Type 1 Diabetes Mellitus

Formerly called insulin-dependent diabetes mellitus (IDDM) or juvenile diabetes, T1DM is characterized by low or absent levels of endogenously produced insulin and dependence on exogenous insulin to prevent development of ketoacidosis, an acute life-threatening complication of T1DM. The natural history includes 4 distinct stages: (1) preclinical β-cell autoimmunity with progressive defect of insulin secretion, (2) onset of clinical diabetes, (3) transient remission “honeymoon period,” and (4) established diabetes associated with acute and chronic complications and decreased life expectancy. The onset occurs predominantly in childhood, with median age of 7-15 yr, but it may present at any age. The incidence of T1DM has steadily increased in many parts of the world, including Europe and the USA. T1DM is characterized by autoimmune destruction of pancreatic islet β cells. Both genetic susceptibility and environmental factors contribute to the pathogenesis. Susceptibility to T1DM is genetically controlled by alleles of the major histocompatibility complex (MHC) class II genes expressing human leukocyte antigens (HLAs). It is also associated with autoantibodies to islet cell cytoplasm (ICA), insulin (IAA), antibodies to glutamic acid decarboxylase (GADA or GAD65), and ICA512 (IA2). T1DM is associated with other autoimmune diseases such as thyroiditis, celiac disease, multiple sclerosis, and Addison disease. There is some suggestion that high dietary intake of omega-3 polyunsaturated fatty acids and vitamin D supplementation in early childhood decreases the incidence of autoimmune T1DM in at-risk children. In some children and adolescents with apparent T1DM, the β-cell destruction is not immune mediated. This subtype of diabetes occurs in patients of African or Asian origin and is distinct from known causes of β-cell destruction such as drugs or chemicals, viruses, mitochondrial gene defects, pancreatectomy, and ionizing radiation. These individuals may have ketoacidosis, but they have extensive periods of remission with variable insulin deficiency, similarly to patients with T2DM.

Type 2 Diabetes Mellitus

The children and adolescents with this type of diabetes are usually obese but are not insulin dependent and infrequently develop ketosis. Some may develop ketosis during severe infections or other stresses and may then need insulin for correction of symptomatic hyperglycemia. This category includes the most prevalent form of diabetes in adults, which is characterized by insulin resistance and often a progressive defect in insulin secretion. This type of diabetes was formerly known as adult-onset diabetes mellitus, non–insulin-dependent diabetes mellitus (NIDDM), or maturity-onset diabetes of the young (MODY).

The presentation of T2DM is typically more insidious than that with T1DM. In contrast to patients with T1DM who are usually ill at the time of diagnosis, children with T2DM often seek medical care because of excessive weight gain and fatigue as a result of insulin resistance and/or an incidental finding of glycosuria during routine physical examination. A history of polyuria and polydipsia is relatively uncommon in these patients. The incidence of T2DM in children has increased by more than 10-fold in many diabetes centers, in part as a result of the epidemic of childhood obesity (Chapter 44). Pediatric T2DM may account for as many as 30% of the new cases of diabetes, especially in obese African and Mexican-American adolescents. Acanthosis nigricans (dark pigmentation of skin creases/flexural areas), a sign of insulin resistance, is present in the majority of patients with T2DM and is accompanied by a relative hyperinsulinemia at the time of the diagnosis (Chapter 644). However, the serum insulin elevation is usually disproportionately lower than that of age-, weight-, and sex-matched nondiabetic children and adolescents, suggesting a state of insulin insufficiency. In some individuals, it may represent slowly evolving T1DM.

In some children with strong family history of T2DM, impaired glucose tolerance may occur in a pattern implying dominant inheritance. This pattern of diabetes has been termed maturity-onset diabetes of the young (MODY) and may require insulin treatment. In MODY, there is no apparent autoimmune destruction of β cells and no HLA association. This subclass of T2DM consists of specific genetic disorders involving mutations in the gene encoding either pancreatic β-cell and liver glucokinase (GK) or in the nuclear transcription factors hepatocyte nuclear factor (HNF) (1α, 4α, or 1β). A defect in the gene regulating glucose transport into the pancreatic β cell, the GLUT2 transporter, may be responsible for other forms of T2DM. The genetic basis of T2DM also includes defects in glycogen synthase, insulin receptors, Rad (Ras associated with diabetes), and possibly apolipoprotein C-III. A recent meta-analysis of the literature suggests that the incidence of T2DM has a complexly inverse relationship with birthweight in some populations and that the influence of birthweight and the factors that contribute to it on T2DM is different for ethnically and genetically different populations.

Other Specific Types of Secondary Diabetes

Examples include diabetes secondary to exocrine pancreatic diseases (cystic fibrosis), other endocrine diseases (Cushing syndrome), and ingestion of certain drugs or poisons (the rodenticide Vacor). Certain genetic syndromes, including those with abnormalities of the insulin receptor, also are included in this category. There are no associations with HLAs, autoimmunity, or islet cell antibodies among the entities in this subdivision.

Web Table 583-2 details the current criteria for the diagnosis of DM. It should be noted that a fasting blood glucose that exceeds 125 mg/dL (6.9 mmol/L) is the accepted criterion for the diagnosis of diabetes.

Web Table 583-2 DIAGNOSTIC CRITERIA FOR IMPAIRED GLUCOSE TOLERANCE AND DIABETES MELLITUS

OGTT, oral glucose tolerance test.

* Symptoms include polyuria, polydipsia, and unexplained weight loss with glucosuria and ketonuria.

From Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Diabetes Care 20(Suppl 1):S5, 1999.

Impaired Glucose Tolerance

The term impaired glucose tolerance (IGT) refers to a metabolic stage that is intermediate between normal glucose homeostasis and diabetes. A fasting glucose concentration of 99 mg/dL (5.5 mmol/L) is the upper limit of “normal.” This choice is near the level above which acute-phase insulin secretion is lost in response to intravenous administration of glucose and is associated with a progressively greater risk of the development of microvascular and macrovascular complications.

Many individuals with IGT (fasting glucose 100-125 mg/dL) are euglycemic in their daily lives and may have normal or nearly normal glycated hemoglobin levels. Individuals with IGT often manifest hyperglycemia only when challenged with the oral glucose load used in the standardized oral glucose tolerance test.

In the absence of pregnancy, IGT is not a clinical entity but rather a risk factor for future diabetes and cardiovascular disease. This may be observed as an intermediate stage in any of the disease processes listed in Web Table 583-1. IGT is often associated with the insulin resistance syndrome (also known as syndrome X or metabolic syndrome), which consists of insulin resistance, compensatory hyperinsulinemia to maintain glucose homeostasis, obesity (especially abdominal or visceral obesity), dyslipidemia of the high-triglyceride or low- or high-density lipoprotein type, or both, and hypertension (Chapter 44). Insulin resistance is directly involved in the pathogenesis of T2DM. IGT appears as a risk marker for this type of diabetes at least in part because of its correlation with insulin resistance. The diagnostic criteria for IGT are presented in Web Table 583-2.

Epidemiology

T1DM accounts for about 10% of all diabetes, affecting 1.4 million in the USA and over 15 million in the world. While it accounts for most cases of diabetes in childhood, it is not limited to this age group; new cases continue to occur in adult life and approximately 50% of individuals with T1DM present as adults. The incidence of T1DM is highly variable among different ethnic groups. The overall age-adjusted incidence of type 1 DM varies from 0.7/100,000 per year in Karachi (Pakistan) to over 40/100,000 per year in Finland (Fig. 583-1). This represents a more than 400-fold variation in the incidence among 100 populations. The incidence of T1DM is increasing in most (but not all) populations and this increase appears to be most marked in populations where the incidence of autoimmune diseases was historically low. Data from Western European diabetes centers suggest that the annual rate of increase in T1DM incidence is 2-5%, whereas some central and eastern European countries demonstrate an even more rapid increase. The rate of increase is greatest among the youngest children. In the USA, the overall prevalence of diabetes among school-aged children is about 1.9/1,000, increasing from a prevalence of 1/1,430 children at 5 yr of age to 1/360 children at 16 yr. Among African Americans, the occurrence of T1DM is 30-60% of that seen in American whites. The annual incidence of new cases in the USA is about 14.9/100,000 of the child population. It is estimated that 30,000 new cases occur each year in the USA, affecting 1 in 300 children and as many as 1 in 100 adults during the lifespan. Rates are similar or higher in most Western European countries and significantly lower in Asia and Africa. But while incidence rates are much higher in European populations, the absolute number of new cases is almost equal in Asia and Europe because the population base is so much larger in Asia. Thus it is estimated that of the 400,000 total new cases of type 1 diabetes occurring annually in all children under age 14 yr in the world, about half are in Asia even though the incidence rates in that continent are much lower, because the total number of children in Asia is larger.

Figure 583-1 Incidence rates of type 1 diabetes mellitus by region and country.

(From Karvonen M, Viik-Kajander M, Moltchanova E, et al: Incidence of type I diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group, Diabetes Care 23:1516–1526, 2000.)

Girls and boys are almost equally affected but there is a modest female preponderance in some low-risk populations (e.g., the Japanese); there is no apparent correlation with socioeconomic status. Peaks of presentation occur in 2 age groups: at 5-7 yr of age and at the time of puberty. The 1st peak may correspond to the time of increased exposure to infectious agents coincident with the beginning of school; the 2nd peak may correspond to the pubertal growth spurt induced by gonadal steroids and the increased pubertal growth hormone secretion (which antagonizes insulin). These possible cause-and-effect relationships remain to be proved. A growing number of cases are presenting between 1 and 2 yr of age, especially in high-risk groups; the average age of presentation is older in low-risk populations. Low-risk groups that migrate to a high-risk country seem to acquire an increased risk; for example, the children of Pakistani immigrants in the United Kingdom (UK) have an incidence rate similar to the local English population and 20 fold higher than the rates in Pakistan. On the other hand, there can be marked differences in incidence rates in various ethnic groups within the same country; for example, incidence rates in the 10-14 yr age group in the USA range from a low of 7.1 in Native Americans, to 17.6 in Hispanics, 19.2 in African-Americans, and 32.9 in whites. These variations also remain unexplained at this time.

Genetics

There is a clear familial clustering of T1DM, with prevalence in siblings approaching 6% while the prevalence in the general population in the USA is only 0.4%. Risk of diabetes is also increased when a parent has diabetes and this risk differs between the 2 parents; the risk is 2% if the mother has diabetes, but 7% when the father has diabetes. In monozygotic twins, the concordance rate ranges from 30-65%, whereas dizygotic twins have a concordance rate of 6-10%. Since the concordance rate of dizygotic twins is higher than the sibling risk, factors other than the shared genotypes (for example the shared intrauterine environment) may play a role in increasing the risk in dizygotic twins. Furthermore, the genetic susceptibility for T1DM in the parents of a child with diabetes is estimated at 3%. It should be kept in mind that although there is a large genetic component in T1DM, 85% of newly diagnosed type 1 diabetic patients do not have a family member with T1DM. Thus, we cannot rely on family history to identify patients who may be at risk for the future development of T1DM as most cases will develop in individuals with no such family history.

MHC/HLA Encoded Susceptibility to Type 1 Diabetes Mellitus

The MHC is a large genomic region that contains a number of genes related to immune system function in humans. These genes are further divided into HLA class I, II, III, and IV genes. Class II genes are the ones most strongly associated with risk of T1DM, but as genetic studies become more detailed it is becoming apparent that some of the risk associated with various HLA types is due to variation in genes in HLA classes other than class II. Overall, genetic variation in the HLA region can explain 40-50% of the genetic risk of T1DM (Fig 583-2).

Figure 583-2 The human leukocyte antigen (HLA) complex (6p21.31). Graphic representation of the HLA complex, showing the relative locations the 3 classes of HLA genes.

(Courtesy of Dr. George Eisenbarth.)

Initially, much of the risk associated with diabetes appeared to be linked to DR3 and DR4 alleles, but the genes of the HLA locus display strong linkage disequilibrium and it is now known that some of the earlier identified risk alleles (like DR3/DR4) confer much of their increased risk because of their linkage with other alleles in the DQ region with which they are tightly linked with relatively low recombination rates.

Some of the known associations include the HLA DR3/4-DQ2/8 genotype; compared to a population prevalence of T1DM of approximately 1/300, DR3/4-DQ2/8 newborns from the general population have a 1/20 genetic risk. This risk of development of T1DM is even higher when the high-risk HLA haplotypes are shared with a sibling or parent with T1DM. Thus, if 1 sibling has T1DM and shares the same high-risk DR3/4-DQ2/8 haplotype with another sibling, then the risk of autoimmunity in the other sibling is 50%. And this risk approaches 80% when siblings share both HLA haplotypes identical by descent. This is known as the relative paradox and points to the existence of other shared genetic risk factors (most likely in the extended HLA haplotype).

With advances in genotyping, further discrimination is now possible and we can identify more specific risk ratios for specific haplotypes. For example, the DRB1*0401-DQA1*0301g-DQB1*0302 haplotype has an odds ratio (OR) of 8.39 while the DRB1*0401-DQA1*0301g-DQB1*0301 has an OR of 0.35, implicating the DQB1*0302 allele as a critical susceptibility allele. There are some dramatically protective DR-DQ haplotypes (e.g., DRB1*1501-DQA1*0102-DQB1*0602 [OR = 0.03], DRB1*1401-DQA1*0101-DQB1*0503 [OR = 0.02], and DRB1*0701-DQA1*0201-DQB1*0303 [OR = 0.02]). The DR2 haplotype (DRB1*1501-DQA1*0102-DQB1*0602) is dominantly protective and is present in 20% of general population but is seen in only 1% of type 1A diabetes patients.

Environmental Factors

The fact that 50% or so of monozygotic twins are discordant for T1DM, the variation seen in urban and rural areas populated by the same ethnic group, the change in incidence that occurs with migration, the increase in incidence that has been seen in almost all populations in the last few decades, and the occurrence of seasonality all provide evidence that environmental factors also play a significant role in the causation of T1DM.

Pathogenesis and Natural History of Type 1 Diabetes Mellitus

In type 1A diabetes mellitus, a genetically susceptible host develops autoimmunity against his or her own β cells. What triggers this autoimmune response remains unclear at this time. In some (but not all) patients, this autoimmune process results in progressive destruction of β cells until a critical mass of β cells is lost and insulin deficiency develops. Insulin deficiency in turn leads to the onset of clinical signs and symptoms of T1DM. At the time of diagnosis, some viable β cells are still present and these may produce enough insulin to lead to a partial remission of the disease (honeymoon period) but over time, almost all β cells are destroyed and the patient becomes totally dependent on exogenous insulin for survival (Fig. 583-3). Over time, some of these patients develop secondary complications of diabetes that appear to be related to how well-controlled the diabetes has been. Thus, the natural history of T1DM involves some or all of the following stages:

Figure 583-3 Proposed model of the pathogenesis and natural history of type 1 diabetes mellitus. IAA, insulin autoantibodies; GADA, glutamic acid decarboxylase antibody; ICA, islet cell antibody; IVGTT, intravenous glucose tolerance test.

(Adapted from Atkinson MA, Eisenbarth GS: Type 1 diabetes: new perspectives on disease pathogenesis and treatment, Lancet 358:221–229, 2001.)

Initiation of Autoimmunity

Genetic susceptibility to T1DM is determined by several genes (see section on genetics), with the largest contribution coming from variants in the HLA system. But it is important to keep in mind that even with the highest risk haplotypes, most carriers will NOT develop T1DM. Even in monozygotic twins, the concordance is 30-65%. A number of factors including prenatal influences, diet in infancy, viral infections, lack of exposure to certain infections, even psychologic stress, have been implicated in the pathogenesis of T1DM, but their exact role and the mechanism by which they trigger or aggravate autoimmunity remains uncertain (Fig. 583-4). What is clear is that markers of autoimmunity are much more prevalent than clinical T1DM, indicating that initiation of autoimmunity is a necessary but not a sufficient condition for T1DM. Whatever the triggering factor, it seems that in most cases of T1DM that are diagnosed in childhood, the onset of autoimmunity occurs very early in life. In a majority of the children diagnosed before age 10 yr, the 1st signs of autoimmunity appear before age 2 yr. Development of autoimmunity is associated with the appearance of several autoantibodies. Insulin associated antibodies (IAA) are usually the 1st to appear in young children, followed by glutamic acid decarboxylase 65 kd (GAD65) and tyrosine phosphatase insulinoma-associated 2 (IA-2) antibodies. The earliest antibodies are predominantly of the IgG1 subclass. Not only is there “spreading” of autoimmunity to more antigens (IAA, and then GAD 65 and IA-2) but there is also epitope spreading within 1 antigen. Initial GAD65 antibodies tend to be against the middle region or the carboxyl-terminal region, while amino-terminal antibodies usually appear later and are less common in children.

Figure 583-4 Schematic representation of the natural history of type 1 diabetes mellitus. Unknown triggers act upon a genetically susceptible host to trigger autoimmunity. Some proportion of those with autoimmunity develop progressive β-Cell loss that eventually leads to clinical diabetes. This is followed by temporary clinical remission (honeymoon period) in most patients. Over time, insulin secretion is almost completely lost and complications may develop in some patients (in direct proportion to the occurrence of hyperglycemia).

Preclinical Autoimmunity with Progressive Loss of β-Cell Function

In some, but not all patients, the appearance of autoimmunity is followed by progressive destruction of β cells. Antibodies are a marker for the presence of autoimmunity, but the actual damage to the β cells is primarily T-cell mediated (Fig. 583-5). Histologic analysis of the pancreas from patients with recent-onset T1DM reveals insulitis, with an infiltration of the islets of Langerhans by mononuclear cells, including T and B lymphocytes, monocytes/macrophages, and natural killer (NK) cells. In the NOD mouse, a similar cellular infiltrate is followed by linear loss of β cells until they completely disappear. But it appears that the process in human T1DM is not necessarily linear and there may be an undulating downhill course in the development of T1DM.

Figure 583-5 Schematic representation of the autoimmune response against pancreatic β cells. An insult to the pancreas leads to the release of β-cell antigens (GAD65), which are taken up by antigen-presenting cells (APCs) and the epitopes presented to the CD4 T cells. Type and stages of activation of APCs as well as the cytokine environment, in which the CD4 T cell priming takes place, dictate the differentiation of autoreactive T cells toward diabetogenic T helper-1 (Th1) cells, Th2 cells, or antigen-specific regulatory T cells. A predominant Th1 autoimmune response results in the recruitment and differentiation of cytotoxic CD8 cells, which attack the pancreatic β cells, leading to a massive release of β-cell antigens (Ag), epitope spreading, and destruction of the pancreatic islets. B, B lymphocyte; DC, dendritic cell; M, macrophage; CTL, cytotoxic cell; TGF-β, tumor growth factor-β; INFγ, interferon-γ; IL, interleukin.

(Adapted from Casares S, Brumeanu TD: Insights into the pathogenesis of T1DM: a hint for novel immunospecific therapies, Curr Mol Med 1:357–378, 2001.)

Role of Autoantibodies

The risk of developing clinical disease increases dramatically with an increase in the number of antibodies; only 30% of children with 1 antibody will progress to diabetes, but this risk increases to 70% when 2 antibodies are present and 90% when 3 are present. The risk of progression also varies with the intensity of the antibody response and those with higher antibody titers are more likely to progress to clinical disease. Another factor that appears to influence progression of β-cell damage is the age at which autoimmunity develops; children in whom IAAs appeared within the 1st 2 yr of life rapidly developed anti–islet cell antibodies and progressed to diabetes more frequently than children in whom the 1st antibodies appeared between ages 5 and 8 yr.

Role of Genetics in Disease Progression

Genetics plays a role in progression to clinical disease. In a large study of healthy children, the appearance of single antibodies is relatively common and usually transient, and does not correlate with the presence of high-risk HLA alleles, but those carrying high-risk HLA alleles are more likely to develop multiple antibodies and progress to disease. Similarly, the appearance of antibodies is more likely to predict diabetes in those with a family history of diabetes versus those with no family history of T1DM. Thus, it may be the case that environmental factors can induce transient autoimmunity in many children, but those with genetic susceptibility are more likely to see progression of autoimmunity and eventual development of diabetes.

Role of Environmental Factors

In addition to genetic factors, environmental factors may also act as accelerators of T1DM after the initial appearance of autoimmunity. This is evident from the fact that the incidence of T1DM can vary severalfold between populations that have the same prevalence of autoimmunity. For instance, the incidence of T1DM in Finland is almost 4-fold higher than in Lithuania, but the incidence of autoimmunity is similar in both countries.

The fact that all children with evidence of autoimmunity do not progress to diabetes indicates that there are “checkpoints” at which the autoimmune process can be halted or reversed before it progresses to full-blown diabetes. This has raised the possibility of preventing T1DM by intervening in the preclinical stage.

Prediction and Prevention

Autoimmunity precedes clinical T1DM, and indicators of maturing autoimmune responses may be useful markers for disease prediction. Individuals at risk for T1DM can be identified by a combination of genetic, immunologic, and metabolic markers. The most informative genetic locus, HLA class II, confers about half of the total genetic risk but has a low positive predictive value (PPV) when used in the general population. Autoantibodies provide a practical readout of β-cell autoimmunity, are easily sampled in venous blood, and have become the mainstay of T1DM prediction efforts. In the first-degree relatives of patients with T1DM, the number of positive d-aab can help estimate the risk of developing T1DM: low risk (single d-aab: PPV of 2-6%), moderate risk (2 d-aab: PPV of 21-40%), and high risk (>2 d-aab: PPV of 59-80%) over a 5 yr period. In children carrying the T1DM highest-risk genotype (HLA-DQB1*0201-DQA1*05/DQB1*0302-DQA1*03), insulitis is almost 10 times more frequent (PPV 21%) than in children with other genotypes (PPV 2.2%). But while autoantibodies are useful for detecting developing T1DM in close relatives of diabetic patients, most cases are sporadic rather than familial, necessitating general population screening. This has been difficult, in part, because the observed autoantibody prevalence greatly exceeds the low disease prevalence in nonrelatives, leading to high false-positive rates.

Pathophysiology

Insulin performs a critical role in the storage and retrieval of cellular fuel. Its secretion in response to feeding is exquisitely modulated by the interplay of neural, hormonal, and substrate-related mechanisms to permit controlled disposition of ingested foodstuff as energy for immediate or future use. Insulin levels must be lowered to then mobilize stored energy during the fasted state. Thus, in normal metabolism, there are regular swings between the postprandial, high-insulin anabolic state and the fasted, low-insulin catabolic state that affect liver, muscle, and adipose tissue (Table 583-1). T1DM is a progressive low-insulin catabolic state in which feeding does not reverse but rather exaggerates these catabolic processes. With moderate insulinopenia, glucose utilization by muscle and fat decreases and postprandial hyperglycemia appears. At even lower insulin levels, the liver produces excessive glucose via glycogenolysis and gluconeogenesis, and fasting hyperglycemia begins. Hyperglycemia produces an osmotic diuresis (glycosuria) when the renal threshold is exceeded (180 mg/dL; 10 mmol/L). The resulting loss of calories and electrolytes, as well as the persistent dehydration, produce a physiologic stress with hypersecretion of stress hormones (epinephrine, cortisol, growth hormone, and glucagon). These hormones, in turn, contribute to the metabolic decompensation by further impairing insulin secretion (epinephrine), by antagonizing its action (epinephrine, cortisol, growth hormone), and by promoting glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis (glucagon, epinephrine, growth hormone, and cortisol) while decreasing glucose utilization and glucose clearance (epinephrine, growth hormone, cortisol).

TABLE 583-1 INFLUENCE OF FEEDING (HIGH INSULIN) OR OF FASTING (LOW INSULIN) ON SOME METABOLIC PROCESSES IN LIVER, MUSCLE, AND ADIPOSE TISSUE*

* Insulin is considered to be the major factor governing these metabolic processes. Diabetes mellitus may be viewed as a permanent low-insulin state that, untreated, results in exaggerated fasting.

The combination of insulin deficiency and elevated plasma values of the counter-regulatory hormones is also responsible for accelerated lipolysis and impaired lipid synthesis, with resulting increased plasma concentrations of total lipids, cholesterol, triglycerides, and free fatty acids. The hormonal interplay of insulin deficiency and glucagon excess shunts the free fatty acids into ketone body formation; the rate of formation of these ketone bodies, principally β-hydroxybutyrate and acetoacetate, exceeds the capacity for peripheral utilization and renal excretion. Accumulation of these keto acids results in metabolic acidosis (diabetic ketoacidosis, DKA) and compensatory rapid deep breathing in an attempt to excrete excess CO₂ (Kussmaul respiration). Acetone, formed by nonenzymatic conversion of acetoacetate, is responsible for the characteristic fruity odor of the breath. Ketones are excreted in the urine in association with cations and thus further increase losses of water and electrolyte. With progressive dehydration, acidosis, hyperosmolality, and diminished cerebral oxygen utilization, consciousness becomes impaired, and the patient ultimately becomes comatose.

Clinical Manifestations

As diabetes develops, symptoms steadily increase, reflecting the decreasing β-cell mass, worsening insulinopenia, progressive hyperglycemia, and eventual ketoacidosis. Initially, when only insulin reserve is limited, occasional hyperglycemia occurs. When the serum glucose increases above the renal threshold, intermittent polyuria or nocturia begins. With further β-cell loss, chronic hyperglycemia causes a more persistent diuresis, often with nocturnal enuresis, and polydipsia becomes more apparent. Female patients may develop monilial vaginitis due to the chronic glycosuria. Calories are lost in the urine (glycosuria), triggering a compensatory hyperphagia. If this hyperphagia does not keep pace with the glycosuria, loss of body fat ensues, with clinical weight loss and diminished subcutaneous fat stores. An average, healthy 10 yr old child consumes about 50% of 2,000 daily calories as carbohydrate. As that child becomes diabetic, daily losses of water and glucose may be 5 L and 250 g, respectively, representing 1,000 calories, or 50%, of the average daily caloric intake. Despite the child’s compensatory increased intake of food, the body starves because unused calories are lost in the urine.

When extremely low insulin levels are reached, keto acids accumulate. At this point, the child quickly deteriorates. Keto acids produce abdominal discomfort, nausea, and emesis, preventing oral replacement of urinary water losses. Dehydration accelerates, causing weakness or orthostasis—but polyuria persists. As in any hyperosmotic state, the degree of dehydration may be clinically underestimated because intravascular volume is conserved at the expense of intracellular volume. Ketoacidosis exacerbates prior symptoms and leads to Kussmaul respirations (deep, heavy, rapid breathing), fruity breath odor (acetone), prolonged corrected Q-T interval (QTc), diminished neurocognitive function, and possible coma. About 20-40% of children with new-onset diabetes progress to DKA before diagnosis.

This entire progression happens much more quickly (over a few weeks) in younger children, probably owing to more aggressive autoimmune destruction of β cells. In infants, most of the weight loss is acute water loss because they will not have had prolonged caloriuria at diagnosis, and there will be an increased incidence of DKA at diagnosis. In adolescents, the course is usually more prolonged (over months), and most of the weight loss represents fat loss due to prolonged starvation. Additional weight loss due to acute dehydration may occur just before diagnosis. In any child, the progression of symptoms may be accelerated by the stress of an intercurrent illness or trauma, when counter-regulatory (stress) hormones overwhelm the limited insulin secretory capacity.

Diagnosis

The diagnosis of T1DM is usually straightforward. Although most symptoms are nonspecific, the most important clue is an inappropriate polyuria in any child with dehydration, poor weight gain, or “the flu.” Hyperglycemia, glycosuria, and ketonuria can be determined quickly. Nonfasting blood glucose greater than 200 mg/dL (11.1 mmol/L) with typical symptoms is diagnostic with or without ketonuria. In the obese child, T2DM must be considered (see Type 2 Diabetes Mellitus, later). Once hyperglycemia is confirmed, it is prudent to determine whether DKA is present (especially if ketonuria is found) and to evaluate electrolyte abnormalities—even if signs of dehydration are minimal. A baseline hemoglobin A_1C (HbA_1c) allows an estimate of the duration of hyperglycemia and provides an initial value by which to compare the effectiveness of subsequent therapy.

In the nonobese child, testing for autoimmunity to β cells is not necessary. Other autoimmunities associated with T1DM should be sought, including celiac disease (by tissue transglutaminase IgA and total IgA) and thyroiditis (by antithyroid peroxidase and antithyroglobulin antibodies). Because significant physiologic distress can disrupt the pituitary-thyroid axis, free thyroxine (T₄) and thyroid-stimulating hormone (TSH) levels should be checked after the child is stable for a few weeks.

Rarely, a child has transient hyperglycemia with glycosuria while under substantial physical stress. This usually resolves permanently during recovery from the stressors. Stress-produced hyperglycemia can reflect a limited insulin reserve temporarily revealed by counter-regulatory hormones. A child with temporary hyperglycemia should therefore be monitored for the development of symptoms of persistent hyperglycemia and tested if such symptoms occur. Formal testing in a child who remains clinically asymptomatic is not necessary.

Routine screening procedures, such as postprandial determinations of blood glucose or screening oral glucose tolerance tests, have yielded low detection rates in healthy, asymptomatic children, even among those considered at risk, such as siblings of diabetic children. Accordingly, such screening procedures are not recommended in children.

Treatment

Therapy is tailored to the degree of insulinopenia at presentation. Most children with new diabetes (60-80%) have mild to moderate symptoms, have minimal dehydration with no history of emesis, and have not progressed to ketoacidosis. Once DKA has resolved in the newly diagnosed child, therapy is transitioned to that described for children with nonketotic onset. Children with previously diagnosed diabetes who develop DKA are usually transitioned to their previous insulin regimen.

Insulin Therapy

Several factors influence the initial daily insulin dose per kilogram of body weight. The dose is usually higher in pubertal children. It is higher in those who have to restore greater deficits of body glycogen, protein, and fat stores and who, therefore, have higher initial caloric capacity. On the other hand, most children with new-onset diabetes have some residual β-cell function (the honeymoon period), which reduces exogenous insulin needs. Children with long-standing diabetes and no insulin reserve require about 0.7 U/kg/day if prepubertal, 1.0 U/kg/day at midpuberty, and 1.2 U/kg/day by the end of puberty. A reasonable dose in the newly diagnosed child, then, is about 60-70% of the full replacement dose based on pubertal status. The optimal insulin dose can only be determined empirically, with frequent self-monitored blood glucose levels and insulin adjustment by the diabetes team. Residual β-cell function usually fades within a few months and is reflected as a steady increase in insulin requirements and wider glucose excursions.

The initial insulin schedule should be directed toward the optimal degree of glucose control in an attempt to duplicate the activity of the β cell. There are inherent limits to our ability to mimic the β cell. Exogenous insulin does not have a 1st pass to the liver, whereas 50% of pancreatic portal insulin is taken up by the liver, a key organ for the disposal of glucose; absorption of an exogenous dose continues despite hypoglycemia, whereas endogenous insulin release ceases and serum levels quickly lower with a normally rapid clearance; and absorption rate from an injection varies by injection site and patient activity level, whereas endogenous insulin is secreted directly into the portal circulation. Despite these fundamental physiologic differences, acceptable glucose control can be obtained with new insulin analogs used in a basal-bolus regimen, that is, with slow-onset, long-duration background insulin for between-meal glucose control and rapid-onset insulin at each meal.

All preanalog insulins form hexamers, which must dissociate into monomers subcutaneously before being absorbed into the circulation. Thus, a detectable effect for regular (R) insulin is delayed by 30-60 min after injection. This, in turn, requires delaying the meal 30-60 min after the injection for optimal effect—a delay rarely attained in a busy child’s life. R has a wide peak and a long tail for bolus insulin (Figs. 583-6 and 583-7). This profile limits postprandial glucose control, produces prolonged peaks with excessive hypoglycemic effects between meals, and increases the risk of nighttime hypoglycemia. These unwanted between-meal effects often necessitate “feeding the insulin” with snacks and limiting the overall degree of blood glucose control. NPH and Lente insulins also have inherent limits because they do not create a peakless background insulin level (see Fig. 583-7C-E). This produces significant hypoglycemic effect during the midrange of their duration. Thus, it is often difficult to predict their interaction with fast-acting insulins. When R is combined with NPH or Lente (see Fig. 583-7E), the composite insulin profile poorly mimics normal endogenous insulin secretion. There are broad areas of excessive insulin effect alternating with insufficient effect throughout the day and night. Lente and Ultralente insulins have been discontinued and are no longer available.

Figure 583-6 Approximate insulin effect profiles. Meals are shown as rectangles below time axis. A, The following relative peak effect and duration units are used: lispro/aspart, peak 20 for 4 hr; regular, peak 15 for 7 hr; NPH/Lente, peak 12 for 12 hr; Ultralente, peak 9 for 18 hr; glargine, peak 5 for 24 hr. Though Lente and Ultralente are no longer manufactured, they are shown to give historical comparison to newer insulin analogs. , Injection time. B, Two Ultralente injections given at breakfast and supper. Note overlap of profiles. C, Composite curve showing approximate cumulative insulin effect for the 2 Ultralente injections. This composite view is much more useful to the patient, parents, and medical personnel because it shows important combined effects of multiple insulin injections with variable absorption characteristics and overlapping durations.

Figure 583-7 Approximate composite insulin effect profiles. Meals are shown as rectangles below time axis. Injections are shown as labeled triangles. L/A, lispro or aspart. Even though the fast- and long-acting insulins are shaded differently to show the addition of 1 insulin effect to another, the profile is changed to show the combined effect. For example, in the breakfast injection in C, the quick decline of L/A effect is blunted by the rising NPH/Lente effect, producing a broad tail, which slowly declines to baseline at supper. All profiles are idealized using average absorption and clearance rates. In typical clinical situations, these profiles vary among patients. A given patient has varying rates of absorption depending on the injection site, physical activity, and other variables. A, L or A pre-meal; glargine at bedtime. The rapid onset and short duration of L or A reduce overlap between pre-meal injections, and there is no extended nighttime action. This reduces the risk of hypoglycemia. Glargine provides a steady basal profile that simplifies prediction of bolus insulin effect. B, L or A pre-meal; Ultralente at breakfast and supper. Ultralente produces a basal profile similar to that seen with glargine. Some excessive insulin effect, however, is seen before supper and at nighttime. C, L or A pre-meal; NPH or Lente at breakfast and supper. The broad peak of NPH or Lente produces substantial risk of hypoglycemia before lunch and during the early hours of the night. The waning insulin effect before supper and breakfast may also allow breakthrough hyperglycemia. D, L or A pre-meal; NPH or Lente at breakfast and bedtime. Moving the evening long-acting insulin helps to cover the pre-breakfast hours, but the risk of nighttime lows persists. E, Regular and NPH or Lente at breakfast and supper. This produces the least physiologic profile, with large excesses before lunch and during the early night, combined with poor coverage before supper and breakfast. Though Lente and Ultralente are no longer manufactured, they are shown to give historical comparison to newer insulin analogs.

Lispro (L) and aspart (A), insulin analogs, are absorbed much quicker because they do not form hexamers. They provide discrete pulses with little if any overlap and short tail effect. This allows better control of post-meal glucose increase and reduces between-meal or nighttime hypoglycemia (see Fig. 583-7A). The long-acting analog glargine (G) creates a much flatter 24-hr profile, making it easier to predict the combined effect of a rapid bolus (L or A) on top of the basal insulin, producing a more physiologic pattern of insulin effect (see Fig. 583-7A). Postprandial glucose elevations are better controlled, and between-meal and nighttime hypoglycemia are reduced.

Ultralente (UL) given twice a day provided a reasonable basal profile (see Fig. 593-6C) and was quite effective when used with lispro or aspart (see Fig. 583-7B). Since UL is no longer available, G may be given every 12 hr in young children if a single daily dose of G does not produce complete 24-hr basal coverage. The basal insulin glargine should be 25-30% of the total dose in toddlers and 40-50% in older children. The remaining portion of the total daily dose is divided evenly as bolus injections for the 3 meals. A simple 3- or 4-step dosing schedule is begun based on the blood glucose level (Table 583-3). As soon as the family is taught to calculate the carbohydrate content of meals, bolus insulin can be more accurately dosed by both the carbohydrate content of the meal as well as the ambient glucose (see Table 583-3).

Table 583-3 SUBCUTANEOUS INSULIN DOSING

Frequent blood glucose monitoring and insulin adjustment are necessary in the 1st weeks as the child returns to routine activities and adapts to a new nutritional schedule, and as the total daily insulin requirements are determined. The major physiologic limit to tight control is hypoglycemia. Intensive control dramatically reduces the risk of long-term vascular complications; it is associated with a 3-fold increase in severe hypoglycemia. Use of insulin analogs moderates but does not eliminate this problem.

Some families may be unable to administer 4 daily injections. In these cases, a compromise may be needed. A 3-injection regimen combining NPH with a rapid analog bolus at breakfast, a rapid-acting analog bolus at supper, and NPH at bedtime may provide fair glucose control. Further compromise to a 2-injection regimen (NPH and rapid analog at breakfast and supper) may occasionally be needed. However, such a schedule would provide poor coverage for lunch and early morning, and would increase the risk of hypoglycemia at midmorning and early night.

Cognitive Function

There is increasing agreement that children with T1DM are at higher risk of developing cognitive difficulties than healthy age-matched peers. Evidence suggests that early-onset diabetes (younger than 7 yr) is associated with cognitive difficulties compared to late-onset diabetes and healthy controls. These cognitive difficulties were primarily observed learning and memory skills (both verbal and visual) and attention/executive function skills. It is likely that impact of diabetes on pediatric cognition appears shortly after diagnosis. Indeed, it has been observed that early-onset diabetes and longer duration of diabetes in children with diabetes adversely affects their school performance and educational achievements.

Coping Styles

Children and adolescents with T1DM are faced with a complex set of developmental changes as well as shifting burdens of the disease. Adjustment problems might affect psychologic well-being and the course of the disease by contributing to poor self-management and poor metabolic control. Coping styles refer to typical habitual preferences for ways of approaching problems and might be regarded as strategies that people generally use to cope across a wide range of stressors. Problem-focused coping refers to efforts directed toward rational management of a problem, and it is aimed at changing the situation causing distress. On the other hand, emotion-focused coping implies efforts to reduce emotional distress caused by the stressful event and to manage or regulate emotions that might accompany or result from the stressor. In adolescents with diabetes, avoidance coping and venting emotions have been found to predict poor illness-specific self-care behavior and poor metabolic control. Patients who use more mature defenses and exhibit greater adaptive capacity are more likely to adhere to their regimen. Coping strategies seem to be age dependent, with adolescents using more avoidance coping than younger children with diabetes.

Nonadherence

Family conflict, denial, and feelings of anxiety find expression in nonadherence to instructions regarding nutritional and insulin therapy and in noncompliance with self-monitoring. The presence of youth perceptions of critical parenting and youth externalizing behavior problems may interfere with adherence, leading to deterioration of glycemic control. In addition, deliberate overdosage with insulin, resulting in hypoglycemia, or omission of insulin, often in association with excesses in nutritional intake and resulting in ketoacidosis, may be pleas for psychologic help or manipulative attempts to escape an environment perceived as undesirable or intolerable; occasionally, they may be manifestations of suicidal intent. Frequent admissions to the hospital for ketoacidosis or hypoglycemia should arouse suspicion of an underlying emotional conflict. Overprotection on the part of parents is common and often is not in the best interest of the patient. Feelings of being different or of being alone, or both, are common and may be justified in view of the restrictive schedules imposed by testing of urine and blood, administration of insulin, and nutritional limitations. Furthermore, concern about the likelihood of complications developing and the decreased life span of patients with diabetes fosters anxiety. Unfortunately, misinformation abounds about the risks of the development of diabetes in siblings or offspring and of pregnancy in young diabetic women. Even appropriate information may cause further anxiety.

Many of these problems can be averted through continued empathic counseling based on correct information and attempts to build attitudes of normality in the patient and a feeling of being a productive member of society. Recognizing the potential impact of these problems, peer discussion groups have been organized in many locales; feelings of isolation and frustration tend to be lessened by the sharing of common problems. Summer camps for diabetic children afford an excellent opportunity for learning and sharing under expert supervision. Education about the pathophysiology of diabetes, insulin dose, technique of administration, nutrition, exercise, and hypoglycemic reactions can be reinforced by medical and paramedical personnel. The presence of numerous peers with similar problems offers new insights to the diabetic child. Residential treatment for children and adolescents with difficult to manage T1DM is an option available only in some centers.

Anxiety and Depression

It has been shown that there are significant correlations between poor metabolic control and depressive symptoms, a high level of anxiety, or a previous psychiatric diagnosis. In a similar way, poor metabolic control is related to higher levels of personal, social, school maladjustment, or family environment dissatisfaction. It is estimated that 20-26% of adolescent patients may develop major depressive disorder (MDD), which is similar to the occurrence rate of MDD in nondiabetic adolescents. The course characteristics of MDD in young diabetic subjects and psychiatric control subjects appear to be similar; however, eventual propensity of diabetic youths for more protracted depressions is greater and there is higher risk of recurrence among young diabetic females. Therefore, the health care providers managing a child or adolescent with diabetes should be aware of their pivotal role as counselor and advisor and should closely monitor the mental health of patients with diabetes.

Fear of Self-Injecting and Self-Testing

Extreme fear of self-injecting (FSI) insulin (injection phobia) is likely to compromise glycemic control as well as emotional well-being. Likewise, fear of finger pricks can be a source of distress and may seriously hamper self-management. Children and adolescents may either omit insulin dosing or refuse to rotate their injection sites because repeated injection in the same site is associated with less pain sensation. Failure to rotate injection sites results in subcutaneous scar formation (lipohypertrophy). Insulin injection into the lipohypertrophic skin is usually associated with poor insulin absorption and/or insulin leakage with resultant suboptimal glycemic control.

Eating Disorders

Treatment of T1DM involves constant monitoring of food intake. In addition, improved glycemic control is commonly associated with increased weight gain. In adolescent females, these 2 factors, along with individual, familial, and socioeconomic factors, can lead to an increased incidence of both nonspecific and specific eating disorders, which can disrupt glycemic control and increase the risk of long-term complications. Eating disorders and subthreshold eating disorders are almost twice as common in adolescent females with T1DM as in their nondiabetic peers. The reports of the frequencies of specific (anorexia or bulimia nervosa) eating disorders vary from 1% to 6.9% among female patients with T1DM. The prevalence of nonspecific and subthreshold eating disorders is 9% and 14%, respectively. About 11% of T1DM adolescent females take less insulin than prescribed in order to lose weight. Among adolescent females with an eating disorder, about 42% of patients misuse insulin, whereas the estimates of insulin misuse prevalence in subthreshold and nondisordered eating groups are 18% and 6%, respectively. While there is little information regarding the prevalence of eating disorders among male adolescents with T1DM, available data suggest normal eating attitudes in most. Among healthy adolescent males who participate in wrestling, however, the drive to lose weight has led to the seasonal, transient development of abnormal eating attitudes and behaviors, which may lead to insulin dose omission in order to lose weight.

When behavioral/psychologic problems and/or eating disorders are assumed to be responsible for poor compliance with the medical regimen, referral for psychologic evaluation and management is indicated. Children and adolescents with injection phobia and fear of self-testing can be counseled by a trained behavioral therapist and benefit from such techniques as desensitization and biofeedback to attenuate pain sensation and psychologic distress associated these procedures. Behavioral therapists and psychologists usually form part of the pediatric diabetes team in most centers and can help assess and manage emotional and behavioral disorders in diabetic children. Evaluation of nurse-delivered motivational enhancement with and without cognitive behavior therapy in adults revealed the combined therapy resulted in modest improvement in glycemic control. However, motivational enhancement therapy alone did not improve glycemic control. While in some studies the effect of therapist-delivered motivational enhancement therapy on glycemic control in adolescents with T1DM lasted as long as intensive individualized counseling continued, in other studies, motivational interviewing was shown to be an effective method of facilitating changes in teenager’s behavior with T1DM with corresponding improvement in glycemic control.

Long-Term Complications: Relation to Glycemic Control

The increasingly prolonged survival of the diabetic child is associated with an increasing prevalence of complications. Complications of DM can be divided into 3 major categories—(1) microvascular complications, specifically, retinopathy and nephropathy; (2) macrovascular complications, particularly accelerated coronary artery disease, cerebrovascular disease, and peripheral vascular disease; and (3) neuropathies, both peripheral and autonomic, affecting a variety of organs and systems (Table 583-10). In addition, cataracts may occur more frequently.

Diabetic retinopathy is the leading cause of blindness in the USA in adults aged 20-65 yr. The risk of diabetic retinopathy after 15 yr duration of diabetes is 98% for individuals with T1DM and 78% for those with T2DM. Lens opacities (due to glycation of tissue proteins and activation of the polyol pathway) are present in at least 5% of those younger than 19 yr. Although the metabolic control has an impact on the development of this complication, genetic factors also have a role, because only 50% of patients develop proliferative retinopathy. The earliest clinically apparent manifestations of diabetic retinopathy are classified as nonproliferative or background diabetic retinopathy—microaneurysms, dot and blot hemorrhages, hard and soft exudates, venous dilation and beading, and intraretinal microvascular abnormalities. These changes do not impair vision. The more severe form is proliferative diabetic retinopathy—manifested by neovascularization, fibrous proliferation, and preretinal and vitreous hemorrhages. Proliferative retinopathy, if not treated, is relentlessly progressive and impairs vision, leading to blindness. The mainstay of treatment is panretinal laser photocoagulation. In advanced diabetic eye disease—manifested by severe vitreous hemorrhage or fibrosis, often with retinal detachment—vitrectomy is an important therapeutic modality. Eventually, the eye disease becomes quiescent, a stage termed involutional retinopathy. A separate subtype of retinopathy is diabetic maculopathy, which is manifested by severe macular edema impairing central vision, for which focal laser photocoagulation may be effective.

Guidelines suggest that diabetic patients have an initial dilated and comprehensive examination by an ophthalmologist shortly after the diagnosis of diabetes is made in patients with T2DM, and within 3-5 yr after the onset of T1DM (but not before age 10 yr). Any patients with visual symptoms or abnormalities should be referred for ophthalmologic evaluation. Subsequent evaluations for both T1DM and T2DM patients should be repeated annually by an ophthalmologist who is experienced in diagnosing the presence of diabetic retinopathy and is knowledgeable about its management (see Table 583-10).

Diabetic nephropathy is the leading known cause of end-stage renal disease (ESRD) in the USA. Most ESRD from diabetic nephropathy is preventable. Diabetic nephropathy affects 20-30% of patients with T1DM and 15-20% of T2DM patients 20 yr after onset. The mean 5-yr life expectancy for patients with diabetes-related ESRD is less than 20%. The increased mortality risk in long-term T1DM may be due to nephropathy, which may account for about 50% of deaths. The risk of nephropathy increases with duration of diabetes (up until 25-30 yr duration, after which this complication rarely begins), degree of metabolic control, and genetic predisposition to essential hypertension. Only 30-40% of patients affected by T1DM eventually experience ESRD. The glycation of tissue proteins results in glomerular basement membrane thickening. The course of diabetic nephropathy is slow. An increased urinary albumin excretion rate (AER) of 30-300 mg/24 hr (20-200 µg/min)—microalbuminuria—can be detected and constitutes an early stage of nephropathy from intermittent to persistent (incipient), which is commonly associated with glomerular hyperfiltration and blood pressure elevation. As nephropathy evolves to early overt stage with proteinuria (AER >300 mg/24 hr, or >200 µg/min), it is accompanied by hypertension. Advanced stage nephropathy is defined by a progressive decline in renal function (declining glomerular filtration rate and elevation of serum blood urea and creatinine), progressive proteinuria, and hypertension. Progression to ESRD is recognized by the appearance of uremia, the nephritic syndrome, and the need for renal replacement (transplantation or dialysis).

Screening for diabetic nephropathy is a routine aspect of diabetes care (see Table 583-10). The American Diabetes Association (ADA) recommends yearly screening for individuals with T2DM and yearly screening for those with T1DM after 5 yr duration of disease (but not before puberty). Twenty-four hour AER (urinary albumin and creatinine) or timed (overnight) urinary AER are acceptable techniques. Positive results should be confirmed by a 2nd measurement of AER because of the high variability of albumin excretion in patients with diabetes. Short-term hyperglycemia, exercise, urinary tract infections, marked hypertension, heart failure, and acute febrile illness can cause transient elevation urinary albumin excretion. There is marked day-to-day variability in albumin excretion, so at least 2 of 3 collections done in a 3- to 6-mo period should show elevated levels before microalbuminuria is diagnosed and treatment is started. Once albuminuria is diagnosed, a number of factors attenuate the effect of hyperfiltration on kidneys: (1) meticulous control of hyperglycemia, (2) aggressive control of systemic blood pressure, (3) selective control of arteriolar dilation by use of angiotensin-converting enzyme (ACE) inhibitors (thus decreasing transglomerular capillary pressure), and (4) dietary protein restriction (because high protein intake increases renal perfusion rate). Tight glycemic control will delay the progression of microalbuminuria and slow the progression of diabetic nephropathy. Previous extensive therapy of diabetes has a persistent benefit for 7-8 yr and may delay or prevent the development of diabetic nephropathy.

Diabetic Neuropathy

Both the peripheral and autonomic nervous systems can be involved, and adolescents with diabetes can show early evidence of neuropathy. This complication can be traced to the metabolic effects of hyperglycemia and/or other effects of insulin deficiency on the various constituents of the peripheral nerve. The polyol pathway, nonenzymatic glycation, and/or disturbances of myoinositol metabolism affecting 1 or more cell types in the multicellular constituents of the peripheral nerve appear likely to have an inciting role. The role of other factors, such as possible direct neurotrophic effects of insulin, insulin-related growth factors, nitric oxide, and stress proteins, seems to be relevant. Peripheral neuropathy may first present in some adolescents with long-standing history of diabetes. Using quantitative sensory testing (QST), abnormal cutaneous thermal perception is a common finding in both upper and lower limbs in neurologically asymptomatic young diabetic patients. Heat-induced pain threshold in the hand is correlated with the duration of the diabetes. There is no correlation between QST scores and metabolic control. Subclinical motor nerve impairment as manifested by reduced sensory nerve conduction velocity and sensory nerve action potential amplitude can be detected during late puberty and after puberty in about 10% of adolescents. Poor metabolic control during puberty appears to induce deteriorating peripheral neural function in young patients. An early sign of autonomic neuropathy such as decreased heart rate variability may present in adolescents with a history of long-standing disease and poor metabolic control. A number of therapeutic strategies have been attempted with variable results. These treatment modalities include (1) improvement in metabolic control, (2) use of aldose reductase inhibitors to reduce byproducts of the polyol pathway, (3) use of α-lipoic acid (an antioxidant) that enhances tissue nitric oxide and its metabolites, and (4) use of anticonvulsants (e.g., lorazepam, valproate, carbamazepine, tiagabine, and topiramate) for treatment of neuropathic pain.

Other complications in diabetic children include dwarfism associated with a glycogen-laden enlarged liver (Mauriac syndrome), osteopenia, and a syndrome of limited joint mobility associated with tight, waxy skin; growth impairment; and maturational delay. The Mauriac syndrome is related to underinsulinization; it is much less common since longer-acting insulins have become available. Clinical features of Mauriac syndrome include moon face, protuberant abdomen, proximal muscle wasting, and enlarged liver due to fat and glycogen infiltration. The syndrome of limited joint mobility is frequently associated with the early development of diabetic microvascular complications, such as retinopathy and nephropathy, which may appear before 18 yr of age.

Prognosis

T1DM is a serious, chronic disease. It has been estimated that the average life span of individuals with diabetes is about 10 yr shorter than that of the nondiabetic population. Although diabetic children eventually attain a height within the normal adult range, puberty may be delayed, and the final height may be less than the genetic potential. From studies in identical twins, it is apparent that despite seemingly satisfactory control, the diabetic twin manifests delayed puberty and a substantial reduction in height when onset of disease occurs before puberty. These observations indicate that, in the past, conventional criteria for judging control were inadequate and that adequate control of T1DM was almost never achieved by routine means.

The introduction of portable devices (insulin pumps) that can be programmed to provide CSII with meal-related pulses is 1 approach to the resolution of these long-term problems. In selected individuals, nearly normal patterns of blood glucose and other indices of metabolic control, including HbA_1C, have been maintained for several years. This approach, however, should be reserved for highly motivated persons committed to rigorous self-monitoring of blood glucose who are alert to the potential complications, such as mechanical failure of the infusion device causing hyperglycemia or hypoglycemia and to infection at the site of catheter insertion.

The changing pattern of metabolic control is having a profound influence on reducing the incidence and the severity of certain complications. For example, after 20 yr of diabetes, there is a decline in the incidence of nephropathy in T1DM in Sweden among children whose disease was diagnosed in 1971-1975 compared with in the preceding decade. In addition, in most patients with microalbuminuria in whom it was possible to obtain good glycemic control, microalbuminuria disappeared. This improved prognosis is directly related to metabolic control.

Pancreas and Islet Transplantation and Regeneration

In an attempt to cure T1DM, transplantation of a segment of the pancreas or of isolated islets has been performed. These procedures are both technically demanding and associated with the risks of disease recurrence and complications of rejection or its treatment by immunosuppression. Complications of immunosuppression include the development of malignancy. Some antirejection drugs, notably cyclosporine and tacrolimus, are toxic to the islets of Langerhans, impairing insulin secretion and even causing diabetes. Hence, segmental pancreas transplantation is generally only performed in association with transplantation of a kidney for a patient with ESRD due to diabetic nephropathy in which the immunosuppressive regimen is indicated for the renal transplantation. Several thousand such transplants have been performed in adults. With experience and newer immunosuppressive agents, functional survival of the pancreatic graft may be achieved for up to several years, during which time patients may be in metabolic control with no or minimal exogenous insulin and reversal of some of the microvascular complications. However, because children and adolescents with DM are not likely to have ESRD from their diabetes, pancreas transplantation as a primary treatment in children cannot be recommended.

Attempts to transplant isolated islets have been equally challenging because of rejection. Research continues to improve techniques for the yield, viability, and reduction of immunogenicity of the islets of Langerhans for transplantation. An islet transplantation strategy (Edmonton protocol) infuses isolated pancreatic islets into the portal vein of a group of adults with T1DM. This therapeutic strategy also involves the use of a new generation of immunosuppressive medications that apparently have lower side-effect profiles than do other drugs. Of 36 consecutive patients with at least 2 yr of follow-up after the initial transplant, 5 (14%) were insulin independent at 2 yr. Although patients experienced minimal side effects from immunosuppressive medications, some complications associated with islet transplantation procedures were observed that included portal vein thrombosis, bleeding related to the percutaneous portal vein access, an expanding intrahepatic and subscapular hemorrhage on anticoagulation (requiring transfusion and surgery). Elevated liver function test results were found in 46% of subjects but resolved in all. However, only half of the patients remained insulin free at 2 yr. It has been suggested that positive long-term clinical outcome is dependent on islet graft composition, especially the presence of high numbers of islet progenitor (ductal-epithelial) cells. There is improved islet engraftment by the peritransplant administration of immunosuppressants, antithymocyte globulin, and etanercept. Long-term monitoring will be needed before the success of these techniques can be assessed.

Regeneration of islets is an approach that could potentially cure T1DM. It is classified into 3 categories:

High-dose immunosuppression and autologous nonmyeloablative hematopoietic stem cell transplantation (AHST) in 11 out of 15 (73.3%) newly diagnosed T1DM patients (aged 14-31 yr) became insulin-free for at least 6 mo, whereas only 4 out of 15 (26.6%) were insulin-free for 21 mo. Subsequently, 8 additional patients were included with mean follow-up period of 28.9 mo. This pilot study demonstrated that with AHST, β-cell function was increased significantly and majority of patients achieved insulin independence with good glycemic control.

Natural History

T2DM is considered a polygenic disease aggravated by environmental factors, such as low physical activity and excessive caloric intake. Most patients are obese, though the disease can occasionally be seen in normal weight individuals. Asians in particular appear to be at risk for T2DM at lower degrees of total adiposity. Some patients may not necessarily meet overweight or obese criteria for age and gender despite abnormally high percentage of body fat in the abdominal region. Obesity, in particular, central obesity, is associated with the development of insulin resistance. In addition, patients who are at risk for developing T2DM exhibit decreased glucose-induced insulin secretion. Obesity does not lead to the same degree of insulin resistance in all individuals and even those who develop insulin resistance do not necessarily exhibit impaired β-cell function. Thus, many obese individuals have some degree of insulin resistance, but compensate for it by increasing insulin secretion. But those who are unable to adequately compensate for insulin resistance by increasing insulin secretion, develop impaired glucose tolerance and impaired fasting glucose (usually, thought not always, in that order). Hepatic insulin resistance leads to excessive hepatic glucose output (failure of insulin to suppress hepatic glucose output), while skeletal muscle insulin resistance leads to decreased glucose uptake in a major site of glucose disposal. Over time hyperglycemia worsens, a phenomenon that has been attributed to the deleterious effect of chronic hyperglycemia (glucotoxicity) or chronic hyperlipidemia (lipotoxicity) on β-cell function and is often accompanied by increased triglyceride content and decreased insulin gene expression. At some point, blood glucose elevation meets the criteria for diagnosis of T2DM (see Web Table 583-2 on the Nelson Textbook of Pediatrics website at www.expertconsult.com), but most patients with T2DM remain asymptomatic for months to years after this point because hyperglycemia is moderate and symptoms are not as dramatic as the polyuria and weight loss accompanying T1DM. Even weight gain may continue. The prolonged hyperglycemia may be accompanied by the development of microvascular and macrovascular complications. In time, β-cell function can decrease to the point that the patient has absolute insulin deficiency and becomes dependent on exogenous insulin. In T2DM, insulin deficiency is rarely absolute, so patients usually do not need insulin to survive. Nevertheless, glycemic control can be improved by exogenous insulin. DKA is uncommon in patients with T2DM, but may occur and is usually associated with the stress of another illness such as severe infection and may resolve when the stressful illness resolves. DKA tends to be more common in African-American patients than in other ethnic groups. Although it is generally believed that autoimmune destruction of pancreatic β cells does not occur in T2DM, autoimmune markers of T1DM—namely, GAD65, ICA512, and IAA—may be positive in up to one third of the cases of adolescent T2DM. The presence of these autoimmune markers does not rule out T2DM in children and adolescents. At the same time, due to the general increase in obesity, the presence of obesity does not preclude the diagnosis of T1DM. While the majority of newly diagnosed diabetics can be confidently assigned a diagnosis of T1DM or T2DM, a few exhibit features of both types and are difficult to classify.

Epidemiology

The latest NHANES data (from 1999-2002) shows that the prevalence of T2DM in 12-19 yr olds in the USA is 1.46/1000. The SEARCH study found that the prevalence of type 2 diabetes in the 10-19 yr old age group in the USA was 15% in 2001 and it is likely that this proportion has increased over time. Certain ethnic groups appear to be at higher risk; for example, Native Americans, Hispanic Americans, and African Americans (in that order) have higher incidence rates than white Americans. While a majority of children presenting with diabetes still have T1DM, the percentage of children presenting with T2DM is increasing and represents up to 50% of the new diabetics in some centers. We, at Children’s Hospital of Wisconsin (Milwaukee), have observed a more than 10-fold increase in incidence of T2DM (from less than 2% to about 22% of new cases of DM) in children aged 10-18 yr in the past decade. Prevalence in the rest of the world varies widely and accurate data are not available for many countries, but it is clear that the prevalence is increasing in every part of the world. Asians in general seem to develop T2DM at lower BMI levels than Europeans. In conjunction with their low incidence of type 1 diabetes, this means that T2DM accounts for a higher proportion of childhood diabetics in many Asian countries.

The epidemic of T2DM in children and adolescents parallels the emergence of the obesity epidemic (Chapter 44). Although obesity itself is associated with insulin resistance, diabetes does not develop until there is some degree of failure of insulin secretion. Thus, when measured, insulin secretion in response to glucose or other stimuli is always lower in persons with T2DM than in control subjects matched for age, sex, weight, and equivalent glucose concentration.

Genetics

T2DM has a strong genetic component; concordance rates among identical twins are in the 60-90% range. But it should be kept in mind that twinning itself increases the risk of T2DM (due to intrauterine growth retardation [IUGR]) and this may distort estimates of genetic risk. In at least 1 study from Denmark, both monozygotic and dizygotic twins have a lifetime concordance of T2DM of around 70%, indicating that shared environmental factors (including the prenatal environment) may play a large role in the development of T2DM. The genetic basis for T2DM is complex and incompletely defined; no single identified defect predominates as does the HLA association with T1DM. Genome-wide association studies have now identified certain genetic polymorphisms that are associated with increased T2DM risk in most populations studied; the most consistently identified are variants of the TCF7L2 (transcription factor 7–like 2) gene, which may have a role in β-cell function. Other identified risk alleles include variants in PPARG and KCNJ11 and at least 18 other genes and the list is growing longer by the day. In addition, other variants increase diabetes risk by increasing the risk of obesity (for example, variants in the FTO gene). But to date, all these identified variants explain only a small portion (probably less than 20%) of the population risk of diabetes and in many cases the mechanism by which these polymorphisms confer risk of T2DM is not clear.

Epigenetics and Fetal Programming

Low birthweight and IUGR are associated with increased risk of T2DM and this risk appears to be higher in low-birthweight infants who gain weight more rapidly in the 1st few years of life. These findings have led to the formulation of the “thrifty phenotype” hypothesis, which postulates that poor fetal nutrition somehow programs these children to maximize storage of nutrients and makes them more prone to future weight gain and development of diabetes. Epigenetic modifications may play a role in this phenomenon, but the detailed molecular mechanisms involved are yet to be determined. But whatever the exact mechanism, prenatal and early childhood environments play an important role in the pathogenesis of T2DM and may do so by epigenetic modification of the genetic code (in addition to other factors).

Environmental and Lifestyle-Related Risk Factors

Obesity is the most important lifestyle factor associated with development of diabetes. This in turn is associated with the intake of high-energy foods, physical inactivity, TV viewing (“screen time”) and low socioeconomic status (in developed countries). Maternal smoking also increases the risk of diabetes and obesity in the offspring. Interestingly, smoking by young adults also increases their own risk of diabetes by as yet unknown mechanisms. In addition, sleep deprivation and psychosocial stress are associated with increased risk of obesity in childhood and with impaired glucose tolerance in adults, possibly via overactivation of the hypothalamic-pituitary-adrenal axis. Many antipsychotics (especially the atypical antipsychotics like olanzapine and quetiapine) and antidepressants (both tricyclic antidepressants and newer antidepressants like fluoxetine and paroxetine) induce weight gain. In addition to the risk conferred by increased obesity, some of these medications may also have a direct role in causing insulin resistance, β-cell dysfunction, leptin resistance, and activation of inflammatory pathways. To complicate matters further, there is evidence that schizophrenia and depression themselves increase the risk of T2DM and the metabolic syndrome, independent of the risk conferred by drug treatment. As a result, both obesity and T2DM are more prevalent in this population and with increasing use of antipsychotics and antidepressants in the pediatric population, this association is likely to become stronger.

Clinical Features

In the USA, T2DM in children is more likely to be diagnosed in Native American, Hispanic American, and African American youth, with the highest incidence being reported in Pima Indian youth, where its prevalence in the 15-19 yr age group is 5%. While cases may be seen as young as 6 yr of age, most are diagnosed in adolescence and incidence increases with increasing age. Family history of T2DM is present in practically all cases. Typically, these patients are obese and present with mild symptoms of polyuria and polydipsia, or are asymptomatic and detected on screening tests. But presentation with diabetic ketoacidosis occurs in up to 10% of cases and may be higher in African Americans. Physical examination frequently reveals the presence of acanthosis nigricans, most commonly on the neck and in other flexural areas. Other findings may include striae and an increased waist-hip ratio. Laboratory testing reveals elevated HbA_1c levels and HbA_1c values are higher at diagnosis among minority youth. Hyperlipidemia characterized by elevated triglycerides and low-density lipoprotein (LDL) cholesterol levels are commonly seen in patients with T2DM at diagnosis. Therefore lipid screening is indicated in all new cases of T2DM. Since hyperglycemia develops slowly and patients may be asymptomatic for months or years after they develop T2DM, screening for T2DM is recommended in high-risk children (Table 583-11) and many patients are diagnosed upon routine screening. The ADA recommends that all youth who are overweight and have at least 2 other risk factors be tested for T2DM beginning at age 10 yr or at the onset of puberty and every 2 yr after that. These risk factors include family history of T2DM in first- or second-degree relatives, history of gestational diabetes in the mother, belonging to certain ethnic groups (i.e., Native Americans, African American, Hispanic, or Asian/Pacific Islander) and having signs of insulin resistance (e.g., acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome). The current recommendation is to use fasting blood glucose as a screening test, but some authorities now recommend that HbA_1c be used as a screening tool and it has the advantage that a fasting sample is not required. In borderline or asymptomatic cases, the diagnosis may be confirmed using a standard glucose tolerance test, but this test is not required if typical symptoms are present or fasting plasma glucose is clearly elevated on 2 separate occasions.

Treatment

Type 2 diabetes is a progressive syndrome that gradually leads to complete insulin deficiency during the patient’s life. A systematic approach for treatment of T2DM should be implemented according to the natural course of the disease, including adding insulin when hypoglycemic oral agent failure occurs. Nevertheless, lifestyle modification (diet and exercise) is an essential part of the treatment regimen and consultation with a dietitian is usually necessary. There is no particular dietary or exercise regimen that has been conclusively shown to be superior but most centers recommend a low-calorie, low-fat diet and 30-60 minutes of physical activity at least 5 times per week. Screen time should be limited to 1-2 hr per day. These children often come from a household environment with a poor understanding of healthy eating habits. Commonly observed behaviors include skipping meals, heavy snacking, and excessive daily television viewing, video game playing, and computer use. Adolescents engage in non–appetite-based eating (i.e., emotional eating, television-cued eating, boredom) and cyclic dieting (“yo-yo” dieting). Treatment in these cases is frequently challenging and may not be successful unless the entire family buys into the need to change their unhealthy lifestyle.

When lifestyle interventions fail to normalize blood glucose, oral hypoglycemic agents are introduced for management of persistent hyperglycemia (Table 583-12). Patients who present with DKA or with markedly elevated HbA_1c (>9.0%) will require treatment with insulin using protocols similar to those used for treating T1DM. Once blood glucose levels are under control most cases can be managed with oral hypoglycemic agents and lifestyle changes, but some patients will continue to require insulin therapy.

The most commonly used oral agent is metformin. Renal function must be assessed before starting metformin as impaired renal function has been associated with potentially fatal lactic acidosis in adults. Significant hepatic dysfunction is also a contraindication, though mild elevations in liver enzymes may not be an absolute contraindication. The usual starting dose is 500 mg bid and this may be increased to a maximum dose of 2,500 mg per day. Abdominal symptoms are common early in the course of treatment, but in most cases will resolve with time.

Other agents like thiazolidinediones (TZDs), sulfonylureas, acarbose, pramlintide, and incretin mimetics are being used routinely in adults, but in pediatrics they constitute 2nd-line agents at this time. Sulfonylureas are widely used in adults, but experience in pediatrics is limited. Sulfonylureas cause insulin release by closing the potassium channel (K_ATP) on β cells. They are occasionally used when metformin monotherapy is unsuccessful or contraindicated for some reason (use in certain forms of neonatal diabetes is discussed in the section on neonatal diabetes). TZDs are not yet approved for use in pediatrics but are occasionally used as insulin sensitizers in patients who are not candidates for metformin treatment for any reason. Pramlintide (Symlin) is an analog of IAPP (islet amyloid polypeptide), which is a peptide that is co-secreted with insulin by the β cells and acts to delay gastric emptying, suppress glucagon, and possibly suppress food intake. It is not yet approved for pediatric use. Incretins are gut-derived peptides like GLP-1 (glucagon like peptide-1), GLP-2, and GIP (glucose-dependent insulinotropic peptide, previously known as gastric inhibitory protein) that are secreted in response to meals and act to enhance insulin secretion and action, suppress glucagon production and delay gastric emptying (among other actions). GLP-1 analogs (e.g., exenatide) and agents that prolong endogenous GLP-1 action (e.g., sitagliptin) are now available for use in adults but are not yet approved for use in children and their use in pediatrics remains experimental at this time.

Complications

In the SEARCH study of diabetes in youth, 92% of the patients with T2DM had 2 or more elements of the metabolic syndrome (hypertension, hypertriglyceridemia, decreased HDL, increased waist circumference), including 70% with hypertension. In addition, the incidence of microalbuminuria and diabetic retinopathy appears to be higher in T2DM than it is in T1DM. In the SEARCH study, the incidence of microalbuminuria among patients who had T2DM of LESS than 5 yr duration was 7-22%, while retinopathy was present in 18.3%. Thus, all adolescents with T2DM should be screened for hypertension and lipid abnormalities and screening for microalbuminuria and retinopathy may be indicated even earlier than it is in T1DM. Sleep apnea and fatty liver disease are being diagnosed with increasing frequency and may necessitate referral to the appropriate specialists. Complications associated with all forms of diabetes and recommendations for screening are noted in Table 583-10 while Table 583-13 lists additional conditions particularly associated with T2DM.

Table 583-13 MONITORING FOR COMPLICATIONS AND CO-MORBIDITIES

From Liu L, Hironaka K, Pihoker C: Type 2 diabetes in youth, Curr Probl Pediatr Adolesc Health Care 34:249–280, 2004.

Prevention

The difficulties in achieving good glucose control and preventing diabetes complications make prevention a compelling strategy. This is particularly true for T2DM, which is clearly linked to modifiable risk factors (obesity, a sedentary lifestyle). The Diabetes Prevention Program (DPP) was designed to prevent or delay the development of T2DM in adult individuals at high risk by virtue of impaired glucose tolerance (IGT). DPP results demonstrated that intensified lifestyle or drug intervention in individuals with IGT prevented or delayed the onset of T2DM. The results were striking. Lifestyle intervention reduced diabetes incidence by 58%; metformin reduced the incidence by 31% compared with placebo. The effects were similar for men and women and for all racial and ethnic groups. Lifestyle interventions are believed to have similar beneficial effects in obese adolescents with IGT. Screening is indicated for at-risk patients (see Table 583-11).

Impaired Glucose Tolerance

The term impaired glucose tolerance (IGT) is suggested as a replacement for terms such as asymptomatic diabetes, chemical diabetes, subclinical diabetes, borderline diabetes, and latent diabetes in order to avoid the stigma associated with the term diabetes mellitus. Such diagnostic labels may influence the choice of vocation, eligibility for health or life insurance, and self-image. Although IGT represents a biochemical intermediate between normal glucose metabolism and that of diabetes, experience has shown that few children with IGT go on to acquire diabetes; estimates range from zero to 10%. There is disagreement about whether the degree of glucose intolerance is useful as a prognostic index of the likelihood of progression, but there is evidence that among the few instances of progression, the insulin response during glucose tolerance testing is severely impaired. Islet cell or insulin autoantibodies as well as the HLA-DR3 or HLA-DR4 haplotype are commonly found in those who go on to develop clinical diabetes. In most obese children with IGT, insulin responses during oral glucose tolerance tests are higher than the mean for age-adjusted but not weight-adjusted control subjects; these individuals have some resistance to the effects of insulin rather than a total inability to secrete it.

In healthy nondiabetic children, the glucose response during an oral glucose tolerance test is similar at all ages. In contrast, plasma insulin responses during the test increase progressively within the age span of about 3-15 yr and are significantly higher during puberty so that interpretation of these responses requires comparison with age- and puberty-adjusted responses.

The performance of the glucose tolerance test should be standardized according to currently accepted criteria. These include at least 3 days of a well-balanced diet containing approximately 50% of calories from carbohydrates, fasting from midnight until the time of the test in the morning, and a dose of glucose for the test of 1.75 g/kg but not more than 75 g. Plasma samples are obtained before ingestion of the glucose and at 1, 2, and 3 hr thereafter. The arbitrarily designated response to the test that identifies IGT is a fasting plasma glucose value of less than 126 mg/dL and a value at 2 hr of more than 140 mg/dL but less than 200 mg/dL (see Web Table 583-2 on the Nelson Textbook of Pediatrics website at www.expertconsult.com). Determination of serum insulin responses during the glucose tolerance test is not a prerequisite for reaching a diagnosis; the magnitude of the response, however, may have prognostic value.

In children with IGT but without fasting hyperglycemia, repeated oral glucose tolerance tests are not recommended. Investigations in such children indicate that the degree of impaired glucose tolerance tends to remain stable or may actually improve over a period of years, except in patients with markedly subnormal insulin responses. Consequently, apart from reduction in weight for the obese child, no therapy is indicated. At this time, the use of oral hypoglycemic agents should be considered investigational.

Genetic Defects of β-Cell Function

Diabetes Mellitus of the Newborn

Neonatal diabetes mellitus is rare, with an estimated incidence of 1 per 100,000 newborns. Onset of classic autoimmune T1DM before the age of 6 mo is most unusual and most cases of diabetes in this age range are caused by genetic mutations.

Genetic Defects of Insulin Action

Various genetic mutations in the insulin receptor (IR) can impair the action of insulin at the IR or impair postreceptor signaling, leading to insulin resistance.

The mildest form of the syndrome with mutations in the IR was previously known as type A insulin resistance. This is associated with hirsutism, hyperandrogenism, and cystic ovaries in females, without obesity. Acanthosis nigricans may be present and life expectancy is not significantly impaired. More severe forms of insulin resistance are seen in 2 mutations in the insulin receptor gene that cause the pediatric syndromes of leprechaunism and Rabson-Mendenhall syndrome.

Cystic Fibrosis-Related Diabetes (Chapter 395)

As patients with cystic fibrosis (CF) live longer, an increasing number are being diagnosed with cystic fibrosis-related diabetes (CFRD). Females appear to have a somewhat higher risk of CFRD than males and prevalence increases with increasing age until age 40 yr (there is a decline in prevalence after that, presumably because only the healthiest CF patients survive beyond that age). There is an association with pancreatic insufficiency and there may be higher risk in patients with class I and class II cystic fibrosis transmembrane conductance regulator (CFTR) mutations. A large multi-center study in the USA reported prevalence (in all ages) of 17% in females and 12% in males. Cross sectional studies indicate that the prevalence of impaired glucose tolerance may be significantly higher than this and up to 65% of children with CF have diminished 1st phase insulin secretion, even when they have normal glucose tolerance. In Denmark, oral glucose tolerance screening of the entire CF population demonstrated no diabetes in patients younger than 10 yr, 12% diabetes in patients aged 10-19 yr, and 48% diabetes in adults aged 20 yr and older. At a Midwestern center where routine annual oral glucose tolerance screening is performed, only about one half of children and one fourth of adults have normal glucose tolerance. The care of these patients is very different from that of patients with T1DM or T2DM, because CFRD patients have distinct pathophysiologic and complicated nutritional and medical problems.

Patients with CFRD have features of both T1DM and T2DM. In the pancreas, exocrine tissue is replaced by fibrosis and fat and many of the pancreatic islets are destroyed. The remaining islets demonstrate diminished numbers of β-, α-, and pancreatic polypeptide-secreting cells. Secretion of the islet hormones insulin, glucagon, and pancreatic polypeptide is impaired in patients with CF in response to a variety of secretagogues. This pancreatic damage leads to slowly progressive insulin deficiency, of which the earliest manifestation is an impaired 1st phase insulin response. As patients age, this response becomes progressively delayed and less robust than normal. At the same time, these patients develop insulin resistance due to chronic inflammation and the use of steroids. Insulin deficiency and insulin resistance lead to a very gradual onset of impaired glucose tolerance that eventually evolves into diabetes. In some cases, diabetes may wax and wane with disease exacerbations and the use of corticosteroids. The clinical presentation is similar to that of T2DM in that the onset of the disease is insidious and the occurrence of ketoacidosis is rare. Islet antibody titers are negative. Microvascular complications do develop, but may do so at a slower rate than in typical T1DM or T2DM. Macrovascular complications do not appear to be of concern in CFRD, perhaps because of the shortened life span of these patients. Several factors unique to CF influence the onset and the course of diabetes. For example: (1) frequent infections are associated with waxing and waning of insulin resistance; (2) energy needs are increased because of infection and pulmonary disease; (3) malabsorption is common, despite enzyme supplementation; (4) nutrient absorption is altered by abnormal intestinal transit time; (5) liver disease is frequently present; (6) anorexia and nausea are common; (7) there is a wide variation in daily food intake based on the patient’s acute health status; and (8) both insulin and glucagon secretion are impaired (in contrast to autoimmune diabetes, in which only insulin secretion is affected).

Impaired glucose tolerance and CFRD are associated with poor weight gain and there is evidence that treatment with insulin improves weight gain and slows the rate of pulmonary deterioration. Because of these observations, the CF foundation recommends routine diabetes screening of all children with CF, starting at age 12 yr. There is some debate over the ideal screening modality; fasting blood glucose is easier to perform but will miss some cases as postprandial glucose may be abnormal before fasting glucose becomes elevated. A 2 hr glucose tolerance test is therefore recommended, though it is possible that simply obtaining a single 2 hr postprandial glucose value may be sufficient. When hyperglycemia develops, the accompanying metabolic derangements are usually mild, and relatively low doses of insulin usually suffice for adequate management. Basal insulin may be started initially, but basal-bolus therapy similar to that used in T1DM will eventually be needed. Some centers also use oral agents (sulfonylureas as well as metformin) but consensus guidelines have not been developed regarding the use of oral agents. Dietary restrictions are minimal as increased energy needs are present and weight gain is usually desired. Ketoacidosis is uncommon but may occur with progressive deterioration of islet cell function. Impaired glucose tolerance is not necessarily an indication for treatment, but patients who have poor growth and inadequate weight gain may benefit from the addition of basal insulin even if they do not meet the criteria for diagnosis of diabetes.

Autoimmune Diseases

Chronic lymphocytic thyroiditis (Hashimoto thyroiditis) is frequently associated with T1DM in children (Chapter 560). As many as 1 in 5 insulin-dependent diabetic patients have thyroid antibodies in their serum; the prevalence is 2-20 times greater than in control populations. Only a small proportion of these patients, however, acquire clinical hypothyroidism; the interval between diagnosis of diabetes and thyroid disease averages about 5 yr. Periodic palpation of the thyroid gland is indicated in all diabetic children; if the gland feels firm or enlarged, serum measurements of thyroid antibodies and thyroid-stimulating hormone (TSH) should be obtained. A confirmed TSH level of greater than 10 µU/mL indicates existing or incipient thyroid dysfunction that warrants replacement with thyroid hormone. Deceleration in the rate of growth may also be due to thyroid failure and is, in itself, a reason for securing serum measurements of thyroxine and TSH concentrations.

When diabetes and thyroid disease coexist, the possibility of autoimmune adrenal insufficiency should be considered. It may be heralded by decreasing insulin requirements, increasing pigmentation of the skin and buccal mucosa, salt craving, weakness, asthenia and postural hypotension, or even frank Addisonian crisis. This syndrome is most unusual in the 1st decade of life, but it may become apparent in the 2nd decade or later.

Celiac disease, which is due to hypersensitivity to dietary gluten, is another autoimmune disorder that occurs with significant frequency in children with T1DM (Chapter 330.2). It is estimated that about 7% of children with T1DM develop celiac disease within the 1st 6 yr of diagnosis, and the incidence of celiac disease is significantly higher in children under 4 yr of age and in girls. Young children with T1DM and celiac disease usually present with gastrointestinal symptoms (abdominal cramping, diarrhea, and gastroesophageal reflux), growth failure due to suboptimal weight gain, and unexplained hypoglycemic reactions due to nutrient malabsorption; adolescents may remain asymptomatic. The diagnosis of celiac disease is considered if serum antiendomysial and/or tissue transglutaminase antibody titers are positive in the presence of normal serum total IgA level. The diagnosis is confirmed on endoscopic evaluation and biopsy of small bowel revealing characteristic atrophy of intestinal villi. Therapy consists of a gluten-free diet, which will alleviate gastrointestinal symptoms and may reduce glycemic excursions.

Circulating antibodies to gastric parietal cells and to intrinsic factor are 2-3 times more common in patients with T1DM than in control subjects. The presence of antibodies to gastric parietal cells is correlated with atrophic gastritis and antibodies to intrinsic factor are associated with malabsorption of vitamin B₁₂. However, megaloblastic anemia is rare in children with T1DM.

A variant of the multiple endocrine deficiency syndrome is characterized by T1DM, idiopathic intestinal mucosal atrophy with associated inflammation and severe malabsorption, IgA deficiency, and circulating antibodies to multiple endocrine organs including the thyroid, adrenal, pancreas, parathyroid, and gonads. In addition, nondiabetic family members have an increased frequency of vitiligo, Graves disease, and multiple sclerosis as well as low complement levels and antibodies to endocrine tissues.

Endocrinopathies

The endocrinopathies listed in Web Table 583-1 on the Nelson Textbook of Pediatrics website at www.expertconsult.com are only rarely encountered as a cause of diabetes in childhood. They may accelerate the manifestations of diabetes in those with inherited or acquired defects in insulin secretion or action.

Drugs

High-dose oral or parenteral steroid therapy usually results in significant insulin resistance leading to glucose intolerance and overt diabetes. The immunosuppressive agents cyclosporin and tacrolimus are toxic to β cells, causing IDDM in a significant proportion of patients treated with these agents. Their toxicity to pancreatic β cells was 1 of the factors that limited their usefulness in arresting ongoing autoimmune destruction of β cells. Streptozotocin and the rodenticide Vacor are also toxic to β cells, causing diabetes.

There are no consensus guidelines regarding treatment of steroid-induced hyperglycemia in children. Many patients on high-dose steroids have elevated blood glucose during the day and evening but become normoglycemic late at night and early in the morning. In general, significant hyperglycemia in an inpatient setting is treated with short acting insulin on an as-needed basis. Basal insulin may be added when fasting hyperglycemia is significant. Outpatient treatment can be more difficult, but when treatment is needed, protocols similar to the basal-bolus regimens used in T1DM are used.

Genetic Syndromes Associated with Diabetes Mellitus

A number of rare genetic syndromes associated with IDDM or carbohydrate intolerance have been described (see Web Table 583-1 on the Nelson Textbook of Pediatrics website at www.expertconsult.com). These syndromes represent a broad spectrum of diseases ranging from premature cellular aging, as in the Werner and Cockayne syndromes (Chapter 84) to excessive obesity associated with hyperinsulinism, resistance to insulin action, and carbohydrate intolerance, as in the Prader-Willi syndrome (Chapters 75 and 76). Some of these syndromes are characterized by primary disturbances in the insulin receptor or in antibodies to the insulin receptor without any impairment in insulin secretion. Although rare, these syndromes provide unique models to understand the multiple causes of disturbed carbohydrate metabolism from defective insulin secretion or from defective insulin action at the cell receptor or postreceptor level.