Diabetes in Childhood and Adolescence
A guideline-based approach to diagnosis, treatment, and follow-up
Background: The incidence of type 1 diabetes mellitus in childhood and adolescence is steadily rising and now stands at 22.9 new cases per year per 100 000 persons up to age 15.
Methods: This review is based on pertinent publications retrieved by a selective literature search, with special attention to the current German S3 guideline on diabetes in childhood and adolescence.
Results: Polydipsia, polyuria, and weight loss are the characteristic presenting symptoms of diabetes mellitus. The acutely presenting patient needs immediate stabilization because of the danger of rapid metabolic decompensation (risk of ketoacidosis, 21.1%). Long-term insulin therapy can be delivered either by subcutaneous injection or by an insulin pump. The goals of treatment are the near-normalization of glucose metabolism (HbA1c <7.5%), the avoidance of acute complications (hypoglycemia and ketoacidosis), the reduction of diabetes-specific sequelae (retinopathy, nephropathy, neuropathy, hypertension, and hyperlipidemia), unrestricted participation in age-appropriate everyday activities, and normal physical and psychosocial development. Children and adolescents with diabetes need individualized treatment with frequent adjustments and holistic overall care so that these goals can be effectively met.
Conclusion: Every physician must be able to diagnose the initial presentation of diabetes and to initiate the first steps in its management. The patient should be referred as soon as possible to a diabetes team that has experience in the treatment of children and adolescents.
The often-quoted adage, attributed to Jean Piaget, that children are not just little adults applies in full force to children and adolescents with diabetes. It provides an apt introductory motto for the German pediatric-diabetological guidelines, which were issued in an updated version in 2016 (1). Type 1 diabetes is the most common metabolic disorder in children and adolescents; type 2 diabetes remains rare in this age group in Central Europe. This article therefore focuses on type 1 diabetes and provides no more than basic information about other types of diabetes.
This article is intended to enable readers from all medical specialties to:
- correctly diagnose the initial presentation of diabetes in a child or adolescent, and initiate the first steps of treatment;
- be acquainted with the special demands associated with the treatment of patients in this age group;
- know the major acute complications and long-term sequelae of diabetes in children and adolescents.
Classification and epidemiology
According to registry data from the year 2010, approximately 32 000 persons in Germany under age 20 have type 1 diabetes (2). The incidence is rising by 3–4% each year and currently stands at 22.9 new cases per year per 100 000 persons up to age 15 (3, e1). This increasing incidence is mainly accounted for by a rise in diabetes among younger children; its cause is unknown. On the other hand, there has not been any rise in type 2 diabetes among children and adolescents in the last 10 years, despite earlier forecasts to the contrary: at present, approximately 3000 children receive a new diagnosis of type 1 diabetes in Germany each year, compared to only about 200 persons under age 20 with a new diagnosis of type 2 diabetes (e2). Siblings of a child with type 1 diabetes have an approximately 5% risk of developing the disease; in children of a parent with type 1 diabetes, the risk lies between 5% and 7% (e3, e4).
Maturity-onset diabetes of the young (MODY), a further variety of diabetes with a molecular genetic but not immunological basis, is about as common among children and adolescents as type 2 diabetes. Of the 14 known types of MODY, types 2 and 3 are the most common; its overall prevalence has been estimated at 2.4 per 100 000 individuals (4). In patients with a negative autoantibody status and an uneventful long-term course of illness, such special types of diabetes should be considered in the differential diagnosis and looked for with molecular genetic studies, as their treatment differs markedly from that of type 1 diabetes. Other varieties of diabetes mellitus in childhood include neonatal diabetes (a genetic condition; ca. 1 per 89 000 live births) and diabetes in the setting of cystic fibrosis (in ca. 2–19% of children and adolescents with this disease) and other rare
syndromes (5, 6). No precise figures on the incidence and prevalence of these rare varieties of diabetes have been published to date. The only available data are derived from individual regions, or from registries (Table 1).
The diagnosis and initial treatment of type 1 diabetes
The diagnosis is made on the basis of typical symptoms (polydipsia, polyuria, weight loss) and blood sugar measurement. The clinical history and a single capillary blood sugar measurement almost always suffice to establish the diagnosis. Further clinical signs can also include an impaired general state of health, shortness of breath, abdominal pain, or vomiting. In earlier times, diabetes was occasionally misdiagnosed as asthma (because of Kussmaul respiration) or possible appendicitis; such errors should not be made in today’s world of rapid laboratory testing. Further laboratory tests that can be performed in case of doubt (diabetes-associated antibodies, oral glucose tolerance test, HbA1c measurement) are not needed for the initial diagnosis and should be left to specialized diabetes treatment centers for differential diagnostic investigation, as indicated.
A young patient with a suspected initial presentation of diabetes mellitus should be seen by a diabetes specialist or in a hospital emergency room on the day of presentation. There must not be even a single day’s delay (and certainly no delay over a weekend). Specialized treatment has been shown to lower the rate of hospitalization over the further course of the illness and to lead to better metabolic outcomes (7, e5). Thus, as soon as the diagnosis is made, the patient should be referred at once for treatment by a diabetes team with pediatric experience (8, e6).
Initial treatment, insulin therapy
The goals of treatment
The elements of treatment from the time the diagnosis is made include insulin therapy, individual self-monitoring of blood sugar, age-adapted and structured patient education, and the psychosocial care of the family (1). The target HbA1c value is <7.5% (58.5 mmol/moL) without simultaneous hypoglycemia (e6, e7). It is currently being discussed whether the target should be lowered to HbA1c <7.0% (53.0 mmol/moL), because modern treatment methods are associated with a lower risk of hypoglycemia (9, 10).
Further parameters for the assessment of metabolic control that have recently come into wide use are the so-called time in range (70–160 mg/dL, equivalent to 3.9–8.9 mmol/L) and other measures of glycemic variability (11).
The mean frequency of blood sugar measurement in children and adolescents is 5 to 6 times per day. It is much higher in some cases (12).
The standard treatment consists of intensified conventional therapy [ICT] with a basal or delayed insulin preparation to cover mealtimes and to correct elevated glucose values, with an individualized schedule for each child or adolescent patient (13). Either human insulins or insulin analogues are used.
For intravenous insulin therapy (e.g., in the treatment of ketoacidosis), normal insulin in used. For intensified insulin therapy with an insulin pen (or, less commonly, with injections via a hypodermic syringe), normal insulin or insulin analogues are used. Insulin pump therapy mainly employs short-acting insulin analogues (1, 14). The available concentrations are U 40, U 100, and U 300. In exceptional cases, diluted insulin preparations (U 10 or U 5) can be specially made for use in infants.
Short-acting human insulins and rapidly acting insulin analogues are available for prandial substitution, with an effect that begins within 15 to 30 minutes and lasts for some 2–4 hours. Because nutritional intake cannot be planned with perfect reliability, a postprandial injection (or an additional postprandial injection) of a rapidly-acting analogue is often recommended, even though this is associated with higher postprandial blood sugar values than when insulin is given preprandially (15, e8). A combination of multiple types of insulin can also be useful. One such comonly used combination involves the administration of a short-acting normal insulin in the morning, to cover the school breakfast without any additional injection, and a rapidly-acting insulin analogue in the afternoon, to enable a better response to a flexible daily schedule with multiple small meals at variable times (14).
Practical aspects of insulin therapy
Suitable sites for subcutaneous administration (either for pen injection or for pump catheter placement) are the abdomen, flanks, buttocks, and thighs. Injections in the arm are difficult and are not recommended because of the thinness of the subcutaneous fat layer.
In general, short (4 or 5 mm) needles should be used, as these reliably reach the subcutaneous tissue without penetrating any more deeply (e9). 6 mm needles can also be used by child and adolescent patients in special cases. The angle of injection should be 90° (perpendicular to the skin). In most cases, a skin fold should be created by a gentle pinch at the injection site, especially in very thin children with little subcutaneous fat. Regular changes of injection site and the meticulous use of a new needle for each injection are important. The injection site need not be disinfected before injections with a syringe or pen, but it certainly must be disinfected before an insulin pump catheter is inserted (e10).
Insulin pump therapy and continuous glucose measurement
Especially in preschool children, insulin pump therapy (continuous subcutaneous insulin infusion, CSII) is often initiated immediately after the diagnosis of diabetes is made. Further indications for pump therapy in children and adolescents are listed in Box 1.
Insulin pump therapy is considered the most nearly physiological type of treatment, as its basic structure consists of the continuous administration of insulin for the patient’s basal requirement with additional boluses for mealtimes or for the correction of elevated glucose values. The fundamental advantage of pump therapy is the continuous administration of insulin for the basal requirement, with programmable, typically hourly adjustments for circadian requirements. This is very important, in particular, because the insulin requirement is lower at night and higher in the morning (dawn phenomenon). Insulin pumps make nocturnal hypoglycemic episodes less frequent while also preventing a rise in the patient’s blood sugar toward morning. Without a pump, this can only be imperfectly achieved, even with the use of modern basal or long-term insulins, and it is even harder in small children. Pump therapy leads to metabolic improvement (16, e11, e12). It was shown in a multicenter cohort study that patients under age 20 who use an insulin pump have less frequent episodes of severe hypoglycemia (9.55 versus 13.97 per 100 patient-years) and lower HbA1c values (8.04% versus 8.22%) than similarly aged patients without a pump (17).
Insulin pumps are generally safe, although scant data are available on the frequency of adverse events. Most of these are due to user error (e13).
A further substantial advantage of insulin pumps is that the insulin is always in the immediate vicinity of the patient, and a bolus can therefore be administered at any time. Modern insulin pumps also incorporate a bolus calculator that determines the dose of insulin to be given by bolus on the basis of the blood sugar level, the quantity of carbohydrate consumed, and other treatment parameters. This is very helpful for patients, as it has been shown in multiple studies that the human calculation of bolus doses is more often erroneous than correct (e14, e15). The carbohydrate component of meals must nevertheless still be weighed or estimated. The use of a bolus calculator, either for intensified insulin therapy or for insulin pump therapy, has been shown to improve the patient’s metabolic state, lessen the frequency of hypoglycemic episodes, and increase safety (18, e14, e16).
Capillary blood glucose measurement by the patient (self-monitoring of blood glucose, SMBG) is the current standard of metabolic monitoring, but this is changing. Systems with continuous glucose monitoring (CGM) measure the interstitial glucose concentration via a subcutaneous sensor every 3–5 minutes and transmit the result to a readout device. This is done either actively and continuously (real-time CGM) or passively by scanning (flash glucose monitoring, FGM). Glucose measurement with a CGM or FGM system can be used as an aid to either intensified insulin therapy or insulin pump therapy. The advantages of systems that monitor blood glucose continuously are clear: they provide a steady stream of values that can be interpreted and acted upon. They can also display trends (with arrows) to help the patient judge the current situation accurately. The additional feature of temporary cessation of basal insulin administration by the pump in response to a low glucose level (“low glucose suspend,” LGS) helps prevent hypoglycemic episodes (19, e17).
According to the literature, therapeutic goals that can be met through the use of a CGM system in a child or adolescent patient with diabetes include reducing the frequency of hypoglycemic episodes (particularly at night) and avoiding serious hypoglycemic episodes in which the patient needs the help of another person (19, e17, e18). In mid-2016, the German Joint Federal Committee (Gemeinsamer Bundesausschuss), addressing the issue of the appropriate prescribing of CGM systems, formulated the indications for them in more practical terms: a CGM system can be prescribed “if the individual therapeutic goals for metabolic control that have been agreed upon by the physician and the patient, cannot be met by other means, with consideration being given to the patient’s living situation with and without such a system” (20).
Flash glucose monitoring (FGM) provides a further opportunity for the bloodless measurement of blood sugar and for the recognition of glycemic trends in child and adolescent patients. FGM systems, unlike CGM systems, have no alarm function when the glucose value rises above or drops below the preset limits. FGM systems have been shown to be sufficiently precise for use in patients with type 1 diabetes (e19).
Insulin pumps and CGM systems are aids to glycemic control that are now reimbursable in Germany if obtained with a doctor’s prescription. The Joint Federal Committee has not yet decided whether to make FGM systems reimbursable as well (although the insurance carriers often already cover the cost of such systems).
Knowledge of the effect of one’s food intake, and in particular of one’s carbohydrate intake, on the blood sugar level is the basic prerequisite for calculation of the appropriate prandial dose of insulin. In intensified insulin therapy, there is no fixed quantity of carbohydrate that should be eaten, or of insulin that should be given. The carbohydrate intake, which used to be measured in bread units (1 bread unit = 12 g of carbohydrate), is now generally measured in so-called carbohydrate units (1 carbohydrate unit = 10 g of carbohydrate). This makes calculations much easier for the patient, so that the instructions on drug packages can be more readily implemented. Ideally, the patient’s food should be weighed before it is eaten and its carbohydrate content calculated with the aid of suitable tables. In everyday life, however, the carbohydrate content is usually just estimated. Instructing the patients in how to do this is a major part of nutritional counseling (21, 22).
In general, the nutritional recommendations for child and adolescent diabetics are the same as those for children and adolescents without diabetes. Nutritional counseling has been shown to lead to improved metabolic control (22, e20). Patients should be taught about all components of food intake and their respective contributions to the daily intake of calories.
Diabetes education when the disease first manifests itself and over its futher course is an integral part of multimodal diabetes treatment. Medical treatment and patient education can succeed only if they are well coordinated with each other (1, e21). Education should be offered to the affected children and adolescents and their parents, as well as to persons caring for the young patients in day-care centers, nursery schools, kindergartens, schools, or residential facilities. Parental education improves the patients’ knowledge base, quality of life, and glycemic outcome (e22). It is important for diabetes education to be supported by all the members of a multiprofessional diabetes management team, and for it to pursue uniform, jointly formulated treatment concepts and goals (23, 24, e23). The curriculum should be structured and adapted to the patient’s age, duration of diabetes, type of insulin
substitution and glycemic self-monitoring, developmental level, comorbidities (if any), lifestyle, and cultural setting (25, e23, e24). Diabetes education should be repeated approximately every two years so that it can remain well adapted to the patient’s stage of psychological development. In Germany, accredited diabetes education programs are available from the Working Group for Pediatric Diabetology (Arbeitsgemeinschaft für Pädiatrische Diabetologie, AGPD) and the German Diabetes Society (Deutsche Diabetes Gesellschaft, DDG). Evidence suggests that improved care and education concepts for children and adolescents with diabetes can contribute to improved glycemic control (2, e25, e26). According to expert opinion, pediatric diabetes education containing a major practical component with an experiential pedagogical approach is preferable to ambulatory classes such as those offered to adults with diabetes (e24).
The structural requirements for a pediatric diabetes unit include, among other things, the presence of a pediatrician who is qualified in diabetology (pediatric board certification with additional certified training in diabetology). The AGPD recommends that the diabetes team should comprise the following staff time equivalents per 100 child and adolescent patients with type 1 diabetes (1, e6):
- 1.0 full-time-equivalent board-certified pediatrician with additional certified training in pediatric diabetology and endocrinology, or else certification as a diabetologist (DDG)
- 1.0 full-time equivalent diabetic counselor (DDG)
- 0.3 full-time equivalent psychologist
- 0.3 full-time equivalent pediatric nurse
- 0.2 full-time equivalent dietician
- 0.2 full-time equivalent social worker
- 0.25 full-time equivalent secretary.
These requirements are considered necessary in Germany as in other countries and have been established by an expert consensus as “good clinical practice.” Deficits in the long-term care of children with diabetes can only be avoided if the diabetes unit has the capacities listed here and uses them to provide regular, multimodal care (26, e27).
The appropriate comprehensive psychosocial care of the patient should begin as soon as diabetes is diagnosed and should extend to the patient’s entire family as well. Diabetes, like any other chronic disease in childhood, imposes a burden on the child and on his or her parents and siblings that can easily become too heavy to bear (e29). Children and adolescents who are socioeconomically disadvantaged or have other premorbid psychosocial problems need special help (1, 27, e30). In an American cross-sectional study (28), 309 young diabetics aged 9 to 14.5 were asked about the quality of the support they received from their primary caregivers in the management of their diabetes. Better support was found to be associated with better control of important diabetes-related parameters. This implies that psychosocial factors play an important role in the quality of metabolic control in children and adolescents with type 1 diabetes. Over the long term, they are among the main determinants of good metabolic control (28, 29).
Many children and adolescents who receive a diagnosis of diabetes display psychiatric abnormalities amounting to an adjustment disorder; most get over this within a year (e30, e31). Factors associated with increased risks to somatic and mental health are listed in Box 2.
Depression, anxiety disorders, stress-related mental disorders, and eating disorders arise more commonly in children and adolescents with type 1 diabetes than in metabolically healthy persons of the same age, although recent studies suggest that these conditions are becoming less common (e32, e33). It is estimated that at least 15% of these children and adolescents are impaired by mental stress during diabetes treatment (29, e34). 14% of these adolescents are mildly depressed, and 8.6% are moderately depressed (e35). These figures underscore the need for the diabetes team to pay attention to the non-somatic component of their patients’ condition, especially in long-term continuing care (e36).
In the past, hypoglycemic episodes were considered the main cause of neurocognitive developmental deficits in children with diabetes, but recent studies have shown that, in particular, chronic hyperglycemia and early disease onset are risk factors for such deficits (30). This finding underscores the need to avoid not only severe hypoglycemic episodes, but also protracted phases of hypoglycemia and high blood-sugar variability, particularly in children and adolescents in vulnerable developmental stages. Nonetheless, the effects that such factors have on school performance are still weaker than the effect of the socioeconomic status of the child’s family (e37).
The most common acute complications of type 1 diabetes are hypoglycemic episodes and diabetic ketoacidosis.
21.1% of children and adolescents with type 1 diabetes have ketoacidosis at the time of their presentation: it is mild in 9.8%, moderate in 5.4%, and severe in 5.9% (30). An evaluation of cumulative data from the German registry of disease courses in patients with diabetes (Diabetes-Patienten-Verlaufsdokumentation-Register) revealed that, during the long-term follow-up of patients with diabetes, the rate of ketoacidosis leading to hospitalization among patients in this age group (0.5–20 years; median, 12.7 years) in Germany is 4.81 per 100 patient-years (31) (Box 3).
Essential components of treatment include rapid circulatory stabilization, the gradual normalization of fluid and electrolyte balance, the normalization of blood sugar, the reduction of acidosis and ketosis, and the avoidance of treatment complications (cerebral edema, hypokalemia) (7, 32).
Mild and moderate hypoglycemic episodes are common acute complications of type 1 diabetes. Severe hypoglycemic episodes leading to hospitalization occur an average of 1.45 times per 100 patient-years. Groups at particular risk include children who have already had a severe hypoglycemic episode in the past 12 months, and immigrant children (31).
The definition and classification of hypoglycemic episodes are not uniform at present. Experts recommend a threshold value of 65–70 mg/dL, corresponding to 3.6–3.9 mmol/L (e7). “Mild” episodes are those that can be alleviated quickly by the administration of rapidly-acting carbohydrates; “severe” ones are those that are associated with impairment or loss of consciousness and can only be alleviated with help from another person. Recompensation is carried out either orally (glucose in the buccal cavity), subcutaneously, intravenously, or intramuscularly (glucose or glucagon).
A uniform definition has been proposed for international use, in which values below 54 mg/dL (3.0 mmol/L) are designated as “clinically relevant” and those in the range of 54–70 mg/dL (3.0–3.9 mmol/L) are designated as a “warning” (33).
Children up to the age of 5 years are at the highest risk of hypoglycemia. They have been shown to benefit from regular care by an experienced diabetes team, from insulin pump therapy, and from the use of a CGM system. One study showed that, over a two-week period of observation, diabetic children with a CGM system had an average of 3 fewer hypoglycemic episodes than children without one (4.4 ± 4.5 vs. 7.4 ± 6.3) (e39). Worry about recurrent episodes of hypoglycemia runs high, particularly among parents, and often impairs the quality of glycemic control when so-called hypo-avoidance behavior leads to higher glucose values (34, e40).
Long-term complications, sequelae, and diagnostic studies for their monitoring and prevention
The normal physical development of children and adolescents is checked by regular measurement of their height, weight, and stage of sexual development. The findings are documented in terms of percentiles among children of the patient’s age.
Screening should be performed at regular intervals for diabetes-specific micro- and macrovascular complications. An overview of suitable methods and the interventions that they may give rise to is provided in Table 2. Screening intervals and methods have been established in Germany and other countries by expert consensus (1, 35).
Near-normoglycemia is recommended as the best way to avoid long-term complications. The HbA1c value cannot, by its nature, reflect fluctuations in the blood sugar level, but it is currently the only surrogate parameter for which valid data are available with respect to the risk of sequelae (e41). Therefore, the HbA1c value should be determined at least once every three months (1). The target value should be <7.5% with simultaneous avoidance of hypoglycemic episodes. This target is the same for patients in all age groups. The American Diabetes Association, in its new guidelines, recommends a target of <7.0% if attainable without frequent hypoglycemic episodes. If the HbA1c value lies between 7.5% and 9%, metabolic optimization is recommended; if it is above 9%, intervention is always necessary (e42).
Associated autoimmune diseases
Young type 1 diabetics have an increased prevalence of thyroid disease (3.7% in patients under age 5, 25.3% in patients aged 15 to 20) and of celiac disease (ca. 10% biopsy-proven) (36–39, e43, e44). An expert consensus therefore recommends that diagnostic studies for Hashimoto thyroiditis (TPO antibodies, TSH and fT4 values, and thyroid ultrasonography) and screening for celiac disease (transglutaminase antibodies or endomysium antibodies) should be performed at the time of diagnosis and once every 1–2 years thereafter, or whenever suggestive symptoms arise (1).
Whenever celiac disease is suspected, biopsy of the small intestine is recommended to confirm the diagnosis (1). In patients with type 1 diabetes, celiac disease is an independent risk factor for the development of retinopathy and nephropathy; therefore, regular serologic testing is recommended (40). The appropriate treatment of antibody-positive but asymptomatic patients is a controversial matter. The nutritional counseling of asymptomatic patients with celiac disease who have high titers of transglutaminase antibodies and a Marsh III lesion should be coordinated with a pediatric gastroenterologist (35).
Type 1 diabetes is the most common metabolic disorder in childhood and adolescence and requires specialized pediatric diabetological treatment and continuing care. Only in this way can the frequent changes in therapy that are necessitated by the patient’s development be carried out in conformity with the pertinent guidelines. The need for care by a multiprofessional team is recognized in Germany and abroad. Such a team must be accessible to all young patients with diabetes and their families. Care far away from one’s place of residence has been clearly shown to lead to poorer metabolic control and to more frequent and longer hospital stays (e10). In view of this fact, the authors call for measures to be taken to ensure full nationwide coverage with pediatric diabetological care facilities. In 2018, the German Diabetes Society commissioned a structural analysis of pediatric diabetological care across the country in order to detect areas where the appropriate care is lacking.
Conflict of interest statement
Dr. Ziegler has served as a paid advisor to Abbott, Novo Nordisk, Lilly, and Roche. He has received lecture honoraria from Novo Nordisk, Animas, and Roche. He has received payment from Roche for authorship of publications related to the topic of this article. He has been paid for conducting clinical trials on behalf of Novo Nordisk, Roche, and Sanofi. He has received financial support from Roche for a research project that he initiated.
Prof. Neu has served as a paid advisor to Novo Nordisk, Lilly, Roche, and Abbott. He has received reimbursement for travel and accommodation expenses and honoraria for the preparation of scientific lectures from Novo Nordisk, Lilly, and Roche. A clinical trial carried out on behalf of Roche was financed by that company.
Manuscript submitted on 1 August 2017, revised version accepted on 30 January 2018.
Translated from the original German by Ethan Taub, M.D.
Prof. Dr. med. Andreas Neu
Klinik für Kinder- und Jugendmedizin
D-72076 Tübingen, Germany
For e References please refer to:
University Children’s Hospital Tübingen:
Prof. Dr. med.
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