Type 1 Diabetes Mellitus

Most children with newly diagnosed type 1 diabetes mellitus (T1DM) present with classic symptoms (polyuria, polydipsia, weight loss) for a few days to several weeks. Other presentations include recent onset of enuresis in a previously toilet trained child, failure to gain weight appropriately in a growing child, perineal candidiasis, especially in a prepubertal child, recurrent skin infections, irritability, and deteriorating school performance.¹ The frequency of diabetic ketoacidosis (DKA) at diabetes onset varies widely by geographic location, ranging from 15% to 67% in Europe and North America, and DKA is even more common in developing countries.^2,3 There is an inverse correlation between the frequency of DKA and the background incidence of T1DM in different populations. DKA at initial presentation is more frequent in infants, toddlers, and preschool age children (up to two thirds of toddlers present in DKA), in children who do not have a first-degree relative with TIDM, and in children whose families are of lower socioeconomic status.²

Prospective follow-up of high-risk subjects shows that the diagnosis of type 1 diabetes can be made in most asymptomatic individuals when metabolic abnormalities are still relatively mild.4,5 The progression of T1DM tends to follow a characteristic clinical course that includes an abrupt onset of classical symptoms that rapidly disappear after insulin replacement therapy is begun. A temporary remission (“honeymoon phase”) often follows with partial recovery of endogenous insulin secretion, demonstrable by plasma C-peptide levels and characterized by stable near-to-normal blood glucose levels and decreasing insulin requirements.¹ Severe DKA and young age at presentation reduce the likelihood of a remission phase. Recurrence or persistence of the autoimmune attack on β cells invariably leads to further β cell destruction and progressive decline in insulin production, leading eventually to complete cessation of insulin production in most cases of childhood onset T1DM.

Type 2 Diabetes Mellitus

Numerous recent studies have examined the characteristics at onset of pediatric type 2 diabetes (T2DM) in various populations. A major difficulty in analyzing and interpreting these studies is the wide range of case definitions used to classify youth as having T2DM. Studies that employ strict criteria for the diagnosis of T2DM show several common characteristics, including obesity, a prominent family history of T2DM, acanthosis nigricans, female preponderance, and average age of presentation in mid puberty. Presentation can range from insidious to severe, and diabetic ketoacidosis is not uncommon, which contrasts with adult-onset T2DM, in which ketoacidosis is rare. Many youth with T2DM present with classic symptoms, including weight loss. Diagnosis in asymptomatic individuals is also common, either as a consequence of the incidental finding of glucosuria or hyperglycemia or as a result of screening individuals at risk. It is likely that many individuals with youth-onset T2DM experience a prolonged period of mild hyperglycemia with minimal or no symptoms.

Initial Management of Newly Diagnosed Type 1 Diabetes Mellitus

Whenever possible, the child with DKA should be cared for in a health care facility that has nursing staff trained in DKA management and access to a clinical chemistry laboratory that can provide frequent and timely measurement of serum chemistries. Children with signs of severe DKA (long duration of symptoms, compromised circulation, depressed level of consciousness) and those at increased risk for cerebral edema (<5 years of age, new-onset diabetes) should be treated in a pediatric intensive care unit or in a children’s ward that specializes in diabetes and can provide equivalent resources and supervision of care.⁹

The goals of initial management of the child with newly diagnosed diabetes mellitus depend on the clinical presentation and include the following: to restore fluid and electrolyte balance, to stabilize the metabolic state with insulin, and to provide basic diabetes education and self-management training for the child (when age and developmentally appropriate) and caregivers (parents, grandparents, guardians, older siblings, daycare providers, and babysitters).

The diagnosis of diabetes in a child is a crisis for the family, who require considerable emotional support and time for adjustment and healing. Shocked, grieving, and overwhelmed parents typically require at least 2 to 3 days to acquire basic or “survival” skills while they are coping with the emotional upheaval that typically follows the diagnosis of diabetes in a child. Even if they are not acutely ill, children with newly diagnosed T1DM usually are admitted to hospital for metabolic stabilization, diabetes education, and self-management training. However, outpatient or home-based management is preferred at some centers that have the appropriate resources.¹⁰ Outpatient or home-based management may offer several advantages: the stress of a hospital stay can be avoided, the outpatient setting or the patient’s home is a more natural learning environment for the child and family, and ambulatory treatment possibly reduces the cost of care for the health care system and the family. The literature comparing initial hospitalization with home-based and/or outpatient management of children who are not acutely ill with newly diagnosed T1DM has recently been critically reviewed. The results are inconclusive owing to insufficient high-quality data. The data suggest that where adequate outpatient and/or home initial management of T1DM in children at diagnosis can be provided, there is no disadvantage in terms of metabolic control nor increase in acute complications, hospitalizations, psychosocial or behavioral problems, or total costs.¹⁰ The decision concerning whether a child with newly diagnosed diabetes should be admitted to hospital depends on several factors. Of these, the most important are the severity of the child’s metabolic derangements, the family’s psychosocial circumstances, and the resources available at the treatment center.

Outpatient Diabetes Care

Goals of Therapy

The Diabetes Control and Complications Trial (DCCT)14,15 and a similar smaller study in Sweden, the Stockholm Diabetes Intervention Study,¹⁶ ended the debate about whether the microvascular complications of diabetes are caused by hyperglycemia and can be prevented or ameliorated. The U.K. Prospective Diabetes Study (UKPDS) in adults with type 2 diabetes^17,18 provided additional scientific evidence for the importance of glycemic control. These clinical trials and long-term follow-up observations of the DCCT cohort unequivocally demonstrate the importance of lowering glycated hemoglobin (HbA1c) values to reduce the risk of development and progression of retinopathy, nephropathy, neuropathy, and macrovascular disease. Treatment regimens that reduce average HbA1c to ≈7% (about 1% above the upper limit of normal) are associated with fewer long-term microvascular and macrovascular complications.^14,15,19 Moreover, improved glycemic control is associated with a sustained decreased rate of development of diabetic complications.^20,21

The aim of diabetes management is to achieve recommended glycemic targets known to reduce the risk for long-term complications; however, no international consensus has been attained on appropriate targets for children of different ages. Biochemical goals of treatment for children and adolescents have recently been published by the International Society for Pediatric and Adolescent Diabetes (ISPAD): ideal <6.05%, optimal <7.5%, and suboptimal 7.5% to 9.0%; action is required when the value exceeds 9.0%.²² The ISPAD guidelines are accompanied by the following statement: “… each child should have their targets individually determined with the goal of achieving a value as close to normal as possible while avoiding severe hypoglycemia as well as frequent mild to moderate hypoglycemia.” The recommendations of a sample of national diabetes organizations are shown in Table 23-1.

Management of young children with diabetes, especially those younger than 5 years old, must balance opposing risks of hypoglycemia (see section on Hypoglycemia below) and future vascular complications. The relative contribution of the prepubertal years to the development of microvascular complications has been uncertain; however, recent evidence indicates that longer prepubertal duration of diabetes increases the risk for retinopathy and, possibly, microalbuminuria in adolescence and young adulthood, but at a slower rate than in the postpubertal years.²³

The risk for microalbuminuria increases steeply with HbA1c >8%.24,25 Based on these considerations, an HbA1c of ≤8.0% is a reasonable general goal for children with diabetes; however, biochemical goals should be individualized, taking into account both medical and psychosocial considerations. Less stringent treatment goals are appropriate for preschool-age children, those with developmental handicaps, psychosocial challenges, and lack of appropriate family support, for children who have experienced severe hypoglycemia or have hypoglycemia unawareness.

Insulin Therapy

Within days to months of diagnosis, most children with T1DM are severely insulin deficient and depend on insulin replacement for survival. The aim of insulin replacement therapy is to simulate as closely as possible patterns of plasma insulin levels that occur in nondiabetic individuals; however, truly physiologic replacement of insulin remains an elusive goal. Insulin pump therapy and multiple daily insulin injections are the two methods that most closely mimic insulin secretion. The first step in choosing an insulin regimen is to establish glycemic goals. For most patients, this means that more than one half of plasma glucose values should fall within the following ranges: preprandial 90 to 130 mg/dL (5 to 7.2 mmol/L), bedtime 100 to 140 mg/dL (5.6 to 7.8 mmol/L), and 1 to 2 hours postprandial <180 mg/dL (10 mmol/L) (see Table 23-1).

In children with severe insulin deficiency, practical considerations, including socioeconomic circumstances, age, supervision of care, ability and willingness to self-administer insulin several times each day, and difficulty maintaining long-term adherence, make physiologic replacement of insulin challenging. No universal insulin regimen can be successfully used for all children with T1DM. The diabetes team has to design an insulin regimen that meets the needs of the individual patient and is acceptable to the patient and/or family members(s) responsible for administering insulin to the child or supervising its administration.

The initial route of insulin administration is determined by the severity of the child’s condition at presentation. Insulin is preferably given intravenously as treatment for DKA. Children who are metabolically stable without vomiting or significant ketosis may be started with subcutaneous (SC) insulin administration. SC insulin treatment in the newly diagnosed child should, ideally, be started with at least three injections per day or a basal-bolus regimen (Table 23-2). Some clinicians have recently started insulin pump therapy at the time of diagnosis, regardless of the severity of presentation or the age of the child.

In addition to severity of metabolic decompensation, the child’s age, weight, and pubertal status guide the initial insulin dose selection. When diabetes has been diagnosed early, before significant metabolic decompensation, 0.25 to 0.5 unit/kg/day usually is an adequate starting dose. When metabolic decompensation is more severe (e.g., ketosis without acidosis or dehydration) the initial dose typically is at least 0.5 unit/kg/day. After recovery from DKA, prepubertal children usually require at least 0.75 unit/kg/day, whereas adolescents require at least 1 unit/kg/day. In the first few days of insulin therapy, while the focus of care is on diabetes education and emotional support, it is reasonable to aim for pre-meal blood glucose levels in the range of 80 to 200 mg/dL and to supplement, if necessary, with 0.05 to 0.1 unit/kg of rapid-acting insulin SC at 3 to 4 hour intervals.

Three major categories of insulin preparations, classified according to their time course of action, are available (Table 23-3). Various insulin replacement regimens consisting of a mixture of short- or rapid-acting insulin and an intermediate- or long-acting insulin are used in children and adolescents (see Table 23-2) and typically are given two to four (or more) times daily. Clear superiority of any one regimen in children and adolescents, in terms of metabolic outcomes, has not been demonstrated.^26,27 All insulin regimens have the same general goal: to provide basal insulin throughout the day and night and additional (prandial) insulin to cover meals and snacks.

When a two-dose regimen is used, the total daily dose is typically divided so that about two thirds is given before breakfast and one third is given in the evening. With a three-dose regimen, short- or rapid-acting insulin is administered before the evening meal, and the second dose of intermediate- or a long-acting insulin is given at bedtime rather than before the evening meal. The initial ratio of rapid- to intermediate-acting insulin at both times is approximately 1:2. Toddlers and young children typically require a smaller fraction of short- or rapid-acting insulin (10% to 20% of the total dose) and proportionately more intermediate- or long-acting insulin. Regular insulin is given at least 30 minutes before eating; rapid-acting insulin (lispro, aspart, glulisine) is given 5 to 15 minutes before eating (depending on the pre-meal blood glucose value). In toddlers and young children with unpredictable eating habits, rapid-acting insulin may be given immediately after the meal (dose based on estimated actual carbohydrate consumed) to prevent hypoglycemia from incorrect insulin dosing owing to the child’s not eating the entire meal.28,29

The optimal ratio of rapid- or short-acting to intermediate- or long-acting insulin for each patient is determined empirically, guided by the results of frequent blood glucose measurements. At least five daily measurements are required initially to determine the effects of each component of the insulin regimen. The blood glucose concentration is measured before each meal, before the bedtime snack, and once between midnight and 4 am. Parents are taught to look for patterns of hyperglycemia or hypoglycemia that indicate the need for an adjustment in the dose. Adjustments are made to individual components of the insulin regimen, usually in 5% to 10% increments or decrements, in response to patterns of consistently elevated (above the target range for several consecutive days) or unexplained low blood glucose levels, respectively. This is referred to as pattern adjustment. The insulin dose is adjusted until satisfactory blood glucose control is achieved with at least 50% of blood glucose values in or close to the individual child’s target range.

At the time of diagnosis, most children have some residual β cell function and within several days to a few weeks often enter a period of partial remission (“honeymoon”), during which normal or nearly normal glycemia is relatively easily achieved with a low dose of insulin. At this stage, the dose of insulin should be reduced to prevent hypoglycemia but should not be discontinued. As destruction of remaining β cells occurs, the insulin dose increases (“intensification phase”), eventually reaching a full replacement dose. The average daily insulin dose in prepubertal children with long-standing diabetes is approximately 0.8 unit/kg/day, and in adolescents 1 to 1.5 units/kg/day.

Medical Nutrition Therapy

Nutritional management is one of the cornerstones of the management of all types of diabetes mellitus, and nutrition education is an essential component of a comprehensive program of diabetes education for patients and their families.⁴⁷ There is no “diabetic diet” per se. Nutrition therapy should be individualized, with consideration given to the patient’s usual eating habits and other lifestyle factors. Monitoring clinical and metabolic parameters, including height and weight, blood pressure, blood glucose, HbA1c, and lipids, as well as quality of life, is crucial to ensure successful outcomes. Diabetes management that combines frequent self-monitoring of blood glucose with intensive insulin therapy and mastery of carbohydrate counting enables children and adolescents to enjoy dietary flexibility while maintaining glycemic control in the target range.

Patients with both T1DM and T2DM have the same goals: namely, to achieve and maintain target blood glucose and HbA1c levels (Table 23-4). The initial focus of medical nutrition therapy (MNT), however, differs between the two major types of diabetes. Children with T2DM typically are obese at presentation, and great emphasis is placed on weight loss, limiting caloric intake, and distributing meals evenly throughout the day. In T2DM, even modest weight reduction alone increases sensitivity to insulin and improves fasting and postprandial plasma glucose levels. Similarly, moderate caloric reduction decreases plasma glucose levels. In adults, structured, intensive lifestyle programs involving participant education, individualized counseling, reduced energy and fat intake (30% of total energy), regular physical activity, and frequent participant contact are necessary to produce long-term weight loss of 5% to 7% of starting weight.⁴⁸ Accordingly, lifestyle changes that lead to weight loss are the cornerstone of therapy in patients with T2DM. In contrast, in the child with T1DM, the primary goal is to match insulin delivery with carbohydrate consumption to achieve blood glucose levels in the age-specific target range (see Table 23-1).

No evidence indicates that the nutritional needs of children with diabetes differ from those of otherwise healthy children. Therefore, nutrient recommendations are based on the requirements of healthy children and adolescents. The total intake of energy must be sufficient to balance the daily expenditure of energy and has to be adjusted periodically to achieve an ideal body weight and to maintain a normal rate of physical growth and maturation.

Treatment

The general goals of treatment for T2DM are the same as those outlined above for T1DM: to normalize fasting and postprandial blood glucose concentrations. However, in addition to blood glucose control, from the outset treatment must include management of comorbidities such as obesity, dyslipidemia, hypertension, and microalbuminuria. The goals of treatment and the recommended standards of care for pediatric patients with T2DM are described in Tables 23-10 and 23-11. The UKPDS showed that intensive glycemic control in T2DM decreased the risk for microvascular complications by up to 25% for each 1% reduction in HbA1c.¹⁸ A multifactorial approach that addresses associated risk factors has been shown in adults to be essential to prevent or reduce complications, including cardiovascular disease (CVD).⁶⁷ Evidence suggests that T2DM in children and adolescents may have a more rapid clinical course; therefore, optimal management is required to prevent diabetes-associated complications.⁶⁸

Currently, no evidence-based guidelines are available for the management of T2DM in children and adolescents; however, as for T1DM, a multidisciplinary diabetes team that consists of a physician, a diabetes nurse educator, a registered dietitian, an exercise physiologist, and a behavioral specialist or social worker is essential. Results of the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study on the treatment of T2DM in children and adolescents are eagerly anticipated. This study is expected to provide much needed information on the natural history of T2DM and the efficacy of various treatments for youth T2DM (Table 23-11).⁶⁹

Comorbidities

Comorbidities associated with T2DM include obesity, metabolic syndrome, hypertension, microalbuminuria, dyslipidemia, and nonalcoholic fatty liver disease. Only hypertension and dyslipidemia are discussed in this section.

Monogenic Diabetes

Diabetes resulting from mutations that primarily reduce β cell function accounts for 1% to 2% of diabetes cases, and numerous genetic subtypes have been described.⁹⁴ Patients who were previously categorized on the basis of their clinical characteristics as having maturity-onset diabetes of the young (MODY) now can usually be classified by specific genetic subgroup. Definition of the genetic subgroup can result in appropriate treatment, genetic counseling, and prognosis.⁹⁴ The term MODY was used to describe children and young adults with autosomal dominantly inherited diabetes that, despite having a young age of onset (at least one family member diagnosed before 25 years of age), was not insulin dependent, as patients had moderate but insufficient circulating C-peptide levels 5 years after diagnosis.^95,96 “Maturity-onset” implies a resemblance to T2DM, but all subtypes are not only different from each other but differ from T2DM. Patients with a clinical diagnosis of T1DM who have a two- or three-generation family history of diabetes with evidence of non–insulin dependence should be suspected of having monogenic diabetes. Absence of pancreatic autoantibodies and detection of C-peptide in the presence of hyperglycemia beyond the honeymoon increase the probability that the patient has monogenic diabetes. Genetic testing for HNF1A mutations (the most common transcription factor mutation that causes monogenic diabetes) is recommended in any young person with apparent T1DM who is antibody negative and has a parent with diabetes, especially if there is preservation of C-peptide in both the child and the parent.⁹⁴ A monogenic form of diabetes should also be suspected in cases of young-onset apparent T2DM when obesity and features of insulin resistance are absent.

The different genetic subtypes are shown in Table 23-12. They differ in terms of age of onset, pattern of hyperglycemia, response to treatment, and associated extrapancreatic manifestations.⁹⁴

Maternally Inherited Diabetes and Deafness

Maternally inherited diabetes associated with young-onset, bilateral sensorineural deafness (MIDD) should raise suspicion for the mitochondrial point mutation, m.3242A>G, which accounts for 1.5% of Japanese patients with diabetes, but only 0.4% in Europeans and other ethnic groups.⁹⁷ Abnormal mitochondrial metabolism results in abnormal adenosine triphosphate (ATP) generation and defective glucose-induced insulin secretion, reduction in β cell mass, and insulin deficiency. The mutation causes mitochondrial dysfunction resulting in myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. The mean age of diagnosis is 37 years (range, 11 to 68 years). Diabetes in MIDD usually presents insidiously, similar to type 2 diabetes; however, approximately 20% of patients have an acute presentation that resembles that of T1DM, and a minority of patients present with DKA.

Most patients with MIDD initially are treated with dietary modifications or oral hypoglycemic agents, but insulin usually is required by 2 years after diagnosis. Patients with impaired mitochondrial function are prone to develop lactic acidosis; therefore, metformin should not be used because of the theoretical risk that it could exacerbate lactic acidosis.

Neonatal Diabetes Mellitus

Diabetes diagnosed before 6 months of age is likely to be caused by one of the monogenic forms of neonatal diabetes, and not by autoimmunity. Diabetes resolves in about half of all patients (transient neonatal diabetes mellitus [TNDM]), and ≈70% of these cases are linked to abnormalities in the chromosome 6q24 region. In about half of patients with permanent neonatal diabetes mellitus (PNDM), mutations are found in KCNJ11 (potassium inwardly rectifying channel, subfamily J, member 11 gene) or ABCC8 (ATP-binding cassette, subfamily C, member 8 gene), which encode the Kir6.2 and SUR1 subunits, respectively, of the ATP-sensitive potassium channel. Mutations in KCNJ11 and ABCC8 can also cause TNDM. Whether diabetes will be transient or permanent is unknown at the time of diagnosis; therefore, testing for 6q24 abnormalities and KCNJ11 mutations should be performed first, followed by testing for ABCC8 mutations if these tests are negative.

Most patients with neonatal diabetes caused by Kir6.2 mutations have permanent rather than transient diabetes. Approximately 20% have neurologic features. The syndrome of developmental delay, epilepsy, and neonatal diabetes (DEND) occasionally is severe. More commonly, however, epilepsy does not occur, and the developmental delay is less severe. Fetal insulin deficiency often causes low birth weight (mean, 2500 g). Diabetes presents from birth to 26 weeks of age, usually with marked hyperglycemia and ketoacidosis. SUR1 neonatal diabetes has a similar phenotype but more commonly causes transient diabetes, and DEND syndrome is rare.

These patients have little or no endogenous insulin secretion, and C-peptide is usually undetectable.⁹⁸ Sulfonylureas bind to the SUR1 subunits of the K_ATP channel and close the channel in an ATP-dependent manner. Most patients with Kir6.2 and SUR1 neonatal diabetes can transfer from insulin to sulfonylurea and achieve good glycemic control.^99–101 Most patients with K_ATP channel mutations are treated with glibenclamide (glyburide) at considerably higher doses (0.4 to 0.8 mg/kg/day) than are customarily used for the treatment of type 2 diabetes; this may cause transient diarrhea.^99,102,103 Glibenclamide binds nonspecifically to SUR subunits in K_ATP channels in nerve, muscle, and brain, in addition to β cells, which ameliorates the neurologic symptoms.¹⁰⁴ Patients with the severe form of DEND may not respond to sulfonylurea therapy.

Heterozygous mutations in the insulin gene (INS) could account for 15% to 20% of cases of PNDM.¹⁰⁵ Affected infants have a low birth weight, which is typical of all subtypes of neonatal diabetes, but do not have extrapancreatic features. Diabetes is permanent and insulin dependent.

Transient neonatal diabetes mellitus (TNDM) is usually diagnosed in the first week of life (range, 1 to 81 days); birth weights (average, 2000 g) of affected infants are typically lower than those of PNDM. In 70% of cases, an abnormality of a region of chromosome 6q24 results in overexpression of the paternally expressed genes PLAGL1 (pleiomorphic adenoma gene–like 1, also termed tumor repressor ZAC) and HYMAI (hydatidiform mole–associated and imprinted gene).106,107 One third of patients with TNDM have macroglossia. Three types of abnormality have been described: 50% of cases of sporadic TNDM are due to paternal uniparental disomy; most familial cases are due to paternal duplication of 6q24; abnormal methylation of the maternal copy of chromosome 6 is found in sporadic cases. Most of the other cases of TNDM have K_ATP channel mutations distinct from those observed in PNDM.^107,108 Therapy is with insulin; however, by a median of 12 weeks, insulin is no longer required.¹⁰⁶ The rate of relapse is 50% to 60% at an average age of 14 years; this results from moderate β cell dysfunction. At the time of relapse, treatment may include dietary modification, oral hypoglycemic agents, and/or insulin.¹⁰⁹

Cystic Fibrosis–Related Diabetes

At centers that routinely evaluate glucose tolerance in patients with cystic fibrosis, the prevalence of cystic fibrosis–related diabetes (CFRD) increases with age: 9% at age 5 to 9 years, 26% at 10 to 20 years, and approximately 50% by 30 years.110,111 Virtually all patients with exocrine insufficiency have β cell dysfunction. Whereas fasting insulin and C-peptide concentrations may be normal, an oral glucose tolerance test (OGTT) shows delayed and blunted peak insulin secretion. With worsening glycemic status, the impairment of first-phase insulin secretion becomes more pronounced. Secretion of other islet hormones, especially glucagon, is also impaired. The primary defect in CFRD is severe but not absolute insulin deficiency; ketoacidosis is rare. Most patients with CF are sensitive to insulin when they are healthy; however, infection and inflammation increase both peripheral and hepatic insulin resistance.¹¹² Insulin resistance can rapidly become severe during infectious exacerbations.

CFRD develops insidiously, and patients may be asymptomatic for years. Impaired glucose tolerance often first becomes evident in situations where insulin resistance is increased, such as acute lung infection, chronic severe lung disease, glucocorticoid therapy, and high-carbohydrate feeding (e.g., oral, intravenous, via nasogastric or gastrostomy tube), and in association with immunosuppressive regimens after lung transplantation.

An insidious decline in clinical status can occur 2 to 6 years before the diagnosis of CFRD, and pulmonary deterioration correlates with the baseline degree of insulin deficiency.¹¹³ Patients with CFRD have worse lung function, poorer nutritional status, and decreased survival compared with nondiabetic CF patients. Among a large cohort followed for 10 years, 25% of patients with CFRD survived at 30 years as compared with 60% of those without CFRD.¹¹⁴ It is important to identify patients with glucose intolerance before the onset of symptoms. Because normal fasting or random plasma glucose levels do not exclude CFRD, annual testing with a 2 hour OGTT should begin at age 10 years, at a time when the patient is clinically well.

The aims of treatment are to eliminate symptoms of hyperglycemia and to maintain adequate nutrition, growth, and lung function. Insulin is the only recommended therapy for CFRD.¹¹⁵ Insulin prevents protein catabolism and improves weight gain and pulmonary function. Because patients with CFRD typically have unusual dietary patterns with wide daily variation in carbohydrate timing and quantity, the ideal insulin replacement regimen is either flexible basal-bolus therapy with long-acting basal insulin (insulin glargine or detemir) combined with rapid-acting insulin with meals and to correct hyperglycemia (Fig. 23-1B), or an insulin pump. Many patients are unwilling, at least initially, to employ an intensive insulin regimen; in these circumstances, an insulin regimen involving fewer injections but providing adequate insulin coverage for the patient’s main carbohydrate-containing meals may be an acceptable compromise. Total daily insulin requirements frequently change and must be adapted to the patient’s individual needs, for example, during acute illness, with glucocorticoid therapy, and during periods of intensive enteral or parenteral nutrition.

CFRD patients require at least 120% to 150% of normal caloric intake for age and gender to maintain their weight. Therefore, diet should never be restricted. Fat should account for 40% of calories, and no restriction is placed on refined sugars. Patients should be taught carbohydrate counting and how to use rapid-acting insulin with meals.

Insulin therapy is not currently recommended for patients with impaired glucose tolerance but without fasting hyperglycemia, unless evidence of persistent poor growth, inability to maintain weight, or unexpected decline in pulmonary function is found. More intensive blood glucose monitoring should be performed during periods of stress such as acute pulmonary exacerbations when increased insulin resistance occurs, leading to hyperglycemia that may temporarily require treatment with insulin. These patients are at significant risk for progression to CFRD with fasting hyperglycemia and should be monitored with annual OGTTs.

Destruction of pancreatic α cells results in glucagon deficiency, and long-term glucocorticoid use can cause adrenocortical insufficiency. Consequently, patients with CFRD are at increased risk for severe hypoglycemia owing to malabsorption and impaired counterregulatory responses.

Self-Monitoring of Blood Glucose

Self-monitoring of blood glucose (SMBG) is the cornerstone of modern diabetes care. Most glucose meters now display plasma values, which are about 10% to 15% higher than those for whole blood. Patients/parents must be taught how to use these data to assess the efficacy of therapy and to adjust the components of their treatment regimen to achieve individual blood glucose goals. Most glucose meters have an electronic memory; however, it is valuable for patients/parents to keep written records of their results and to analyze the data for patterns and trends and to make adjustments when necessary. For most patients with T1DM, SMBG should be performed at least four times daily: before each meal and at bedtime. To minimize the risk for nocturnal hypoglycemia, blood glucose (BG) should be measured between midnight and 4 am once each week or every other week, and whenever the evening dose of insulin is adjusted. If HbA1c targets are not being met, patients should be encouraged to measure BG levels more frequently, including 90 to 120 minute after meals. Frequency of BG monitoring is an important predictor of glycemic control in children with T1DM.¹¹⁶ The optimal frequency of SMBG for patients with T2DM is not known but should be sufficient to facilitate attainment of the individual patient’s glycemic goals. Children who are able to perform SMBG independently must be properly supervised because it is not unusual for children to fabricate data with disastrous consequences.

Continuous Glucose Monitoring

The technology for continuous glucose monitoring (CGM) has evolved rapidly over the past several years. Current CGM devices measure glucose in the interstitial fluid by means of a short, thin subcutaneous probe that can be used for 3 to 7 days. The accuracy of CGM devices is improving but is not yet considered sufficient to substitute for SMBG performed with portable glucose meters. Furthermore, each newly placed CGM probe must be calibrated during a period of stable glycemia over several hours by performing simultaneous capillary blood glucose measurements. It is important to note that there is a several minute lag between actual plasma glucose and interstitial glucose concentrations. Thus, current CGM devices cannot substitute for SMBG; they are used as an adjunct to provide blood glucose information between SMBG measurements.¹¹⁷

The latest generation of continuous glucose monitoring devices reports the estimated plasma glucose values in real time (RT-CGM) every 1 to 5 minutes via a user interface. Several such RT-CGM devices are commercially available and have been approved for use in the United States and Europe. Information from RT-CGM allows the user to detect the early phases of a hyperglycemic or hypoglycemic episode, thereby enabling corrective action to be taken after confirmatory SMBG. Short-term (3 month) uncontrolled trials of current-generation RT-CGM have demonstrated improved hemoglobin A1c concentrations and a high level of patient satisfaction.¹¹⁸ Whether use of RT-CGM will lead to durable improvements in glycemia and/or reduction in risk of acute diabetic complications is unknown and is the subject of ongoing investigation.

Symptoms and Signs of Hypoglycemia

Symptoms of hypoglycemia are caused by neuronal deprivation of glucose and may be autonomic (sweating, shaking, pallor, palpitations) or neuroglycopenic (difficulty concentrating, blurred vision, confusion, drowsiness, odd behavior, slurred speech, loss of coordination), or a combination of both autonomic and neuroglycopenic symptoms. The most common signs and symptoms of hypoglycemia in diabetic children are pallor, weakness, tremor, hunger, fatigue, drowsiness, sweating, and headache.136,137 In contrast to adolescents, autonomic symptoms are less common in children younger than 6 years old, whose symptoms of hypoglycemia are more often neuroglycopenic or nonspecific in nature.¹³⁷ Behavioral changes (irritability, erratic behavior, inconsolable crying) are often the primary manifestation of hypoglycemia in young children, and this difference has important implications for parent education on hypoglycemia. Also, in contrast to adult patients, who usually are able to distinguish between autonomic and neuroglycopenic symptoms, children and their parents report that symptoms tend to cluster.¹³⁸ The coalescence of autonomic and neuroglycopenic symptoms in children may indicate that both types of symptoms are generated at similar glycemic thresholds.

Biochemical hypoglycemia (with or without symptoms) is defined by the American Diabetes Association as any plasma glucose level ≤70 mg/dL.¹³⁹ This is the plasma glucose level at which counterregulatory hormone responses are activated and awareness of symptoms occurs. It should be noted, however, that these responses may be triggered at higher glucose levels in healthy 8- to 16-year-olds and in children and adolescents with T1DM who have poor glycemic control.¹⁴⁰ Hypoglycemia is classified in terms of its severity as mild, moderate, or severe. Most episodes are mild.¹³⁷ Cognitive impairment usually does not accompany mild hypoglycemia, and older children are able to recognize the symptoms and treat themselves. Mild symptoms abate within about 15 minutes after treatment with a rapidly absorbed form of carbohydrate. Moderate hypoglycemia has both neuroglycopenic and adrenergic symptoms (e.g., mood changes, irritability, decreased attentiveness, drowsiness, behavior change). Preschool-age children invariably require assistance with treatment because they often are confused and their judgment may be impaired; also, weakness and lack of coordination may make self-treatment difficult. Moderate hypoglycemia causes more protracted symptoms and may require a second treatment with oral carbohydrate. Severe hypoglycemia is characterized by sufficient cognitive impairment that the assistance of another person is needed for treatment. Such events include episodes of unresponsiveness, unconsciousness, or convulsions requiring emergency treatment with glucagon or intravenous glucose. This definition is difficult to apply to very young children, who, by definition, require assistance for treatment of all episodes of hypoglycemia.

Children who have had diabetes for several years may describe a change in their symptoms over time. Autonomic symptoms tend to occur less frequently and to become more muted, and neuroglycopenic symptoms (e.g., drowsiness, difficulty concentrating, lack of coordination) are more common. Patients must learn to recognize the change in symptoms to prevent severe episodes.¹⁴¹ The blood glucose concentration at which symptoms occur varies among patients, and the threshold may vary in the same individual in parallel with antecedent glycemic control. Children with poorly controlled diabetes experience symptoms of hypoglycemia at higher blood glucose concentrations than those with good glycemic control, similar to adults with diabetes.^140,142

Impact of Hypoglycemia on the Child’s Brain

Numerous studies have documented cognitive impairments and academic difficulties in children and adolescents diagnosed with T1DM in early childhood. Global intellectual deficits have been described, as well as specific neurocognitive impairments in memory, visuospatial skills, and attention (see reference 143 for review). Neuropsychological complications have been detected within 2 years of onset of diabetes.^144,145 Children with long-term diabetes, especially those who developed the disease before the age of 6 years appear to be at greatest risk. However, it is difficult to dissect out the contributions of metabolic disturbances (hyperglycemia and hypoglycemia) and the psychosocial effects of chronic disease in a young child.¹⁴⁶ Evidence linking hypoglycemia to neuropsychological defects has been found. For example, Rovet et al. observed specific defects associated with a history of severe hypoglycemic events,^147,148 whereas Golden et al. found no evidence of an association with severe episodes and thought that asymptomatic hypoglycemia may be more important.¹⁴⁹ Impaired intellectual development without a clear relationship to experienced hypoglycemia has also been reported.¹⁵⁰ Thus, cognitive impairments in children with early-onset diabetes mellitus may result from a number of factors whose relative importance is still unclear, including severe hypoglycemia, recurrent asymptomatic hypoglycemia, psychosocial effects of chronic illness, and chronic hyperglycemia.^146,151 The neurocognitive sequelae of intensive diabetes management in children whose brains are still developing are still largely unknown. Preliminary findings suggest poorer memory skills, presumably as the consequence of recurrent and severe hypoglycemia.¹⁵²

Even in the absence of typical symptoms, cognitive function deteriorates at low blood glucose levels.¹⁵³ Moderate and severe hypoglycemia is disabling, affects school performance, and makes driving a car or operating dangerous machinery hazardous^153–156; the utmost effort should be made to avoid such events. Repeated or prolonged severe hyperinsulinemic hypoglycemia can cause permanent central nervous system damage, especially in very young children. Fortunately, hypoglycemia is a rare cause of death in children with T1DM.¹⁵⁷

Frequency of Hypoglycemia

The true frequency of mild (self-treated) symptomatic hypoglycemia is almost impossible to ascertain because mild episodes are quickly forgotten and/or are not recorded. In a 12-month population-based study, Aman et al.¹³⁶ found that mild episodes (managed by the child without assistance) occurred in 97% of children and occurred at least once a week in 53%. More recently, Tupola et al.¹⁵⁸ prospectively examined the frequency of hypoglycemia (blood glucose <54 mg/dL) in 161 children and adolescents predominantly treated with multiple doses of insulin, who were asked to document hypoglycemia episodes in a 3 month diary. Fifty-two percent of the clinic population experienced episodes of hypoglycemia (0.6 hypoglycemia events per patient per month), of which 77% were mild.

The literature is replete with reports of the frequency of severe hypoglycemia in children and adolescents with diabetes.158–183 However, various methods of collecting data, variability among clinic populations, ages of patients, therapeutic methods, intensity of treatment, and definitions of severe hypoglycemia make interpretation of the data and comparisons among the reports difficult.^146,184 For example, in some studies, severe hypoglycemia is defined as loss of consciousness or seizure, whereas others included children who required assistance with treatment. In young children, all episodes of hypoglycemia require the assistance of a third party for treatment, regardless of the severity of the symptoms. It is not surprising, therefore, that the reported incidence of moderate or severe hypoglycemia varies widely in the pediatric diabetes population. The highest incidence of hypoglycemia in the DCCT was seen in intensively treated adolescents, with the rate of hypoglycemia requiring assistance reaching 85.7 events per 100 patient-years and 26.7 episodes of seizure or coma per 100 patient-years. Recent prospective studies with strict definitions of hypoglycemic events and well-described populations continue to show disturbingly high rates of severe hypoglycemia; younger children and patients with tight glycemic control are at greatest risk.^{171,176,178,185–187} However, the rate of severe hypoglycemia appears to have decreased in recent years.^{178–181,183,188} Studies of severe hypoglycemia published since 2000 that included both children and adolescents report an incidence rate of 8 to 36 episodes of severe hypoglycemia per 100 patient-years.^{116,178–180,183,188} A recent study from Asia and the Western Pacific Region, which defined severe hypoglycemia as any episode requiring assistance in the previous 3 months, reported an incidence of 73 per 100 patient-years, with significant variation among the participating countries.¹⁸² The widespread use of CSII and the availability of insulin analogues that can more closely mimic physiologic insulin replacement have contributed to the reduction in risk for severe hypoglycemia (Table 23-13).

Many, but not all, studies have found an increased frequency of severe hypoglycemia in younger children* and in association with lower hemoglobin A1c concentrations.† Other factors associated with a higher risk for moderate and severe hypoglycemia are a prior history of severe hypoglycemia,^{163,168,187,190} relatively higher doses of insulin and low C-peptide secretion,‡ longer duration of diabetes,^{165,171,174,181} male gender,^167,190 psychiatric disorders,¹⁷⁸ and underinsurance^178,186 (Table 23-14).

Causes of Hypoglycemia in Diabetes Mellitus

Hypoglycemia is the result of a mismatch between insulin dose, food consumed, and recent exercise. The numerous reasons it may occur in patients with T1DM are shown in Table 23-15.

Patient errors related to insulin dosage, erratic meal or snack times, decreased food intake, or unplanned exercise account for 50% to 85% of episodes of hypoglycemia in children and adolescents.136,161,163–165,169 After years of living with diabetes, some patients and/or their parents conduct their routine diabetes self-care practices without carefully thinking about the intricate interplay among insulin, food, and exercise.¹⁹¹

New and improved methods of replacing insulin (CSII and MDI regimens using rapid- and long-acting insulin analogues), education that specifically focuses on hypoglycemia,¹⁹² behavioral education approaches such as blood glucose awareness training, and intermittent continuous glucose monitoring may enable patients to maintain improved glycemic control with less risk for severe hypoglycemia than was previously possible.^180,183,188 These claims have yet to be confirmed in large prospective studies. Several reports have shown that insulin pump therapy is associated with fewer hypoglycemic events despite improved glycemic control.^{188,193–195} This may be so because CSII permits lower (and adjustable) rates of basal insulin delivery compared with injection therapy, especially after exercise and at night when hypoglycemia is most common. Rapid-acting insulin analogues decrease the frequency of hypoglycemia,¹⁷³ and basal-bolus therapy combining long-acting insulin analogues (glargine, detemir) with pre-meal rapid-acting insulin analogues (lispro, aspart) decreases the incidence of nocturnal hypoglycemia when compared with regimens using NPH combined with Regular insulin³⁶ or insulin aspart.³⁷

Nocturnal Hypoglycemia

Hypoglycemia, often asymptomatic, frequently occurs during sleep.¹⁹⁶ Moderate and severe hypoglycemia are more common during the night and early morning (before breakfast) than during the daytime.^171,197 In the DCCT, 55% of severe hypoglycemia events occurred during sleep and 43% occurred between midnight and 8 am.^190,197 In children, up to 75% of severe hypoglycemia occurs during the nighttime hours.¹⁷¹

Both children and adults studied either in the hospital or at home with frequent intermittent or continuous blood glucose measurements during the night show a high incidence (14% to 47%) of asymptomatic hypoglycemia (see references 146 and 196 for review). Episodes during sleep may exceed 4 hours in duration, and up to half of these episodes may go undetected because the subject does not awake from sleep. The incidence of hypoglycemia on any given night is affected by numerous factors, including the insulin regimen, the timing and content of meals and snacks, and antecedent physical activity.¹⁹⁸ Long after strenuous physical exercise has ended, a sustained increase in insulin action on muscle and liver is seen, along with blunting of the counterregulatory response to hypoglycemia.^199,200 The highest frequency of asymptomatic nocturnal hypoglycemia occurs in children younger than 10 years of age.^201–205 Low blood glucose concentrations in the early morning (before breakfast) are associated with a higher frequency of preceding nocturnal hypoglycemia. Knowledge of this fact is useful in counseling patients to modify the evening insulin regimen and bedtime snack to prevent more severe nocturnal hypoglycemia.

Sleep impairs counterregulatory hormone responses to hypoglycemia in normal subjects and in patients with diabetes mellitus.206,207 Because a rise in plasma epinephrine is normally the main hormonal defense against hypoglycemia, impaired counterregulatory hormone responses to hypoglycemia explain the increased susceptibility to hypoglycemia during sleep. Furthermore, asymptomatic nocturnal hypoglycemia may impair counterregulatory hormone responses.²⁰⁸ Thus, impaired defenses against hypoglycemia during sleep may contribute to the vicious cycle of hypoglycemia, impaired counterregulatory responses, and unawareness of hypoglycemia while either awake or asleep. Recurrent asymptomatic nocturnal hypoglycemia is therefore an important cause of hypoglycemia unawareness, which, in turn, leads to more frequent and severe hypoglycemia due to failure to experience autonomic warning symptoms before the onset of neuroglycopenia.²⁰⁹

Treatment

The goal is to restore the blood glucose level to normal as quickly as possible; aim to raise the blood glucose to 100 mg/dL. Except in preschool-age children, most episodes of symptomatic hypoglycemia are self-treated with rapidly absorbed carbohydrate such as glucose tablets, juices, soft drinks, candy, crackers, or milk. Glucose tablets raise blood glucose levels more rapidly than orange juice or milk, and the dosage is easily calibrated.²¹⁰ Glucose tablets are the treatment of choice for children old enough to chew and safely swallow large tablets. The recommended dose is 0.3 grams glucose per kg body weight (5 to 20 grams, depending on the child’s body weight). The blood glucose concentration should be re-measured 15 minutes after treatment, and if the value does not exceed 70 to 80 mg/dL, treatment should be repeated. The glycemic response to oral glucose usually lasts less than 2 hours. Therefore, unless a scheduled meal or snack is due within an hour, the patient should be given a snack or a meal containing carbohydrate and protein.

Hypoglycemia frequently occurs when a child with diabetes is unable to consume or absorb oral carbohydrate because of nausea and vomiting caused by an intercurrent illness (e.g., gastroenteritis) or when oppositional behavior and food refusal occur in very young children. To maintain blood glucose concentrations in a safe range, parents seek emergency medical attention or attempt to force-feed oral carbohydrate to an ill child, which often leads to more vomiting. Mini-dose glucagon raises blood glucose by 60 to 90 mg/dL within 30 minutes, and its effect lasts approximately 1 hour. This method is effective in managing most situations of impending hypoglycemia at home. Using a U-100 insulin syringe and after dissolving 1 mg glucagon in 1 mL of diluent, children ≤2 years should receive 2 “units” (20 µg) of glucagon SC, and children older than 2 years should receive 1 unit (10 µg) per year of age up to 15 units (150 µg). If the blood glucose concentration does not increase within 30 minutes, twice the initial dosage should be administered.211,212

Severe reactions (unresponsiveness, unconsciousness, or convulsions) require emergency treatment with parenteral glucagon (IM or SC). The usual recommended dose is 0.5 mg if the child is <12 years and 1 mg if >12 years, or 10 to 30 mcg/kg.213,214 Glucagon raises blood glucose levels within 5 to 15 minutes and usually relieves symptoms of hypoglycemia. Symptoms of experimentally induced hypoglycemia in diabetic children are relieved within 10 minutes of giving glucagon by SC or IM injection. Mean blood glucose and plasma glucagon levels are slightly but not significantly higher after IM than SC injection. In children with diabetes and in healthy adults,²¹⁵ no important differences have been noted between the effects of glucagon injected either SC or IM. The plasma glucagon levels attained are higher than those in the peripheral venous or portal blood of healthy adults during insulin-induced hypoglycemia, and they are probably higher than is necessary for maximal effect. The increase in blood glucose concentration after glucagon administration is sustained for at least 30 minutes. Therefore, it is unnecessary to repeat the dose or force the child to eat or drink for at least 30 minutes. Intranasal glucagon has a similar effect, but it is not available in the United States.²¹⁶ In an emergency department or hospital, the preferred treatment is intravenous glucose (0.3 g per kg). After bolus administration of glucose, the glycemic response is transient; therefore, intravenous glucose infusion should continue until the patient is able to swallow safely.

If severe hypoglycemia was prolonged and the patient has had a seizure, complete recovery of cognitive and neurologic function may take many hours despite restoration of normal blood glucose levels.²¹⁷ Permanent hemiparesis or other neurologic sequelae are rare^218,219; however, the postictal period may be complicated by headache, lethargy, nausea, vomiting, and muscle ache.

Morbidity and Mortality of DKA in Children

DKA is the leading cause of acute morbidity and mortality in children with type 1 diabetes.⁹ Reported mortality rates from DKA in national population-based studies are reasonably constant in the range of 0.15% to 0.31%. In areas with sparse medical facilities, the risk of dying from DKA is greater, and children may die before receiving treatment.¹⁵⁷ Cerebral edema accounts for 57% to 87% of all deaths from DKA.^225,226 The incidence of cerebral edema has been fairly consistent between national population-based studies, at 0.46% in Canada to 0.87% in the United States. Mortality rates from cerebral edema in population-based studies are 21% to 25%. Significant morbidity occurs in 10% to 26% of survivors. Other causes of DKA-related morbidity and mortality include hypokalemia, hyperkalemia, hypoglycemia, sepsis, and other central nervous system (CNS) complications such as thrombosis.⁹

Cerebral edema typically occurs 4 to 12 hours after the start of treatment for DKA but can occur before treatment has begun or at any time during treatment. Symptoms and signs are variable and include onset of headache, change in neurologic status (restlessness, irritability, drowsiness, deterioration in level of consciousness), inappropriate slowing of the heart rate, and an increase in blood pressure.²²⁷ Cerebral edema is more common in children with severe DKA, new-onset T1DM, younger age, and longer duration of symptoms. The cause of cerebral edema remains poorly understood²²⁸ (Table 23-16).

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