CHAPTER 154

Diabetes Mellitus

Jennifer K. Yee, MD, and Catherine S. Mao, MD

Diabetes mellitus is the second most common chronic illness after asthma among children in developed countries. Diabetes mellitus is a metabolic imbalance that results from insulin deficiency, impairment of insulin action, or both. Advancement in the knowledge of the pathophysiology supports the assessment that diabetes is a heterogeneous disease involving immunologic, environmental, and genetic factors. This has led to a categorization of diabetes based on its pathophysiology rather than the therapeutic intervention. Diabetes associated with absolute insulin deficiency and impaired beta cell function is called type 1 (DM1) (previously juvenile onset or insulin-dependent), and diabetes associated with insulin resistance as well as impaired beta cell function is called type 2 (DM2) (previously adult onset or non-insulin-dependent).

Epidemiology

Overall, diabetes affects 9.4% of the population in the United States. The prevalence among adults age 18 years and older is 12.4%, while the prevalence among children and adolescents younger than 20 years is 0.23%. Diabetes mellitus type 1 and DM2 have been increasing in incidence among youth. From 2002–2003 to 2012–2013, DM1 increased from an incidence of 19.5 cases in 100,000 youths per year to an incidence of 21.7 in 100,000 youths per year. In the same time frame, DM2 increased from an incidence of 9.0 cases in 100,000 youths per year to 12.5 in 100,000 youths per year. Additionally, the populations affected by DM1 and DM2 seem to differ. Type 1 diabetes mellitus is seen equally among girls and boys, with the highest incidence among white youth. Type 2 diabetes mellitus is more prevalent among girls and has the highest incidence among black, Mexican American, and Native American populations. The peak age of presentation for DM1 is between 5 and 15 years. Less is known about DM2 in children, but previous studies show a mean age of 13.8 years at presentation.

The SEARCH for Diabetes in Youth Study is a population-based, observational study of physician-diagnosed diabetes among youth younger than 20 years from centers based in 5 states—South Carolina, Ohio, Colorado, California, and Washington. Much of the current epidemiologic data concerning DM1 and DM2 among youth in the United States has been determined from the data collected in this study.

Monogenic forms of diabetes are uncommon, comprising approximately 1% of all diabetes cases, which include neonatal diabetes (onset in the first 6 months after birth), and maturity-onset diabetes of the young.

Clinical Presentation

Children can vary in their clinical presentation from being asymptomatic to having fulminant metabolic imbalance (Box 154.1). Type 1 diabetes mellitus commonly presents with a classic triad of polydipsia, polyuria, and polyphagia. The most consistent presenting concern is increased urinary frequency, manifested as nighttime polyuria or secondary enuresis. Alterations in appetite and thirst are most commonly recognized when disease onset occurs in the preschool years, likely because parents and guardians are most able to monitor eating and drinking behaviors during the child’s first few years. Weight loss can be variable but is more common in DM1 than in DM2. Recent trends indicate that diabetic ketoacidosis (DKA) occurs at the time of initial presentation in up to 31.1% in DM1 and 5.7% in DM2. Diabetic ketoacidosis presents with vomiting, polyuria, dehydration, and Kussmaul respirations. Children and adolescents with DM2 also report having the classic triad of symptoms but often are identified through screening urinalysis. Type 2 diabetes mellitus is strongly associated with obesity (body mass index ≥95th percentile [see Chapter 155]), acanthosis nigricans, and having a first-degree relative with DM2.

Pathophysiology

The patient with DM1 has an absolute insulin deficiency resulting from autoimmune destruction of the beta cells of the pancreas. The disease process is thought to be triggered by an environmental factor, such as a virus or toxin, in the genetically susceptible individual. Exposure occurs in early childhood, but disease progression can be variable. More than 90% of affected individuals carry human leukocyte antigen-DR3 or -DR4. Discordance of disease among twins supports the theory that DM1 involves an environmental exposure in genetically susceptible individuals. Twin studies show evidence of a preclinical autoimmune process, which also has predictive value in identifying susceptible individuals at risk for developing DM1. Immune changes include an increase in activated T-cells expressing human leukocyte antigen– DR, islet cell antibodies (ICA), insulin autoantibodies, glutamic acid decarboxylase (GAD) antibodies, and islet antigen 2 (Table 154.1).

Abbreviations: DM1, type 1 diabetes mellitus; GAD, glutamic acid decarboxylase; IA-2, islet antigen 2; IAA, insulin autoantibodies; ICA, islet cell antibodies.

^a Individuals with first-degree relative with type 1 diabetes.

Disordered immune function, in which some antigenic components of pancreatic islet cells are not recognized as self, seems to be the pathogenic mechanism for the development of DM1. It is generally believed that at least 90% of beta cell mass must be destroyed before problems with glycemic regulation are manifest. Endogenous insulin deficiency, occurring as a natural consequence of islet cell destruction, results in the inappropriate use of carbohydrate. Cellular uptake of glucose by liver, muscle, and adipose tissue is blocked. Synthesis of glycogen, protein, and fat is reduced, and a catabolic state marked by lipolysis, proteolysis, and ketone body formation ensues. Increased serum glucose and ketones present an overwhelming osmotic load to the kidneys, resulting in urinary losses of volume and cations (Na⁺, K⁺, NH₄).

The autoimmune phenomena described previously are not evident in DM2 as demonstrated by the absence of ICAs, insulin autoantibodies, and GAD antibodies. This disease, which is characterized by resistance to insulin, may assume different presentations in childhood. The more traditional form of DM2 presents in older children and adolescents and is strongly associated with obesity and having a first-degree relative with DM2. Like adults with DM2, insulin resistance is present, but the existence of a relative insulin deficiency is necessary to develop DM2.

Differential Diagnosis

Diagnosis is usually straightforward given the symptomatology, except in children who present at a very young age. Although the onset of diabetes is rare before 1 year of age, the disease may present with nonspecific symptoms (ie, irritability, vomiting, tachypnea, poor weight gain). When diabetes presents before 1 year of age, or in a child with a strong family history of diabetes and no evidence of autoantibodies or insulin resistance, monogenic causes of diabetes warrant consideration. Chemotherapeutic agents (eg, L-asparaginase) and a variety of medications (eg, corticosteroids, diuretics, oral contraceptives, phenytoin, epinephrine) may induce glucose intolerance. Immunosuppressants taken by transplant recipients also cause hyperglycemia. Glycosuria without evidence of ketosis or elevated blood glucose occurs in certain renal conditions (eg, Fanconi syndrome, carbohydrate malabsorption syndromes, heavy metal intoxication). Transient hyperglycemia, with or without glycosuria, may occur in response to physiological stress (eg, burns, trauma, hyperosmolar dehydration). In most of these cases, glucose regulation returns to normal within several days.

Evaluation

Evaluation should focus on the diagnosis of diabetes (ie, hyperglycemia) and the category because DM1 and DM2 can have different treatment modalities and disease courses.

History

The history should focus on classic symptomatology and whether a family history of diabetes exists. Up to 80% of youth with DM2 will report a positive family history of diabetes, compared with 20% of youth with DM1. Additionally, exogenous causes of diabetes should be ruled out. Obtaining a history of viral infections or chemical exposures during early childhood may be useful (Box 154.2).

Physical Examination

Growth parameters should be measured and plotted on standard growth curves. Obesity is present in 96% of youth with DM2, compared with 24% of youth with DM1. Although DM1 usually is associated with weight loss as part of the presenting symptomatology, even those patients with obesity and with DM2 may have lost weight prior to presentation. Youth with uncomplicated DM1 may have an unrevealing physical examination, whereas those with DM2 may have physical findings associated with obesity. One study demonstrated that 60% of adolescents with DM2 had acanthosis nigricans and 32% had hypertension at presentation. An intercurrent infection may trigger the symptomatology and should always be sought in cases of ketoacidosis. The child who presents with ketoacidosis may have evidence of vomiting, dehydration, Kussmaul respirations, or in severe cases, altered mental status.

Laboratory Tests

Initial laboratory tests should include evaluation of the serum and urine for glucose and ketones. For the patient presenting with DKA, evaluation should also include a full chemistry panel to assess for metabolic acidosis, hypokalemia, and serum osmolality. After the diagnosis of diabetes is suspected, further testing can assist in categorizing the type of diabetes. Tests include anti-GAD and anti-ICAs, the presence of which support the diagnosis of DM1 (Table 154.1) and insulin and C peptide levels, the latter of which is a marker of insulin levels. Insulin and C peptide levels are usually higher in patients with DM2 because they have insulin resistance rather than an absolute insulin deficiency. Insulin reserve can be measured by determining the basal and stimulated levels of C peptide (≥0.6 ng/mL basal level, ≥1.5 ng/mL 90 minutes after nutritional supplement such as Sustacal or Ensure High Protein). In categorizing diabetes, it is important to note that some individuals with DM1 can have insulin reserves up to 2 years after diagnosis.

Oral glucose tolerance tests may be necessary to confirm the diagnosis of diabetes in cases in which the onset of symptoms is not obvious. Two-hour postprandial values greater than or equal to 200 mg/dL or fasting glucose of 126 mg/dL or higher are evidence of diabetes. The introduction of the intravenous glucose tolerance test with measurement of first-phase insulin release has allowed early diagnosis of individuals at risk for the disease prior to development of symptoms.

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