Prediabetes or T2D?

In pediatric patients, the relatively rapid progression of prediabetes to type 2 diabetes mellitus (T2D) requires pediatricians to know whom, when, and how to screen for these conditions and to anticipate the likely development of comorbidities in children who develop T2D.

In contrast to T2D in adults, the disease is generally more aggressive in children, and metformin failures are more common. Accordingly, complications such as hypertension, cardiovascular issues, eye disease, and kidney disease can appear just a few years after diagnosis.

To prevent such sequelae, timely screening can help identify young persons at risk, ideally even before they develop prediabetes,¹ a condition marked by impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) not yet meeting diagnostic criteria for diabetes.

The American Diabetes Association (ADA)² and the American Academy of Pediatrics³ (AAP) diagnostic criteria for prediabetes include any of the following:

·      IFG: fasting (no caloric intake for ≥8 hours) plasma glucose 100 mg/dL to 125 mg/dL;

·      IGT: plasma glucose 140 mg/dL to 199 mg/dL, 2 hours after oral glucose tolerance test (OGTT);

·      Hemoglobin A_1C (HbA_1C) 5.7% to 6.4%.

The Centers for Disease Control and Prevention (CDC) criteria for being overweight and obese are as follows:

·      Overweight: body mass index (BMI; weight in kg divided by height in m²) 85th to 95th percentile for age and gender.

·      Obese: BMI above 95th percentile.

Rising T2 tide

As childhood obesity rates have risen over the past 3 decades,⁴ so have rates of diabetes and prediabetes in this population. As of 2000, an estimated 2 million US children aged 12 to 19 years-including 1 in 6 overweight adolescents-suffered from prediabetes.⁴ Between 1999 and 2008, the proportion of US adolescents aged 12 to 19 years who had either prediabetes or diabetes jumped from 9% to 23%.⁵

As for T2D, a landmark study showed that its prevalence among US children and adolescents grew an estimated 30.5% between 2001 and 2009.⁶ This study (the SEARCH for Diabetes in Youth Study) showed that in comparison to type 1 diabetes mellitus (T1D), T2D remains relatively uncommon in children. However, the incidence of T2D has been catching up in recent years. Among adolescents, incidence rates of T1D and T2D are roughly equal, with the greatest number of new T2D cases being diagnosed among ethnic minorities and older teenagers.^7,8

Backdrop of β cell failure

The etiology of T2D involves a combination of genetic factors and environmental influences, leading to insulin resistance and the failure of pancreatic β cells to regulate glucose metabolism.⁹ As in adults, certain children appear to progress over time from normal glucose tolerance to an intermediate stage of abnormal glucose metabolism, during which they exhibit IFG and/or IGT.¹

Obese children are hyperinsulinemic and have approximately 40% lower insulin-stimulated glucose uptake than nonobese peers.¹⁰ In other words, increased weight resulting from poor dietary habits and lack of exercise can contribute to insulin resistance. The β cells may still produce insulin but peripheral tissues including muscle, fat, and the liver cannot properly utilize it.

Whereas obesity represents the primary driver of insulin resistance, critical determinants of insulin sensitivity include not just obesity, but also the balance between visceral versus subcutaneous abdominal fat.¹¹ In addition, insulin resistance appears to be directly related to hepatic steatosis and the percentage of liver fat.¹²

To overcome insulin resistance, the pancreatic islets, which usually make up about 2% of the pancreas, must produce more insulin, which in turn requires them to expand (islet hypertrophy). As long as the islets can compensate, a person with insulin resistance may remain normoglycemic and will not develop T2D.

In some patients, however, a primary defect in the β cells causes them ultimately to fail, resulting in hyperglycemia and progression to diabetes. Some studies suggest that a preexisting and perhaps genetically determined risk factor may be critical for β cell dysfunction to ensue. For example, multiple genome-wide association studies have implicated a gene variant of TCF7L2 in T2D risk. Other genetic factors that may confer T2D risk include epigenetic changes occurring in utero arising from conditions such as maternal diabetes or insufficient placental blood flow. Epigenetic changes may affect the regulation of gene transcription, or the process by which DNA is transcribed into RNA, which is then translated into a protein in the developing cell. Only genes that are transcribed will be expressed and exert their intended impact in the cell.

NEXT: Confirming a T2D diagnosis

Diagnosing T2D

To confirm a diagnosis of T2D, patients must meet any of the following criteria²:

·      Fasting glucose ≥126 mg/dL. Wherever possible, the ADA recommends this method of glucose testing because it is convenient and easily performed.

·      Glucose ≥200 mg/dL 2 hours after OGTT. Use an initial glucose load based on the child's weight: 1.75 mg glucose/kg, up to a maximum of 75 g (the standard adult dose).

·      Diabetes mellitus (DM) symptoms (polyuria, polydipsia, unexplained weight loss) and random glucose ≥200 mg/dL.

·      HbA_1C ≥6.5%. This test remains somewhat controversial. Although recommended by the ADA for diagnosing pediatric T2D, HbA_1C testing performs less reliably in children than in adults.^13,14 Accordingly, pediatricians rely more heavily on the first 3 criteria. Consider HbA_1C if compliance with fasting instructions or follow-up visits makes fasting glucose impractical.

In the absence of unequivocal hyperglycemia, the results should be confirmed by repeat testing.

Clinical presentation and screening criteria

Patients with T2D can present anywhere along a continuum from asymptomatic early disease to advanced disease with life-threatening complications (Table 1).

The ADA guidelines recommend screening children at risk for T2D as follows:

·      When: at age 10 years or the onset of puberty, whichever occurs first (rescreen patients with normal results every 3 years thereafter);

·      Whom: overweight or obese children (BMI ≥85th percentile) with any 2 of these risk factors:

o   Family history of T2D in first-degree or second-degree relatives;

o   Maternal history of diabetes or gestational diabetes;

o   Race/ethnicity: African American, Asian American, Latino, Native American, Pacific Islander;

o   Signs of insulin resistance or associated conditions (acanthosis nigricans [darkening of skin pigment on skin folds or inflection points], hypertension, dyslipidemia, polycystic ovary syndrome, or babies small for gestational age).

T1D versus T2D

Before 1990, physicians could somewhat safely assume that any overweight or obese child with diabetes had T2D, and that most children and adolescents diagnosed with diabetes would have healthy weights, suggesting T1D. However, as rates of childhood obesity have climbed, these assumptions no longer apply because T1D increasingly occurs in overweight or obese children. The high variability of disease presentation and progression may further complicate the difficulty of distinguishing between T1D and T2D.² Making the distinction as early as possible is crucial, however, because treatment, education, and dietary counsel differ markedly between these diagnoses.¹⁵

To help guide diagnosis, pediatric T1D and T2D typically differ regarding these parameters^16-18:

·      Insulin and C-peptide: Both are low in most young persons with T1D. These values are low in some children with T2D but are often detectable and may be elevated. Because the insulin test cannot distinguish between insulin produced endogenously or injected therapeutically, physicians often order these tests together. Level of C-peptide reflects endogenous insulin secretion. Originally attached to insulin secreted from the pancreas, this amino acid is cleaved off as the pancreas processes insulin.

·      Insulin resistance: Common clinical signs include acanthosis nigricans. Only around 12% of young persons with T1D present with acanthosis, versus 50% to 90% of those with T2D.

·      Islet autoantibodies: These antibodies are directed against specific islet proteins including insulin, glutamic acid decarboxylase (GAD)-65, islet cell antibody (ICA)-512, and zinc transporter 8. They are increased in most children and adolescents with T1D, but rarely in T2D.

·      Ketoacidosis: It is a common misconception that patients with T2D cannot have diabetic ketoacidosis (DKA). Children with T1D are indeed more likely to present with ketoacidosis. However, 5% to 10% of adolescents diagnosed with T2D present with ketoacidosis, often with a precipitating factor such as an infection.

·      Age at diagnosis: Although rising obesity rates have blurred this criteria somewhat, nearly all children diagnosed with T2D are aged at least 10 years (mean, 13.5 years), while 50% of children with T1D are diagnosed before age 10 years.

·      Family history: Between 75% and 90% of young persons with T2D have a close relative with DM, versus 10% or fewer of those with T1D.

NEXT: How to manage T2D and control comorbidities

Managing prediabetes and T2D

With prediabetic patients, the strong association between diabetes and obesity mandates that the first treatment priority is avoiding obesity. To that end, the dearth of data regarding antiobesity drugs in prediabetic adolescents requires emphasizing weight management and increased exercise.^19,20

In children with T2D, minimizing complications requires normalizing glucose and HbA_1C levels.^2,3 In this regard, the lifestyle interventions mentioned above may suffice for mild, asymptomatic cases, and they remain important for all children with T2D. However, most patients eventually need drug therapy, using 1 or both of the only 2 agents approved by the US Food and Drug Administration (FDA) for diabetes in children:

Metformin. Working mainly in the liver, this oral insulin sensitizer constitutes first-line therapy for virtually all patients with T2D. It can be considered for initial monotherapy in asymptomatic patients with milder hyperglycemia (126 mg/dL-200 mg/dL) or HbA_1C <8.5%, in the absence of ketoacidosis. Metformin may reduce appetite in some patients. However, it is not approved for prediabetes and must not be given to patients with renal or hepatic dysfunction.

The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study followed 699 children with T2D treated with metformin and other options for up to 6 years. More than half of metformin-treated patients experienced gastrointestinal upset such as diarrhea.²¹ Best practices include educating patients that gastrointestinal adverse effects often subside within 1 month of use; if needed, revert to a lower/previous dose but try not to discontinue medication. Because metformin also causes urinary loss of vitamins, patients taking it should take a daily multivitamin as well.

To maximize compliance, begin dosing at 500 mg once daily, gradually increasing to the recommended 1000 mg BID. Discontinue if patients experience severe vomiting or rapidly declining liver or renal function.

Regarding efficacy, the TODAY study showed that around half of participants failed metformin monotherapy at a median of 11.5 months.

Insulin. Patients who fail metformin therapy require insulin injections, as do those presenting with ketosis, DKA, blood glucose ≥250 mg/dL, or HbA_1C >9%, and those in whom physicians cannot distinguish between T1D and T2D.³ Dosing is highly individualized, based on factors such as the product's formulation and the child's weight, insulin sensitivity, activity level, glucose level, and glucose target. Newer therapeutics including colesevelam (a bile acid-binding resin) and glucagon-like peptide 1 (GLP-1) analogues are under study for use in adolescents with T2D, but none are yet approved.

Controlling comorbidities

Along with a high rate of metformin failure, children and adolescents with T2D carry a higher risk for cardiovascular and other complications versus adults with the disease²² and children with T1D.²³ Hypertension and dyslipidemia largely drive these risks.²⁴ Moreover, the TODAY study showed both the onset and progression of complications including hypertension and nephropathy to be particularly aggressive in pediatric T2D.²⁵

To screen for these and other comorbidities, the ADA recommends the tests shown in Table 2.

Conclusion

The aggressiveness and complexity of T2D in children and adolescents, coupled with increasing childhood obesity, demand a multifaceted approach that targets clinical and lifestyle factors appropriate for each individual patient. In prediabetic children, weight reduction strategies attempt to forestall the development of T2D. Interventions for patients with T2D also can include metformin, with or without insulin. Preventing and combating T2D is a family affair, requiring significant education and support networks for patients all along the prediabetes-T2D continuum.

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17. Dabelea D, Pihoker C, Talton JW, et al; SEARCH for Diabetes in Youth Study. Etiological approach to characterization of diabetes type: the SEARCH for Diabetes in Youth Study. Diabetes Care. 2011;34(7):1628-1633.

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20. Type 2 diabetes in children and adolescents. American Diabetes Association. Diabetes Care. 2000;23(3):381-389.

21. TODAY Study Group; Zeitler P, Hirst K, Pyle L, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med. 2012;366(24):2247-2256.

22. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405-412.

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24. Eppens MC, Craig ME, Cusumano J, et al. Prevalence of diabetes complications in adolescents with type 2 compared with type 1 diabetes. Diabetes Care. 2006;29(6):1300-1306.

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Mr Jesitus is a medical writer based in Colorado. He has nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article. Dr Kim is a pediatric endocrinologist, Rady Children’s Hospital-San Diego, California, and assistant professor, Division of Pediatric Endocrinology, University of California, San Diego, School of Medicine.