Management of Type 1 Diabetes in Children in the Outpatient Setting.

Abstract

Pediatricians should be aware of diabetes treatment advances, which can lead to optimal control of type I diabetes in the outpatient setting.After completing this article, readers should be able to: Provide a concise summary of the epidemiology, pathophysiology, and initial presentation of type 1 diabetes in children.Highlight routine diabetes management and screening recommendations.Review the available insulin preparations used in pediatric type 1 diabetes management.Illustrate contemporary diabetes technology and its role in improving diabetes care.The year 2021 marked the hundredth anniversary of the discovery of insulin by Frederick Banting and Charles Best. (1) This landmark discovery transformed type 1 diabetes from a fatal to a chronic disease. During the past hundred years, type 1 diabetes management has evolved tremendously. Currently, we live in an exciting era of diabetes care that not only provides children with reliable lifesaving insulin but, with recent advancements in insulin delivery and blood glucose monitoring, also promotes a return to normal childhood activities with a hope for reduced long-term complications.Management of type 1 diabetes in outpatient settings is a complex yet rewarding process. The advancements in diabetes technology and the availability of new preparations of insulin have made optimal control of type 1 diabetes in children a feasible task. In this article, we provide a comprehensive review of the current cutting-edge approaches to children with type 1 diabetes. Furthermore, we explore and discuss the available insulin delivery systems and how they may improve outcomes for children with type 1 diabetes.The incidence of type 1 diabetes seems to be steadily increasing, (2)(3) with a prevalence among youth in the United States estimated to be 1.54 to 1.93 per 100,000 younger than 20 years. (4)(5) The prevalence of this disease is disproportionately higher among non-Hispanic white individuals compared with all other ethnic groups. Native Americans have the lowest incidence of type 1 diabetes. (4) The peak incidence of diagnosis is bimodal, with a peak between 5 and 9 years of age and another peak between 10 and 14 years of age. (6)(7)It is essential to differentiate between the different types of diabetes in children. Although type 1 diabetes continues to be the most common form of diabetes in children, there has been an increase in the incidence of type 2 diabetes as well. This increase has been associated with the rise of prevalence of obesity among youth in the United States and worldwide. Note, though, that the presence of obesity in a child with new-onset diabetes is not sufficient to determine the presence of type 2 diabetes over type 1. Therefore, measuring diabetes autoantibodies is frequently necessary to make that differentiation (Table 1).One form of diabetes mellitus that is often overlooked is monogenic diabetes, or maturity-onset diabetes of the young (MODY), which is a group of genetic forms of diabetes that vary in severity from normal variance with no need for treatment to progressive forms that require insulin treatment similar to type 1 diabetes. In their analysis from the SEARCH for Diabetes in Youth study, Pihoker et al (10) found that 1.2% of children with diabetes have MODY. (11) When a child presents with new-onset diabetes, a clinician should suspect MODY in the presence of negative diabetes antibodies and a strong family history of diabetes mellitus.Type 1 diabetes results from insulin insufficiency due to β-cell destruction from an autoimmune process occurring in genetically susceptible individuals exposed to environmental and immunologic factors. (12) The progression toward overt type 1 diabetes typically goes through 3 consecutive stages: the first stage is manifested by the presence of 2 or more autoantibodies in a presymptomatic and normoglycemic individual; the second stage comprises the presence of autoantibodies with glucose intolerance in a presymptomatic patient; and the third stage begins when the patient starts experiencing the typical symptoms of diabetes mellitus (polyuria, polydipsia, weight loss, and development of diabetic ketoacidosis [DKA]). (13)(14)The 4 main autoantibodies found in patients with type 1 diabetes are glutamic acid decarboxylase, tyrosine phosphatase, insulin, and zinc transporter 8 antibodies. The presence of 2 or more of these antibodies in a patient with a genetic propensity for type 1 diabetes places the lifelong risk of developing symptomatic type 1 diabetes close to 100%; the 5- and 10-year risk is approximately 44% and approximately 70%, respectively. (15)Although preventable, approximately one-third of children with new-onset diabetes present with DKA in the United States. (16)(17) This high incidence identifies an area for needed improvement in the identification and management of children with new-onset diabetes. (18)Typical clinical symptoms associated with type 1 diabetes are polyuria, polydipsia, and nocturia. New onset of recurrent bed-wetting is not uncommon in young children with type 1 diabetes. Weight loss is frequently seen at the time of new-onset type 1 diabetes diagnosis. If unrecognized, these symptoms can rapidly progress to abdominal pain, recurrent emesis, dehydration, weakness, and lethargy, (19) which are all symptoms of DKA.In the clinic setting, when new-onset diabetes mellitus is suspected in a child, the presence of 1 or more of the following laboratory findings confirms the diagnosis: A random plasma glucose level greater than or equal to 200 mg/dL (≥11.1 mmol/L) in the presence of classic symptoms of type 1 diabetes as described previously herein.A fasting glucose level greater than or equal to 126 mg/dL (≥7.0 mmol/L).A 2-hour glucose level greater than or equal to 200 mg/dL (≥11.1 mmol/L) after a 1.75–g/kg of glucose load (maximum of 75 g).A glycohemoglobin level greater than or equal to 6.5%.If the child presents with symptoms suggestive of DKA, additional laboratory test results should be obtained. Cashen and Petersen (19) detailed the diagnostic criteria and management of DKA in a review article.Once the diagnosis of new-onset diabetes mellitus is established, insulin therapy should be started. Delay in initiating insulin therapy may lead to progression to DKA.For non–critically ill children with new-onset type 1 diabetes, there is a debate about whether inpatient diabetes management is required. Many experts argue that inpatient management for new-onset diabetes is not cost-effective and does not lead to better long-term metabolic outcomes. (20)(21) Despite that argument, many countries around the world, and many centers in the United States, opt to admit patients with new-onset diabetes to provide extensive and multidisciplinary diabetes education, to monitor for adverse reactions to treatment, and to ensure that the patients and their families are comfortable with starting the diabetes management journey at home.Regardless of the setting of initial diabetes education, the diabetes treatment team should include an expert in pediatric diabetes (pediatrician or endocrinologist), a diabetes educator with expertise in pediatric-onset diabetes, a dietitian, a social worker, and a mental health specialist to help the child and the family cope with the psychological burden of this chronic disease.At this time, due to the nature of the disease, intensive insulin therapy is the only treatment for patients with type 1 diabetes. This is established through a daily multiple-injection regimen or via a continuous subcutaneous insulin infusion device (insulin pump).Although common practice is to use insulin in the form of basal (insulin that is administered regardless of the patient’s feeding status) and prandial (ie, administered before or around meals/snacks) insulin for the management of type 1 diabetes in children, note that insulin therapy should be individualized and titrated based on the need of the child, the child’s lifestyle, and the child’s blood glucose patterns throughout the day. (22)Throughout the past century, insulin preparations have advanced tremendously from purified extract from the pancreas in 1921 to modified insulin analogues using recombinant DNA technology today. (23)Exogenous insulin preparations are broadly divided into 2 categories: rapid-acting/short-acting insulin analogues and basal insulin analogues. In each of these categories, the advancements in genetic engineering and recombinant DNA technology have allowed for the invention of different types of insulin products that vary in onset of action, peak, and length of effect (Table 2). (23)These forms of insulin differ from each other by small alterations in the amino acid structure of the insulin molecule. In 1982, regular recombinant human insulin (Humulin®; Eli Lilly and Co, Indianapolis, IN) was the first genetically engineered medication ever approved by the Food and Drug Administration (FDA). (22) This was followed by Novolin® R (Novo Nordisk Inc, Plainsboro, NJ) in 1991. To improve the insulin absorption process when administered subcutaneously, newer insulin analogues were produced: lispro (Humalog®; Eli Lilly and Co) was approved by the FDA in 1996, aspart (NovoLog®; Novo Nordisk Inc) in 2000, and glulisine (Apidra®; sanofi-aventis US, Bridgewater, NJ) in 2004. (1) These analogues are more rapidly absorbed, metabolized, and excreted than human regular insulin, providing a more ideal way to dose insulin with meals for patients with diabetes. Recently, ultra-rapid-acting insulin preparations were introduced to the market. In January 2020, Fiasp® (Novo Nordisk Inc), an ultra-rapid-acting insulin aspart, was approved by the FDA for use in children as young as 2 years old. The intent of the ultra-rapid-acting insulin is to make it easier for patients with diabetes to administer insulin for carbohydrate coverage right before, while, or even within 20 minutes after eating. (23)These forms of insulin are designed to be administered once a day to maintain steady glucose levels throughout the day. Similar to short-acting insulin, forms of long-acting insulin differ in their amino acid structures. In the United States, glargine (Lantus® [sanofi-aventis US] and Basaglar® [Eli Lilly and Co]) and determir (Levemir®; Novo Nordisk Inc) are long-acting insulin forms approved for use in children for diabetes management. In 2016, the FDA approved use of the ultra-long-acting insulin degludec (Tresiba®; Novo Nordisk Inc) in children.Before embarking on the different ways to manage type 1 diabetes in children at home, it is critical to mention the tremendous social and psychological impact of this disease on children and their families on starting the journey of self-management.The optimal method to manage type 1 diabetes at home differs significantly among patients based on their age, eating habits, lifestyles, parental level of education, socioeconomic status, and many other factors. However, it is established that the constant gold standard is to deliver an intensive insulin regimen via multiple daily injections or a continuous insulin infusion device (insulin pump). (22)To determine the total daily dose of insulin, the patient's age, weight, and pubertal status are considered. The usual initial total daily insulin dose is 0.5 to 1.0 U/kg.To maintain insulin replacement as close to physiologic as possible, a combination of long- and short-acting insulin preparations is usually needed. A ratio of 40% to 50% of long-acting insulin and 50% to 60% of short-acting insulin is widely acceptable as an initial dosing regimen. In most scenarios, long-acting insulin is administered once a day. Short- or rapid-acting insulin preparations are typically administered preprandially to prevent hyperglycemia after eating. The timing of insulin administration is adjusted based on the child's eating habits and the pattern of their glucose trends associated with food. In certain situations, rapid-acting insulin is given between meals in patients with significant hyperglycemia or an illness. The dose of short-acting insulin is calculated based on insulin-to-carbohydrate ratios, or fixed insulin doses based on the amount of carbohydrates the child eats with every meal. To provide flexibility, insulin doses are tailored to the child's carbohydrate intake with every meal, hence carbohydrate counting with insulin-to-carbohydrate ratios is generally the preferred method when the patient and/or the family can apply these skills after inpatient or outpatient education. Preprandial or between-meal hyperglycemia is treated with correction doses of short-acting insulin. This is usually calculated based on a glucose target and correction factor or on a sliding scale.Insulin doses are adjusted frequently after diagnosis depending on glucose level patterns. Many diabetes centers invest time and effort to educate patients and families on monitoring patterns of hypoglycemia and hyperglycemia and on self-adjusting insulin doses. Avenues of communication with the diabetes management teams are open for questions and concerns from families of children with diabetes.To clarify the process outlined previously herein, we provide a practical example. A 10-year-old boy presents with a 2-week history of polyuria, polydipsia, and weight loss. At presentation he is found to have a random glucose level of 285 mg/dL (15.8 mmol/L) and a glycohemoglobin level of 8.9%. The remainder of his evaluation ruled out DKA. After discussing the diagnosis of diabetes mellitus with the child and his family, the diabetes team, in coordination with the child’s family and primary care provider, decided to admit him to the hospital for diabetes management and education. The child's weight is 32 kg and he is prepubertal. The diabetes treatment team decided to start him on a daily multiple-injection insulin regimen.Because the boy is prepubertal and appeared well-hydrated, his initial total daily dose of insulin is calculated based on 0.7 U/kg (a value of 0.5–1.0 U/kg per day); the decision to choose the initial dose depends on the setting (whether the child is observed in the hospital or at home), the age of the child, and pubertal status. Typically, lower doses are chosen in younger, lean, and prepubertal children. Total daily dose = 32 × 0.7 = 22.4 U per day (rounded to 22 U daily)Dose of long-acting insulin = 22 × 50% = 11 U to be administered at bedtime dailyFor short-acting insulin dose, the team decided to calculate based on a carbohydrate ratio and correction factors as follows: ○ To estimate the insulin-to-carbohydrate ratio, the