Type 2 diabetes is becoming more common in children due to the increasing incidence of obesity in the pediatric population. Children with type 2 diabetes usually present with obesity, symptoms suggestive of insulin resistance and a confirmatory laboratory test of an elevated random plasma glucose or fasting plasma glucose concentration or an elevated hemoglobin A1C percentage. The classical symptoms of diabetes such as polydipsia, and polyuria are usually seen late in the presentation of type 2 diabetes in children. Metformin should be used in all children with type 2 diabetes.
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Insulin crystals

Image: “Insulin crystals”. Credit: NASA/Marshall. License: Public Domain


Overview

Type 2 diabetes is a multi-systemic metabolic disease that affects the vascular, renal, hepatic, nervous and endocrinological systems and is characterized by hyperinsulinemia, insulin-resistance, a clear correlation with central obesity, and impaired glucose homeostasis. Therefore, children with type 2 diabetes are usually obese, have dyslipidemia and have hyperglycemia.

Epidemiology of Type 2 Diabetes in Children

Before we dive in the different treatment options for type 2 diabetes in children, we should point out few points concerning the epidemiology of type 2 diabetes in children.

The most recent epidemiological studies estimate the prevalence of type 2 diabetes in children between 12 and 19 years of age to be as high as 23 %. African American children and other non-white ethnic groups have a higher incidence of type 2 diabetes compared to white children.

According to a recent study, the estimated annual incidence of type 2 diabetes in white children younger than 20 years of age was 3 per 100,000 while the annual incidence of the disease was significantly higher in African American children with an estimated figure of 15.7 per 100,000.

An incidence peak was observed in children aged between 15 and 19 years. Girls seem to have a slightly higher risk of developing type 2 diabetes compared to boys.

Pathophysiology of Type 2 Diabetes

The main pathophysiological change observed in type 2 diabetic children is similar to adults. The pancreatic beta-cells show impaired insulin secretion and the peripheral tissues show reduced insulin sensitivity. Central obesity and dyslipidemia are believed to play a crucial role in the development of insulin resistance in children and adults.

Due to the reduced insulin sensitivity in the peripheral tissues, pancreatic beta-cells try to compensate by increasing their secretion of insulin. This is believed to result in a vicious cycle that eventually leads to beta-cell exhaustion and further impair the function of the pancreatic beta-cells.

Clinical Presentation of Type 2 Diabetes in Children

The diagnosis of type 2 diabetes in children is difficult as severe and classical diabetic symptoms are usually present at late stages. Children with type 2 diabetes are usually obese.

The characteristic symptoms of type 2 diabetes in children include polyuria, polydipsia and blurred vision. In contrast to type 1 diabetes, weight loss and diabetic ketoacidosis are not common presentations of type 2 diabetes in children.

The previously mentioned symptoms are believed to be linked to the hyperosmolar state due to hyperglycemia. Symptoms of insulin resistance should also be sought in these children and they include acanthosis nigricans, dyslipidemia and elevated blood pressure. Females with signs and symptoms suggestive of type 2 diabetes and insulin resistance should be evaluated for the possibility of polycystic ovary syndrome.

Diagnostic Workup for Type 2 Diabetes in Children

The diagnosis of type 2 diabetes in children can be confirmed by the presence of the classical clinical symptoms in addition to certain laboratory findings. A random plasma glucose concentration above 200 mg/dL when combined with the classical diabetic symptoms is usually enough to confirm the diagnosis in children.

A fasting plasma glucose concentration of more than 126 mg/dL can also be used to confirm the diagnosis of type 2 diabetes in children regardless of the presence of the classical symptoms. An elevated hemoglobin A1C level of 6.5 % or more is also diagnostic of type 2 diabetes in children.

Due to the delayed presentation of the classical symptoms of diabetes in children, it is recommended to perform a random plasma glucose test or a fasting plasma glucose test in any child who has a body mass index above the 85th percentile especially when they have family history of type 2 diabetes or when they show symptoms suggestive of peripheral insulin resistance.

Treatment of Type 2 Diabetes in Children

In this discussion, we will focus on the efficacy and safety of oral hypoglycemic agents in the management of type 2 diabetes in children. Before we discuss the different treatment options, we should emphasize the goals of treatment of type 2 diabetes in children.

The goals are to achieve a hemoglobin A1C that is less than 7 %, a fasting plasma glucose concentration between 70 and 130 mg/dL and the prevention of the microvascular and macrovascular complications of type 2 diabetes.

Non-pharmacological management of type 2 diabetes in children

Unfortunately, lifestyle modifications alone very rarely succeed in lowering the plasma glucose levels to our previously set goals in children. Regardless, children should still be encouraged to partake in moderate to vigorous physical exercise for several reasons.

Moderate to vigorous exercise for approximately 60 minutes per day is known to decrease peripheral insulin resistance, to help children lose weight, to improve their mode, and to improve the efficacy of the oral hypoglycemic agents that can be used to treat type 2 diabetes. Additionally, moderate to vigorous exercise will lower the risk of cardiovascular disease in children.

Children should be also encouraged to eat a healthier diet. Intake of sugar-sweetened juices and other high-calorie beverages should be limited while the intake of fruits and vegetables should be increased.

Oral hypoglycemic agents in children

When a child presents to the health care provider because of type 2 diabetes, an important decision about prescribing insulin or not has to be made. Usually, when the child is not symptomatic, hemoglobin A1C is < 9 % and random plasma glucose concentration is below 250 mg/dL, insulin therapy should be delayed.

Children who meet the above criteria should be started on metformin combined with lifestyle modifications. Metformin is very effective in lowering the random plasma glucose concentration, the hemoglobin A1C percentage and in helping children lose weight.

The maximum dose of metformin in children is usually 2 grams per day. This maximum dose should be reached gradually. Children with impaired renal function should receive a lower dosage of metformin combined with close monitoring of renal function due to the slightly increased risk of developing lactic acidosis.

Thiazolidinediones such as rosiglitazone are being evaluated for the treatment of type 2 diabetes in children. The efficacy of rosiglitazone is inferior compared to metformin for the management of hyperglycemia in children and the safety of the drug is questionable. Therefore, thiazolidinediones have not been approved so far for the management of type 2 diabetes in children except for research purposes.

Children who do not respond to metformin alone or who have contraindications to metformin might benefit from adding a sulfonylurea. Glimepiride from 1 to 8 mg once daily and glipizide at 2.5 mg twice daily have been evaluated for the management of type 2 diabetes in children and found to be effective and safe.

The use of sulfonylureas in children is considered as off-label because the Food and Drug Administration did not label them to be used in children but is common and acceptable in the clinical practice.

While meglitinides such as repaglinide and nateglinide have been used as adjunctive therapy in the management of type 2 diabetes in adults, their use in children is not approved. Alpha-glucosidase inhibitors such as acarbose can be used as adjunctive therapy for the management of type 2 diabetes in children but they are usually poorly tolerated due to the common gastrointestinal side effects such as diarrhea and abdominal cramps.

Glucagon-like peptide-1 agonists such as exenatide are being studied in the pediatric population and they appear to be effective but they are not approved in children. This group of oral hypoglycemic agents are very effective in lowering the hemoglobin A1C percentage and we hope they can be approved soon to treat type 2 diabetes in children.

The main reason of delayed approval is the lack of randomized clinical trials in children and the possibility of poor tolerability due to common side effects such as nausea, vomiting, headache and diarrhea. These agents can cause hypoglycemia which has been argued to be more hazardous to the developing brain than hyperglycemia, a point that can also delay the approval of using these agents in children.

The amylin analog Pramlintide can be used for the management of type 1 diabetes in children but is not approved for the management of type 2 diabetes due to the very high risk of severe hypoglycemia.

Fortunately, metformin with lifestyle modifications with or without sulfonylureas is usually sufficient for the treatment of type 2 diabetes in children.

Insulin and Type 2 Diabetes in Children

Insulins are safe and effective in the management of hyperglycemia in children. The most commonly used insulins in children are aspart, glulisine, lispro, regular, neutral protamine Hagedorn, detemir, and glargine.

The discussion of insulins’ use in the management of type 2 diabetes in children is not covered in this article but there are certain points that should be emphasized about when to use insulin in a child with type 2 diabetes.

Children who present with diabetic ketoacidosis and thin children with type 2 diabetes might benefit from an insulin without any delay. Additionally, children who present with a random plasma glucose concentration of 250 mg/dL or more should be started on insulin. Children who have a hemoglobin A1C percentage of more than 9 % are better-off with insulin therapy from the beginning.

The use of insulin in the management of type 2 diabetes in children is usually temporary. The rationale behind the temporary use of insulin is the hypothesis that using exogenous insulin would allow the beta-cells to rest and recover. After the initial period of using insulin, the child can be gradually titrated down from insulin and maintained on oral hypoglycemic therapy.

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