Tye 1 DM

Type 1 Diabetes: Current Concepts in Epidemiology, Pathophysiology, Clinical Care, and Research
Mary Joyce Gan, MD, Anastasia Albanese-ONeill, RN, CDE, and Michael J. Haller, MD
Type 1 diabetes (T1D) is an autoimmune disease mediated by a combination of genetic and environmental triggers resulting in lymphocytic inltration of pancreatic islets, destruction of beta cells, and lifelong dependency on exogenous insulin. Although T1D is prevalent (1 in 300) and its incidence is steadily increasing worldwide (3% per year), the exact geneenvironment interactions precipitating the disease remain unknown. Living with T1D is challenging for patients, families, and caregivers. Because of the relative paucity of pediatric
endocrinologists, general pediatricians and other subspecialists may occasionally be faced with the task of managing diabetes-related complaints. Herein, we provide a comprehensive review of the natural history, pathophysiology, and contemporary management of T1D. In addition, recent advances in T1D research are discussed. Curr Probl Pediatr Adolesc Health Care 2012;42:269-291
Preface: Living with Type 1 Diabetes, A Personal StoryAnastasia Albanese-ONeill, RN, CDE
The Diagnosis
Our daughter, now 10, was diagnosed with type 1 diabetes (T1D) at the age of 16 months. She was the rst and remains the only person in our family diagnosed with diabetes. As with most parents of a newly diagnosed child, my husband and I were fairly ignorant about the disease. Until her diagnosis, our daughters development had been unremarkable, except perhaps to us as rst time parents. In hindsight, we now know that our then toddler exhibited all of the classic symptoms of T1D: frequent urination, extreme thirst, and insatiable hunger. She regularly had full diapers and often stood up in her crib at night calling out for water. Approximately 4 weeks before her diagnosis, we repeatedly took her to visits with her primary care physician with fairly vague complaints, such as faFrom the Department of Pediatrics, University of Florida, Gainesville, FL. Curr Probl Pediatr Adolesc Health Care 2012;42:269-291 1538-5442/$ - see front matter 2012 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.cppeds.2012.07.002
tigue, irritability, and weight loss, along with the specic complaint of constant thirst. During these visits, we often saw a different care provider in what was a large pediatric primary care practice. Perhaps we failed to effectively communicate our concerns about her thirst, hunger, and wet diapers, but at each clinical appointment she was given a routine examination and was sent home without a diagnosis. The following week, we ew to Seattle for a weekend vacation. Throughout the trip, she was irritable, fatigued, and occasionally stumbled when she walked. She was extremely thirsty and hungry. We went through what seemed like an endless supply of diapers. On the 2-hour ight home, she ate an entire container of cherry tomatoes and soaked through another diaper. Although we had been to the doctor just a week earlier, we resolved to make an appointment for the next day. Meanwhile, my husband searched online for information related to her symptoms and I called my mother to share my concerns. It was during that conversation that the word diabetes came up for the rst time. My mother suggested we specically mention diabetes at the appointment and ask that she be screened. The next day at the doctors ofce was busy. It was the end of u season and the waiting rooms were full. Our distress became acute when our daughter vomited
Curr Probl Pediatr Adolesc Health Care, November/December 2012
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as we waited to be seen. Her breathing seemed labored and she continued to ask for something to eat or drink. When we met with the doctor, we immediately asked about diabetes. We were told she was too young to have diabetes and, besides, they would have to use a catheter to get a urine sample. Were we willing to put her through an invasive procedure, they asked? We assured them the catheter would be unnecessary and, as we suspected, she was able to provide a urine sample in short order. Based on the results, we were sent to the laboratory immediately for a blood draw. The line in the laboratory was long. When it was our turn, the technician had a difcult time drawing blood and our daughter was, not surprisingly, screaming and crying. Because the technician continued to search for a vein, the doctor appeared, demanded to know what was taking so long, and took us back upstairs where a specialist was able to draw blood and start an intravenous (IV) catheter. When the results came back, we were advised that we needed to take an ambulance to the intensive care unit (ICU) at a childrens hospital across town. We spent 2 days in the ICU and 3 more days on the regular hospital oor. While our daughter was in the ICU, we learned that she was in diabetic ketoacidosis (DKA) and was at risk for coma and possibly death. We were told that there was no cure for T1D and that many marriages fail when a child is diagnosed with a chronic disease. After we were moved out of the ICU, we learned how to check blood sugars and give insulin injections. We learned the difference between clear and cloudy insulins, how to count carbohydrates, and how to keep a log of numbers and insulin doses. We were sent home with 2 large boxes of supplies and a sense of dread. What did this mean for our child? For our family?
A Childhood With Diabetes

During the rst 6 months after our daughters diagnosis with T1D, we felt we simply did our best to survive. Our child had been going to an in-home day care in our neighborhood before she was diagnosed, but the family who managed the facility told us that they did not feel comfortable having our daughter there any longer. We found ways to work from home, hired a nanny, and recruited family members to help. We put job promotions that might mean moving to a new city or demand more time away from home on hold. We put off having another child.
We tried to learn what we could about diabetes and how to manage it. Our daughter was initially put on neutral protamine Hagedorn (NPH) and regular insulin, and her bedtime dose was one-fourth of a unit of NPH scheduled at 10 PM. We have vivid memories from that rst month of struggling to draw up the dose accurately, of icking the syringe over and over again to get air out, of hoping there was more insulin than air in the syringe, and of creeping into her room to attempt insulin injections without waking her up. We turned up the heat so she didnt need pajamas in order to expose the maximum possible number of injection sites. We set up a home laboratory where we diluted insulin ourselves. We checked her blood sugar at midnight and at 3 AM each night, as advised, to make sure her blood sugar wasnt so low it would impair her brain development. We called friends at the American Diabetes Association (ADA) and asked who the best pediatric endocrinologist was in town. We changed doctors with the assistance and blessing of our current one, who managed all patients with pediatric diabetes in 2 states and was self-admittedly overwhelmed. Our new doctor immediately prescribed a shortacting insulin in place of regular and urged us to put our daughter on an insulin pump. After his advice, she went on an insulin pump 1 week after her second birthday. The transition was challenging, but the pump was, indeed, a blessing. Her blood glucose numbers were initially high as we titrated basal rates and carbohydrate ratios, and also due to our lack of expertise. Although we experienced a few technical difculties early on, we soon became procient with the device and she began to enjoy tremendous freedom in terms of diet and schedule. With time, her grandparents also learned to push the right buttons and it even had a remote control. Life settled into a routine. Nine years later, our daughter is still on the insulin pump. The version she has now has many more features than her initial device, including a calculator that can suggest insulin doses based on current blood glucose and carbohydrate intake. Her hemoglobin A1c (HbA1c) hovers around 7%, and she has so far adjusted well psychologically to the diagnosis. That said, her body is beginning to change biochemically as she enters puberty. The related uctuations in hormones often result in unanticipated changes in blood sugar. Simultaneously, she is starting to manage her diabetes more independently, and so, we nd ourselves seeking to nd a balance between ideal
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blood glucose numbers and reinforcing her condence cose. This gives us condence in the care she provides. in her ability to self-manage effectively. Our hope is to The school nurse has also become an ally and an stay as engaged as we can without smothering her. advocate and is a critical member of our care team. Because we know that diabetes is stressful to manage As we watch our daughter grow and mature, we have at any age, we feel that no preadolescent should go great hope for the future. We hope ongoing research through it alone. She checks her blood sugars 5-7 efforts will eventually discover a pathway toward times a day, sometimes independently, sometimes prevention and cure, and we nd comfort in seeing and with a reminder. She knows the carbohydrate counts using the technology that has allowed marked imfor familiar foods, but we help with new foods or at provements in diabetes care today. restaurants. We download her blood glucose log from Introduction her pump weekly and go over it together. The all too frequent story of lost opportunities to We have tried, as a rule, to be open about the fact diagnose T1D before ketoacidosis and the ensuing that she has diabetes. Her friends, teachers, and challenges of living a life dependent on insulin should coaches are all aware. In many cases, we have discovcompel the general pediatrician, and subspecialist ered that she is something of a diabetes ambassador, alike, to read this review. Herein, we provide a and that people often embrace learning more about the working knowledge of the pathophysiology, natural disease because of her openness. In our minds, evhistory, and clinical care of T1D. In addition, we eryone has something, whether that something is review ongoing basic and translawearing glasses, or not being good tional research efforts aimed at at math, or having diabetes. It is ameliorating T1D. In short, T1D is nothing to be ashamed of or hide, a presumed autoimmune disease and the more this message is reinBecause the incidence of forced, the better. T1D continues to increase characterized by directed attack of the pancreatic beta cells. During the There are some days that diabeworldwide at a rate of largely silent preclinical phase of the tes fades into the background and nearly 3% per year, we disease, beta-cell destruction may others when it cannot be avoided. must be ever vigilant to persist for weeks, months, or even Unanticipated high blood sugars mean nding noncarbohydrate ensure early and accurate years until insulin production is rst unable to maintain normal glucose menu items on the y, and low diagnosis. metabolism and then, with more seblood sugars can mean stopping in vere insulin deciency, is unable to the middle of a dance rehearsal or inhibit fatty acid metabolism. The volleyball game or examination at end result for far too many children is the concurrent school to check blood glucose and treat the low. Our diagnosis of T1D and DKA. daughter has also found wonderful friends at diabetes Because the incidence of T1D continues to increase camp. We see these as essential relationships, as she worldwide at a rate of nearly 3% per year, we must be tells us that these friends understand her and get ever vigilant to ensure early and accurate diagnosis. what its like to live with diabetes. Although the tools available to manage T1D continue to Slumber parties are fun for our daughter, but often improve with analog insulin, continuous glucose monistressful for us because we worry about extremes in tors (CGMs), insulin pumps, and better understanding of blood glucose and the short- and long-term conseways to mitigate complications, living with T1D remains quences. Still, our anxiety is well worth her ability to a challenge. As we strive to improve our basic underparticipate in the rituals of a normal childhood. standing of the epidemiology and pathophysiology of We are grateful to have an endocrinologist who is this complex disease, we hope that ongoing research available and compassionate, who is up-to-date on efforts will eventually provide a pathway to the prevendiabetes research and management, and who is a true tion and cure of T1D. Until the day comes when T1D is partner in our childs diabetes management. Our relegated to the pages of medical history, pediatricians daughters pediatrician is also knowledgeable about must develop and maintain an appropriate index of diabetes, and knows how to put it in context during suspicion when evaluating children with symptoms poroutine (nondiabetes) appointments and understands tentially consistent with T1D. how prescribed medications might impact blood glu-
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Etiology
T1D is thought to be a classic autoimmune disease primarily seen in genetically susceptible hosts exposed to any number of putative environmental triggers. The result is the activation of immune cells armed with a unique specicity for killing pancreatic beta cells. As such, 60%-90% of patients who die within 6 months of being diagnosed with T1D have lymphocytic inltration of the pancreatic islets with destruction of the beta cells and depletion in insulin content as seen by immunohistochemistry.1,2 The process of beta-cell destruction begins when macrophages and dendritic cells present betacell antigens to naive CD4 T-cells through the major histocompatibility complex. Through a series of interleukin signaling, CD4 T-cells are activated, which in turn activate CD8 T-cells directly responsible for causing beta-cell death.3 Beta-cell death results in the release of additional intracellular antigens and permits antigenpresenting cells further access to typically sequestered self-antigens. Ongoing sampling of these autoantigens leads to activation of additional autoreactive T-cells through amplication of the initial autoimmune response (epitope spreading). As further evidence of the immune specicity in T1D, the alpha and delta cells remain entirely unharmed.
TABLE 1. Risk of Type 1 Diabetes
General population First degree relative with T1D Offspring of affected mother Offspring of affected father Concordance rates In monozygotic twins In dizygotic twins DR3/DR4 () in the general population Random sibling risk Sibling HLA identical to affected sibling Sibling shares DR3/DR4 with affected sibling
1 in 300-400 1 in 20 1 in 50 1 in 14 1 1 1 1 1 1 in in in in in in 2-3 (30%-50%) 10-16 (6%-10%) 40 20 7 4
T1D, type 1 diabetes; HLA, human leukocyte antigen. Adapted from Winter, Pediatric Endocrinology. New York, NY: Informa Healthcare USA, Inc; 2007:83-99.8
Genetic Susceptibility to T1D

Susceptibility to T1D is a heritable trait. However, 85% of cases occur in the absence of an affected rst-degree relative. Diabetes with onset before age 5 years is a marker of high familial risk and suggests a major role for genetic factors. Siblings of children with onset of T1D before the age of 5 years have a 3to 5-fold greater cumulative risk of diabetes by age 20 years compared with siblings of children diagnosed between 5 and 15 years of age.4 Individuals with an affected rst-degree relative have a 1 in 20 (5%) lifetime risk of developing T1D, compared with a 1 in 300 (0.3%) lifetime risk for the general population.5 As evidence of presumed environmental and potential epigenetic factors, children of an affected father have a 1 in 14 (7%) risk, whereas children of an affected mother carry only a 1 in 50 (2%) risk.6 Monozygotic twins have a concordance rate of 30%-50%, whereas dizygotic twins have a concordance rate of 6%-10%.7 (Table 1). Inheritance of susceptibility to and protection from T1D are multifactorial and polygenic. The association of specic human leukocyte antigen (HLA)-loci and
T1D was rst recognized in the 1970s for HLA-B alleles. Subsequently, DR alleles, DQB1, and A1 alleles were all discovered to predispose to T1D. At the University of Florida, a study involving 1000 patients with T1D showed that approximately 95% express at least 1 HLA-DR3 and/or DR4 allele. Forty percent of T1D patients are heterozygous for HLADR3 and DR4, compared with only 3% in the general population. After DR3/DR4 heterozygosity, DR4 homozygosity is the next highest risk genotype, followed by DR3 homozygosity and DR4/DRX heterozygosity (X non-DR3/DR4 allele). Only 5% of T1D patients lack both HLA-DR3 and DR4.8,9 As implied previously, there are also alleles that protect against T1D (HLA-DR2, HLA-DR5, and HLA-DQB1*0602).10 Only 1 in 15,000 persons with HLA-DQB1*0602 develops T1D.11 In African-Americans, although HLA-DR4 is associated with T1D, DR3 is not. Thirty percent of African-Americans with T1D lack both DR3 and DR4 alleles. The prevalence of islet cell autoantibody positivity at diabetes onset in African-Americans is also considerably lower than in Non-Hispanic Whites (40% in African-Americans vs 75% in Non-Hispanic Whites Americans) and provides additional evidence of the etiologic heterogeneity of T1D.
Environmental Triggers of T1D

Environmental factors are thought to play a signicant role in triggering T1D. The discordance rate in identical twins is one of the best observations supporting the existence of environmental triggers in T1D.12 A comprehensive list of proposed environmental triggers of beta-cell autoimmunity is outside the scope of this review but a brief list includes: diet, cows milk
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protein exposure (bovine serum albumin and betalactoglobulin), vitamin D deciency, viral infections (ie, coxsackie A or B, enterovirus, rubella, cytomegalovirus, ECHO virus, EpsteinBarr virus, mumps, retrovirus), drugs, toxins (alloxan-like or streptozotocin-like agents that induce oxidant beta-cell damage), and stress. To date, no one specic environmental trigger has been found to clearly and denitively cause T1D. Not surprisingly, gene-environment interactions are highly variable from person to person. Genetic factors may predominate in risk for the young, whereas environmental exposures may become more important with advancing age. As such, The Environmental Determinants of Diabetes in the Young (TEDDY) study, an international multicenter prospective effort, with sites in Finland, Germany, Sweden, and the United States (Colorado, Washington, and Georgia/Florida), was initiated in 2003 in an attempt to identify the environmental triggers of T1D in genetically susceptible individuals.13
Epidemiology
Incidence and Prevalence
Epidemiologic patterns of T1D provide insight into the etiology, natural history, and complications of the disease. T1D accounts for 5%-10% of the total cases of diabetes worldwide.14 Conversely, type 2 diabetes (T2D) is characterized by insulin resistance and betacell dysfunction and dominates the literature and thought processes of most physicians treating diabetes. Despite recent increases in the rate of T2D in youth, T1D has been, and continues to be, the most common type of diabetes in children and adolescents.15 Findings from large T1D registry studies, such as the World Health Organization Multinational Project for Childhood Diabetes (DIAMOND Project), the SEARCH for Diabetes in Youth (SEARCH), and the Epidemiology and Prevention of Diabetes (EURODIAB), show global variation in the incidence, prevalence, and temporal trends in T1D. With few exceptions, population-based T1D registries show an increasing incidence of T1D over time. The DIAMOND Project, initiated by the World Health Organization in 1990 to describe the incidence and trends of T1D in children worldwide for the period of 1990-1999, analyzed children aged 14 years or younger in 57 countries (Figure 1).16 The age-adjusted incidence of T1D varied from 0.1 per 100,000 per year
in China and Venezuela to 40.9 per 100,000 per year in Finland. According to the 1990-1999 data, the average annual increase in incidence was 2.8% (95% condence interval [CI]: 2.4%-3.2%) per year. The trends in incidence grouped by continent showed statistically signicant increases all over the world (4.0% in Asia, 3.2% in Europe, and 5.3% in North America), except in Central America and the West Indies where the trend was a decrease of 3.6%. Only among the European populations did the trend in incidence diminish with age.16 The DIAMOND registry showed that the highest incidence rates were among European and North American populations, varying from 4 to 41 per 100,000 per year in Europe and from 11 to 25 per 100,000 per year in North America. Among African populations, incidence ranged between 1 and 9 per 100,000 per year. The incidence among South American populations varied between 1 and 10 per 100,000 per year. In Central America and the West Indies, the range of variation was from 2 to 17 per 100,000 per year. Asian populations had a low incidence of T1D at 1 per 100,000 per year.16 Because of public health concern about the increasing incidence of T1D and T2D, the Centers for Disease Control and Prevention (CDC) and the National Institute of Diabetes and Digestive and Kidney Diseases funded the SEARCH study in the United States in 2001. SEARCH is an ongoing multiethnic observational study conducted in 6 centers that encompass the racial/ethnic diversity of the United States. The primary goal is to estimate the prevalence and incidence of T1D and T2D in youth 20 years of age. In 2001, approximately 3.5 million children 20 years of age were under surveillance at the SEARCH research centers, and the overall prevalence of diabetes (type 1, type 2, or unspecied) was 1.8 per 1000. SEARCH estimated that 154,369 youth had physiciandiagnosed diabetes in 2001.17 Since 2002, the number of children 20 years of age under surveillance to estimate diabetes incidence has been approximately 5.5 million. The overall incidence of diabetes in 2002 and 2003 was estimated to be 24.3 per 100,000 per year. SEARCH estimated that 15,000 youths are diagnosed with T1D annually.18 Combined data from the Colorado Insulin-Dependent Diabetes Mellitus study registry and the SEARCH study reveal that the incidence of T1D has increased in the past 3 decades.19
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The incidence of T1D was 14.8 per 100,000 per year (95% CI: 14.0-15.6) in 1978-1988 and was 23.9 per 100,000 per year (95% CI: 22.2-25.6) in 2002-2004 for the state of Colorado. During this 26-year period, the incidence of T1D increased by 2.3% (95% CI: 1.6-3.1) per year with signicant increases for both non-Hispanic white (NHW) and Hispanic youth.
Risk Factors for Development of T1D

Age. T1D is the predominant type of diabetes in children, accounting for 85% of all diabetes cases in youth 20 years of age worldwide.17 The DIAMOND Project reported that T1D incidence rates rise from infancy and peak during puberty (ages 10-14 years).16,20 In their pooled data, 10- to 14-year-old children had higher risk than 5- to 9-year-old children, who had higher risk than 0- to 4-year-old children.16 However, relative annual increases in incidence rates have recently been highest in the 0- to 4-year-age group (5.4%, 95% CI: 4.8-6.1) compared with the 5- to 9-year-age group (4.3%, 95% CI: 3.8-4.8) and the 10to 14-year-age group (2.9%, 95% CI: 2.5-3.3).21 Although T1D risk declines and then stabilizes during young adulthood (15-29 years), risk does not entirely disappear.15 Approximately 25% of T1D patients are diagnosed as adults.7 In addition, up to 10% of adults initially diagnosed with T2D are found to have antibodies associated with T1D.22 In these patients, the pace of beta-cell destruction tends to be attenuated; hence, the term latent autoimmune diabetes of adults (LADA) has been used to describe these cases.23 Gender. Although most autoimmune diseases affect females more than males, girls and boys are equally affected with T1D in pediatric cases.24 Race/Ethnicity. Incidence of T1D is highest among NHW. In 2002-2003, the incidence of T1D in NHW children 10 years old was 23 per 100,000 per year. Incidence rates are considered intermediate in African Americans (13 per 100,000 per year) and Hispanics (12 per 100,000 per year) and low in American Indians (5.2 per 100,000 per year) and Asian Pacic Islanders (6.9 per 100,000 per year).20 Across all racial/ethnic groups, incidence rates peaked at 5-9 years and 10-14 years.20
Duration of symptoms was 2 weeks in only 25% of the children, although this was more common in children 5 years of age. This suggests that efforts to improve understanding of the classic symptoms of T1D would increase early diagnosis and reduce the severity of metabolic derangement at presentation. DKA, dened as pH 7.3, was reported in 42% of children (33% with pH 7.1-7.3 and 9% with pH 7.1). Not surprisingly, in centers with more cases of T1D and, therefore, more familiarity with the disease, children were far less likely to be diagnosed with DKA at presentation.
Natural History and Prediction of T1D

Islet-Specic Autoantibodies. Islet-specic autoantibodies are often present months to years before the onset of clinical T1D and persist for varying durations after onset. Although not thought to be a causative factor of the disease, autoantibodies are a useful tool because they provide serologic evidence of ongoing autoimmune attack. Islet autoantibodies may rst appear early in life and are predictive of the later development of T1D, with 90%-95% of newly diagnosed patients exhibiting at least one positive autoantibody.26-29 Islet autoantibodies have not been detected in any other destructive form of diabetes, such as cystic brosis or hemochromatosis-induced diabetes, although children with these diseases can develop concurrent T1D. Autoantibodies associated with T1D include (1) islet cell autoantibodies (ICA), (2) glutamic acid decarboxylase autoantibodies (GADA), (3) insulinoma associated 2 autoantibodies (IA-2A), (4) insulin autoantibodies (IAA), and (5) recently described zinc transporter autoantibodies (ZnT8A). The number of islet autoantibodies present in a patients serum provides useful T1D risk information; the presence of multiple islet autoantibodies is far more predictive than any single islet autoantibody or specic combination of antibodies (see Figure 2).30 Islet Cell Autoantibodies (ICA). ICA are detected by using indirect immunouorescence after incubating thin sections of frozen pancreas with the patients serum. Because of the cost and expertise required to perform this assay, some practitioners prefer to use the biochemical antibodies described later. That said, ICA remain helpful in the prediction and diagnosis of T1D. At the time of diagnosis, 70%-80% of Caucasian children with T1D have ICA. The frequency then falls to 25% by 5 years and to 5% by 10 years into the disease process.31 About 5%-15% of patients with
Epidemiology of New-Onset T1D

In a report by the EURODIAB group, polyuria was the most common presenting symptom (96%), followed by weight loss (61%) and fatigue (52%).25
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FIG 1. Age-standardized incidence of type 1 diabetes in children under 14 years of age (per 100,000 per year). Adapted from The DIAMOND Project Group, Diabet Med 2006;23:857-66.17 (Color version of gure is available online.)
FIG 2. Natural history of type 1 diabetes. Adapted from Haller et al, Pediatr Clin North Am 2005;52:1553-78,8 and Winter, Pediatric Endocrinology. New York, NY: Informa Healthcare USA, Inc; 2007:83-99.9 (Color version of gure is available online.)
clinically apparent T2D are ICA positive.32 With time, these patients tend to progress to insulin dependence. These individuals also express higher frequencies of the T1D-associated HLA-DR3 and DR4 alleles.8 Nondiabetic individuals who have higher ICA titers have an increased risk for the development of T1D,8 and newly-diagnosed T1D patients who have higher ICA titers are at higher risk to more rapidly lose endogenous C-peptide secretion.33 Glutamic Acid Decarboxylase Autoantibodies (GADA). GADA converts glutamate to the inhibitory neurotransmitter gamma-amino butyric acid in the nervous system. Atkinson et al,34 showed that 64
kDa autoantibodies were highly predictive of T1D. Since this initial report in 1990, many studies have conrmed that GADA in nondiabetic individuals predict the later development of T1D. Additionally, GADA in patients with clinical T2D correlates with a more rapid requirement for insulin-based therapy and likely indicates that the patient has a component of T1D. Similar to ICA, GADA are measurable in 70%-80% of patients with new-onset T1D. The difference lies in the persistence of GADA several years into the disease process. For that reason, GADA testing is preferred over ICA in adults with presumed LADA because documentation of autoantibody status provides rationale for early initiation of insulin therapy. Insulinoma Associated 2 Autoantibodies (IA-2A). IA-2A is a transmembrane protein that is a member of the protein tyrosine phosphatase family. Besides the islets, IA-2A is found in other endocrine tissues, such as the pituitary gland. The immunoreactivity of the C-terminal portion of IA-2A is most highly associated with T1D. At the onset of T1D, IA-2A is less commonly found (approximately 60%) than ICA or GADA.35 Insulin Autoantibodies (IAA). The only beta-cell specic autoantigen is insulin. IAA are found in approximately 40%-50% of children with newly diagnosed T1D.36 In nondiabetic individuals, IAA alone does not strongly predict the development of
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T1D. However, IAA together with ICA are highly predictive of the eventual development of T1D, as demonstrated in Diabetes Prevention Trial-Type 1 (DPT-1).36 Blood testing for IAA should be carried out before insulin treatment is started. Once insulin is exogenously injected (for 10 days), IAA measurement is no longer valid because exogenous insulin can elicit insulin antibody responses that are indistinguishable from autoantibody production. However, the concentration of insulin antibodies is usually much higher than IAA.37 Insulin antibodies can arise even with human insulin therapy. Zinc Transporter 8 (ZnT8). The zinc transporter ZnT8 (Slc30A8), a transmembrane protein that concentrates zinc in insulin secretory granules, was recently found to be targeted by autoantibodies in 60%-80% of new-onset T1D and up to 30% of patients with autoimmune disorders associated with T1D. Conversely, ZnT8A were seen in 2% of controls and 3% of T2D patients. Perhaps, more importantly, for identifying those with presumed T1D, ZnT8A were found in 26% of T1D patients who were negative for ICA, GADA, IA2A, and IAA.38 T1D patients followed from birth showed ZnT8A as early as 2 years of age, and levels increased to disease onset. Available diagnostic tests show high specicities and sensitivities that complement current T1D autoantibody assays for GADA, IA2A, IAA, and ICA.39 The combined measurement of ZnT8A, GADA, IA2A, and IAA raises autoimmunity detection rates to 98% at disease onset.38 In summary, islet-specic autoantibodies are of immense value in predicting T1D and in conrming the presence of autoimmunity in patients with nonclassical T1D phenotypes. Specically, because an increasing proportion of our pediatric population is now overweight or obese, children with new-onset T1D may easily be confused with T2D patients if autoantibody status is unknown. When the etiology new-onset diabetes is questioned, the use of autoantibodies is critical to ensure proper classication and management.
symptoms of weight loss, polyuria, and polydipsia. In children, the third member of the classic diabetes triad, polyphagia, is often absent because ketosis can cause anorexia. Perhaps most importantly, nonspecic symptoms, such as vomiting, abdominal discomfort, constipation, and headache (common presenting complaints in the outpatient setting), should not be overlooked as possible signs of new onset T1D. Additionally, enuresis in a previously toilet-trained child, nocturia, pyogenic skin infections, recurrent candidal rash in babies and toddlers, and monilial vaginitis in teenage girls also require consideration of diabetes.
Presentation With DKA

Approximately 30% of children with new-onset diabetes present in DKA. Most cases of DKA present with vomiting, abdominal pain, hyperventilation (Kussmaul breathing), lethargy, confusion, dehydration, and the distinctive fruity breath odor of ketosis. DKA is caused by a severe deciency in circulating insulin. Although exquisitely robust concentrations of insulin are required to maintain normal glucose, small amounts of insulin are required to prevent the lipolysis associated with DKA. As such, when patients develop ketoacidosis, their effective insulin stores are fully depleted. Lipolysis results in the formation of ketone bodies (B-hydroxybutyrate and acetoacetate), which provide an alternate source of energy in the absence of insulin but also induce a metabolic acidosis. Ongoing dehydration and electrolyte loss from osmotic diuresis compound the metabolic acidosis. Criteria for the diagnosis of DKA are as follows: (1) hyperglycemia, (2) venous pH 7.3, and/or (3) bicarbonate 15 mmol/L, with associated glycosuria, ketonuria, and ketonemia. Categorization of severity of DKA is as follows: mild: pH 7.3 and bicarbonate 15 mmol/L; moderate: pH 7.2 and bicarbonate 10 mmol/L; and severe: pH 7.1 and bicarbonate 5 mmol/L. Approximately 1% of episodes of DKA are complicated by clinical cerebral edema, and the overall mortality from pediatric DKA in the United States is approximately 0.5%. Cerebral edema typically occurs 4-12 hours after initiation of treatment of DKA but may develop any time during treatment. Signs and symptoms include headache, deterioration in level of consciousness, bradycardia, and hypertension. The exact mechanism by which cerebral edema occurs is unknown, but proposed mechanisms include cerebral ischemia/hypoxia and the generation of inammatory
Clinical Presentation
Insulin deciency resulting in prolonged hyperglycemia and ketoacidosis explains the typical presenting
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mediators, disruption of cell membrane ion transport and aquaporin channels, generation of intracellular organic osmolytes (myoinositol and taurine), and increased cerebral blood ow.40 Increased risk for cerebral edema is associated with: (1) attenuated rise in actual serum sodium concentrations during treatment for DKA, (2) severe acidosis, (3) treatment with bicarbonate for correction of acidosis, (4) greater hypocapnia, after adjusting for the degree of acidosis, at presentation, and (5) elevated blood urea nitrogen at presentation (reecting greater dehydration).40 Most studies show no association between the risk of developing cerebral edema and the degree of hyperglycemia present at the diagnosis of DKA.41,42
Hyperglycemic Hyperosmolar Syndrome (HHS)
HHS, characterized by extreme blood glucose elevation and hyperosmolality without substantial ketosis, is uncommon in children but deserves discussion because of its high mortality rate. Diagnostic features of HHS are as follows: (1) hyperglycemia 600 mg/dL, (2) serum osmolality 330 mOsm/kg, and (3) the absence of signicant ketosis and acidosis (serum bicarbonate 15 mmol/L, urine dipstick ketones either negative or trace or acetoacetate concentrations 15 mg/dL). These patients T2D. present with more profound dehyContemporary dration and electrolyte loss than Management patients in DKA. Intake of large volumes of sweetened drinks (soda and tea) before Outpatient Management at Onset presentation is a common historical nding in HHS.43 Most children with new-onset diabetes can receive However, some patients in DKA can have severe initial management and education as outpatients. Howhyperosmolality, which can complicate the recogni44 ever children under the age of 3 and those patients with tion of HHS as a distinct entity. severe dehydration, mental status changes, ketoacidosis, or lack of access to outpatient services typically require hospitalization for initial stabilization and treatment. The Obese Child With New-Onset Diabetes Outpatient management is preferable when possible, Given the growing epidemic of obesity, clinicians not only because the inpatient setting is unfamiliar and must remember that being overweight or obese does stressful for families but also as the clinic setting is not protect nor spare individuals from autoimmune typically more conducive for education given its ready disease. Therefore, when an obese child presents with access to diabetes supplies and teaching materials. In
polyuria, polydipsia, and hyperglycemia, the differential diagnosis should include both T1D and T2D. A missed or delayed diagnosis of T1D could result in a failed opportunity to prevent DKA. Moreover, because children with T2D can develop glucose toxicity and sufciently severe beta-cell deciency to result in DKA, clinicians must also be careful not to label all new onset patients as having T1D. Ketonemia and ketonuria usually are not typically seen in T2D, but may be present. Pancreatic islet autoantibodies generally are absent in T2D but have been reported in patients with a T2D phenotype. These cases highlight the heterogeneity and cross-over of these 2 distinct diseases. Some investigators have coined the terms double diabetes or type 1.5 diabetes to describe children with characteristics of Given the growing both diseases. Our preference is to epidemic of obesity, not use such terms, and we, inpediatricians must stead, consider all children with remember that evidence of autoimmunity to have autoimmune diseases do T1D while also acknowledging the presence of a T2D phenotype. This not spare those who are emphasizes the importance of overweight or obese. As monitoring for and treating any such, when an obese child associated comorbidities. The depresents with polyuria, nitive classication of diabetes as T1D or T2D can be deferred until polydipsia, and autoantibody status is conrmed. hyperglycemia, careful However, treatment with insulin consideration should be should always be initiated in pagiven to making a tients who present with ketosis or severe hyperglycemia. diagnosis of T1D versus
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addition, outpatient management generally reduces the initial economic impact of T1D treatment and management. Typically, outpatient management begins with teaching the patient and caregiver survival skills, which include blood glucose monitoring, insulin mixing, insulin injection, and management of hypoglycemia and ketonuria. Initial educational sessions should be simple and concise to avoid information overload for the patient and caregiver while trying to cope with the initial shock of the T1D diagnosis. Over the next several visits, the patient and caregiver progressively can be educated on advanced management techniques, as well as the goals for glycemic control.
usually unnecessary. An easily calculated alternativetwice the maintenance ratetypically provides only a slight underestimation of maintenance plus decit uid replacement. For example, a 30-kg child who is 10% dehydrated has a uid decit of 3000 mL. After receiving the initial 20 mL/kg normal saline uid bolus (600 mL), the child still has a remaining decit of 2400 mL. His maintenance rate is 70 mL/h. If half of his remaining decit (1200 mL) is to be replaced over the rst 8 hours, his maintenance plus decit rate should be 220 mL/h for the rst 8 hours. If the remainder of his decit (1200 mL) plus maintenance over the next 16 hours is calculated, the uid rate should be 145 mL/h for the next 16 hours. Using the formula of twice the Emergency Room and Inpatient Management maintenance rate gives a rate of 140 mL/h over the Fluid Replacement. The most important initial inentire 24 hours. Although this is slight underestimatervention for a child in DKA is uid replacement. tion of the calculated decit replacement rate, most Children in DKA are usually estimated to be 7%-10% children treated with twice the maintenance rate are dehydrated. An initial bolus of 20 mL/kg of 0.9% adequately rehydrated after 24 hours and ready for oral sodium chloride should be adminhydration. Thus, the twice mainteistered to ensure hemodynamic nance rate rule is a simple and stability. Repeat boluses should be accepted method of calculating given only if blood pressure and rates for children in DKA. The most important initial uid tissue perfusion are inadequate. Intravenous Insulin Replaceintervention for a child in ment. By the time the initial uid Because children in DKA are usuDKA is uid replacement. bolus has been given, results of ally hyperosmolar, uid replacement should always be with norserum pH and bicarbonate should mal saline. All replacement and be available, and the decision to maintenance uids should be proceed with IV insulin or with given as 0.9% sodium chloride until glucose is added. subcutaneous insulin can be made. Children with T1D In addition to this isotonic uid, 40-60 mEq/L of and an initial pH of 7.2 or bicarbonate of 10 potassium usually is required for adequate potassium mEq/L require IV insulin replacement, usually at 0.1 replacement. Increased potassium is needed as the U/kg/h of regular insulin. Boluses of IV insulin should acidosis is corrected because K/H exchange causes not be given because there is no demonstrated benet serum potassium to move into the intracellular space. In and there is an increased risk of hypokalemia and addition, potassium levels fall with insulin administration cerebral edema. Similarly, there is no rationale for through the stimulation of sodium-potassium adenosine administering bicarbonate to correct acidosis because triphosphatase. the administration of bicarbonate may precipitate hyOnce the initial uid bolus has been given, the pokalemia, increase osmolality, and contribute to risk remaining uid decit and the childs maintenance of cerebral edema. Insulin reverses ketogenesis uid rate should be calculated. Standard maintenance promptly, and clearance of blood ketones, as well as uid rates for children are calculated as follows: 4 renal bicarbonate generation, is sufcient to correct mL/kg/h for the rst 10 kg, 2 mL/kg/h for the next 10 acidosis. kg, and 1 mL/kg/h for each additional kilogram. Monitoring During Treatment of DKA. Blood gluAlternatively, 1500 mL/m2 can be used to calculate cose concentration should be checked before and at the maintenance uids. One-half of the uid decit can be end of IV uid boluses and hourly during insulin replaced in the rst 8 hours and the remainder of the administration. Serum pH and electrolytes should be decit can be given over the next 16 hours. However, checked every 2 hours. Once blood glucose concenexperience has shown that this precise calculation is tration decreases to 300 mg/dL, the IV uids should
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TABLE 2. Available Insulin Preparations and their Proles of Action
Type of insulin Rapid-acting analogs Lispro (Humalog) Aspart (Novolog) Glulisine (Apidra) Short-acting analog Regular (soluble) Intermediate-acting analog NPH (isophane) Long-acting analogs Glargine (Lantus) Detemir (Levemir) Intermediate-/Rapid-acting analogs Humalog mix 75/25 (75% NPH/25% lispro) Novolog mix 70/30 (70% NPH/30% aspart) Intermediate-/short-acting analogs Humulin 70/30 (70% NPH/30% regular) Novolin 70/30 (70% NPH/30% regular)
Onset 15 to 30 minutes 15 to 30 minutes 15 to 30 minutes 30 minutes to 1 hours 1 to 2 hours 2 to 4 hours 2 to 4 hours 15 to 30 minutes 10 to 20 minutes 30 to 60 minutes 30 minutes
Peak 30 minutes to 2 hours 30 minutes to 2 hours 30 minutes to 2 hours 2 to 5 hours 2 to 12 hours Negligible Negligible Dual Dual Dual Dual
Duration 3 hours 3 hours 3 hours 5 to 8 hours 14 to 18 hours 20 to 24 hours 16 to 20 hours 10 to 16 hours 10 to 16 hours 10 to 16 hours 10 to 16 hours
NPH, neutral protamine Hagedorn. Adapted from Mehta and Wolfsdorf, Endocrinol Metab Clin North Am 2010;39:573-93,45 and Lyles et al, Pediatric Endocrinology. New York, NY: Informa Healthcare USA, Inc.; 2007:125-54.46
be changed to 0.45% sodium chloride and dextrose added. The additional dextrose is needed to ensure continued metabolic disposal of the ketones, a process that requires both insulin and a supply of glucose. Thus, the insulin drip rate should not be decreased until the acidosis has completely resolved. Once acidosis has resolved, subcutaneous insulin treatment can be started. The IV insulin drip is usually discontinued 1 hour after giving the rst subcutaneous injection, at which point the subcutaneous insulin should have been sufciently absorbed. Initial Subcutaneous Insulin Replacement. The goal of insulin therapy is to mimic the 2 basic components of physiological insulin secretion: (1) basal secretion, which suppresses lipolysis and balances hepatic glucose production with glucose use, and (2) prandial secretion, which allows for glucose uptake after food consumption and inhibition of hepatic glucose production. Specic insulin regimens will be discussed in detail below but most children require a total insulin dose of 0.8-1 U/kg/d, whereas pubertal children may require as much as 1-1.5 U/kg/day. For a limited time after the initial diagnosis, the remaining beta cells recover from glucose toxicity and regain function. This period, known as the honeymoon, typically starts 2-3 weeks after diagnosis but is extremely variable in duration (because of the heterogeneity of beta-cell mass in newly diagnosed patients). The typical honeymoon in children diagnosed between 6 and 10 years of age generally lasts 3-6
months. During this honeymoon phase, patients may require progressive decreases in their initial insulin dosages. Patients and caregivers are advised to call the diabetes specialist or diabetes nurse on a daily basis for guidance in decreasing doses to prevent the hypoglycemia commonly seen during this period.
Insulin
In the 1980s, animal-source insulin was largely replaced by insulin produced by recombinant DNA technology. Details of currently used insulins are provided in Table 2. In brief, regular insulin is a short-acting prandial insulin with a signicant basal component. NPH insulin is an intermediate-acting insulin that has a broad peak action that provides basal as well as prandial coverage. Aspart, glulisine, and lispro are rapid-acting analog insulins that closely mimic physiological prandial insulin secretion. Detemir and glargine are long-acting insulins that have minimal peak action and provide basal insulin supply.
Insulin Regimens
NPH/Rapid-Acting Insulin Regimens
The combination of NPH and a rapid analog allows for a simple 2-3 times per day dosing regimen, which does not require carbohydrate counting. Typically, two-thirds of the total insulin dose is given in the morning and one-third in the evening with two-thirds
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of the morning dose and one-third of the evening dose as NPH. Some practices divide the evening dose such that the rapid analog component is given before dinner and the NPH component before bed. The peak action of morning NPH obviates the need for lunchtime insulin. The principal drawback of this regimen is the need for consistent timing and quantity of meals and snacks. The pharmacokinetics of NPH require that the patient eat to match this insulins peak action. The childs daily schedule must include breakfast, lunch, a midafternoon snack, dinner, a bedtime snack, and sometimes a midmorning snack. Premixed (intermediate plus rapid- or short-acting) insulin is available for patients or caregivers who have difculty in preparing the mixture either because of compliance issues or low literacy. However, the use of premixed insulin preparations limits the ability to adjust the rapid-, short-, or intermediate-acting insulin independently. In patients using subcutaneous injections, the measurement of urine ketone concentration is recommended when the blood glucose concentration is 300 mg/dL or anytime the patient has nausea and vomiting. Insulin deciency results in decreased cellular uptake of glucose and forces the body to resort to fat metabolism for usable energy. Ketone bodies are produced in the liver when fatty acids are converted into beta-hydroxybutyrate (-OHB), acetoacetate, and acetone. Blood ketone vs urine ketone testing differs in that -OHB is measured in the blood while acetoacetate and acetone are tested in the urine. Blood testing is particularly helpful in the diagnosis and monitoring of DKA facilitating earlier treatment because of the earlier detection of ketones in the blood. Moreover, -OHB is a more accurate measure of recovery because it decreases in serum well ahead of the decrease in urine ketones. Currently, the Precision Xtra (Abbot Laboratories, USA) is the only meter available to assess blood ketones. Physiological ketosis (as a result of fasting especially during infancy and pregnancy, prolonged exercise, or a high-fat ketogenic diet) must be differentiated from DKA. Children demonstrate more physiological ketosis than adults because of their limited stores of liver glycogen relative to their larger brain glucose requirements. Serum levels of -OHB 0.6 mmol/L are normal. If levels reach 1.0-1.5 mmol/L, supplemental insulin in the amount of 10% of the total daily insulin (TDI) should be given as either regular insulin or rapid-acting analog along with supplemental uids.
When the -OHB level is 1.5-3 mmol/L, 20% of the TDI should be given. Blood ketone levels 3 mmol/L dictate immediately sending the patient to the emergency room. Serum ketones should be rechecked every 4-6 hours (if supplemental regular insulin has been administered) or every 2-4 hours (if supplemental rapid-acting analog was given) until ketones decrease or clear.
Basal-Bolus Insulin Regimens

For those motivated and capable patients, the use of basal insulin (detemir or glargine) with bolus (rapid-acting analog) allows the most exibility of any multiple daily injection regimen. However, basalbolus regimens can require numerous daily injections depending on the number of meals and snacks consumed. Moreover, the requirement to accurately count carbohydrates can be overwhelming for some families and children with limited mathematic abilities. When initiating basal-bolus therapy, glargine is typically given as a single pre-bed dose, whereas detemir most often requires twice daily dosing. Because of their long duration of action and minimal variation in concentration, glargine and detemir can be given at any time of the day, provided the timing remains consistent from day-to-day. The calculation of the rapid-acting insulin dose is based on both the premeal glucose concentration (using a correction factor) and the anticipated carbohydrate intake (using an insulinto-carbohydrate [I:C] ratio). Additional adjustments may be necessary for the level of activity around mealtime. The correction factor (CF), which is the decrease in blood glucose (in mg/dl) provided by 1 unit of subcutaneous rapid acting insulin, can be estimated using the formula, CF 1800/TDI. The I:C ratio is the number of grams of carbohydrate covered by 1 unit of insulin such that a 2-hour postmeal glucose shows no excursion from baseline. The I:C ratio can be calculated using the formula, I:C 450/TDI. Because insulin sensitivity increases at night and with exercise, half corrections are often used at bedtime to avoid unwanted overnight hypoglycemia.
Continuous Subcutaneous Insulin Infusion (CSII)

CSII, or insulin pump therapy, was introduced in the late 1970s. Since then, advances in technology have resulted in smaller and smarter user-friendly devices that have incorporated safety and memory functions,
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as well as features that facilitate the calculation and delivery of the appropriate insulin boluses. The insulin pump is also able to provide variable amounts of basal insulin throughout the day, mimicking normal betacell function. Rapid-acting analogs, such as aspart, glulisine, and lispro, are used in insulin pumps. Features vary by manufacturer and model but may include functions such as bolus calculators (based on blood glucose and carbohydrate quantity); temporary basal rates and suspension modes (for use during exercise or prolonged hypoglycemia); multiple I:C ratios, sensitivity factors, and blood glucose targets; squarewave or extended boluses for meals with prolonged effects on glycemia; alarms for problems, such as occlusion and low insulin reservoir; reminders for blood glucose checking and insulin boluses; calculations of active insulin to prevent repeated doses of insulin from inducing hypoglycemia; electronic logbook software for documentation of glucose levels, carbohydrate intake, and insulin doses received; integrated food databases; wireless communication with remote glucose meters; and most recently integration with CGMs.45 Patients using CSII receive meal boluses using I:C ratios much like basal-bolus patients. In addition CSII patients receive correction insulin using a modied correction factor that consists of an insulin sensitivity factor (ISF) and a blood glucose target. The ISF refers to the drop in blood glucose provided by 1 unit of subcutaneous rapid insulin while the blood glucose target may be adjusted for the patients age and may be varied by the time of day. For example, infants and toddlers have a target of 100-180 mg/dl (110-200 at bedtime). School-age children should have target of 90-180 mg/dL. Pubertal-age children should have lower target blood glucose levels of 90-130 mg/dL. The ISF, target glucose, and I:C can be preprogrammed such that entry of the current glucose concentration and amount of carbohydrates to be eaten will provide the user with the recommended amount of insulin to bolus. This eliminates the need for the user to manually perform the calculation. The patient or caregiver then can choose to override or execute the pumps suggested bolus amount. Because there is no subcutaneous insulin depot with the use of CSII, the risk of DKA is increased because any interruption in insulin delivery (site malfunction, insulin tubing kink, pump failure, etc) typically leaves the patient with 1-2 hours of active insulin on board. As such, not all patients are appropriate candidates for
CSII. Ideal patients will have demonstrated motivation to achieve optimal glycemic control, a history of compliance with insulin therapy and clinic visits, consistent blood glucose monitoring, and accurate carbohydrate counting skills. Though no specic HbA1c requirements exist for the initiation of pump therapy, we rarely see success when initiating CSII in children with HbA1c 9%.46 Because of the increased risk for ketoacidosis during CSII, measurement of urine ketones should be performed when blood glucose concentrations are 240 mg/dL. Blood ketone concentrations can be measured in place of urine ketones. In fact, blood ketone testing is more sensitive in detecting early ketoacidosis than urine testing.47 Constant vigilance is required to ensure normal function of the entire CSII system and avoid DKA. If 2 consecutive blood glucose levels are 240 mg/dL or if moderate to large urine ketones are present, the pump site and tubing must be changed and a subcutaneous injection should be given to stop the potential development of DKA. Similarly, rotation of the pump insertion site is critical in preventing lipohypertrophy with resultant erratic insulin absorption. Sites must be changed routinely every 2-3 days and are ideally done in the morning so that glucose checking throughout the day will detect any problems during the waking hours.46 Indicators of site problems include redness, swelling, induration, or discharge. Signs of infusion set problems include air in the tubing, loose connection between cartridge and reservoir, insulin leakage at the infusion site, kinked cannula, air or blood in the infusion set, and loose adhesive backing caused by sweat or water activities.46
Ongoing Management
Blood Glucose. Self-monitoring of blood glucose (SMBG) should be performed at least 4 times per day: before breakfast, lunch, dinner, and at bedtime, regardless of insulin regimen. Patients on basal-bolus regimens using multiple daily injections or pump therapy should additionally measure blood glucose before snacks so that appropriate doses of rapid-acting insulin can be taken. Several studies have demonstrated that the frequency of SMBG is the best single predictor of overall glycemic control.48 When initiating pump therapy or changing insulin regimens, more frequent monitoring is necessary throughout the day and night. To determine if meal or correction doses are appropriate, 2-hour postinsulin testing is needed to assess the effectiveness of the I:C or ISF. When patients have
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consistently high fasting glucose concentrations, 2 AM blood glucose monitoring should be performed before increasing evening insulin or overnight basal insulins to ensure that the patient is not becoming hypoglycemic in the middle of the night and rebounding because of the release of counter-regulatory hormones (Somogyi phenomenon). As an additional guide to avoid hypoglycemia, we advise patients that insulin adjustments are necessary if, within a week, they experience 3 glucose measurements 60 mg/dL, 2 measurements 50 mg/dL at the same time of day, or 1 unexplained measurement 40 mg/dL. Continuous Glucose Monitors. Commercially available continuous glucose sensors are based on measuring interstitial uid glucose concentrations. These devices use glucose oxidase reactions to measure an electric current generated when glucose reacts with oxygen. CGMs generally provide a glucose signal for 3-7 days. Because of real-time differences in blood glucose and interstitial uid glucose concentrations, CGM values are not as accurate as conventional blood glucose determinations. As such, the real advantage of CGM over conventional SMBG is the determination of glucose trends. Wearing a CGM does not automatically improve diabetes control, but studies have demonstrated improved A1c with reduced rates of hypoglycemia in both children and adults who wear the CGM routinely.49 Blood glucose trend data are particularly helpful for the patient on a day-to-day basis and helpful for health care providers in deciphering complete glucose proles. In particular, data on nocturnal glycemic patterns can be gathered, and treatment changes, if necessary, can be made with a higher degree of condence.50
for most children and 200 mg/day if the child has elevated low-density lipoprotein cholesterol.
Multidisciplinary Diabetes Team

The primary focus in the medical care of a child with T1D is education. The physicians major responsibility is to ensure that the patient and family members are knowledgeable about the complications associated with T1D and insulin therapy. Although the patient should ideally take the lead role in diabetes management, each member of the diabetes team plays a critical role as the patients advocate. The team, in addition to the primary care physician, consists of a diabetes specialist, diabetes educator, dietitian, and mental health professional, who work together to assess, educate, and treat the patient.45 Good communication among the team members is important to ensure that the patient receives accurate and consistent advice. A member of the diabetes team must be accessible to the patient or family member at any time for questions or concerns about sick day management, hypoglycemia or hyperglycemia, diabetes supplies, and so on. The dietitian assesses the familys knowledge of food and nutrition at the initial visitation and constructs a meal plan appropriate to the particular child. At least an annual review of the patients nutritional status by the dietitian is desirable. Food label reading and carbohydrate counting are 2 concrete areas that the dietitian discusses at the initial education sessions at the time of diagnosis. These are reinforced periodically during outpatient follow-up visits. Assessment of the protein and saturated fat intake is also important.51 The social worker assesses the strengths and weaknesses of the family in relation to emotional issues, nancial and community support, educational attainment, and so on. It is usually the social workers assessment and recommendations that determine whether prompt involvement of a clinical psychologist or psychiatrist is necessary. The social worker can be particularly useful in families with limited nancial resources to help them obtain support for diabetes medications and supplies and transportation to clinic appointments.51 The diabetes nurse educator plays a pivotal role and must become involved with the family as early as possible, usually during the time of initial diagnosis. The nurse educator ensures that the family has at least survival skills, which usually requires 3-5 days of teaching. The educational process continues at each
Medical Nutrition Therapy

Children with diabetes should be encouraged to maintain a healthy age-appropriate diet without concentrated sweets. Daily caloric requirements for children can be estimated by using the formula 1000 kcal 100 kcal per year of age. Most children should obtain their caloric intake from a balanced diet containing 50%-60% carbohydrates, 30% fat, and 10%-20% protein. Protein intake should not exceed 0.8 g/kg/day if the child has evidence of nephropathy. Fat should be limited to 30% of caloric intake if the child is overweight. Saturated fat should be 10% of daily calories for most children and 7% of calories if the child has elevated low-density lipoprotein cholesterol. Finally, cholesterol should be limited to 300 mg/day
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clinic visit, and, if necessary, special educational sessions are set up with the diabetes educator outside the routine clinic schedule.51
Sick-Day Management
The stress of illness (eg, infection, injury, pain) causes increased release of counter-regulatory hormones cortisol, glucagon, catecholamines, and growth hormone, which increase hepatic glucose production, oppose insulin action and thereby decrease peripheral glucose use, and stimulate ketogenesis. Hyperglycemia and ketosis may ensue. If there is no supplemental insulin added to the customary insulin doses, the patient remains insulin decient and resistant. Of note, hypoglycemia with ketosis is also possible, usually seen with gastrointestinal illness because of vomiting, diarrhea, and malabsorption. The primary goal in sick-day management is to avoid ketoacidosis. Families and clinicians must be reminded that exogenous insulin must be provided to inhibit ketogenesis even if the patient is unable or unwilling to eat. Timely administration of supplemental insulin and oral uids frequently prevents the need for emergency room visit or hospitalization. With illness, urine must be checked for ketones even if the blood glucose concentration is low or normal, with repeat testing at least every 2-3 hours. For trace or small ketonuria, an increase in oral uids is necessary. For moderate to large ketonuria, an additional 10%20% of the total daily dose can be given as regular insulin, which may have to be repeated every 4-6 hours until ketonuria resolves. Insulin adjustments can be challenging when the child has a gastrointestinal illness that may produce hypoglycemia because of transient malabsorption or decreased oral intake. Oral hydration at home with frequent small amounts of clear liquids is preferred, but nausea and/or vomiting may necessitate IV hydration in the hospital. The blood glucose concentration determines whether sugar-free or sugar-containing uids should be consumed. Juice, regular soda, or sugar-containing gelatin of amounts between 3 and 8 oz depending on age and body size (or 2 mL per pound of body weight per hour)52 should be encouraged. In children with gastroenteritis, sodium and potassium should also be replaced with uids, such as broth, soda, or fruit juice. For children on CSII or glargine, insulin adjustment is easier because the pump basal rate or the glargine dose is adequate to inhibit lipolysis and ketogenesis
should the child refuse to eat. In this case, bolus insulin is given only if the child consumes carbohydrates. Patients using CSII can also manage hypo- or hyperglycemia on sick days by programming a temporarily decreased or increased basal rate. In addition, more frequent SMBG is necessary. In children who receive standard combinations of NPH and rapidacting analogs and there is inability to orally consume carbohydrates, small amounts of easily absorbable glucose may be necessary to avoid hypoglycemia, as omission of NPH is not an option. The dose of rapid-acting analog can be held until immediately after the child has eaten to determine if, and how much of, the dose should be given.
Management of Hypoglycemia
Besides illness, other causes of hypoglycemia include intentional or unintentional insulin overdose (ie, miscalculation of correction dose or carbohydrate coverage, or both), inadequate or delayed meal or snack, and strenuous exercise (which can have an effect up to 24 hours later). Signs and symptoms of hypoglycemia include dizziness, shakiness, sweating, personality changes, irritability, anxiety, changes in vision, weakness, headache, inability to concentrate, tachycardia, or palpitations. Glucose concentration should be measured if any of the above symptoms are present. If glucose concentrations are 70 mg/dL, 15 g of fast-acting carbohydrate should be consumed in the form of 3-4 glucose tablets, 4 oz of juice, one-third can of regular soda, or 1 tube of glucose gel. Solid food should not be eaten until the blood glucose is 70 mg/dL because intestinal absorption of the fast-acting carbohydrate is slowed when fat and protein are present. Treatment with another 15 g of fast-acting carbohydrate may have to be repeated, with SMBG every 10-15 minutes, until the blood glucose is 70 mg/dL. Once this goal is achieved, a snack (sandwich, granola bar, crackers, cereal) should be given to sustain euglycemia. For infants and toddlers, additional signs and symptoms of hypoglycemia include temper tantrums, combativeness, falling asleep at unexpected times, pallor, and seizure. To reduce the risk of severe hypoglycemia, blood glucose 80 mg/dL should be treated with 15 g of rapid-acting carbohydrate (4 oz of juice). Once blood glucose are 80 mg/dL, breast feeding, bottle feeding or a snack should be given. If the child is unable to drink, glucose gel, cake icing, or honey should be placed between the gums
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It is imperative that the entire medical and surgical team be aware of the patients T1D diagnosis. All patients with T1D require insulin regardless of their oral intake. For patients using basal-bolus or CSII therapy and undergoing elective surgery, minimal adjustment to the insulin regimen is required. Typically, the basal insulin dose or basal pump rate can continue unchanged, and meal or correction insulin is simply withheld as the patient is made NPO in preparation for surgery. For those using set doses of NPH and rapid analog, the morning NPH dose is typically cut in one-half and the rapid analog is held. Ideally, any procedure should be scheduled as the rst Exercise case of the day. Once insulin adjustments have been SMBG should be performed before and after exermade, the most important consideration with surgery cise because inter- and intrapatient is frequent monitoring of blood responses to exercise are variable. glucose concentration before, durBecause exercise improves insulin ing, and after the procedure. If the sensitivity, blood glucose concenglucose decreases to 200 mg/dL All patients with T1D trations may decrease many hours intraoperatively, dextrose should require insulin regardless be added to IV uids. Depending after exercise. Conversely, blood of their oral intake. glucose concentrations may spike on the procedure, decreased oral after beginning exercise as a result intake may occur postoperatively of epinephrine and cortisol surges. and insulin requirements may be That said, most patients require diminished. More commonly, the 15 g of carbohydrate (taken without insulin) to mainphysiological stress associated with surgery necessitain blood glucose for every hour of exercise. Still, the tates a slightly increased insulin dose to correct postgoal is to make insulin dose adjustments that prevent operative hyperglycemia. hypoglycemia and thus avoid the need to consume extra carbohydrates. Eating additional carbohydrates to prevent hypoglycemia is counterproductive, espePatient Care Issues in Different Age cially for patients who are overweight. In patients with Groups known sensitivity to exercise, insulin doses may be decreased by 10% or 20% the night before or the Infant Issues morning of planned activity.46 For those on CSII, Frequent blood glucose monitoring, observation of temporary basal rates can be reduced by similar carbohydrate intake, administration of insulin, and fear amounts. of hypoglycemia and its complications substantially inAlthough most insulin pumps are now waterproof, crease stress and anxiety for parents of a child with T1D. exercise in which a pump cannot be worn or might be In addition, parents must deal with erratic eating and lost (swimming in an ocean, lake, etc) may require play. Fortunately, infants adapt quickly to nger pricktemporary disconnection. During these times, approing and subcutaneous injections, with subsequent rappriate caution must be taken to avoid ketosis. When id-acting analogs making insulin injections after meals disconnection is required and the preactivity blood possible and safe. Parents of infants with T1D should glucose is 150 mg/dL, we recommend providing a have immediate access to the diabetes team whenever bolus equivalent to 1 hour of the patients basal rate.
and cheeks, or glucagon 0.5 mg (0.5 mL) IM or SQ should be injected. Glucagon is supplied as a dry powder and comes in emergency kits containing a 1 mg vial and a needle/syringe prelled with diluent. For children 8 years of age, 0.5 mg should be injected. For older children, 1 mg should be injected. Glucagon can be injected through clothing intramuscularly, and the child should be turned on their side because postdose vomiting is common. After injecting glucagon, EMS should be called and blood glucose concentration should be checked every 5-10 minutes until hypoglycemia has resolved and the patient is able to take oral glucose. If the child is still unconscious after 10 minutes, additional glucagon should be given. There is no risk of overdose with glucagon, although additional benet is lost once all hepatic stores of glycogen are released.
We also recommend maximum disconnection time of 1 hour with blood glucose monitoring and bolusing performed hourly as needed.
Elective Surgery
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possible and should be knowledgeable of all available resources for support.
Toddler Issues
Parents often expect adolescents to take full responsibility of their diabetes management. However, teens, despite their growing desire Issues With School-Aged established under the for independence, should not be Children authority of the expected or allowed to manage Because diabetes care has become Rehabilitation Act of 1973 their diabetes without supervision. To support the adolescents tranmore intensive, it is essential that and ensures that services sition to independent diabetes school personnel be trained to perare in place to assist management, parents and physiform basic and emergency diabetes management skills. Although cer- students with special needs cians must maintain realistic blood glucose goals and provide reasonwho are in a regular tainly preferable, this does not imply able oversight. Unfortunately, the that each and every school must education setting. period of adolescence is frequently have a nurse available at all times. associated with poor adherence In cases in which a nurse is not and risk taking. The potentially available, teachers and coaches can compounded adverse consequences of diabetes and be taught to provide basic diabetes care. Parents should smoking, alcohol and substance use, sexual activity, or arrange for diabetes care in the school by developing a careless driving must be thoroughly discussed. 504 plan in coordination with the appropriate school The stress of social pressure, schoolwork, and puberty personnel, school nurse, and teachers. This 504 plan is make adolescence a particularly challenging time to federally mandated, having been established under the manage diabetes. Increased growth hormone and sex authority of the Rehabilitation Act of 1973. It ensures steroid production additionally result in physiological that services are in place to assist students with special insulin resistance that can boost insulin requirements needs. A sample 504 plan and an excellent book discussto 1.5-2 U/kg/day. Therefore, some pediatric endocriing diabetes and school issues are available on the nologists may use metformin as an adjunct therapy in National Diabetes Education Program (http://ndep. adolescents with insulin resistance. nih.gov/media/youth_schoolguide.pdf) and ADA Age-Appropriate HbA1c Goals (http://www.diabetes.org/assets/pdfs/schools/ SAS-Booklet-2010.pdf) web sites. HbA1c goals must be age appropriate to minimize Ensuring that school personnel are trained and readthe frequency of serious hypoglycemia while trying to ily can access the appropriate resources and tools also decrease the risk for microvascular and macrovascular
Despite rapidly developing verbal and nonverbal communication skills, toddlers remain incapable of understanding the need for painful procedures such as blood glucose monitoring and insulin injections, and thus are more prone to behaviors, such as screaming, kicking, biting, and hurtful comments. To most effectively cope with these responses, parents are encouraged to provide the required diabetes interventions without imparting additional negative experiences for the child. A nonemotional approach to the glucose monitoring and insulin injection, followed with positive reinforcement when the child is cooperative, is typically the most successful approach. Furthermore, consistency is critical in teaching toddlers that their diabetes care is non-negotiaA 504 plan is a federally ble and not amenable to argument. mandated document
requires that parents provide the designated diabetes school ofcial with all the necessary supplies (ie, insulin, syringes, back-up pump sites and tubing, test strips, glucose meter, rapid-acting carbohydrates to treat hypoglycemia, and glucagon). The childs health care team is responsible for supplying school personnel with specic protocols for treating hypoglycemia, checking for urine ketone levels, and administering insulin. Frequent communication between school nurses and the childs diabetes care team is important to continuously adjust insulin doses and promote age-appropriate HbA1c goals. We emphasize to parents that T1D should not keep children from participating in any school or after-school activities and that school should not be a barrier to achieving optimal control of diabetes.
Adolescent Issues
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complications. Children who experience recurrent hypoglycemia at an early age (5 years old) are believed to be at increased risk for long-term neuropsychological impairment. Thus, pre-meal glycemic goals for infants and toddlers should be 100-180 mg/dL, overnight levels 110-200 mg/dL, and an HbA1c goal between 7.5% and 8.5%. School-aged children (6-12 years) should begin to tighten their control with premeal glucose levels of 100-180 mg/dL, overnight levels 100 mg/dL, and HbA1c value of 8%. In adolescents, the issues of adolescent rebellion and independence require a somewhat more individualized approach. Once a child is in the teenage years, premeal blood glucose levels should be 90-130 mg/dL, and the childs lifetime goal should be to maintain an HbA1c value of 7%. However, this goal is difcult for most teens to achieve, and the ADA has recommended an HbA1c goal of 7.5% for this age group, with an ideal HbA1c value of 7% if achievable without hypoglycemia.
Diabetes Camp
Diabetes camps provide a unique opportunity to educate and socialize children with diabetes. Children who are initially reluctant to attend a diabetes camp often leave camp with a new sense of acceptance of their diabetes and renewed interest in maintaining near-normal blood glucose control. Most diabetes camps are residential camps staffed by experienced pediatric diabetes nurses, psychologists, and physicians. Strict observation of blood glucose monitoring and insulin administration is required to ensure that no child becomes acidotic. Daily insulin adjustments must be made because most children are much more active at diabetes camp than at home, increasing their risk for hypoglycemia.
Recent Advances in T1D Research

Having discussed the etiology, presentation, and management of T1D, we will complete our review with a brief discussion of ongoing research.
Prevention Strategies
Oral Insulin. The use of low-risk antigen-specic immunotherapies has been the focus of previous and ongoing prevention studies. Insulin has long been investigated as an autoantigen that may be manipulated to augment the natural history of T1D. Animal
studies rst demonstrated proof of principle that immunomodulatory effects of recurrent exposure to oral insulin could prevent diabetes.53 As a result, the Diabetes Prevention Trial Type 1 (DPT-1) (NCT0004984) was organized to determine if either subcutaneous or oral insulin could prevent or delay the onset of T1D in humans. Although both oral and parenteral insulin showed excellent safety proles, the DPT-1 failed to show therapeutic benet for either investigational approach. However, the studys major success was in proving that a large multicenter T1D collaborative was feasible. Furthermore, a post hoc review of DPT-1 data showed that at-risk patients (ie, 5-year risk, 25%-50%) who received oral insulin and had high IAA levels experienced a considerable delay in the onset of T1D.54 Based on these provocative data, the T1D TrialNet clinical trials network is currently performing a properly powered study to determine if oral insulin can indeed delay the onset of T1D in individuals with insulin autoantibodies and at least 1 additional T1D related autoantibody (NCT004119562). Relatives of patients with T1D are currently being screened to determine if they qualify for participation in the oral insulin study by participating in the TrialNet Pathway to Prevention Study, which aims to identify and track patients at risk for developing T1D (NCT00097292). Because insulin is a likely target autoantigen in T1D, similar studies focusing on achieving tolerance through alternative mechanisms of insulin delivery have been explored by other study groups. The Finnish Diabetes Prediction and Prevention Project, in which intranasal insulin was administered to genetically atrisk autoantibody positive subjects, failed to show a benet54 (NCT00223613). The Australian Intranasal Insulin Trial I, a safety study performed in adults, documented immune changes consistent with mucosal tolerance to insulin.55 Intranasal Insulin Trial II is now underway and is evaluating a larger population through determining the effect of different doses of intranasal insulin in preventing or slowing the onset of T1D56 (NCT00336674). In addition, the Primary Oral/ Intranasal Insulin Trial will be attempting primary prevention in a dose-nding study to provide oral or intranasal insulin to genetically at-risk infants who have not yet developed T1D-associated autoantibodies.57 Recently, interventional efforts using insulin B-chain immunotherapy in patients with newly diagnosed T1D were reported to show specic T-cell responses to the nonmetabolically active insulin, but
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no effect on C-peptide, when compared with placebo.58 Glutamic Acid Decarboxylase 65 (GAD65). GAD65 is another autoantigen that has been targeted for potential therapeutic use in T1D. Similar to insulin, strong preclinical data from the nonobese diabetic (NOD) mouse suggest that vaccination with GAD65 possibly prevents T1D.59 Early safety and dose-nding studies of GAD65 were performed in adult patients with latent autoimmune diabetes, with subjects receiving 2 subcutaneous doses of GAD65 or placebo. Patients were followed up for 24 weeks, with no adverse events noted. The 20-g dose demonstrated preservation of endogenous beta-cell function. A follow-up phase II trial showed preservation of beta-cell function with no treatment-related adverse events60 (NCT00435981). Patients with T1D who received 20 g of GAD65 had fasting C-peptide levels at 24 weeks that were increased compared with placebo, and increased fasting and stimulated C-peptide levels from baseline to 24 weeks.60 Earlier administration (ie, within 6 months of disease onset) appeared more efcacious, albeit the number of these subjects were limited. Based on these encouraging phase I and II data, TrialNet is performing a phase III placebocontrolled randomized trial of GAD65 in patients with newly diagnosed T1D (NCT00529399). Similar industry-sponsored studies are being conducted concurrently in Europe and the United States.
Intervention Strategies
Most T1D intervention studies have used immunosuppressive regimens to control autoimmunity and preserve beta-cell function. These were performed using drugs such as azathioprine,61 cyclosporine,62 and antithymocyte globulin (ATG) and prednisone.63 Many of these immunosuppressive agents showed initial promise in preserving C-peptide but were nonetheless abandoned because of intolerable side-effect proles and limited efcacy. Because experts struggle to develop both safe and effective therapies, they may be forced to accept the paradox that therapies with the immunologic capacity to effectively reverse T1D may already exist but may only succeed at the cost of inducing potential short- and long-term side effects that are worse than living with diabetes. Anti-CD3. Depletion of autoreactive T-cells is a logical approach to interdicting the disease process in T1D. Preclinical data from the NOD mouse have shown that monoclonal antibodies to CD3 are capable
of preventing and reversing diabetes.64,65 Two different anti-CD3 products, teplizumab and otelixizumab, have recently been used in human intervention studies (NCT00378508 and NCT00451321, respectively). Although leading to short-term T-cell depletion after administration, anti-CD3 antibodies may selectively increase the production of regulatory T-cells thought to counter the effector T-cell response responsible for islet destruction. Published studies of anti-CD3 therapy were promising and suggested that C-peptide may be preserved for as long as 18-24 months after therapy.66,67 That said, a study involving the anti-CD3 product otelixizumab was recently abandoned because of failure to achieve interim efcacy goals. Anti-CD20. The anti-CD20 monoclonal antibody rituximab downregulates B-lymphocyte signaling of T-cells and, therefore, may reduce the ability of cytotoxic T-cells to induce islet injury in the pathogenesis of T1D. Preclinical data with antiB-lymphocyte activities have shown efcacy in preventing and reversing diabetes in the NOD mouse.68,69 Now part of the standard therapeutic armamentarium for rheumatoid arthritis, non-Hodgkin lymphoma, and transplant rejection, rituximab has also shown recent promise in the treatment of lupus and multiple sclerosis. Within TrialNet, rituximab was administered to patients with new-onset T1D within 100 days of diagnosis in a randomized placebo-controlled trial to determine if 4-weekly intravenous infusions safely preserve C-peptide. Preservation of C-peptide was noted 1 year after rituximab was administered (NCT00279305) but the effect waned after 2 years. Nevertheless, these studies demonstrated that altering B-cell function could indeed alter the course of T1D. AntiInterleukin-1 Beta (Canakinumab). Canakinumab is a human monoclonal antibody targeted at interleukin-1 beta. This drug was initially developed as a therapy for rheumatoid arthritis, although that indication was abandoned. Canakinumab is approved for the treatment of cryopyrin-associated periodic syndromes. A recent 2-arm multicenter placebo-controlled trial of canakinumab was performed in 66 new-onset T1D patients. Although the drug demonstrated excellent tolerability with almost no side-effect prole, canakinumab failed to demonstrate any capacity to preserve C-peptide when compared with placebo (NCT00947427). Cytotoxic T-Lymphocyte Antigen-4 Immunoglobulin (CTLA-4). CTLA-4 is expressed on the surface of T-helper cells and transmits an inhibitory signal to
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T-cells by blocking the stimulatory effect of CD28 binding.70,71 CTLA-4 may play an important role in the function of tolerance-inducing regulatory T-cells. Furthermore, polymorphisms in the CLTA-4 gene are known to associate with autoimmune diseases, including T1D.71 Therefore, CTLA-4 immunoglobulin (CTLA4 Ig) is a selective T-cell costimulation modulator and has already gained Food and Drug Administration approval for the treatment of rheumatoid arthritis (abatacept). Using a similar rationale, CTLA-4 Ig was proposed as another potential nonantigen-specic therapy for T1D. The TrialNet consortium is performing a randomized double-blind placebo-controlled trial of CTLA-4 Ig/placebo in patients with recently diagnosed T1D (NCT00505375). Results of this trial are expected in late 2012. Antithymocyte Globulin. ATG, a polyclonal antihuman T-cell antibody, has long been a critical part of transplantation and cancer therapy because of its effect of nonspecic T-cell depletion.72 Recovery from Tcell depletion after ATG therapy has been associated with an increase in regulatory T-cells and, therefore, offers a potential advantage in resetting the immune system in patients with autoimmunity.73 ATG represents another example of a powerful nonantigenspecic agent, and has been used either alone or in combination for treating various autoimmune conditions, including Wegner granulomatosis, lupus, rheumatoid arthritis, multiple sclerosis, scleroderma, aplastic anemia and myelodysplastic syndromes, and even T1D.74-83 An ongoing study of ATG is being performed by the National Institutes of Health Immune Tolerance Network using patients with recently diagnosed T1D (NCT00515099) and will report data in late 2012. ATG and Granulocyte Colony-Stimulating Factor (GCSF). Although ATG monotherapy is indeed promising, an ATG-based protocol that includes a second agent, GCSF, may have even greater potential for preserving beta-cell mass. Perhaps the best support for this assertion comes from data generated in a study in Brazil, in which young adults with very-recent onset T1D received cyclophosphamide, GCSF, and ATG in what was termed a nonmyeloablative autotransplantation84 (NCT00315133). The idea of immune depletion followed by regulatory T-cell mobilization or reinfusion has strong preclinical data supporting the assertion that this approach may be able to ameliorate autoimmunity.85 Although patients who received this combination therapy experienced considerable mor-
bidity (eg, neutropenia, alopecia, testicular dysfunction), they also beneted from a remarkable degree of therapeutic efcacy. Of 23 treated subjects, 20 experienced at least 1 month of insulin independence, with most being insulin free for more than a year. This study also represents one of the rst reports of a sustained increase in the stimulated C-peptide values in patients with T1D.84,86 Although the results are undeniably proof of the potential for aggressive immunoablative therapy in treating T1D, the side-effect prole of this particular combination is unacceptable to most physicians caring for children with T1D.87 Because our group has long supported the concept of safe combination therapies, we have attempted to deconstruct the Brazilian combination using the NOD mouse model to guide development of a lower-risk therapy for humans. By excluding cyclophosphamide and relying on a combination of only low-dose ATG and GCSF, we were recently able to show a durable reversal of diabetes in 75% of NOD mice, although ATG alone was only able to reverse disease in 33% of animals.85 In addition, we showed that the combination therapy provided the most robust increase in regulatory T-cells and, perhaps more importantly for clinical application, enabled reversal of diabetes at higher initial glucose values than ATG alone. Given these exciting preclinical data, our group recently began planning for an analogous human trial designed to study the safety and potential efcacy of low-dose ATG (2.5 mg/kg total dose) and 12 weeks of pegylated GCSF therapy (6 mg, every 2 weeks). Cell Therapies. Cell therapies may eventually provide a means to both control autoimmunity and replace damaged beta cells. Although outside the scope of this review, sources such as umbilical cord blood regulatory T-cells, mesenchymal stem cells, and even T1Dspecic induced pluripotent stem cells have demonstrated proof of concept and are in the process of being evaluated in current or planned clinical trials.88,89
Conclusions
T1D is a common childhood diagnosis and must remain on the busy pediatricians differential diagnosis, especially during u season. Simple and inexpensive tests can exclude or conrm the diagnosis, yet studies reveal that children with symptoms are often evaluated by pediatricians multiple times before diagnosis. Because the only assured way to prevent the
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potential devastating complications of cerebral edema in these individuals is to avoid DKA, early diagnosis is critical. Once the diagnosis is established and the child is safely started on insulin, attention must shift to the long-term challenge of achieving tight glycemic control to avoid complications. Some 90 years after the discovery of insulin, T1D has been converted from a uniformly fatal disease to a chronic disease. Although we have gained a tremendous understanding of the natural history of this disease, additional efforts are needed to achieve our ultimate goal of safely and reliably preventing and reversing T1D.
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Type 1 Diabetes: Current Concepts in Epidemiology, Pathophysiology, Clinical Care, and Research

Curr Probl Pediatr Adolesc Health Care, November/December 2012

A Childhood With Diabetes

Curr Probl Pediatr Adolesc Health Care, November/December 2012

TABLE 1. Risk of Type 1 Diabetes

1 in 300-400 1 in 20 1 in 50 1 in 14 1 1 1 1 1 1 in in in in in in 2-3 (30%-50%) 10-16 (6%-10%) 40 20 7 4

Genetic Susceptibility to T1D

Environmental Triggers of T1D

Curr Probl Pediatr Adolesc Health Care, November/December 2012

Curr Probl Pediatr Adolesc Health Care, November/December 2012

Risk Factors for Development of T1D

Natural History and Prediction of T1D

Epidemiology of New-Onset T1D

Curr Probl Pediatr Adolesc Health Care, November/December 2012

Curr Probl Pediatr Adolesc Health Care, November/December 2012

Presentation With DKA

Curr Probl Pediatr Adolesc Health Care, November/December 2012

Hyperglycemic Hyperosmolar Syndrome (HHS)

Curr Probl Pediatr Adolesc Health Care, November/December 2012

TABLE 2. Available Insulin Preparations and their Proles of Action

Curr Probl Pediatr Adolesc Health Care, November/December 2012

Basal-Bolus Insulin Regimens

Continuous Subcutaneous Insulin Infusion (CSII)

Curr Probl Pediatr Adolesc Health Care, November/December 2012

Curr Probl Pediatr Adolesc Health Care, November/December 2012

Multidisciplinary Diabetes Team

Medical Nutrition Therapy

Curr Probl Pediatr Adolesc Health Care, November/December 2012

Curr Probl Pediatr Adolesc Health Care, November/December 2012

Curr Probl Pediatr Adolesc Health Care, November/December 2012

possible and should be knowledgeable of all available resources for support.

Curr Probl Pediatr Adolesc Health Care, November/December 2012

Recent Advances in T1D Research

Curr Probl Pediatr Adolesc Health Care, November/December 2012

Curr Probl Pediatr Adolesc Health Care, November/December 2012

Curr Probl Pediatr Adolesc Health Care, November/December 2012

Curr Probl Pediatr Adolesc Health Care, November/December 2012

Curr Probl Pediatr Adolesc Health Care, November/December 2012

Curr Probl Pediatr Adolesc Health Care, November/December 2012

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