category: Biguanides

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.

Drug Category: Sulfonylureas

These agents promote insulin release from the pancreas.

Drug Category: Meglitinides

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

Drug Category: Alpha-glucosidase inhibitors

These agents lower postprandial glucose by slowing glucose absorption; they also delay the hydrolysis of ingested complex carbohydrates and disaccharide. They must be taken immediately before meals.

Drug Category: Thiazolinediones (glitazones)

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 improving insulin sensitivity. The drug is highly selective and is a potent agonist for 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.

The controversial results of a recently published meta-analysis reporting the increased risk of myocardial infarction and heart-related death in patients treated with rosiglitazone prompted the US Food and Drug Administration (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 take individualized decisions regarding their care. A large scale phase IV trial specifically designed to study cardiovascular outcomes of rosiglitazone is underway. Whether this warning also applies to the other thiazolidinedione, pioglitazone, is unknown.

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 evaluated for cardiovascular outcomes-An interim analysis." 
• "Coronary heart disease outcomes in patients receiving antidiabetic agents."

Drug Category: Incretin Mimetic

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

Drug Category: Amylin analogue

Synthetic analogue of human amylin, a naturally occurring hormone made in pancreas beta cells. Slows gastric emptying, suppresses postprandial glucagon secretion, and regulates food intake through centrally mediated appetite modulation. Indicated to treat type 1 or type 2 diabetes in combination with insulin. Administered before mealtime for patients who have not achieved desired glucose control despite optimal insulin therapy. Helps 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, Hgb A1C levels) compared with insulin alone. Additionally, less insulin use and reduction in body weight also observed.

Drug Category: Dipeptidyl peptidase IV (DPP-4) inhibitor

This agent blocks the action of dipeptidyl peptidase IV (DDP-4), which is known to degrade incretin.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

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

Further Outpatient Care

• The goal of treatment is normalization of glycemia. Blood sugar monitoring should be done 2-3 times daily and more often than this when treatment is being adjusted.
• The patient should be seen every 3 months at the diabetes clinic and more often, as necessary, when treatment adjustment being done.
• HbA_1c values should be monitored at each quarterly visit.
• Albuminuria 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.
• Statins may be needed to treat hypercholesterolemia.
• Angiotensin-converting enzyme inhibitors are the agents of choice to treat hypertension and microalbuminuria.
• Growth assessment is important.

In/Out Patient Meds

• Oral agents
• Insulin

Deterrence/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.
• The American Diabetes Association has established the following criteria when testing for diabetes is being considered:
• • Overweight (eg, BMI at the 85th percentile for age and sex, weight at the 85th percentile, weight 120% of ideal for height)
  • Plus any 2 of the following factors:
    • Family history of type 2 diabetes in first- 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.
• In children who do not meet the criteria described above but in whom diabetes is highly suspected, clinical judgment should be applied.

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 minimize the occurrence of complications in children.
• Acute complications of type 2 diabetes include hyperglycemia, diabetic ketoacidosis, hyperglycemic-hyperosmolar state, and hypoglycemia.
• Complications from insulin resistance include hypertension, dyslipidemia, and PCOS.
• As many as 4% of patients with type 2 diabetes initially present in a hyperglycemic-hyperosmolar coma, which is potentially fatal if not recognized and treated promptly.
• Long-term complications include the following:
• • Nephropathy
  • Neuropathy
  • Retinopathy
  • Coronary artery disease

Prognosis

• After 30 years of postpubertal diabetes, 44.4% of people with type 2 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 in the past 20 years; however, it has not for those with type 2.
• 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. It can be supposed that mortality rates and standardized mortality ratios in type 2 diabetes would be higher than those in type 1 diabetes, given that the major cause of death in type 1 diabetes is end-stage renal disease.

Patient Education

• Education is an essential component of the treatment plan; it is a continuing process involving the child, family, and all members of the diabetes team. The following strategies may be employed:
• • 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 importance of compliance with drug regimen
  • Practical skills training
    
    
    • 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 continuous 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.
• For excellent patient education materials see the eMedicine articles Obesity in Children and Diabetes and for more information on diabetes see the Diabetes Center. All these materials may be printed free of charge.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize and treat hypoglycemia
• Failure to look for and recognize potential complications (eg, nephropathy, retinopathy) of type 2 diabetes
• Failure to educate the patient about potential side effects of oral hypoglycemic agents (eg, presence of ketonuria or of any condition predisposing to the accumulation of lactate in patients on metformin)
• Failure to promptly recognize and treat hyperglycemic hyperosmolar state can eventually lead to cerebral edema and death

Special Concerns

• Sexual health
• • Provide advice about contraception.
  • Provide advice about genital hygiene, sexually transmitted diseases, and fungal infections.
• Pregnancy
• • Emphasize the importance of good glycemic control before and during pregnancy.
  • Discuss the effect of maternal diabetes on the fetus.
  • Recognized 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.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Alberti G, Zimmet P, Shaw J, et al. Type 2 diabetes in the young: the evolving epidemic: the international diabetes federation consensus workshop. Diabetes Care. Jul 2004;27(7):1798-811. [Medline].
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• American Diabetes Association. Screening for type 2 diabetes. Diabetes Care. Jan 2004;27 Suppl 1:S11-4. [Medline].
• American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. Jan 2004;27 Suppl 1:S15-35. [Medline].
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• Bavdekar A, Yajnik CS, Fall CH, et al. Insulin resistance syndrome in 8-year-old Indian children: small at birth, big at 8 years, or both?. Diabetes. Dec 1999;48(12):2422-9. [Medline].
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• Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone Evaluated for Cardiovascular Outcomes -- An Interim Analysis. N Engl J Med. Jun 5 2007;[Medline]. [Full Text].
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• Pinhas-Hamiel O, Zeitler P. Insulin resistance, obesity, and related disorders among black adolescents. J Pediatr. Sep 1996;129(3):319-20. [Medline].
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• 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].
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• 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. Jul 2000;58(1):302-11. [Medline].
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Article Last Updated: Jul 5, 2007