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.