Diabetes Screening, Diagnosis, and Therapy in Pediatric Patients With Type 2 Diabetes

Abstract and Introduction

Abstract

The dramatic rise in the incidence and prevalence of type 2 diabetes mellitus in the pediatric and adolescent populations has been associated with the ongoing epidemic of overweight, obesity, insulin resistance, and metabolic syndrome seen in these age groups. Although the majority of pediatric patients diagnosed with diabetes are still classified as having type 1 diabetes, almost 50% of patients with diabetes in the pediatric age range (under 18 years) may have type 2 diabetes. Screening of high-risk patients for diabetes and prediabetes is important. Prompt diagnosis and accurate diabetes classification facilitate appropriate and timely treatment and may reduce the risk for complications. This is especially important in children because lifestyle interventions may be successful and the lifelong risk for complications is greatest.

Treatment usually begins with dietary modification, weight loss, and a structured program of physical exercise. Oral antidiabetic agents are added when lifestyle intervention alone fails to maintain glycemic control. Given the natural history of type 2 diabetes, most if not all patients will eventually require insulin therapy. In those requiring insulin, improved glycemic control and reduced frequency of hypoglycemia can be achieved with insulin analogs. It is common to add insulin therapy to existing oral therapy only when oral agents no longer provide adequate glycemic control.

Introduction

The incidence of type 2 diabetes in children and adolescents has reached epidemic proportions in the United States.[1] Recent reports indicate that as many as 45% of pediatric patients diagnosed with diabetes in the United States have type 2 diabetes.[1] Furthermore, the prevalence of type 2 diabetes may be underestimated due to misclassification of the disease.[2] Prior to the late 1990s, only 1% to 2% of children diagnosed with diabetes mellitus in the United States had type 2 diabetes. Since then, owing to a combination of greater awareness, increased screening, and higher incidence, the prevalence of type 2 diabetes among US children has not only increased, but is expected to continue to grow and to exceed that of type 1 diabetes.[3] If this increase in the incidence and prevalence of type 2 diabetes is not reversed, our society will face devastating consequences in terms of the health of future generations and the increasing burden on the healthcare system.[1] To address these issues, we need to understand why this epidemic is occurring and to reassess our current approaches to the medical management of this disease in children.[4] In the present article, we review the risk factors for diabetes and explore the current and emerging strategies for screening, diagnosis, and management of type 2 diabetes in the pediatric and adolescent populations.

Risk Factors

The risk factors for type 2 diabetes are well recognized[4]:

• Obesity/sedentary lifestyle;

• Race/ethnicity;

• Family history;

• Pubertal augmentation of growth hormone and insulin-like growth factor secretory dynamics;

• Polycystic ovary syndrome, hyperandrogenism;

• Intrauterine exposure to maternal diabetes; and

• Low birth weight and poor infant growth.^[5-8]

The recent increase in the prevalence of type 2 diabetes in pediatric patients is believed to be associated with changes in nutrition, insufficient physical activity, and the increasing number of young people who are overweight or obese.[3] The risk for type 2 diabetes is especially high among ethnic minorities, such as African-American, Hispanic, Asian-American, Pacific Islander, Native American, and Alaska Native children.[9] In one study, when compared with non-Hispanic white children and adolescents, Hispanic and African-American children and adolescents were far more likely to be diagnosed with type 2 than type 1 diabetes (odds ratio [95% confidence interval]: 6.2 [2.2, 17.9] and 2.8 [1.3, 6.2], respectively).[10]

Obesity

Children with type 2 diabetes are often obese: As many as 80% are overweight at the time of diagnosis.[1,2,4] The body mass index (BMI) in one series of children with type 2 diabetes ranged from 27 to 38 kg/m² and was greater than the 85th percentile for age and sex in most cases. Twenty-two percent of children and adolescents in the United States are “at risk of overweight” (BMI ≥ 85th percentile) or are overweight (BMI ≥ 95th percentile).[11] The risk of being overweight is especially high in Mexican-American and non-Hispanic black adolescents.[9,12,13] Unfortunately, only a small percentage of overweight children and adolescents are successful with lifestyle interventions designed to control weight.[14]

Metabolic Syndrome

The risks for insulin resistance and the metabolic syndrome are prevalent among obese children and adolescents in the United States, and the degree of insulin resistance increases with body weight.[15] These patients also display elevations of C-reactive protein and reductions in adiponectin levels, which are associated with an increased risk for cardiovascular disease.[15]

Diabetic Complications

Adult patients with early onset of diabetes (between 18 and 44 years of age) have a higher risk for cardiovascular disease than patients who develop diabetes later in life.[16] Patients with relatively early-onset diabetes had a 14-fold elevation of relative risk for myocardial infarction (MI) compared with controls, whereas patients with onset of diabetes after age 45 had a smaller -- but still very significant -- increased risk for an MI relative to control subjects. It is likely that children and adolescents with type 2 diabetes will have an even higher risk for MI later in life than adult patients with relatively early-onset diabetes.

Screening for Type 2 Diabetes in Pediatric Patients

Appropriate screening of high-risk children can be expected to result in earlier diagnosis, earlier initiation of treatment, and a better likelihood of achieving adequate glycemic control. Thus, early screening programs should help reduce the risk for complications.

The recommendations for diabetes screening in children developed by a consensus panel convened by the American Diabetes Association (ADA) are shown in Table 1. For children with a known risk factor, screening is recommended at 10 years of age or at the onset of puberty, whichever occurs earlier,[17] and should be repeated every 2 years.[1,17]

Table 1.

Recommendations for Screening for Type 2 Diabetes in Children

Criteria* “At risk for overweight” (body mass index > 85th percentile for age and sex; or weight for age, sex, and height > 85th percentile; or weight > 120% of ideal for height)          Plus Any two of the following risk factors Family history of type 2 diabetes in first- or second-degree relative Race/ethnicity (Native American, African American, Hispanic American, Asian American, Pacific Islander) Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovary syndrome) Age for initiation of screening: 10 years or at onset of puberty if puberty occurs at a younger age Frequency of screening: every 2 years Measurement: fasting plasma glucose preferred

^*Clinical judgment should be used to screen for diabetes in high-risk patients who do not meet these criteria.

Copyright 2000 American Diabetes Association. From Diabetes Care, Vol. 23, 2000; 381-389. Adapted with permission from The American Diabetes Association.

Prediabetes

Prediabetes is defined as impaired fasting glucose (IFG) (glucose level ≥ 100 mg/dL but ≤ 125 mg/dL) or impaired glucose tolerance (IGT) (2-hour postprandial ≥ 140-199 mg/dL). Whereas IGT has been extensively studied in adults, there are very few studies in children.[18] Similarly, the mechanisms underlying insulin sensitivity and secretion have not been examined in this population.[18] However, adolescents with prediabetes and obese children likely represent the earliest stages of impaired glucose metabolism. Accordingly, these 2 groups may be useful in examining the early pathophysiologic changes underlying this metabolic dysfunction. Furthermore, in evaluating these 2 populations, the confounding effects of aging on insulin sensitivity and secretion may be bypassed.[18] Several studies have reported a high prevalence of prediabetes in obese children and adolescents[19]; screening for prediabetes should be considered for these and other high-risk children.[19,20]

Diagnosis and Classification of Diabetes in Pediatric Patients

A confirmed random plasma glucose level of ≥ 200 mg/dL in conjunction with symptoms of diabetes is considered diagnostic of diabetes.[21] Children with either a fasting plasma glucose level of ≥ 126 mg/dL or a 2-hour oral glucose tolerance test result of ≥ 200 mg/dL should be given a provisional diagnosis of diabetes.[17] These results should be confirmed by using another fasting plasma glucose or an oral glucose tolerance test on a separate occasion.[17]

Diabetes usually can be classified as type 1 or type 2 on the basis of the patient's clinical presentation (Table 2).[1] Children with type 1 diabetes tend to have a short duration of symptoms, which often include recent weight loss, polydipsia, and polyuria,[1] and they frequently present with ketosis and ketoacidosis.[2]

Table 2.

Clinical Presentation of Pediatric Patients With Type 1 vs Type 2 Diabetes^[1,4,23]

Clinical Presentation	Type 1 Diabetes	Type 2 Diabetes
Onset	Abrupt	Insidious
Family history of type 2 diabetes	Uncommon	Common
Insulin resistance or metabolic syndrome	Uncommon	Common
Obesity	Not typically present; may be thin	Typically present
Polyuria	Symptomatic	Mild or absent
Polydipsia	Symptomatic	Mild or absent
Ketonuria	Usually present	Present in up to 33% of patients[4]
Ketoacidosis	Present in 30% to 40% of patients at diagnosis	Present in 5% to 25% of patients at diagnosis[4]Higher risk in African Americans
Hypertension	Not typically present	Typically present
Hyperlipidemia	Not typically present	Typically present
Sleep apnea	Not typically present	Often present
Acanthosis nigricans	Not present	Often present
Polycystic ovary syndrome	Not present	May be present (females)
C-peptide levels	Low*	Normal or elevated†
Beta-cell autoimmune markers (autoantibodies to islet cells, GAD, and/or insulin)	Often but not always present (> 70%)[4,23]	Absent or low (< 35%)[4,23]

GAD = glutamic acid decarboxylase

^*May be higher during the “honeymoon phase”

^†May be lower at time of presentation due to acute glucotoxicity

In some pediatric patients, differentiation of type 1 and type 2 diabetes may be considerably more challenging.[1,22] Type 1 diabetes can present in obese, insulin-resistant patients who have many features resembling type 2 diabetes but who also have a much higher propensity to develop ketoacidosis. Measurement of C-peptide levels or of antibodies to glutamic acid decarboxylase (GAD) can be useful.[1] C-peptide levels are generally low in children with type 1 diabetes, with little or no increase after administration of oral or intravenous glucose. More than 70% of children with type 1 diabetes have antibodies to GAD, islet cells, or insulin. In contrast, children with type 2 diabetes typically have a normal or elevated C-peptide level at the time of presentation, consistent with insulin resistance. However, the presence of C-peptide is not diagnostic of type 2 diabetes because it can be present in the “honeymoon phase” of type 1 diabetes. Islet cell autoantibodies are generally absent in children with type 2 diabetes, but the presence of such markers does not exclude a diagnosis of type 2 diabetes.[23] Further studies to refine the diagnostic criteria are currently in progress.

Treatment of Type 2 Diabetes in Pediatric Patients

Effective management of the young patient with diabetes begins by establishing the goals of care, which should be communicated effectively to the patient and to his or her family.[20] Extensive diabetes education provided directly by the physician, nurse, or a certified diabetes educator to the patient and family is also needed early in the treatment plan.[20,24] Ideally, the provided education should include information in regard to diet, weight loss, weight maintenance, physical activity and exercise, self-monitoring of blood glucose (SMBG), prevention and management of hypoglycemia, testing and management of ketosis, instructions when to call the healthcare professional or to seek emergency care, insulin injection technique (when insulin is initiated), control of other risk factors for cardiovascular disease (eg, smoking prevention or cessation), and management of intercurrent illnesses. Although compliance with treatment is a common challenge in diabetes management, it often is particularly challenging for many children and adolescents.[25,26] Family support and understanding of the diabetes management plan are essential to ensure that pediatric patients remain compliant with lifestyle adjustments and pharmacologic therapies.[20] For example, increased parental involvement in insulin administration has been correlated with increased adherence to blood glucose monitoring, which, in turn, is a predictor of improved glycemic control.[25]

Currently, there are few data from controlled clinical trials on the effects of glycemic control in children with type 2 diabetes younger than 13 years, and protocols for the management of diabetes in pediatric patients vary considerably. Many of the medications commonly used in adults to control hyperglycemia as well as the comorbidities associated with diabetes (eg, hypertension and hyperlipidemia) have not been approved in the United States for use in children. Currently, among oral agents for type 2 diabetes, only metformin (Glucophage, by Bristol-Myers Squibb) and glimepiride (Amaryl, by sanofi-aventis) are approved by the US Food and Drug Administration (FDA) for use in children. Thiazolidinediones (pioglitazone [Actos, by Takeda Pharmaceuticals], rosiglitazone [Avandia, by GlaxoSmithKline]), meglitinides (repaglinide [Prandin, by Novo Nordisk Pharmaceuticals], nateglinide [Starlix by Novartis Pharmaceuticals]), alpha-glucosidase inhibitors (acarbose [Precose, by Bayer]), exenatide (Byetta, by Amylin Pharmaceuticals and Eli Lilly and Co.), pramlintide (amylin [Symlin, by Amylin Pharmaceuticals]), and dipeptidyl peptidase (DPP)-IV inhibitors (sitagliptin [Januvia, by Merck & Co.]) have not been approved for use in children. Further, several of the insulin analogs introduced during the past 10-15 years have not been specifically approved by the FDA for use in children. Available insulin analogs include the rapid-acting analogs (lispro [Humalog, by Eli Lilly and Co.], aspart [NovoLog, by Novo Nordisk Pharmaceuticals], and glulisine [Apidra, by sanofi-aventis]), the basal insulin analogs (insulin glargine [Lantus, by sanofi-aventis] and insulin detemir [Levemir, by Novo Nordisk Pharmaceuticals]), and the fixed-ratio “premixed” combinations (Humalog Mix, by Eli Lilly and Co. and NovoLog Mix, by Novo Nordisk Pharmaceuticals). With the exception of the premixed formulations, pediatric data are available to varying degrees in the prescribing information of the other analogs. Recently, insulin aspart has been approved for use in continuous subcutaneous insulin infusion (CSII) and subcutaneous injection in children and adolescents with type 1 diabetes.[27]

As with adults, the goal of therapy for children with diabetes is to achieve near-normal glycemia while minimizing the risk for hypoglycemic reactions.[28] The ADA recommends a glycated hemoglobin (A1C) target level of less than 7.0%. Lower A1C targets are recommended by the American College of Endocrinology (ACE) and the American Association of Clinical Endocrinologists (AACE) (≤ 6.5%), as well as by the International Diabetes Federation (IDF) (< 6.5%). In view of the fact that the condition is lifelong and expected to be progressive in terms of beta-cell function loss, it is essential to lower the A1C so that it is as close to the normal range as possible, and the risk for hypoglycemic episodes must be adequately controlled. The recent study of type 1 diabetes by Weinzimer and colleagues[27] used age-specific targets: A1C < 6.5% for subjects less than 6 years of age and < 8% for subjects ages 6-18. These targets should be individualized depending on the ease of attaining control, patient adherence and motivation, parental and other support systems, and the risks for hypoglycemia.

For pediatric patients, it is common to relax the goals for glycemia and use more frequent SMBG because the risk for hypoglycemia may outweigh the benefits of strict control.[29] For patients with severe or frequent hypoglycemic episodes (especially nocturnal hypoglycemia), it is important to increase the frequency of SMBG. In my experience, for patients with persistent problems with hypoglycemia, it may be necessary to adjust the goals for glycemic control on the basis of clinical judgment of the balance of risk to benefit. Continuous glucose monitoring may be especially valuable in these patients.

Management of Hypoglycemia

It is essential to closely monitor pediatric patients for signs and symptoms of hypoglycemia. Children younger than 6 or 7 years are likely to lack the cognitive ability to recognize and respond to hypoglycemic symptoms.[20] Hypoglycemia is unlikely in such young patients with type 2 diabetes unless they are treated very aggressively. Generally, hypoglycemic events in type 2 diabetes present with mild-to-moderate symptoms (weakness, fatigue, difficulty concentrating, and confusion) and can be treated with small amounts of a rapidly absorbed carbohydrate. More severe symptoms occur less frequently but may include loss of consciousness and seizures. In a study intended to assess nocturnal hypoglycemia in 70 children and adolescents on insulin, hypoglycemia was asymptomatic in 49%.[20,30]

Goals and Guidelines

Although standard guidelines for the management of type 2 diabetes in children are not available, guidance is provided in a joint position statement issued by the ADA and the American Academy of Pediatrics.[1] The ideal goal of treatment in pediatric patients with type 2 diabetes is to achieve normalization of blood glucose levels and A1C values, thereby reducing the risk for the acute and chronic complications associated with diabetes.[1] Initial treatment of type 2 diabetes in children depends on clinical presentation.[1] Asymptomatic children with no evidence of type 2 diabetes initially may have their hyperglycemia managed with lifestyle interventions. However, most will require drug therapy that often includes an oral antidiabetic agent, preferably an insulin sensitizer, such as metformin.[1] Insulin therapy is recommended for children with a clinical presentation of dehydration, ketosis, and acidosis.[1] Although clinical studies investigating intensive therapy in pediatric patients with type 2 diabetes are not available, the clinical benefits that have been seen following intensive therapy in adults are expected to be applicable to children as well. It is reasonable to expect that the results of the Diabetes Complication and Control Trial involving children and adolescents with type 1 diabetes would also be applicable to pediatric patients who have type 2 diabetes with comparable levels of duration and of quality of glycemic control.

The ACE and AACE have recently issued new guidelines in regard to the management of patients with both type 1 and type 2 diabetes.[31] The European Association for the Study of Diabetes (EASD) and the European Society of Cardiology (ESC) have also issued guidelines.[32] However, these guidelines were written primarily for diabetes management in the adult patient. The Lawson Wilkins Pediatric Endocrine Society and other organizations have recently issued guidelines with regard to CSII specifically in pediatric patients.[33] Considering the expanding array of potential treatment options, updated guidelines on the general management of pediatric patients with type 2 diabetes are needed.

Lifestyle Intervention

Lifestyle intervention must include nutritional counseling, dietary modification, and implementation of a systematic program of physical exercise. Recommendations from the National Diabetes Education Program encourage taking simple steps to increase overall activity in daily life (ie, taking the stairs when possible, family walks after dinner rather than watching television, walking fast at the mall, and involvement in sports).[34] Medical nutrition counseling should be provided to both children and their parents.[20] Successful disease management with lifestyle modification should encompass a return to a “normal” weight level (ie, below the 85th percentile for age and height and preferably as close as possible to the ideal body weight [50th percentile], normal linear growth, and attainment of blood glucose levels as close to the normal range as possible [A1C < 7.0%, per ADA, or < 6.5%, per ACE/AACE and IDF]). Although lifestyle intervention can be effective for controlling diabetes in a small percentage of patients in the short term, less than 10% of pediatric patients with type 2 diabetes achieve adequate glycemic control with lifestyle modification and exercise; most patients will require pharmacologic therapy.[1]

Oral Pharmacotherapy

To date, the only oral agents for diabetes that have been approved by the FDA for use in children are the biguanide metformin (for ages ≥ 10 years) and the sulfonylurea glimepiride.[3,35,36] Metformin is usually the first agent used in pediatric patients who require oral antidiabetic therapy.[1,3] Metformin usually results in modest weight loss, in contrast to insulin or sulfonylureas, which generally are associated with weight gain. Young obese patients generally respond well to metformin. Metformin is contraindicated in patients with impaired renal function because of concerns about lactic acidosis and should not be used in patients with known hepatic disease, hypoxemic conditions, severe infections, or alcohol abuse.[1,3]

Clinical data on the use of oral agents other than metformin in pediatric patients are limited.[37] On the basis of studies in adults, sulfonylureas generally provide a similar degree of improvement in glycemic control to that of metformin but are associated with weight gain and a modest risk for hypoglycemia. Some research has suggested a potential link between the use of sulfonylureas and the acceleration in loss of beta-cell function.[38,39]

Dual therapy

When therapy with either metformin or sulfonylureas alone fails to achieve adequate glycemic control, the 2 agents may be combined. As a general rule, each agent can be used at about one half to two thirds of its maximal dose. Clinicians should refer to the FDA-approved Prescribing Information to determine the appropriate initial dose prior to commencing this or any antidiabetic therapy. Dosage must be carefully individualized and take into consideration weight and body surface area. If dual therapy with oral agents fails to achieve glycemic control, some practitioners have considered off-label use of a third oral agent of a different class, eg, thiazolidinediones, such as rosiglitazone or pioglitazone. Although such use has not been approved by the FDA, this off-label use has been employed by a number of endocrinologists, especially for adult patients. Clearly, additional research on the use of additional oral agents in pediatric patients within the early stages of disease progression is warranted. Further, in light of the data that have emerged with regard to an associated risk for cardiac complications (eg, ischemia, MI) with rosiglitazone, pediatric use may not be advisable[40] because the potential benefit of a third oral agent (particularly a thiazolidinedione) may be outweighed by the risk for side effects (eg, fluid retention, weight gain, and risk for congestive failure) and financial costs.

The relatively new DPP-IV inhibitor, sitagliptin, is another oral agent for use in adults. Use of sitagliptin has not been reported in the pediatric population and has not been approved by the FDA. Similarly, the injectable incretin mimetic exenatide is an effective option in adults but has not been studied or approved by the FDA for use in the pediatric population.

Inevitably, oral monotherapy becomes insufficient at controlling hyperglycemia in most patients. This has been demonstrated in the United Kingdom Prospective Diabetes Study (UKPDS), wherein adult patients treated with a sulfonylurea at the beginning of the study required additional pharmacotherapy after 6 years.[41] Similarly, randomization of obese patients to metformin resulted in a diminishing percentage of patients achieving A1C < 7.0% over time.[42] This is a consequence of the progressive loss of beta-cell function that occurs in type 2 diabetes and may be aggravated by poor glycemic control.[4]

Insulin Therapy

Insulin therapy is especially important for symptomatic children or those who fail to achieve appropriate glycemic goals despite diet, exercise, weight loss, and use of 1 or 2 oral antidiabetic agents.[1] Insulin therapy should be considered for children who exhibit acute deterioration of glycemic control,[1] who have intolerance or contraindications to oral agents, who are nonadherent to oral regimens,[37] or who fail to achieve target levels for glycemic control despite appropriate use of oral agents and attempts at lifestyle changes. Insulin dosages must be individualized on the basis of age, weight, insulin sensitivity, dietary habits, school schedule, level of physical activity, and social and cultural factors, and should mimic the normal physiologic pattern of insulin release insofar as possible.[20,43]

Numerous insulin preparations are available (Table 3). These are grouped according to their pharmacokinetics and duration of action. Insulin preparations are divided into those that are suitable for providing a “basal” rate to cover metabolic needs in the absence of food consumption and those (rapid-acting insulin analogs) that are designed to cover the glucose load following a meal. In addition, one can use premixed fixed-ratio combinations of rapid-acting and intermediate-acting insulin.

Table 3.

Currently Available Insulin Formulations^[31,68]

Insulin, Generic Name (Brand)	Onset	Peak	Effective Duration
Rapid-acting
Insulin aspart injection (NovoLog)	5-15 min	30-90 min	< 5 hr
Insulin lispro injection (Humalog)	5-15 min	30-90 min	< 5 hr
Insulin glulisine (Apidra)	5-15 min	30-90 min	< 5 hr
Short-acting
Regular human (Humulin R by Eli Lilly and Co., Novolin R by Novo Nordisk Pharmaceuticals)	30-60 min	2-3 hr	5-8 hr
Intermediate-acting, basal
NPH insulin (Humulin N by Eli Lilly and Co., Novolin N by Novo Nordisk Pharmaceuticals)	2-4 hr	4-10 hr	10-16 hr
Long-acting, basal
Insulin glargine injection (Lantus)*,†	2-4 hr‡	No pronounced peak	20-24 hr
Insulin detemir injection (Levemir)*,†;[69,70]	2-4 hr	No pronounced peak	6-23 hr
Premixed§
75% insulin lispro protamine suspension, 25% insulin lispro injection (Humalog Mix 75/25)∥	5-15 min	Sustained, unimodal, skewed	10-16 hr
70% insulin aspart protamine suspension, 30% insulin aspart injection (NovoLog Mix 70/30)	5-15 min	Sustained, unimodal, skewed	10-16 hr
70% NPH insulin, 30% regular human insulin (Humulin 70/30 by Eli Lilly and Co., Novolin 70/30 by Novo Nordisk Pharmaceuticals)	30-60 min	Sustained, unimodal, skewed	10-16 hr

NPH = neutral protamine Hagedorn

^*May require 2 daily injections in patients with type 1 diabetes mellitus

^†Assumes 0.1-0.2 U/kg per injection. Onset and duration may vary by injection site; in addition, for insulin detemir the duration of action has been reported to be dose-dependent (ranging from 6 hours at 0.1 U/kg to 23 hours at 1.6 U/kg).

^‡Time to steady state

^§Contrary to popular belief, the premixed insulin formulations do not result in 2 discrete peaks of insulin activity separated by a nadir; there is only a single skewed, asymmetric peak located between that of the peaks that would be expected for rapid-acting insulin analogs and intermediate-acting insulin. The peak is asymmetric, with a skewing toward the longer time.^[63,64]

^∥A mixture of 50% insulin lispro and 50% lispro protamine suspension is also available.

Basal insulin

The currently available options for basal coverage include neutral protamine Hagedorn (NPH) insulin, insulin glargine, insulin detemir, and CSII, ie, the “insulin pump.”

NPH insulin

NPH insulin is an intermediate-acting insulin with a mean duration of action that is approximately 12 hours.[44] NPH insulin also shows substantial variability in insulin levels between subjects and with repeated administration. This results in significant variability in the action profile and increases the risk for hypoglycemia.[44] Children often sleep up to 12 hours per night. Because SMBG is rarely performed during the night, many episodes of hypoglycemia are unrecognized.[30] Thus, children may be more vulnerable to the serious consequences of nocturnal hypoglycemia. Clinical trials in adults[45] and pediatric patients[28,46] have reported that use of NPH insulin results in a higher frequency of nocturnal hypoglycemia than use of insulin glargine.

Insulin glargine

Insulin glargine provides continuous 24-hour basal coverage with no pronounced peak and with considerably better predictability than NPH insulin.[47] Such an extended basal coverage probably accounts for the lower risk for nocturnal hypoglycemia associated with insulin glargine, compared with the intermediate-acting insulin, NPH insulin. Although there are limited clinical data showing the benefits of insulin glargine in pediatric patients with type 2 diabetes, the efficacy and safety of this insulin have been demonstrated in several trials involving pediatric patients with type 1 diabetes and adults with type 2 diabetes.[45,48] The incidence of nocturnal hypoglycemia (2 consecutive blood glucose measures < 50 mg/dL between the hours of 10:30 PM and 8:00 AM) among pediatric patients with type 1 diabetes has been consistently lower with use of insulin glargine than with use of NPH insulin.[28,46] The beneficial effects of insulin glargine in adults with type 2 diabetes have been demonstrated in the Treat-to-Target trial. In this study, more than half of the patients receiving either insulin glargine or NPH insulin were able to reduce A1C levels below 7.0%. However, significantly more patients in the insulin glargine group were able to achieve this A1C target without any documented nocturnal hypoglycemic events (33.2% vs 26.7% for NPH insulin, P < .05).[45] Of note, a large (N = 4961) study by Davies and colleagues compared 2 simple insulin glargine dose-titration algorithms (one in which the patients self-adjusted their doses) and demonstrated that both algorithms were associated with high adherence rates and resulted in safe and effective use of basal insulin in type 2 diabetes.[49] On the basis of clinical experience, patients with type 1 diabetes and some with type 2 diabetes may need twice-daily injections to provide full 24-hour basal coverage. In particular, for adults receiving more than 50-80 U of insulin glargine per day, it may be advisable to split the dose between the morning and evening injections. In the relatively unusual event that a child with diabetes requires such a large dose of basal insulin, this dosing strategy should be considered.

Insulin detemir

Owing to the relatively recent introduction of insulin detemir into the US marketplace, there is less clinical experience with it than with insulin glargine. As is the case with insulin glargine, use of insulin detemir results in a lower frequency of hypoglycemic episodes than has been observed with use of NPH insulin: In a study of adults with type 2 diabetes, use of insulin detemir was associated with a risk for nocturnal hypoglycemic events that was 55% lower than that associated with NPH insulin.[50] The pharmacokinetic/pharmacodynamic profile of insulin detemir may be more reproducible than that of other basal insulin products in terms of within-patient variability.[51] There have been reports that the duration of action for insulin detemir is shorter than that of insulin glargine and significantly shorter than 24 hours, resulting in the need for twice-daily rather than daily administration in all patients with type 1 diabetes and many patients with type 2 diabetes. In a clinical study by Raslova and colleagues, most patients (69%) using an insulin detemir-based basal-bolus insulin regimen for type 2 diabetes required twice-daily dosing of insulin detemir.[52]

CSII

CSII can be used to provide insulin therapy for patients who fail to achieve glycemic targets when using multiple daily injections (MDIs). Little data are available for pediatric patients with type 2 diabetes. However, CSII has been effectively and safely used in pediatric patients with type 1 diabetes and may be beneficial in a small but significant number of pediatric patients with type 2 diabetes. It is likely to benefit patients who require multiple basal rates depending on the time of day or whose schedules (in terms of meals and physical activity) require the enhanced flexibility of an insulin pump and justify the increased expense and complexity of this mode of insulin administration.[53,54] Use of the pump requires a very well-educated, intelligent, compliant, and well-motivated patient.[55,56] In the case of children, use of CSII also requires an excellent support system from the parents, family, school, and others.

Prandial coverage

In addition to 24-hour basal insulin coverage, patients usually also require appropriate replacement of prandial (bolus) insulin. Prandial insulin options include regular human insulin and rapid-acting analogs.

Regular human insulin

For many years, from the time of discovery of insulin to the mid-1990s, regular human insulin had been used as the mainstay of premealtime insulin therapy.[57] However, the long duration between injection and peak serum concentration, and the even longer interval between injection and peak activity, means that regular human insulin should ideally be given 30 minutes (or more) before a meal. Even though an injection may be administered well in advance of a meal, regular human insulin generally fails to achieve a physiologic profile. Accordingly, it is difficult to prevent a large postprandial peak following a meal. The slow action profile of regular human insulin often results in delayed hyperinsulinemia and late postprandial or nighttime hypoglycemia.[58] Accordingly, regular insulin is not recommended for preprandial administration, and has been replaced by the rapid-acting insulin analogs.

Rapid-acting insulin analogs

Rapid-acting human insulin analogs (lispro, aspart, and glulisine) have kinetics that mimic the physiologic postmeal rise in insulin and therefore can provide better postprandial glucose coverage with less risk for delayed hypoglycemia.[59] If desired, these rapid-acting analogs can be introduced in a stepwise manner in patients with type 2 diabetes, starting with one injection at the largest daily meal and subsequently adding additional injections for the second and then the third largest meals as needed. These insulin analogs can also be used for coverage of snacks for those individuals who are able to accurately and reliably utilize carbohydrate counting to estimate the approximate glucose load, and they can provide the flexibility that is often needed for pediatric patients.[58,60]

Use of a “basal” rate provided by a long-acting insulin analog (insulin glargine or insulin detemir) combined with a rapid-acting insulin usually results in the need for 4 (and occasionally 5) injections per day. Use of MDIs is greatly facilitated with the convenience and accuracy provided by the use of insulin pens.[61,62]

Premixed, fixed-ratio combinations of rapid-acting insulin analogs and intermediate-acting insulin

Many patients have been treated with premixed insulins that provide a combination of a rapid-acting insulin with an intermediate-acting insulin -- the so-called biphasic insulins. Although mixtures with regular human insulin are still available, use of a rapid-acting analog is clearly superior in these combinations (Table 3) in terms of providing a more physiologic profile and thus reducing the risk for delayed hypoglycemia.

This option provides less flexibility (in terms of the ability to adjust to changes in meal size, glycemic index, and timing or exercise) than MDIs (basal-bolus). Doses cannot be adjusted for divergent changes in carbohydrate load at breakfast and lunch or for divergent insulin requirements at dinner and overnight. Contrary to a popular misconception, there is only a single peak or maximum for the insulin action curve of the biphasic insulins.[63-65] Use of biphasic insulin has the advantage of requiring only 2 injections per day (as commonly practiced) rather than 4 injections per day in the basal-bolus regimens. However, the biphasic insulin regimens do not have the flexibility of MDI regimens and may fail to achieve target levels of glycemic control as reflected in A1C, postprandial excursions, and frequency of hypoglycemic events. When this is the case, it is important to advance the therapy to MDI.

Summary of Ability to Achieve Glycemic Control

Table 4 presents a summary of the ability of various regimens to achieve good glycemic control at various times of the day and in relationship to meals. These generalizations are based on clinical experience and do not necessarily apply to any individual patient, but they can serve as a guide with regard to the pros and cons of various regimens.

Table 4.

Comparison of Treatment Regimens

Relative Ability to Achieve Satisfactory Glycemic Control
	Morning	Afternoon	Evening	Overnight	Comments
Oral Agents Only*
Metformin	+ +	+	+	+ + +	Assists with weight loss; effective in young patients; fasting values improved due to reduced nocturnal gluconeogenesis; morning values improved due to carryover of these improved fasting values
SUs	+	+	+	+	Risk for hypoglycemia; may promote weight gain; contraindicated in pregnancy; theoretical possibility of more rapid deterioration of beta-cell function with use of these drugs; earlier failure of SUs than metformin or a thiazolidinedione[39]
Oral Agents + Insulin
Long-acting insulin + SU†;	+ +	+	+	+ + + +	Excellent control of overnight glycemia; provides basal insulin; SU provides coverage for meals
Metformin + short-acting insulin analog 3 times daily before meals	+ + +	+ + +	+ + +	+ + +	Utilizes short-acting insulin to cover meals; uses metformin to cover overnight hepatic glucose production
Insulin Only†
Long-acting insulin analog (once daily or twice daily)	+	+	+	+ + + +	Excellent control of overnight glycemia but not responsive to the glycemic load of meals
Rapid-acting insulin analog (3 times daily)‡	+ + +	+ + +	+ + +		Responsive to the glycemic load of meals; does not cover basal insulin requirements
Premixed (rapid-acting insulin and intermediate-acting insulin [or protamine] in a fixed ratio) (typically twice daily)‡	+ +	+	+ +	+	Premixed provides less control of after-lunch glycemia and overnight glycemia (no way to compensate for changes in timing of lunch relative to breakfast or glycemic load of lunch, or for timing of dinner relative to bedtime)
Long-acting insulin (once daily or twice daily), plus rapid-acting insulin (3 times daily before meals)	+ + + +	+ + + +	+ + + +	+ + + +	Basal-bolus or multiple daily injection regimens provide more physiologic insulin replacement if used with good compliance, appropriate intensity of SMBG, and effective self-adjustment of insulin dosage
CSII	+ + + +	+ + + +	+ + + +	+ + + +	Maximal flexibility; increased cost and complexity

CSII = continuous subcutaneous insulin infusion; SMBG = self-monitoring of blood glucose; SU = sulfonylurea

^*Alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, exenatide, and dipeptidyl peptidase-IV inhibitors are not currently approved for use in children and adolescents, thus limiting therapeutic options. However, off-label usage does occur.

^†;Increased risk for hypoglycemia, increased need for SMBG, and promotes weight gain.

^†In some variations, may be given once daily (before largest meal) or 3 times daily (before each meal).

Results of ongoing studies, such as the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY), are expected to help provide more insight about management options for this patient population. The TODAY study has been designed to determine the best treatment strategies to improve glycemia, reduce complications, and ameliorate insulin resistance and beta-cell failure in pediatric type 2 diabetes.[4]

Other Considerations

The management of type 2 diabetes in children and adolescents carries several special considerations that do not arise when type 2 diabetes presents later in life. These include the following:

1. Type 2 diabetes is a lifelong, progressive condition. The lifestyle habits and routines developed early in childhood and adolescence are likely to remain for the rest of the patient's life. These include diet; physical activity/exercise; and adherence to medications/insulin, SMBG, and other aspects of diabetes care and healthcare in general. Thus, medical nutritional therapy and education in regard to lifestyle are especially important in the pediatric and adolescent patient.

2. These patients are at extremely high risk for development of cardiovascular disease and other complications of diabetes early in life. Accordingly, there is the need for early and aggressive treatment, management of glycemic control, and avoidance of additional risk factors for cardiovascular disease (eg, smoking, hypertension, and dyslipidemia).

3. It is essential to include the family in the care of the child or adolescent with diabetes. Family members need to be involved in terms of interventions with regard to the patient's dietary habits; the patient's physical activity, exercise habits, and self-image in terms of obesity; and thorough understanding of diabetes and its complications and management.

4. Puberty is associated with insulin resistance, which peaks at age 12 in girls and age 13 in boys, and may be an important time for careful reassessment of children with risk factors for type 2 diabetes.

5. There is a significant psychological burden imposed on these patients by the addition of the frequent concomitant stigma of obesity. Referrals for psychiatric or psychological interventions may be warranted in some cases, especially when significant depression or anxiety is noted or when treatment compliance is an issue.

6. Pregnancy is not uncommon during adolescence. Pregnancy confers increased insulin resistance. In the event that a pregnancy is planned or desired, it is essential to achieve excellent glycemic control in the several weeks preceding conception and throughout the entire pregnancy and the postpartum period.

7. Birth control pills have been associated with increased insulin resistance, venous thrombosis, and increased risk for cardiovascular disease (when used in adults). The extent of these effects depends on the nature of the preparations used.

8. There is the risk that access to healthcare may be interrupted as adolescents transition from the care of their pediatrician to a primary care clinician or to other specialists who care for adult patients. For patients with diabetes, it is especially important to maintain continuity of care.

9. There is a high frequency of eating disorders among adolescents and young adults who leave home and begin college. Prevention or management of such disorders becomes particularly important for those patients with diabetes.

10. Screening of the patient's siblings, parents, and other family members for type 2 diabetes is recommended.

11. When patients of any age are using handwritten logbooks to record their SMBG values, there is the possibility that they will falsify their records.^[66,67] This problem may be more severe among children and adolescents. Accordingly, there is an important advantage to downloading the results stored in the memory of the patient's glucose meter, which reduces but does not eliminate the possibility of falsification of glucose data.

12. Female patients should be monitored for possible development of polycystic ovary syndrome.

13. Female patients anticipating pregnancy should be instructed in the need to achieve excellent glycemic control before conception, as in the case of patients with type 1 diabetes.

Conclusions

An alarming number of children and adolescents have or are at risk of developing type 2 diabetes. With the rising prevalence of this disease in children and adolescents, it is important for all healthcare professionals to assess pediatric patients for risk factors associated with type 2 diabetes. Prompt and accurate screening, diagnosis, and classification of diabetes in children with risk factors are critical to ensure that appropriate therapies are initiated in a timely manner. Screening for prediabetes will become increasingly important for early intervention in terms of lifestyle changes, hopefully leading to avoidance or delay of the development of diabetes.

Management plans for all children with diabetes must include medical nutrition counseling and lifestyle interventions. Oral antidiabetic agents also may be useful in children with type 2 diabetes. The progressive decline of pancreatic beta-cell function observed in adult patients with type 2 diabetes and the well-known natural history of the disease imply that most children with type 2 diabetes will require insulin replacement within 10 years of onset of the disease.

Although there are only limited data with regard to the effects of strict glycemic control in pediatric patients with type 2 diabetes, many of these patients may benefit from the flexibility of long-acting insulin analogs coupled with rapid-acting insulin analogs given at mealtime (ie, basal-bolus therapy involving MDI). Others may have their diabetes successfully managed with a regimen of 2 injections per day of a premixed insulin analog.

Most of the treatment strategies discussed here have been extensively evaluated in large clinical trials involving adults with type 2 diabetes.[4] Similar well-designed, large clinical trials employing such treatment regimens in children and adolescents with type 2 diabetes are needed.