Diagnosis, Therapy and Follow-Up of Type 1 Diabetes Mellitus in Children and Adolescents

Causes and background

The DDG practice recommendation on diabetes in children and adolescents is regularly updated in the second half of the year as part of the guideline collection of the German Diabetes Society (DDG) and is based to a large extent on the current S3 Guideline from 2023. It was prepared on behalf of the DDG and its Working Group for Pediatric Diabetology AGPD, and, as of 2024, the German Society for Pediatric and Adolescent Endocrinology and Diabetology (DGPAED).

Epidemiology and types of diabetes in childhood and adolescence

Type 1 diabetes

Type 1 diabetes accounts for over 90% of diabetes cases at a young age (under 25 years of age) in Europe. In 2020, an estimated 32230 children and adolescents aged 0 to 17 years (37655 aged 0 to 19 years) were living with type 1 diabetes in Germany [1] [2]. The prevalence of type 1 diabetes continued to be higher in boys than in girls in 2020; the gender differences were significant

The mean annual incidence rate increased by 3–4% per year until ten years ago [3] [4] [5]; after which it slowed down somewhat and was+1% per year between 2014–2019 [6] [7]. For the period 2014–2019, the incidence for children and adolescents up to the age of 17 was estimated at 25.7/100000/year, which corresponds to approximately 3500 new cases per year across Germany [6]. In 2020, the incidence rose to 29.2/100000/year, with continued higher rates in boys than in girls (boys: 31.9 vs. girls: 26.5/100000/year) In comparison, type 1 diabetes occurs much less frequently in adults.

Type 2 diabetes

The incidence and prevalence figures of paediatric type 2 diabetes are significantly lower in Germany than in the UK [8] or in the USA [9] [10] [11]. Between 2014 and 2019, an average of 200 children and adolescents aged 11 to 17 were newly diagnosed with type 2 diabetes each year [6]. In 2020, an estimated 819 children and adolescents aged 10 to 19 years were living with type 2 diabetes in Germany (10.8 per 100000 persons; girls 12.8; boys 9.0 per 100000 persons) The incidence of type 2 diabetes in children and adolescents (6–17 years) increased between 2011 (0.8/100000/year) and 2019 (1.3/100000/year) including during the COVID-19 pandemic [12]. In 2021, the increase in boys was significantly higher than expected, leading to a reversal of the gender ratio In 2021, the incidence was 1.73/100000/year for girls and 2.16/100000/year for boys and was significantly higher in 12- to 17-year-olds than in 6- to 11-year-olds (3.39 vs. 0.53/100000/year) [12] Other forms of diabetes can be found in the section “Other forms of diabetes in childhood and adolescence”.

Risk factors, prevention and early detection of diabetes

Type 1 diabetes

Type 1 diabetes is characterized by 3 stages:

• Stage 1: multiple (≥ 2) diabetes-associated autoantibodies, normal blood glucose levels, no clinical symptoms;

• Stage 2: multiple (≥ 2) diabetes-associated autoantibodies, elevated blood glucose levels (dysglycaemia defined as elevated fasting plasma glucose (100–125 mg/dl (5.6–6.9 mmol/l)), and/or 2-h plasma glucose 140–199 mg/dl (7.8–11.0 mmol/l) in an oral glucose tolerance test (oGTT), and/or HbA_1c of 5.7–6.4% (39–47 mmol/mol) or an increase in HbA_1c by 10%), no clinical symptoms;

• Stage 3: diabetes-associated autoantibodies, elevated blood glucose levels (hyperglycaemia), clinical symptoms [13].

85% of children with 2 diabetes-associated autoantibodies and 92% of children with 3 autoantibodies develop clinical type 1 diabetes (stage 3) within 15 years and>99% within their lifetime); compared to ~15% of children with only one diabetes-associated autoantibody [15], [16] [Fig. 1].

Fig. 1 Stage classification of type 1 diabetes (T1D).

International consensus guidelines have recently been published describing the practical procedure for dealing with children with positive autoantibodies in stages 1 and 2 of type 1 diabetes [14].

Interventions to prevent or delay the progression of type 1 diabetes after islet autoantibody development are classified as secondary prevention. Teplizumab, a monoclonal antibody that targets the T-cell surface marker CD3, is already available as a therapy that has shown a median delay of 2.7 years in the progression of type 1 diabetes from stage 2 to stage 3 (not yet approved in Germany) [17] [18]. Other substances are in clinical trials. The onset of type 1 diabetes requiring treatment (stage 3) in patients with stage 1 or 2 diabetes can currently only be delayed, but not prevented. Nevertheless, early detection plays a decisive role in the diagnosis and treatment of diabetes. The aim of early detection of clinically not yet symptomatic type 1 diabetes is to prevent diabetic ketoacidosis at the time of manifestation [19] [20] [21] [22] and at the same time to optimize the timing of starting insulin therapy. The possible advantages and potential disadvantages of screening, e. g. at preschool age, are in discussion [14].

Manifestation: diagnostics and therapy

Classification

Currently, 4 types of diabetes mellitus are distinguished [23]

1. Type 1 diabetes (consequence of autoimmune beta-cell destruction with diabetes-associated antibodies), rare: idiopathic

2. Type 2 diabetes (due to a progressive loss of insulin secretion by the beta cell, often because of insulin resistance due to overweight or obesity)

3. Other specific types of diabetes (type 3 diabetes, subtypes): A: Genetic defects of beta cell function B: Genetic defects of insulin efficacy C: Disease of the exocrine pancreas D: Diabetes due to endocrinopathies; E: Medicinally- or chemically-induced diabetes; F: Diabetes caused by infections; G: Rare forms of immune-mediated diabetes; H: Other genetic syndromes occasionally associated with diabetes.

4. Gestational diabetes (any form diagnosed for the first time during pregnancy).

The most common form of diabetes in childhood and adolescence is type 1 diabetes [24] with an increasing incidence worldwide [25] [174].

Diagnostic criteria for diabetes mellitus requiring treatment (at least one criterion):

• HbA_1c≥6.5% (48 mmol/mol Hb)

• Occasional/plasma glucose≥200 mg/dl (11.1 mmol/l) in the presence of symptoms

• 2-h plasma glucose≥200 mg/dl (11.1 mmol/l) in the oral glucose tolerance test (oGTT)

• Fasting plasma glucose≥126 mg/dl (7.0 mmol/L).

Type 1 diabetes is characterized by an autoimmune process with progressive destruction of the insulin-producing beta cells of the pancreas. The determination of diabetes-associated autoantibodies can help in diagnosis. If at least one of the following diabetes-associated autoantibodies is positive, islet cell antibodies (ICA), insulin autoantibodies (IAA), autoantibodies against glutamate decarboxylase of the B-cell (GAD65A), autoantibodies against tyrosine phosphatase (IA-2^a) and IA-2ß, or autoantibodies against the zinc transporter 8 of the B-cell (ZnT8), the diagnosis of type 1 diabetes can be made with corresponding clinical symptoms [13] [26] [27]. The first occurrence of antibodies is age dependent. Diabetes-associated antibodies are very rarely found before the age of 6 months. When it manifests, there is usually autoimmunity with multiple antibodies: ICA 60–90% positive, GAD 65–80%, IA-2 60–80%, ZnT8 60–80% [28].

In the case of negative or only one positive antibody, another form of diabetes should always be considered.

The development of absolute insulin deficiency in children and adolescents with type 1 diabetes can lead to severe hyperglycaemia, ketonemia and signs of dehydration, or a severely derailed metabolic state (ketoacidosis). These require initial intravenous insulin therapy, as well as fluid and electrolyte substitution according to a standardized plan, e. g. with a balanced full electrolyte solution [29] [30] [31] regardless of a presumed pathogenesis, since in the presence of ketosis, a (temporary) absolute insulin deficit can also be present in type 2 diabetes (see ketoacidosis).

The above criteria also apply to the diagnosis of type 2 diabetes and a clinical diagnosis should be performed from the age of 10 if the patient is overweight (BMI>90th percentile) and at least two of the following risk factors are present: Type 2 diabetes in 1st/2nd degree relatives, belonging to an elevated-risk group (e. g., people of Latino, African, or Asian descent), extreme obesity (body mass index [BMI]>99.5th percentiles), signs of insulin resistance, or changes associated with insulin resistance (arterial hypertension, dyslipidaemia, elevated transaminases, polycystic ovary syndrome, acanthosis nigricans).

Insulin therapy for type 1 diabetes

The standard of care for children and adolescents with type 1 diabetes is intensified insulin therapy, if possible, with an insulin pump and glucose sensor (as an Automated Insulin Delivery [AID] system).

All insulin therapy should be performed as part of comprehensive, personalized diabetic consultation and training as well as with the support of the family [Fig. 2].

Fig. 2 Principles of insulin therapy for children and adolescents with type 1 diabetes. ICT, intensified conventional insulin therapy; CSII, continuous subcutaneous insulin infusion; CGM, continuous glucose monitoring; TiR, time-in-range; AID, Automated Insulin Delivery. Source: German Diabetes Society (DDG), S3 Guideline: Diagnosis, Therapy and Follow-Up of Type 1 Diabetes Mellitus in Children and Adolescents German Association of the Scientific Medical Professional Societies/AWMF registration number: 057–016. Version 4, 2023. https://register.awmf.org/assets/guidelines/057–016l_S3_Diagnostik-Therapie-Verlaufskontrolle-Diabetes-mellitus-Kinder-Jugendliche_2023–11.pdf. [rerif]

Rapid-acting insulin and insulin analogues

Normal insulin should be used for intravenous insulin treatment. Ultra-fast-acting and rapid-acting insulin analogues and short-acting human insulin show differences in children in terms of onset and duration of action and, depending on the situation for prandial substitution in children and adolescents, should be used flexibly in conventional insulin therapy, ICT with insulin pens [32] [33] [34] [35].

Ultra-fast-acting or fast-acting insulin analogues should be used in insulin pump therapy.

Long-acting insulin and long-acting insulin analogues

Neutral Protamine Hagedorn [NPH] insulin as well as first and second generation of long-acting insulin analogues can be used individually for basal insulin substitution in children and adolescents with ICT with an insulin pen [36] [37] [38] [39] [40] [41] [42] [43] [44].

Adjunctive, blood glucose-lowering therapies, such as metformin or sodium glucose linked transporter 2 SGLT-2 inhibitors, should generally not be used in type 1 diabetes in childhood and adolescence [45] [46].

Diabetes and technology

Digital insulin pens

The use of digital insulin pens for ICT in children and adolescents has been increasing in recent years. With the digital insulin pens, the amount and time of the insulin delivered can be stored and digitally forwarded to software or app. This makes it possible to document insulin administration for the adjustment of therapy parameters and, in particular, to use bolus calculators in combination with data on glucose trends. It is also easier to assess treatment adherence and families and children/young people themselves can use reminder functions to avoid missing boluses [47] [48] [49].

Insulin pump therapy

Insulin pump therapy should be offered to all children and adolescents with type 1 diabetes immediately after manifestation or with ICT therapy if they or their parents/caregivers are able to use this form of therapy safely. The possibility of further developing towards an AID system must be given, see below, [50] [51] [52] [53].

The use of insulin pumps has increased significantly in all age groups in recent years [54]. Meta-analyses and systemic reviews show that insulin pump therapy in all age groups achieves a small improvement in HbA_1c compared to ICT therapy, which is significant in individual studies [50] [52], and is associated with a reduced risk of severe hypoglycaemia and diabetic ketoacidosis [55]. Early initiation of insulin pump therapy is associated with significantly lower HbA_1c levels, a higher proportion of children and adolescents reaching the previous HbA_1c target of<7.5%, lower rates of hypoglycaemic coma and hospitalization, lower systolic blood pressure and higher HDL cholesterol levels [51].

Continuous glucose monitoring (CGM)

CGM has significantly changed the management of type 1 diabetes in children and adolescents. Registry data show that the vast majority is now provided with a CGM device (Holl, German Health Report 2024). A systematic review and other controlled studies show that CGM, especially in combination with automatic insulin switch-off, reduces hypoglycaemias and hypoglycaemia anxiety as well as improves the quality of life, together with an increase of time-in-range (TIR) and improved HbA_1c levels The HbA_1c reduction is greatest in children and adolescents with initially higher HbA_1c levels and at the start of use, but also in the long term, especially if it is started promptly after manifestation [57].

A recent DPV evaluation of over 32,000 young people with type 1 diabetes (aged 1.5–25 years) showed that CGM use can significantly reduce severe hypoglycaemias and ketoacidosis compared to blood glucose self-monitoring [58].

CGM should be offered to all children and adolescents with type 1 diabetes and ICT or insulin pump therapy immediately if they or their parents/caregivers are able to use this form of therapy safely. The selection of the CGM system should be made individually, according to the needs and circumstances of each patient. The possibility of further developing towards an AID system must be given [56] [57] [59] [60].

The successful application of these systems depends on proper training, as well as the ability and motivation to deal with the technologies.

Automated insulin delivery (AID) systems

CGM systems have now reached such a high level of measurement quality that automated therapeutic decisions and on-demand automated insulin delivery have become possible. For this, CGM and insulin pumps are combined to form an AID system. An algorithm continuously calculates the insulin dose from the measured glucose values, taking into account individual user data, therapy settings and the target value, and delivers it at short minute intervals, or switches off temporarily. AID systems are also known as hybrid closed-loop (HCL) systems. Manual delivery of an insulin bolus at mealtimes remains necessary.

The use of an AID system leads to a further significant improvement in TiR in children aged 6–13 years compared to sensor-supported insulin pump therapy (SAP) [61]. This significant improvement in TiR already occurs on the first day of use of the AID system. In addition, the time in the hypoglycaemic range (< 70 mg/dl,<3.9 mmol/l) is further significantly reduced. Compared to sensor-assisted insulin pump therapy, treatment with an AID system also improves metabolic control in young children (2–6-year-olds) with type 1 diabetes over a period of 16 weeks (HbA_1c reduction of 0.4%, 8.7% more time in the target range of 70–180 mg%, 3.9–10 mmol/l, and 8.5% less time in the hyperglycaemic range>180 mg/dl,>10 mmol/l [62]. In the group of adolescents and young adults, a different randomized study over 6 months shows that the use of an AID system results in a significant increase in TIR and a reduction in HbA_1c [63]. It is noteworthy that the greatest differences in the TIR in favour of the AID systems can be observed at night between 01:00 and 08:00 [64]. This was summarized in a systematic review [65].

Children and adolescents with an AID system also spend significantly more time in range during sports or increased activity compared to the previous standard therapy [66].

There are considerable differences between the available AID systems. The diabetes care team should be fully informed about this in order to provide appropriate in-depth training, close clinical support and guidance in the choice of system for the children and adolescents, and their families. Device-specific training and information about the underlying algorithm in the system is required in addition to general training on the use of insulin pumps with CGM systems by means of a structured, company-independent training program, e. g. SPECTRUM. Regardless of this, mandatory technical instruction is necessary.

The algorithms differ in the approval requirements (age, body weight, minimum and maximum insulin requirement) and the way in which the required amount of insulin is calculated, setting options for the precision of the correction and the therapy targets, as well as separation of automatic correction boluses and automatic basal rate or joint delivery of both components as a bolus. They also differ in the inclusion of meals and activities in the calculations.

Attention should be paid to upgradeable models, both in terms of the algorithms and the control options.

An AID system should be offered to all children and adolescents with type 1 diabetes and insulin pump therapy immediately if they or their parents/caregivers are able to use this form of therapy safely. The selection of the AID system should be made individually, according to the needs and circumstances of each patient and the currently-valid approvals [61] [62] [63].

Therapy goals and parameters

Children and adolescents with diabetes mellitus should be cared for by a team with experience in paediatric diabetology (paediatricians with additional recognised training in diabetology or paediatricians with further training in paediatric endocrinology and diabetology or “DDG diabetologist” paediatricians, diabetes consultants, dieticians or nutritionists as well as trained psychologists and social workers with diabetology experience).

Depending on the childʼs age and existing family resources, care measures should be aimed at empowering both the family’s competence and the child/adolescent in dealing with diabetes as well as strengthening independence and personal responsibility.

The following medical targets are in the foreground when caring for paediatric patients with diabetes mellitus:

• Avoidance of acute metabolic derailments, especially severe hypoglycaemia or ketoacidosis or diabetic coma,

• Prevention of diabetes-related micro- and macrovascular secondary complications, even in the subclinical stage. This requires glucose control that minimizes the risk of secondary diseases (see below) as well as early diagnosis and treatment of additional risk factors (hypertension, hyperlipidaemia, obesity and avoidance of nicotine consumption),

• Normal physical development (height growth, weight gain, onset of puberty), age-appropriate performance,

• Psychosocial development of children and adolescents unimpaired by diabetes,

• Inclusion and participation in daycare, school and vocational training,

• As little impairment as possible due to diabetes and its treatment.

Individual therapy targets should be formulated together with the child or adolescent and his or her family (HbA_1c value, percentage of TiR, behavioural changes that come with risk-taking lifestyles, etc.).

The target HbA_1c value should be<7.0% (< 53 mmol/mol) without any severe hypoglycaemic events.

In addition, sensor parameters such as the Glucose Management Indicator (GMI), the time-in-range ([TiR] 70–180 mg/dl, 3.9–10 mmol/l) of>70% and time-below-range (TbR)<4% (time below the target range) should be used. Glucose fluctuations should be kept as low as possible (coefficient of variation [CV]<36%) [67] [68] [69] [70], [Table 1].

Table 1 Therapeutic targets for all children and adolescents with diabetes.

Number of days with active CGM use: 14 days preferred

Percentage of available data from active CGM usage:>70% of data from 14 days

Mean glucose value: personalised target values

GMI: set to personalised target values

Glycaemic variability%CV:<36%;

%TiR 70 to 180 mg/dL, 3.9–10 mmol/l:>70%

%TbR<70 mg/dL,<3.9 mmol/l:<4%

%TbR<54 mg/dL,<3.0 mmol/l:<1%

%TaR>180 mg/dL,>10 mmol/l:<25%

%TaR>250 mg/dL,>13.9 mmol/l:<5%

[acc. to 86]

GMI, Glucose Management Indicator; CV, Coefficient of Variation; TiR, Time-in-Range; TbR, Time-below-Range; TaR, Time-above-Range.

The GMI is a new measurand that replaces the estimated HbA_1c value. The GMI provides an estimate of the A1C value based on an average of the CGM glucose values that a person had over a period of several weeks [71].

Nutritional therapy

The dietary recommendations for children and adolescents with diabetes mellitus are based on the recommendations for a balanced diet at the population level and do not differ from the recommendations for a balanced diet for healthy children and adolescents of the same age (D-A-CH reference values, the current recommendations of the German Nutrition Society, concept of an optimized mixed diet for children and adolescents in Germany [72] [73]). Nutrition specialists (dieticians/ecotrophologists) with an in-depth knowledge of paediatric and adolescent nutrition and insulin therapy should provide this counselling [73]. Nutritional counselling should be based on cultural and ethnic family traditions as well as on the cognitive and psychosocial circumstances of young people and their families.

Regular checks of height, weight, and body mass index (BMI) are necessary to record optimal growth and to avoid a restrictive diet or overeating that can lead to excessive weight gain [74]. The total energy intake should be adapted to the age and stage of development of the child. Furthermore, unhealthy eating behaviours should be prevented.

Acute complications

Acute metabolic disorders manifest themselves in the form of diabetic ketoacidosis (DKA) or hypoglycaemia, rarely hyperglycaemic hyperosmolar syndrome (HHS).

Diabetic ketoacidosis (DKA)

Diabetic ketoacidosis is a potentially life-threatening disease. It should be treated immediately in a specialized facility by a diabetes team experienced with children. There should be a written treatment plan for treating diabetic ketoacidosis in children and adolescents in all treatment clinics ([Table 2]) [75] [76] [77].

Table 2 Medicinal treatment of ketoacidosis (taking into consideration the control of electrolytes, pH, blood glucose, ketone bodies).

Treatment goal/indication	Medicine	Dose	Chron. sequence/timeframe
Initial stabilisation of cardiovascular system, if necessary	NaCl 0.9%	10–20 ml/kg IV	Immediately over 1–2 h
Fluid resuscitation after initial cardiovascular stabilisation	NaCl 0.9% or Ringer’s solution, after 4–6 h NaCl 0.45% also possible	Maximum daily IV dose<1.5 to 2 times the maintenance requirement in relation to age/weight/body	Over 24–48 h
Glucose reduction	Normal insulin	0.1 U/kg/h IV, for younger children 0.05 U/kg/h	Begin insulin administration 1–2 h after start of volume administration; No interruption of insulin delivery up to pH>7.3; Lowering of glucose by 2–5 mmol/l/h (36–90 mg/dl/h)
Avoidance of hypoglycaemia	Glucose	Final concentration: 5% glucose/0.45% NaCl solution	Start from BG as of 15 mmol/l (270 mg/dl) or at lowering of BG>5 mmol/l/h (90 mg/dl/h)
Potassium replacement	KCl	Initial infusion 40 mmol/l volume; 3–6 mmol/kg/day IV; not>0.5 mmol/kg/h	For hypokalaemia immediately, for normokalaemia together with the start of insulin administration, in the case of hyperkalaemia only after resumption of urine production; continuous administration until volume compensation has been fully completed
Phosphate replacement	Potassium phosphate	In severe hypophosphatemia, half the potassium substitution as potassium phosphate	Until phosphate levels normalize

Diagnosis of diabetic ketoacidosis

The biochemical criteria for ketoacidosis include: pH<7.3 or bicarbonate<18 mmol/L, hyperglycaemia>11 mmol/l/>200 mg/dl associated with serum ketone detection or ketonuria.

In rare cases, ketoacidosis can occur with near-normal glucose levels (euglycaemic ketoacidosis).

Three grades of severity of ketoacidosis are distinguished according to international agreement: mild (pH<7.3; bicarbonate level<18 mmol/l), moderate (pH<7.2; bicarbonate level<10 mmol/l), severe (pH<7.1; bicarbonate level<5 mmol/l).

The biochemical criteria correlate with the clinical signs of increasingly severe dehydration and the deep, laboured, normal frequency breathing (Kussmaul’s respiration) as an expression of acidosis.

The following targets are to be pursued in ketoacidosis:

Stabilisation of cardiovascular system with initial volume bolus using isotonic solution; subsequent balanced fluid and electrolyte compensation, compensation of acidosis and ketosis by insulin therapy to lower blood glucose levels. The top priority is to avoid complications of therapy (cerebral oedema, hypokalaemia, severe hypophosphatemia) The information on drug therapy of diabetic ketoacidosis can be found in [Table 2].

During the treatment of diabetic ketoacidosis, hourly blood glucose measurements and, depending on the clinical condition, at least 2–4 hourly laboratory tests (electrolytes, urea, blood gases, phosphate levels) should be performed, as well as a determination of the ketones in serum or urine until these are no longer detectable. In severe ketoacidosis, clinical observation and monitoring should be performed hourly, at minimum [78] [79] [80].

Patients with severe ketoacidosis and an increased risk of cerebral oedema should be treated immediately by a diabetes team experienced with children in an intensive care unit or a specialized diabetes unit with comparable equipment; patients with severe ketoacidosis and suspected cerebral oedema should be treated in an intensive care unit [78] [79].

Patients with obvious signs of cerebral oedema should be treated with mannitol or hypertonic saline solution before further diagnostic measures (magnetic resonance imaging [MRI]) are initiated in accordance with the S3 Guideline. The following warning signs and symptoms of cerebral oedema should be taken note of in particular:

Headache, persistent decrease in heart rate (> 20 beats per minute), inadequate increase in blood pressure, falling oxygen saturation, change in neurological status (restlessness, irritability, somnolence, incontinence), specific neurological signs (abnormal motor and verbal response to pain stimuli, pupillary reaction, anisocoria, cranial nerve paralysis), secondary clouding [75] [78] [79] [81] [82] [83] [84] [85].

Hypoglycaemias

Hypoglycaemia is the most common acute complication in diabetes. A distinction is made between autonomic, i. e. adrenergic (sweating, trembling, palpitations, pallor) and neuroglycopenic symptoms (difficulty concentrating, visual disturbances, slurred speech, confusion, impaired memory function, dizziness, loss of consciousness). Initially, the autonomic signs appear.

A distinction is made [86] between the following degrees of severity:

Risk of hypoglycaemia: Glucose<70 mg/dl (3.9 mmol/l). Countermeasures needed.

Clinically-relevant hypoglycaemia: Glucose<54 mg/dl (3.0 mmol/l). Immediate response and therapy (oral administration of fast-acting carbohydrates) required.

Severe hypoglycaemia (coma, convulsions, severe cognitive dysfunction): no specific glucose threshold; can only be corrected by external help (glucagon administration).

There is an increased risk of acute hypoglycaemia, for example, in the case of deviations from the daily routine (e. g. extraordinary sporting activity), skipping meals, acute illnesses with limited carbohydrate intake (gastrointestinal infections), impaired hypoglycaemia perception, after alcohol consumption and with associated diseases such as celiac disease, hypothyroidism and Morbus Addison’s disease [87] [88] [172].

Children and adolescents with type 1 diabetes should always carry fast-acting carbohydrates in the form of dextrose or the like, in order to be able to act immediately in the event of mild hypoglycaemia and thus prevent severe hypoglycaemia.

Parents or other primary caregivers should be instructed in emergency measures (administering carbohydrates and glucagon).

If a hypoglycaemia perception disorder is present, a higher glucose level should be temporarily targeted [87] [88] [172].

A CGM system or an AID system should be used, as these have been shown to reduce the risk of hypoglycaemia.

Telemedicine and video consultations

Telemedicine can be provided immediately as a video consultation or at a later date, e. g. as an e-mail response. In the field of diabetology, the services include the discussion of glucose values, insulin adjustment with therapy adjustments, discussion of laboratory findings, but also advice on current issues or on social law or socio-medical topics. The form of contact most similar to personal contact is the video consultation. In particular, the video conferencing option can also be used for individual or group training on assorted topics.

The advantages of video consultations for patients or families are the ability to attend appointments and receive consultation all while forgoing the (longer) journey to the clinic or practice and thus travel and waiting times, absence from home/workplace, school cancellations and costs for transport. Even if the video consultation appointment takes a similar amount of time as the consultation in the clinic or practice, video consultation can positively affect the workflow in the clinic and practice by being more time-efficient [89] [90].

If more frequent therapy adjustments and consultations are necessary to improve the metabolic situation, telemedical forms of contact should also be offered [91] [92] [93] [94]. However, structural, spatial and personnel requirements must be created for this, and adequate reimbursement must be provided by the cost carriers.

Diabetes training

Diabetes education is an integral part of any diabetes therapy, as successful treatment can only be achieved through the continuous self-management of patients and their families in everyday life. However, without appropriate medical treatment, training is not very successful [95] [96].

Children and adolescents with diabetes, their parents or other primary caregivers should have continuous access to structured, quality-controlled training and counselling services tailored to their personal situation from the time they are diagnosed. Caregivers of children with diabetes in institutions (e. g. teachers in primary schools, educators in daycares, after-school care centres and nurseries) should receive training specific to the child [97] [98] [99] [100].

The training should be conducted by a multi-professional paediatric diabetes team with proper knowledge of age-specific needs, possibilities, and requirements that current diabetes therapies place on patients and their families. All team members should participate in the training and work toward formulating and achieving uniform therapy concepts and targets. In addition to the transfer of knowledge, the focus is on promoting self-management and integrating diabetes therapy into the age-appropriate everyday life of the children and their families.

The training curricula should first capture the needs, personal attitudes, prior knowledge, learning ability and willingness to learn of patients, their parents, and other primary caregivers. In addition, each training sequence should be individually tailored to age, cognitive maturity, diabetes duration, type of insulin substitution and glucose self-monitoring, present comorbidities, lifestyle, cultural characteristics of families, language and diabetes type [100] [101] [102].

Structured diabetes education must be clearly distinguished from technical instruction, e. g. on the use of CGM systems, insulin pumps or other diabetes technologies offered by manufacturers. This instruction does not meet the requirements for promoting self-management of diabetes in everyday life, e. g. the correct responses and, if necessary, insulin administration depending on current requirements, glucose levels, diet, exercise, stress and individual medical recommendations. The learning process should be accompanied by evaluated training media that are oriented towards the cognitive development and needs of children and adolescents. The same applies to training materials for parents which should include parenting tasks and age-specific diabetes therapy of their children.

Diabetic training is a continuous process and can only be successful through repeated needs-based offers (at least every 2 years) during long-term care. New therapy concepts, e. g. the start of insulin pump therapy, continuous glucose monitoring (CGM), an AID therapy or new life phases should be accompanied by additional training.

Psychological and social risks, comorbidities, and interventions

International studies show that psychosocial and socioeconomic factors are important determinants of therapy behaviour and thus of the quality of metabolic control in children and adolescents with type 1 diabetes and type 2 diabetes. Children and adolescents with chronically inadequate metabolic control, including recurrent diabetic ketoacidosis, are more likely to have psychosocial problems or psychiatric disorders than young people with more stable metabolic control [95] [103] [104] [105] [106]. Other risks include, for example, unstable family constellations, low socio-economic status, migration, cultural specifics, unfavourable parenting style, physical or mental illness of the parents. These should be recorded in the anamnesis when diabetes is diagnosed and over its course. If necessary, the interdisciplinary team should offer the families and other caregivers psychosocial counselling and therapeutic help for diabetes management [107] [108] [109] [110] [111].

Children and adolescents with type 1 diabetes have an increased risk of psychological comorbidities compared to metabolically healthy peers [110] [112] [113] [114] [115]. The same applies to adolescents with type 2 diabetes [116] [117] [118]. Therefore, continuous attention should be paid to signs of psychological stress or comorbidity (e. g. distress, anxiety, depression, eating disorder, ADHD) and, if necessary, professional diagnostics should be performed. If a psychologically-relevant disorder is present, paediatric and adolescent psychiatrists or psychotherapists should be consulted in order to initiate co-treatment if necessary. The aim is for treatment to be coordinated between psychotherapists/psychiatrists and the diabetes team [110] [113] [119] [120] [121].

Long-term complications and preventive examinations

Cardiovascular disease is the leading cause of morbidity and mortality in diabetes patients. This is why the prevention of micro- and macrovascular secondary complications in childhood and adolescence is crucial.

Important risk factors for cardiovascular complications are albumin excretion, LDL cholesterol, triglycerides, blood pressure, HbA_1c value, overweight or obesity and smoking. A glycaemic metabolic state that is as normal as possible significantly reduces the risk of micro- and macrovascular diseases. The HbA_1c value and time-in-range (TIR) should be checked regularly.

Screening and early diagnosis are essential:

• Blood pressure measurement: Regular measurements at every visit to the doctor, at least once a year. If the values are abnormal (> 90th percentile or≥130/80 mmHg from the age of 13), a 24-hour blood pressure measurement should be performed.

• Nephropathy screening: Annual screening for albuminuria should be done from the age of 11 or after 5 years of diabetes. A urine sample is used to determine the albumin-creatinine ratio, preferably from the first morning urine (definition of albuminuria:≥3 mg/mmol or≥30 mg/g).

• Lipid screening (total cholesterol, HDL cholesterol, non-HDL cholesterol, LDL cholesterol, lipoprotein (a) and triglycerides): Within the first year of diagnosis and every 2–3 years if levels are normal (LDL cholesterol<100 mg/dl).

• Retinopathy screening: From the age of 11 or after 5 years of diabetes, a binocular fundoscopy in mydriasis should be performed every two years by an experienced ophthalmologist.

• Neuropathy screening: From the age of 11 or after 5 years of diabetes, annually, consisting of anamnesis of symptoms (numbness, pain), examination of the feet (foot pulses), assessment of the sensation of touch and vibration (monofilament, tuning fork test) and self-reflexes.

Treatment measures:

• Hypertension: For children with blood pressure values>the 95th percentile in the long-term blood pressure measurement, ACE inhibitors or AT1 antagonists are recommended. Lifestyle interventions such as physical activity, limiting salt intake and weight management are essential.

• Albuminuria: If increased albumin excretion is detected, treatment with ACE inhibitors or AT1 antagonists is recommended, as these can slow the progression of nephropathy. Blood pressure control and glycaemic control are important here as well.

• Hyperlipidaemia: For LDL cholesterol levels>100 mg/dl, lifestyle intervention with dietary therapy is recommended. Statin drug therapy should be given to children≥8 years of age if 6 months after lifestyle intervention: LDL cholesterol>160 mg/dl (> 4.14 mmol/L), or LDL cholesterol>130 mg/dl (> 3.36 mmol/l) and at least 1 risk factor is present: hypertension, albuminuria, obesity, mean HbA_1c≥8% in the last year, elevation of lipoprotein (a)>30 mg/dl or positive family history of premature cardiovascular disease.

• Neuropathy: The most important measure for prevention and treatment is close to normal blood glucose control. For symptoms or subclinical signs, specific symptomatic therapy, including pain management and physical therapy, may be required.

Adolescents with diabetes and risk factors should be intensively informed about the need for improved metabolic control. Any improvement in HbA_1c and time-in-range can reduce long-term complications. Comprehensive information about and treatment of any additional risk factors is crucial to prevent micro- and macrovascular diseases.

Diabetes and sport

Physical exercise/sport is an important part of the treatment of type 1 diabetes in all age groups. Children, adolescents, their families, and caregivers should receive regular training on how to deal with diabetes management in sports activities and be motivated to do regular sports activities.

It is important to perform regular or continuous monitoring of glucose (self-measurement of blood glucose [SMBG]; CGM) before, during and after exercise [122] [123] [124]. An individual target glucose range, depending on e. g. the type of sport, duration and intensity, fitness level and the risk of hypoglycaemia should be determined before the start of the activity, e. g. 100–180 mg/dl or 5.6–10 mmol/l. Glucose trends/courses must be taken into account. If glucose levels are elevated (≥ 252 mg/dl or≥14 mmol/l) and elevated ketones (≥ 1.5 mmol/l in the blood or 2+or 4 mmol/l in the urine), the patient should not do exercise. For ketone levels of 0.6 to 1.4 mmol/l, these should be treated before starting exercise. If hypoglycaemia is detected before the start of the sporting activity, sports should be avoided altogether, depending on the severity of the hypoglycaemia (glucose<54 mg/dl or<3.0 mmol/l). For glucose levels between 54–70 mg/dl (3.0–3.9 mmol/l), glucose levels should be checked more frequently and treated with carbohydrates (e. g. 20 g glucose). A hypoglycaemic event (night-time hypoglycaemia) can occur during and after sporting activity and is still possible for up to 24 hours afterwards (glycogen muscle replenishment effect). A glucose value≤90 mg/dl (≤ 5 mmol/l) before the start of sporting activity should be treated with e. g. 10–20 g glucose.

Insulin pumps with PLGS can reduce the occurrence of hypoglycaemia during and after exercise [125]. The use of an automated insulin delivery (AID) system during exercise can also increase the time-in-range (70–180 mg/dl, 3.9–10 mmol/l) in children and adolescents with type 1 diabetes without an increased risk of hypoglycaemia [65] [126]. As a result, this could significantly reduce the need for snacks before exercise.

Management of acute illnesses (sick day management)

Acute illnesses, especially those associated with fever, can lead to elevated glucose levels and increased insulin requirements. This is caused by increased stress hormone levels, which can lead to increased glycogenolysis, increased gluconeogenesis and insulin resistance [127]. In contrast, diseases associated with nausea, diarrhoea and vomiting are more likely to lead to low glucose levels. This is due to lower food intake, poorer nutrient absorption in the gastrointestinal tract, delayed gastric emptying or higher passage of stools in gastroenteritis. In an acute illness, there may be a higher risk of a severe metabolic lapse in the sense of diabetic ketoacidosis and of severe hypoglycaemia.

Insulin doses should be adjusted depending on the situation and insulin administration should never be omitted under any circumstances. It is important to ensure that sufficient fluids and electrolytes are consumed. Regular monitoring of blood glucose/tissue glucose and ketones (preferably in the blood) and close coordination with the diabetes team and a structured approach should be followed. This is especially true for therapy with an AID system.

Operations on children and adolescents with diabetes

Surgical interventions lead to a complex neuroendocrine stress reaction of the body by which even healthy patients can develop hyperglycaemia and catabolism. There is evidence of an increased rate of wound infections dependant on hyperglycaemia. Preoperative hyperglycaemia is an independent predictor of infectious complications and length of hospital stay [128] [173]. The metabolic adjustment should therefore be optimized before elective surgery.

A blood glucose target value of 5–10 mmol/l (90–180 mg/dl) should be aimed for perioperatively [128] [129] [173]. A written SOP on perioperative management should be available for the individual types of minor to major operations.

In principle, both insulin pump and CGM can be used in many types of surgery, under the supervision of experienced diabetes teams. For specific recommendations, refer to the S3 Guideline.

Other forms of diabetes in childhood and adolescence

Type 2 diabetes

Characteristic features of type 2 diabetes are a gradual onset, obesity, and signs of insulin resistance (acanthosis nigricans, polycystic ovary syndrome). As a rule, there are no diabetes-specific autoantibodies (ICA, GAD, IA2, IAA, ZnT8) present as well as a lack of or only a low tendency to ketosis, and an increased C-peptide level.

With regard to the diagnostic criteria for diagnosing diabetes, please refer to the section “Manifestation: diagnostics and therapy”.

Individual therapy targets should be formulated during care measures (behavioural changes that come with risk-taking lifestyle, increase in physical activity, blood glucose target range, HbA_1c value) and the competence of the adolescent and their family in dealing with diabetes as well as self-management and personal responsibility should be encouraged.

The target fasting glucose should be<126 mg/dl and the target HbA_1c value should be<7%. A lower target value may be appropriate for some patients if this can be achieved without significantly increased side effects [130]. In addition to the lifestyle intervention, pharmacological therapy should be started when type 2 diabetes is diagnosed ([Fig. 3]). Blood glucose monitoring should be individualized and should consider pharmacological therapy. Continuous glucose measurement should then be implemented if several daily insulin injections or pump therapy are administered.

Fig. 3 Diagram for treating type 2 diabetes in children and adolescents BG, blood glucose; GLP-1, glucagon-like peptide-1; SGLT-2, sodium glucose linked transporter 2. Source: German Diabetes Society (DDG), S3 Guideline: Diagnosis, Therapy and Follow-Up of Type 1 Diabetes Mellitus in Children and Adolescents German Association of the Scientific Medical Professional Societies/AWMF registration number: 057–016. Version 4, 2023. https://register.awmf.org/assets/guidelines/057–016l_S3_Diagnostik-Therapie-Verlaufskontrolle-Diabetes-mellitus-Kinder-Jugendliche_2023–11.pdf. [rerif]

Concomitant diseases (dyslipidaemia, hypertension, microvascular complications) can already occur at manifestation or after a short duration of the disease, so that they should be screened from the time of diagnosis.

MODY

Genetic forms of diabetes that manifest in childhood to young adulthood are referred to by the acronym MODY (Maturity-Onset Diabetes of the Young) and are named according to the genetic cause. In Europe, they have a prevalence of about ~2.5%–6.5% of all paediatric diabetes cases [131] [132] [133] and are therefore slightly more common than type 2 diabetes, and only slightly rarer than antibody-negative type 1 diabetes. Therefore, genetic diagnosis should be considered for every antibody-negative diabetes case in childhood and adolescence, especially if there are cases of diabetes in first-degree relatives, if a relevant stimulable residual C-peptide can still be detected after 5 years, or if a clinical suspicion of type 2 diabetes is not accompanied by other characteristics of a metabolic syndrome [134] [135]. The most common causes of MODY are GCK-MODY (mild, largely constant hyperglycaemia throughout life) and the HNF-associated forms (HNF1A/HNF4A/HNF1B-MODY; progressive hyperglycaemia). Other mutations that are regularly found in MODY are ABCC8 and KCNJ11.

Management should be based on the MODY type [136]. Among the more common forms, GCK-MODY usually does not require lifelong drug or dietary therapy [137] the HNF-associated forms are often initially responsive to sulfonylureas, but usually require insulin therapy over the course of time.

Neonatal diabetes mellitus (NDM)

Neonatal diabetes is defined as diabetes that is diagnosed within the first 6 months of life. After the first 6 months of life, the incidence shifts significantly towards type 1 diabetes. Therefore, molecular diagnostics for monogenic diabetes should be performed promptly for every manifestation of diabetes in the first six months of life, as well as for every patient with antibody-negative diabetes in the second six months of life [136] [138].

Approximately 50% of patients experience remission within the first few months of life (transient neonatal diabetes mellitus, TNDM) and approximately 50% of patients have a persistent form of the disease. In non-consanguineous families, ABCC8 and KCNJ11-associated forms are prevalent with 50–60%. In consanguineous families, the genetic causes are much more heterogeneous. Some forms also have extra-pancreatic manifestations, so that it important to always perform a complete good clinical diagnostic with regard to associated malformations/symptoms. Because of genetic heterogeneity, a simultaneous examination of all NDM genes using next generation sequencing (NGS) is often useful and can identify a genetic cause in well over 80% of children [138].

Depending on the extent of the hyperglycaemic and even ketoacidosis lapse, insulin and fluid therapy are normally used for the initial compensation, based on the procedure for compensation for type 1 diabetes. Particular attention must be paid due to the low insulin requirement and the particular risk for young infants for osmotic and electrolyte shifts. If insulin therapy is still necessary in the course of the disease, this should usually be done by means of CSII.

ABCC8-, KCNJ11- or 6q24-associated NDM responds to oral sulfonylureas in about 90% of patients [139] [140] [141]. Early initiation of treatment with sulfonylureas is associated with a better therapy response [139] [142] and a better neurological outcome [143] [144]. Therefore, genetic diagnostics should be initiated early in order to be able to decide on the option of sulfonylurea therapy at an early stage. In the case of extra-pancreatic manifestations, it is important to ensure proper treatment of possible comorbidities (e. g., exocrine pancreatic insufficiency in pancreatic hypoplasia, etc.).

Diabetes in cystic fibrosis (CFRD)

Clinically, the main symptom of insulin resistance is impaired and delayed insulin secretion. Microvascular complications are increasingly coming into focus as the life expectancy of patients with cystic fibrosis (CF) increases. Children with cystic fibrosis should receive an oral glucose tolerance test annually from the age of 10; HbA_1c is not a recommended screening parameter. Insulin should be used as standard therapy [145]. Alternatively, a therapy attempt with repaglinide can be made, which can achieve similar therapeutic successes to insulin, at least temporarily [146] [147]. Even after a diagnosis of diabetes, a high-calorie, high-fat diet should be followed in the case of cystic fibrosis; calorie reduction is contraindicated.

Associated autoimmune diseases

20% to 25% of patients with type 1 diabetes are diagnosed with another autoimmune disease [148] [149]. The prevalence of thyroid disease and celiac disease is increased in young people with type 1 diabetes compared to people without diabetes [148] [149] [150]. Both diseases can occur without the presence of obvious clinical symptoms [151] [152].

Diagnostics and therapy of thyroid diseases

In children and adolescents with type 1 diabetes, thyroid-stimulating hormone (TSH) determination and thyroid autoantibodies (anti-thyroid peroxidase [TPO] antibodies) should be performed at diabetes manifestation, and then every 1–2 years in asymptomatic individuals. A more frequent TSH determination should be performed in case of symptoms of thyroid dysfunction, struma or positive thyroid autoantibodies [148] [149] [150] [153]. Regular screening for thyroid dysfunction in asymptomatic children and adolescents with type 1 diabetes is justified by the high prevalence of autoimmune hypothyroidism of about 10%, the often absent obvious clinical signs [154] and the potential effects of untreated hypothyroidism on growth in height [154], the final height [155] [156], and the glycaemic variability [157].

In the case of pathological TSH value, free thyroxine (fT4) and triiodothyronine (fT3) should be determined, and a thyroid sonography should be performed with Doppler ultrasound. It is used to determine the volume and to detect the inhomogeneous, anechoic structure as a diagnostic criterion for Hashimotoʼs thyroiditis.

For the therapy of autoimmune hypothyroidism or struma, L-thyroxine should be used according to the therapy plan ([Fig. 4]).

Fig. 4 For the therapy of autoimmune hypothyroidism or struma, L-thyroxine should be used according to the therapy plan. TSH, thyroid-stimulating hormone; fT4: free thyroxine. Source: German Diabetes Society (DDG), S3 Guideline: Diagnosis, Therapy and Follow-Up of Type 1 Diabetes Mellitus in Children and Adolescents German Association of the Scientific Medical Professional Societies/AWMF registration number: 057–016. Version 4, 2023. https://register.awmf.org/assets/guidelines/057–016l_S3_Diagnostik-Therapie-Verlaufskontrolle-Diabetes-mellitus-Kinder-Jugendliche_2023–11.pdf. [rerif]

Diagnostics and therapy of celiac disease

Children and adolescents with type 1 diabetes are to be examined for celiac disease in the event of diabetes manifestation and at intervals of 2 years and in the case of associated symptoms [148] [150] [158] [159] [160]. At the age of 6 years, asymptomatic, screening-positive children had lower bone density, lower weight, lower body mass index and lower height compared to seronegative children [161].

The determination of autoantibodies against tissue transglutaminase 2 of the class immunoglobulin A (IgA) (tTG-IgA-Ak) is used to determine celiac disease. Autoantibodies against tissue transglutaminase 2 and endomysium (EMA) of class IgA show the highest specificity for serological celiac disease diagnostics In order to rule out an IgA deficiency syndrome or a secondary IgA deficiency, the total IgA should be determined in parallel. In more recent guidelines, the diagnosis of celiac disease in children with≥10-fold increased serum IgA antibodies against transglutaminase and positive IgA antibodies against endomysium in a second serum sample is considered possible solely on the basis of serological diagnostics without duodenal biopsy and without specific symptoms and without HLA diagnostics [158] [162].

If coeliac disease is confirmed, a gluten-free diet should be followed [158] [163] [164] [165].

Primary adrenocortical insufficiency (Addison’s disease)

Approximately 1% to 3% of patients with type 1 diabetes have positive anti-adrenal autoantibodies against 21-hydroxylase [149] [152] [166] [167]. The mean prevalence of adrenocortical insufficiency in patients with type 1 diabetes was 0.2% to 0.4% [148] [149].

Clinical signs of primary adrenocortical insufficiency (Addison’s disease) include increasing hypoglycaemia, unexplained decrease in the insulin requirement, increased skin pigmentation, adynamia, weight loss, and hypotension. The treatment of Addisonʼs disease consists of adequate life-long substitution of hydrocortisone; a mineralocorticoid (fludrocortisone) may also need to be administered.

Rehabilitation

In-patient rehabilitation can be carried out:

• In the case of persistently poor skills in dealing with diabetes,

• After the in-patient primary therapy of the newly diagnosed diabetes mellitus if initial training cannot be provided near the patient’s home (in the form of follow-up treatment),

• In the case of long-term inadequate metabolic control under out-patient care conditions, e. g. recurrent hypoglycaemia or ketoacidosis,

• If there are diabetic secondary complications which are either already present or imminent in the short-term,

• In the event of serious disruptions to activities and/or to the child or adolescent being able to participate in age-appropriate activities or in everyday life, e. g. frequent sick days (Participation) (§ 4 SGB 9; Federal Working Group for Rehabilitation/Bundesarbeitsgemeinschaft Rehabilitation) [168] [169].

Inclusion and participation

Despite many therapeutic improvements and technical innovations, the management and inclusion of a child with diabetes continues to be a challenge for the family and caregivers. Children with diabetes are sometimes restricted in their participation in school and daycare [170]. The following prerequisites should be met for the successful inclusion and participation of children and adolescents with diabetes mellitus: Ensuring the care of children and adolescents with diabetes mellitus in educational institutions (e. g. with the help of school health professionals) with the avoidance of stigmatisation and exclusion and avoidance of family stress situations (financial, psychological) [170] [171]. Information on appropriate contact points should be provided.

Imprint (German)

The evidence-based guideline was prepared on behalf of the German Diabetes Society (Deutsche Diabetes Gesellschaft – DDG).

• DDG President: Prof. Dr. med. Monika Kellerer (2019–2021)

• DDG President: Prof. Dr. Andreas Neu (2021–2023)

• DDG President: Prof. Andreas Fritsche (from 2023)

Expert group appointed by the DDG Board, members of the AGPD:

• Dr. Martin Holder (Coordinator), Stuttgart

• Dr. Ralph Ziegler (Coordinator), Münster

• Marie Auzanneau, Ulm

• PD Dr. Torben Biester, Hanover

• Sarah Biester, Hanover

• Karina Boss, Berlin

• Dr. Louisa van den Boom, Kirchen (Bonn)

• Dr. Thekla von der Berge, Hanover

• Dr. Stephanie Brandt-Heunemann, Ulm

• Prof. Dr. Thomas Danne, Hanover

• Dr. Nicolin Datz, Hanover

• Dr. Axel Dost, Jena

• Dr. Markus Freff, Darmstadt

• PD Dr. Angela Galler, Berlin

• Prof. Dr. Reinhard Holl, Ulm

• Prof. Dr. Clemens Kamrath, Giessen

• PD Dr. Thomas Kapellen, Leipzig

• Prof. Dr. Beate Karges, Aachen

• Prof. Dr. Olga Kordonouri, Hanover

• Monika Kriechbaum-Hubacsek, Ulm

• Dr. Sebastian Kummer, Düsseldorf

• Prof. Dr. Karin Lange, Hanover

• Dr. Silvia Müther, Berlin

• Dr. Kirsten Mönkemöller, Cologne

• Prof. Dr. Andreas Neu, Tübingen

• Prof. Dr. Klemens Raile, Berlin

• Dr. Felix Reschke, Hanover

• Dr. Heike Saßmann, Hanover

• PD Dr. Simone von Sengbusch, Lübeck

• PD Dr. Katharina Warncke, Munich

• Dr. Julian Ziegler, Tübingen

Representatives of other organisations that participated in the preparation of the guideline and coordinated the recommendations and commented on the content of the guideline:

• Prof. Dr. Roland Schweizer, DGKJ, Tübingen

• Prof. Dr. Martin Wabitsch, AGA, Ulm

• Andrea Witt, Patient Representative, diabetesDE, Dersau

• Prof. Dr. Joachim Wölfle, DGKED, Erlangen

Methodological processing (literature research, evidence review, method report, consensus conference, moderation), editing and organisation:

• Simone Witzel, AWMF Guideline Consultant, Berlin: Moderation of consensus meetings

• Dr. Monika Nothacker, AWMF Guideline Consultant, Berlin: Introduction and consultation of scientific methodological work as well as moderation of a consensus meeting

• Prof. Dr. Jos Kleijnen, KSR Evidence, Escrick York UK: Implementation of the systematic Literature research

• Dr. med. Vladimir Patchev, ExSciMed, Eichenau: Independent evidence review of the literature on the recommendations

• Dr. Rebekka Epsch, DDG Office, Berlin: Organisational cooperation on the part of the DDG over the course of the editorial processing of the guidelines: Andrea Haring, Berlin

Further documents relating to this guideline:

All documents on the guideline are available on the AWMF website under the register number 057–016: German Diabetes Society (DDG), S3 Guideline: Diagnosis, Therapy and Follow-Up of Type 1 Diabetes Mellitus in Children and Adolescents German Association of the Scientific Medical Professional Societies/AWMF registration number: 057–016. Version 4, 2023. https://register.awmf.org/assets/guidelines/057–016l_S3_Diagnostik-Therapie-Verlaufskontrolle-Diabetes-mellitus-Kinder-Jugendliche_2023–11.pdf.

German Diabetes Association: Clinical Practice Guidelines

This is a translation of the DDG clinical practice guideline published in Diabetologie 2024; 19 (Suppl 2): S167–S185. DOI 10.1055/a-2374-0813

• References

• 1 Buchmann M, Tuncer O, Auzanneau M. et al. Inzidenz, Prävalenz und Versorgung von Typ-1-Diabetes bei Kindern und Jugendlichen in Deutschland: Zeittrends und sozialräumliche Lage. J Health Monit 2023; 8: 59-81
• 2 Stahl-Pehe A, Kamrath C, Prinz N. et al. Prevalence of type 1 and type 2 diabetes in children and adolescents in Germany from 2002 to 2020: A study based on electronic health record data from the DPV registry. J Diabetes 2022; 14: 840-850
• 3 Ehehalt S, Blumenstock G, Willasch AM. et al. Continuous rise in incidence of childhood Type 1 diabetes in Germany. Diabet Med 2008; 25: 755-757
• 4 Neu A, Ehehalt S, Bendas A. et al. Incidence of childhood type 1 diabetes in Germany: A nationwide survey over a period of ten years. Pediatr Diabetes 2013; 14: 119
• 5 Rosenbauer J, Castillo K, Stahl-Pehe A. Recent incidence trends of type 1 diabetes in children and adolescents in Germany. Pediatr Diabetes 2014; 15: 78
• 6 Robert Koch-Institut (RKI). RKI Diabetes Surveillance Kooperationsprojekte. 2020 2020.
• 7 Roche EF, McKenna AM, Ryder KJ. et al. Is the incidence of type 1 diabetes in children and adolescents stabilising? The first 6 years of a National Register. Eur J Pediatr 2016; 175: 1913-1919
• 8 Abbasi A, Juszczyk D, van Jaarsveld CHM. et al. Body Mass Index and Incident Type 1 and Type 2 Diabetes in Children and Young Adults: A Retrospective Cohort Study. J Endocr Soc 2017; 1: 524-537
• 9 Dabelea D, Bell RA, D’Agostino RB. et al. Incidence of diabetes in youth in the United States. JAMA 2007; 297: 2716-2724
• 10 Lawrence JM, Divers J, Isom S. et al. Trends in Prevalence of Type 1 and Type 2 Diabetes in Children and Adolescents in the US, 2001–2017. JAMA 2021; 326: 717-727
• 11 Neu A, Feldhahn L, Ehehalt S. et al. Type 2 diabetes mellitus in children and adolescents is still a rare disease in Germany: A population-based assessment of the prevalence of type 2 diabetes and MODY in patients aged 0-20 years. Pediatr Diabetes 2009; 10: 468-473
• 12 Denzer C, Rosenbauer J, Klose D. et al. Is COVID-19 to Blame? Trends of Incidence and Sex Ratio in Youth-Onset Type 2 Diabetes in Germany. Diabetes Care 2023; 46: 1379-1387
• 13 American Diabetes Association (ADA). Standards of Medical Care in Diabetes-2022. Diabetes Care 2022; 45
• 14 Philip M, Achenbach P, Addala A. et al. Consensus Guidance for Monitoring Individuals with Islet Autoantibody-Positive Pre-Stage 3 Type 1 Diabetes. Diabetes Care 2024; 47: 1-23
• 15 Krischer JP, Liu X, Lernmark Å. et al. Characteristics of children diagnosed with type 1 diabetes before vs after 6 years of age in the TEDDY cohort study. Diabetologia 2021; 64: 2247-2257
• 16 Ziegler AG, Rewers M, Simell O. et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA 2013; 309: 2473-2479
• 17 Herold KC, Bundy BN, Long SA. et al. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med 2019; 381: 603-613
• 18 Sims EK, Bundy BN, Stier K. et al. Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals. Sci Transl Med 2021; 13: eabc8980
• 19 Elding Larsson H, Vehik K, Bell R. et al. Reduced prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes in young children participating in longitudinal follow-up. Diabetes Care 2011; 34: 2347-2352
• 20 Hekkala AM, Ilonen J, Toppari J. et al. Ketoacidosis at diagnosis of type 1 diabetes: Effect of prospective studies with newborn genetic screening and follow up of risk children. Pediatr Diabetes 2018; 19: 314-319
• 21 Hummel S, Carl J, Friedl N. et al. Children diagnosed with presymptomatic type 1 diabetes through public health screening have milder diabetes at clinical manifestation. Diabetologia 2023; 66: 1633-1642
• 22 Jacobsen LM, Vehik K, Veijola R. et al. Heterogeneity of DKA Incidence and Age-Specific Clinical Characteristics in Children Diagnosed With Type 1 Diabetes in the TEDDY Study. Diabetes Care 2022; 45: 624-633
• 23 American Diabetes Association (ADA). 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2022. Diabetes Care 2022; 45
• 24 Mayer-Davis EJ, Lawrence JM, Dabelea D. et al. Incidence Trends of Type 1 and Type 2 Diabetes among Youths, 2002–2012. N Engl J Med 2017; 376: 1419-1429
• 25 Patterson CC, Harjutsalo V, Rosenbauer J. et al. Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989–2013: A multicentre prospective registration study. Diabetologia 2019; 62: 408-417
• 26 International Society for Pediatric and Adolescent Diabetes (ISPAD). ISPAD Clinical Practice Consensus Guidelines 2022. 2022 https://www.ispad.org/page/ISPADGuidelines2022
• 27 Watkins RA, Evans-Molina C, Blum JS. et al. Established and emerging biomarkers for the prediction of type 1 diabetes: A systematic review. Transl Res 2014; 164: 110-121
• 28 Zhang L, Eisenbarth GS. Prediction and prevention of Type 1 diabetes mellitus. J Diabetes 2011; 3: 48-57
• 29 Arslanian S, Bacha F, Grey M. et al. Evaluation and Management of Youth-Onset Type 2 Diabetes: A Position Statement by the American Diabetes Association. Diabetes Care 2018; 41: 2648-2668
• 30 Kuppermann N, Ghetti S, Schunk JE. et al. Clinical Trial of Fluid Infusion Rates for Pediatric Diabetic Ketoacidosis. N Engl J Med 2018; 378: 2275-2287
• 31 Rewers A, Kuppermann N, Stoner MJ. et al. Effects of Fluid Rehydration Strategy on Correction of Acidosis and Electrolyte Abnormalities in Children With Diabetic Ketoacidosis. Diabetes Care 2021; 44: 2061-2068
• 32 Bode BW, Iotova V, Kovarenko M. et al. Efficacy and Safety of Fast-Acting Insulin Aspart Compared With Insulin Aspart, Both in Combination With Insulin Degludec, in Children and Adolescents With Type 1 Diabetes: The onset 7 Trial. Diabetes Care 2019; 42: 1255-1262
• 33 Danne T, Lüpke K, Walte K. et al. Insulin detemir is characterized by a consistent pharmacokinetic profile across age-groups in children, adolescents, and adults with type 1 diabetes. Diabetes Care 2003; 26: 3087-3092
• 34 Danne T, Råstam J, Odendahl R. et al. Parental preference of prandial insulin aspart compared with preprandial human insulin in a basal-bolus scheme with NPH insulin in a 12-wk crossover study of preschool children with type 1 diabetes. Pediatr Diabetes 2007; 8: 278-285
• 35 Wadwa RP, Laffel LM, Franco DR. et al. Efficacy and safety of ultra-rapid lispro versus lispro in children and adolescents with type 1 diabetes: The PRONTO-Peds trial. Diabetes Obes Metab 2023; 25: 89-97
• 36 Chase HP, Arslanian S, White NH. et al. Insulin glargine versus intermediate-acting insulin as the basal component of multiple daily injection regimens for adolescents with type 1 diabetes mellitus. J Pediatr 2008; 153: 547-553
• 37 Danne T, Philotheou A, Goldman D. et al. A randomized trial comparing the rate of hypoglycemia-assessed using continuous glucose monitoring in 125 preschool children with type 1 diabetes treated with insulin glargine or NPH insulin (the PRESCHOOL study). Pediatr Diabetes 2013; 14: 593-601
• 38 Danne T, Tamborlane WV, Malievsky OA. et al. Efficacy and Safety of Insulin Glargine 300 Units/mL (Gla-300) Versus Insulin Glargine 100 Units/mL (Gla-100) in Children and Adolescents (6-17 years) With Type 1 Diabetes: Results of the EDITION JUNIOR Randomized Controlled Trial. Diabetes Care 2020; 43: 1512-1519
• 39 Hemmingsen B, Metzendorf M-I, Richter B. Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus. Cochrane Database Syst Rev 2021; 3 CD013498
• 40 Liu M, Zhou Z, Yan J. et al. A randomised, open-label study of insulin glargine or neutral protamine Hagedorn insulin in Chinese paediatric patients with type 1 diabetes mellitus. BMC Endocr Disord 2016; 16: 67
• 41 Robertson KJ, Schoenle E, Gucev Z. et al. Insulin detemir compared with NPH insulin in children and adolescents with Type 1 diabetes. Diabet Med 2007; 24: 27-34
• 42 Schober E, Schoenle E, van Dyk J. et al. Comparative trial between insulin glargine and NPH insulin in children and adolescents with type 1 diabetes. Diabetes Care 2001; 24: 2005-2006
• 43 Thalange N, Bereket A, Larsen J. et al. Insulin analogues in children with Type 1 diabetes: A 52-week randomized clinical trial. Diabet Med 2013; 30: 216-225
• 44 Urakami T, Mine Y, Aoki M. et al. A randomized crossover study of the efficacy and safety of switching from insulin glargine to insulin degludec in children with type 1 diabetes. Endocr J 2017; 64: 133-140
• 45 Libman IM, Miller KM, Dimeglio LA. et al. Effect of Metformin Added to Insulin on Glycemic Control Among Over-weight/Obese Adolescents With Type 1 Diabetes: A Randomized Clinical Trial. JAMA 2015; 314: 2241-2250
• 46 Liu Y-S, Chen C-N, Chen Z-G. et al. Vascular and metabolic effects of metformin added to insulin therapy in patients with type 1 diabetes: A systematic review and meta-analysis. Diabetes Metab Res Rev 2020; 36: e3334
• 47 Adolfsson P, Björnsson V, Hartvig NV. et al. Improved Glycemic Control Observed in Children with Type 1 Diabetes Fol-lowing the Introduction of Smart Insulin Pens: A Real-World Study. Diabetes Ther 2022; 13: 43-56
• 48 Adolfsson P, Hartvig NV, Kaas A. et al. Increased Time in Range and Fewer Missed Bolus Injections After Introduction of a Smart Connected Insulin Pen. Diabetes Technol Ther 2020; 22: 709-718
• 49 Toschi E, Slyne C, Greenberg JM. et al. Examining the Relationship Between Pre- and Postprandial Glucose Levels and Insulin Bolus Timing Using Bluetooth-Enabled Insulin Pen Cap Technology and Continuous Glucose Monitoring. Diabetes Technol Ther 2020; 22: 19-24
• 50 Dos Santos TJ, Donado Campos JDM, Argente J. et al. Effectiveness and equity of continuous subcutaneous insulin infusions in pediatric type 1 diabetes: A systematic review and meta-analysis of the literature. Diabetes Res Clin Pract 2021; 172: 108643
• 51 Kamrath C, Tittel SR, Kapellen TM. et al. Early versus delayed insulin pump therapy in children with newly diagnosed type 1 diabetes: Results from the multicentre, prospective diabetes follow-up DPV registry. Lancet Child Adolesc Health 2021; 5: 17-25
• 52 Qin Y, Yang LH, Huang XL. et al. Efficacy and Safety of Continuous Subcutaneous Insulin Infusion vs. Multiple Daily Injections on Type 1 Diabetes Children: A Meta-Analysis of Randomized Control Trials. J Clin Res Pediatr Endocrinol 2018; 10: 316-323
• 53 Rosner B, Roman-Urrestarazu A. Health-related quality of life in paediatric patients with Type 1 diabetes mellitus using insulin infusion systems. A systematic review and meta-analysis. PLoS ONE 2019; 14: e0217655
• 54 Schöttler H, Auzanneau M, Best F. et al. Insulinpumpe, kontinuierliche und kapilläre Glukosemessung bei Kindern, Jugendlichen und Erwachsenen mit Diabetes mellitus: Daten des DPV-Registers zwischen 1995–2019. Diabetol Stofffwechs 2020; 15: 477-486
• 55 Karges B, Schwandt A, Heidtmann B. et al. Association of Insulin Pump Therapy vs Insulin Injection Therapy With Severe Hypoglycemia, Ketoacidosis, and Glycemic Control Among Children, Adolescents, and Young Adults With Type 1 Diabetes: 1358–1366. JAMA 2017; 318: 1358-1366
• 56 de Ridder F, den Brinker M, de Block C. The road from intermittently scanned continuous glucose monitoring to hybrid closed-loop systems. Part B: Results from randomized controlled trials. Ther Adv Endocrinol Metab 2019; 10 2042018819871903
• 57 Evans M, Welsh Z, Ells S. et al. The Impact of Flash Glucose Monitoring on Glycaemic Control as Measured by HbA_1c: A Meta-analysis of Clinical Trials and Real-World Observational Studies. Diabetes Ther 2020; 11: 83-95
• 58 Karges B, Tittel SR, Bey A. et al. Continuous glucose monitoring versus blood glucose monitoring for risk of severe hypo-glycaemia and diabetic ketoacidosis in children, adolescents, and young adults with type 1 diabetes: A population-based study. Lancet Diabetes Endocrinol 2023; 11: 314-323
• 59 Champakanath A, Akturk HK, Alonso GT. et al. Continuous Glucose Monitoring Initiation Within First Year of Type 1 Dia-betes Diagnosis Is Associated With Improved Glycemic Outcomes: 7-Year Follow-Up Study. Diabetes Care 2022; 45: 750-753
• 60 Laffel LM, Kanapka LG, Beck RW. et al. Effect of Continuous Glucose Monitoring on Glycemic Control in Adolescents and Young Adults With Type 1 Diabetes: A Randomized Clinical Trial. JAMA 2020; 323: 2388-2396
• 61 Kanapka LG, Wadwa RP, Breton MD. et al. Extended Use of the Control-IQ Closed-Loop Control System in Children With Type 1 Diabetes. Diabetes Care 2021; 44: 473-478
• 62 Ware J, Allen JM, Boughton CK. et al. Randomized Trial of Closed-Loop Control in Very Young Children with Type 1 Diabetes. N Engl J Med 2022; 386: 209-219
• 63 Isganaitis E, Raghinaru D, Ambler-Osborn L. et al. Closed-Loop Insulin Therapy Improves Glycemic Control in Adolescents and Young Adults: Outcomes from the International Diabetes Closed-Loop Trial. Diabetes Technol Ther 2021; 23: 342-349
• 64 Bombaci B, Passanisi S, Alibrandi A. et al. One-Year Real-World Study on Comparison among Different Continuous Subcutaneous Insulin Infusion Devices for the Management of Pediatric Patients with Type 1 Diabetes: The Supremacy of Hybrid Closed-Loop Systems. Int J Environ Res Public Health 2022; 19: 10293
• 65 Zeng B, Gao L, Yan Q. et al. Automated Insulin Delivery Systems in Children and Adolescents With Type 1 Diabetes: A Systematic Review and Meta-analysis of Outpatient Randomized Controlled Trials. Diabetes Care 2023; 46: 2300-2307
• 66 Eckstein ML, Weilguni B, Tauschmann M. et al. Time in Range for Closed-Loop Systems versus Standard of Care during Physical Exercise in People with Type 1 Diabetes: A Systematic Review and Meta-Analysis. J Clin Med 2021; 10: 2445
• 67 Beck RW, Bergenstal RM, Cheng P. et al. The Relationships Between Time in Range, Hyperglycemia Metrics, and HbA_1c . J Diabetes Sci Technol 2019; 13: 614-626
• 68 Diabetes Control and Complications Trial Research Group. Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial. J Pediatr 1994; 125: 177-188
• 69 Karges B, Tittel SR, Bey A. et al. Continuous glucose monitoring versus blood glucose monitoring for risk of severe hypo-glycaemia and diabetic ketoacidosis in children, adolescents, and young adults with type 1 diabetes: A population-based study. Lancet Diabetes Endocrinol 2023; 11: 314-323
• 70 Lind M, Pivodic A, Svensson A-M. et al. HbA_1c level as a risk factor for retinopathy and nephropathy in children and adults with type 1 diabetes: Swedish population based cohort study. BMJ 2019; 366: l4894
• 71 Bergenstal RM, Beck RW, Close KL. et al. Glucose Management Indicator (GMI): A New Term for Estimating A1C From Continuous Glucose Monitoring. Diabetes Care 2018; 41: 2275-2280
• 72 Kersting M, Kalhoff H, Lücke T. Von Nährstoffen zu Lebensmitteln und Mahlzeiten: Das Konzept der Optimierten Mischkost für Kinder und Jugendliche in Deutschland. Aktuel Ernahrungsmed 2017; 42: 304-315
• 73 Annan SF, Higgins LA, Jelleryd E. et al. ISPAD Clinical Practice Consensus Guidelines 2022: Nutritional management in children and adolescents with diabetes. Pediatr Diabetes 2022; 23: 1297-1321
• 74 Gilbertson HR, Reed K, Clark S. et al. An audit of the dietary intake of Australian children with type 1 diabetes. Nutr Diabetes 2018; 8: 10
• 75 Fiordalisi I, Novotny WE, Holbert D. et al. An 18-yr prospective study of pediatric diabetic ketoacidosis: An approach to minimizing the risk of brain herniation during treatment. Pediatr Diabetes 2007; 8: 142-149
• 76 Glaser N, Fritsch M, Priyambada L. et al. ISPAD clinical practice consensus guidelines 2022: Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Pediatr Diabetes 2022; 23: 835-856
• 77 Glaser NS, Wootton-Gorges SL, Buonocore MH. et al. Frequency of subclinical cerebral edema in children with diabetic ketoacidosis. Pediatr Diabetes 2006; 7: 75-80
• 78 Glaser N, Fritsch M, Priyambada L. et al. ISPAD clinical practice consensus guidelines 2022: Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Pediatr Diabetes 2022; 23: 835-856
• 79 Craig ME, Twigg SM, Donaghue KC. et al. National evidence-based clinical care guidelines for type 1 diabetes in children, adolescents and adults. Canberra: Australian Government Department of Health and Ageing; 2011
• 80 Edge JA, Jakes RW, Roy Y. et al. The UK case-control study of cerebral oedema complicating diabetic ketoacidosis in children. Diabetologia 2006; 49: 2002-2009
• 81 Banks CJ, Furyk JS. Review article: Hypertonic saline use in the emergency department. Emerg Med Australas 2008; 20: 294-305
• 82 Franklin B, Liu J, Ginsberg-Fellner F. Cerebral edema and ophthalmoplegia reversed by mannitol in a new case of insulin-dependent diabetes mellitus. Pediatrics 1982; 69: 87-90
• 83 Hanas R, Lindgren F, Lindblad B. Diabetic ketoacidosis and cerebral oedema in Sweden – a 2-year paediatric population study. Diabet Med 2007; 24: 1080-1085
• 84 Roberts MD, Slover RH, Chase HP. Diabetic ketoacidosis with intracerebral complications. Pediatr Diabetes 2001; 2: 109-114
• 85 Muir AB, Quisling RG, Yang MCK. et al. Cerebral edema in childhood diabetic ketoacidosis: Natural history, radiographic findings, and early identification. Diabetes Care 2004; 27: 1541-1546
• 86 Battelino T, Danne T, Bergenstal RM. et al. Clinical Targets for Continuous Glucose Monitoring Data Interpretation: Recommendations From the International Consensus on Time in Range. Diabetes Care 2019; 42: 1593-15603
• 87 Clarke W, Jones T, Rewers A. et al. Assessment and management of hypoglycemia in children and adolescents with diabetes. Pediatr Diabetes 2008; 9: 165-174
• 88 Pacaud D, Hermann JM, Karges B. et al. Risk of recurrent severe hypoglycemia remains associated with a past history of severe hypoglycemia up to 4 years: Results from a large prospective contemporary pediatric cohort of the DPV initiative. Pediatr Diabetes 2018; 19: 493-500
• 89 Braune K, Boss K, Schmidt-Herzel J. et al. Shaping Workflows in Digital and Remote Diabetes Care During the COVID-19 Pandemic via Service Design: Prospective, Longitudinal, Open-label Feasibility Trial. JMIR Mhealth Uhealth 2021; 9: e24374
• 90 von Sengbusch S, Doerdelmann J, Lemke S. et al. Parental expectations before and after 12-month experience with video consultations combined with regular outpatient care for children with type 1 diabetes: A qualitative study. Diabet Med 2021; 38: e14410
• 91 Crossen SS, Marcin JP, Qi L. et al. Home Visits for Children and Adolescents with Uncontrolled Type 1 Diabetes. Diabetes Technol Ther 2020; 22: 34-41
• 92 Gandrud L, Altan A, Buzinec P. et al. Intensive remote monitoring versus conventional care in type 1 diabetes: A randomized controlled trial. Pediatr Diabetes. 2018 10.1111, Online ahead of print
• 93 Reid MW, Krishnan S, Berget C. et al. CoYoT1 Clinic: Home Telemedicine Increases Young Adult Engagement in Diabetes Care. Diabetes Technol Ther 2018; 20: 370-379
• 94 von Sengbusch S, Eisemann N, Mueller-Godeffroy E. et al. Outcomes of monthly video consultations as an add-on to regular care for children with type 1 diabetes: A 6-month quasi-randomized clinical trial followed by an extension phase. Pediatr Diabetes 2020; 21: 1502-1515
• 95 Cameron FJ, de Beaufort C, Aanstoot HJ. et al. Lessons from the Hvidoere International Study Group on childhood diabetes: Be dogmatic about outcome and flexible in approach. Pediatr Diabetes 2013; 14: 473-480
• 96 de Weerdt I, Visser AP, Kok GJ. et al. Randomized controlled multicentre evaluation of an education programme for insulin-treated diabetic patients: Effects on metabolic control, quality of life, and costs of therapy. Diabet Med 1991; 8: 338-345
• 97 American Association of Diabetes Educators (ADCES). Management of Children With Diabetes in the School Setting. Diabetes Educ 2019; 45: 54-59
• 98 Jackson CC, Albanese-OʼNeill A, Butler KL. et al. Diabetes care in the school setting: A position statement of the American Diabetes Association. Diabetes Care 2015; 38: 1958-1963
• 99 Lange K, Klotmann S, Saßmann H. et al. A pediatric diabetes toolbox for creating centres of reference. Pediatr Diabetes 2012; 13: 49-61
• 100 Martin D, Lange K, Sima A. et al. Recommendations for age-appropriate education of children and adolescents with diabetes and their parents in the European Union. Pediatr Diabetes 2012; 13: 20-28
• 101 Arslanian S, Bacha F, Grey M. et al. Evaluation and Management of Youth-Onset Type 2 Diabetes: A Position Statement by the American Diabetes Association. Diabetes Care 2018; 41: 2648-2668
• 102 Gemeinsamer Bundesausschuss (G-BA). Richtlinie des Gemeinsamen Bundesausschusses über die 21. Änderung der DMP-Anforderungen-Richtlinie (DMP-A-RL): Änderung der Anlage 7 (DMP Diabetes mellitus Typ 1) und der Anlage 8 (DMP Diabetes mellitus Typ 1 und Typ 2 – Dokumentation). 2020. Zugriff am 25.09.2022 unter https://www.gba.de/downloads/40-268-6304/2020-01-16_DMP-A-RL_Aenderung-Anlage-7-8-DMP-Diabetes-mellitus_Servicedokument.pdf
• 103 Fegan-Bohm K, Minard CG, Anderson BJ. et al. Diabetes distress and HbA_1c in racially/ethnically and socioeconomically diverse youth with type 1 diabetes. Pediatr Diabetes 2020; 21: 1362-1369
• 104 Gruhn MA, Lord JH, Jaser SS. Collaborative and Overinvolved Parenting Differentially Predict Outcomes in Adolescents With Type 1 Diabetes. Health Psychol 2016; 21
• 105 Hood KK, Rausch JR, Dolan LM. Depressive symptoms predict change in glycemic control in adolescents with type 1 diabetes: Rates, magnitude, and moderators of change. Pediatr Diabetes 2011; 12: 718-723
• 106 Stanek KR, Noser AE, Patton SR. et al. Stressful life events, parental psychosocial factors, and glycemic management in school-aged children during the 1 year follow-up of new-onset type 1 diabetes. Pediatr Diabetes 2020; 21: 673-680
• 107 DeCosta P, Grabowski D, Skinner TC. The psychosocial experience and needs of children newly diagnosed with type 1 diabetes from their own perspective: A systematic and narrative review. Diabet Med 2020; 37: 1640-1652
• 108 Dehn-Hindenberg A, Saßmann H, Berndt V. et al. Long-term Occupational Consequences for Families of Children With Type 1 Diabetes: The Mothers Take the Burden. Diabetes Care 2021; 44: 2656-2663
• 109 Schwartz DD, Cline VD, Axelrad ME. et al. Feasibility, acceptability, and predictive validity of a psychosocial screening program for children and youth newly diagnosed with type 1 diabetes. Diabetes Care 2011; 34: 326-331
• 110 Zenlea IS, Mednick L, Rein J. et al. Routine behavioral and mental health screening in young children with type 1 diabetes mellitus. Pediatr Diabetes 2014; 15: 384-388
• 111 Zhao X, Ai Z, Chen Y. et al. The Effectiveness of Parenting Interventions on Psychosocial Adjustment in Parents of Children and Adolescents with Type 1 Diabetes: A Meta-Analysis. Worldviews Evid Based Nurs 2019; 16: 462-469
• 112 Berger G, Waldhoer T, Barrientos I. et al. Association of insulin-manipulation and psychiatric disorders: A systematic epidemiological evaluation of adolescents with type 1 diabetes in Austria. Pediatr Diabetes 2019; 20: 127-136
• 113 Cooper MN, Lin A, Alvares GA. et al. Psychiatric disorders during early adulthood in those with childhood onset type 1 diabetes: Rates and clinical risk factors from population-based follow-up. Pediatr Diabetes 2017; 18: 599-606
• 114 Dybdal D, Tolstrup JS, Sildorf SM. et al. Increasing risk of psychiatric morbidity after childhood onset type 1 diabetes: A population-based cohort study. Diabetologia 2018; 61: 831-828
• 115 Reynolds KA, Helgeson VS. Children with diabetes compared to peers: Depressed? Distressed? A meta-analytic review. Ann Behav Med 2011; 42: 29-41
• 116 Browne JL, Nefs G, Pouwer F. et al. Depression, anxiety and self-care behaviours of young adults with Type 2 diabetes: Results from the International Diabetes Management and Impact for Long-term Empowerment and Success (MILES) Study. Diabet Med 2015; 32: 133-140
• 117 Roberts AJ, Bao H, Qu P. et al. Mental health comorbidities in adolescents and young adults with type 2 diabetes. J Pediatr Nurs 2021; 61: 280-283
• 118 Today Study Group. Longitudinal Association of Depressive Symptoms, Binge Eating, and Quality of Life With Cardiovascular Risk Factors in Young Adults With Youth-Onset Type 2 Diabetes: The TODAY2 Study. Diabetes Care 2022; 45: 1073-1081
• 119 Butwicka A, Frisén L, Almqvist C. et al. Risks of psychiatric disorders and suicide attempts in children and adolescents with type 1 diabetes: A population-based cohort study. Diabetes Care 2015; 38: 453-459
• 120 Luyckx K, Verschueren M, Palmeroni N. et al. Disturbed Eating Behaviors in Adolescents and Emerging Adults With Type 1 Diabetes: A One-Year Prospective Study. Diabetes Care 2019; 42: 1637-1644
• 121 Reinehr T, Dieris B, Galler A. et al. Worse Metabolic Control and Dynamics of Weight Status in Adolescent Girls Point to Eating Disorders in the First Years after Manifestation of Type 1 Diabetes Mellitus: Findings from the Diabetes Patienten Verlaufsdokumentation Registry. J Pediatr 2019; 207: 205-212.e5
• 122 Burckhardt MA, Chetty T, Smith GJ. et al. Use of Continuous Glucose Monitoring Trends to Facilitate Exercise in Children with Type 1 Diabetes strukturierten. Diabetes Technol Ther 2019; 21: 51-55
• 123 Moser O, Riddell MC, Eckstein ML. et al. Glucose management for exercise using continuous glucose monitoring (CGM) and intermittently scanned CGM (isCGM) systems in type 1 diabetes: Position statement of the European Association for the Study of Diabetes (EASD) and of the International Society for Pediatric and Adolescent Diabetes (ISPAD) endorsed by JDRF and supported by the American Diabetes Association (ADA). Pediatr Diabetes 2020; 21: 1375-1393
• 124 Riddell MC, Milliken J. Preventing exercise-induced hypoglycemia in type 1 diabetes using real-time continuous glucose monitoring and a new carbohydrate intake algorithm: An observational field study. Diabetes Technol Ther 2011; 13: 819-825
• 125 Cherubini V, Gesuita R, Skrami E. et al. Optimal predictive low glucose management settings during physical exercise in adolescents with type 1 diabetes. Pediatr Diabetes 2019; 20: 107-112
• 126 Dovc K, Macedoni M, Bratina N. et al. Closed-loop glucose control in young people with type 1 diabetes during and after unannounced physical activity: A randomised controlled crossover trial. Diabetologia 2017; 60: 2157-2167
• 127 Laffel LM, Limbert C, Phelan H. et al. ISPAD Clinical Practice Consensus Guidelines 2018: Sick day management in children and adolescents with diabetes. Pediatr Diabetes 2018; 19: 193-204
• 128 Kapellen T, Agwu JC, Martin L. et al. ISPAD clinical practice consensus guidelines 2022: Management of children and adolescents with diabetes requiring surgery. Pediatr Diabetes 2022; 23: 1468-1477
• 129 Thiele AG, Heckenmüller M, Bartelt H. et al. Review of Leipzig protocol for intravenous insulin infusion in pediatric patients with type 1 diabetes during intercurrent illness and surgery. Pediatr Diabetes 2019; 20: 421-426
• 130 American Diabetes Association (ADA) Professional Practice Committee. 14. Children and Adolescents: Standards of Care in Diabetes-2024. Diabetes Care 2024; 47: S258-S281
• 131 Fendler W, Borowiec M, Baranowska-Jazwiecka A. et al. Prevalence of monogenic diabetes amongst Polish children after a nationwide genetic screening campaign. Diabetologia 2012; 55: 2631-2635
• 132 Shepherd M, Shields B, Hammersley S. et al. Systematic Population Screening, Using Biomarkers and Genetic Testing, Identifies 2.5% of the U.K. Pediatric Diabetes Population With Monogenic Diabetes. Diabetes Care 2016; 39: 1879-1888
• 133 Johansson BB, Irgends HU, Molnes J. et al. Targeted next-generation sequencing reveals MODY in up to 6.5% of antibody-negative diabetes cases listed in the Norwegian Childhood Diabetes Registry. Diabetologia 2017; 60: 625-635
• 134 Johnson SR, Carter HE, Leo P. et al. Cost-effectiveness Analysis of Routine Screening Using Massively Parallel Sequencing for Maturity-Onset Diabetes of the Young in a Pediatric Diabetes Cohort: Reduced Health System Costs and Improved Patient Quality of Life. Diabetes Care 2019; 42: 69-76
• 135 Stankute I, Verkauskiene R, Blouin JL. et al. Systematic Genetic Study of Youth With Diabetes in a Single Country Reveals the Prevalence of Diabetes Subtypes, Novel Candidate Genes, and Response to Precision Therapy. Diabetes 2020; 69: 1065-1071
• 136 Greeley SAW, Polak M, Njølstad PR. et al. ISPAD Clinical Practice Consensus Guidelines 2022: The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes 2022; 23: 1188-1211
• 137 Steele AM, Shields BM, Wensley KJ. et al. Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia. JAMA 2014; 311: 279-286
• 138 De Franco E, Flanagan SE, Houghton JAL. et al. The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study. Lancet 2015; 386: 957-963
• 139 Babiker T, Vedovato N, Patel K. et al. Successful transfer to sulfonylureas in KCNJ11 neonatal diabetes is determined by the mutation and duration of diabetes. Diabetologia 2016; 59: 1162-1166
• 140 Bowman P, Mathews F, Barbetti F. et al. Long-term Follow-up of Glycemic and Neurological Outcomes in an International Series of Patients With Sulfonylurea-Treated ABCC8 Permanent Neonatal Diabetes. Diabetes Care 2021; 44: 35-42
• 141 Garcin L, Mericp V, Fauret-Amsellem AL. et al. Neonatal diabetes due to potassium channel mutation: Response to sulfonylurea according to the genotype. Pediatr Diabetes 2020; 21: 932-941
• 142 Thurber BW, Carmody D, Tadie EC. et al. Age at the time of sulfonylurea initiation influences treatment outcomes in KCNJ11-related neonatal diabetes. Diabetologia 2015; 58: 1430-1435
• 143 Beltrand J, Elie C, Busiah K. et al. Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations. Diabetes Care 2015; 38: 2033-2041
• 144 Shah RP, Spruyt K, Kragie BC. et al. Visuomotor performance in KCNJ11-related neonatal diabetes is impaired in children with DEND-associated mutations and may be improved by early treatment with sulfonylureas. Diabetes Care 2012; 35: 2086-2088
• 145 Ode KL, Ballman M, Battezzati A. et al. ISPAD Clinical Practice Consensus Guidelines 2022: Management of cystic fibrosis-related diabetes in children and adolescents. Pediatr Diabetes 2022; 23: 1212-1228
• 146 Ballmann M, Hubert D, Assael BM. et al. Open randomised prospective comparative multi-centre intervention study of patients with cystic fibrosis and early diagnosed diabetes mellitus. BMC Pediatr 2014; 14: 70
• 147 Ballmann M, Hubert D, Assael BM. et al. Repaglinide versus insulin for newly diagnosed diabetes in patients with cystic fibrosis: A multicentre, openlabel, randomised trial. Lancet Diabetes Endocrinol 2018; 6: 114-121
• 148 Mäkimattila S, Harjutsalo V, Forsblom C. et al. Response to Comment on Mäkimattila et al. Every Fifth Individual With Type 1 Diabetes Suffers From an Additional Autoimmune Disease: A Finnish Nationwide Study. Diabetes Care 2020; 43: 1041-1047
• 149 Nederstigt C, Uitbeijerse BS, Janssen LGM. et al. Associated auto-immune disease in type 1 diabetes patients: A systematic review and meta-analysis. Eur J Endocrinol 2019; 180: 135-144
• 150 Hughes JW, Riddlesworth TD, Dimeglio LA. et al. Autoimmune Diseases in Children and Adults With Type 1 Diabetes From the T1D Exchange Clinic Registry. J Clin Endocrinol Metab 2016; 101: 4931-4937
• 151 Husby S, Koletzko S, Korponay-Szabó IR. et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 2012; 54: 136-160
• 152 Mahmud FH, Elbarbary NS, Fröhlich-Reiterer E. et al. ISPAD Clinical Practice Consensus Guidelines 2018: Other complications and associated conditions in children and adolescents with type 1 diabetes. Pediatr Diabetes 2018; 19: 275-286
• 153 Lazarus J, Brown RS, Daumerie C. et al. 2014 European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J 2014; 3: 76-94
• 154 Saari A, Pokka J, Mäkitie O. et al. Early Detection of Abnormal Growth Associated with Juvenile Acquired Hypothyroidism. J Clin Endocrinol Metab 2021; 106: e739-e748
• 155 Dujovne NV, Gazek NA, Lazzati JM. et al. Variables predictivas de talla baja adulta en pacientes con hipotiroidismo adquirido grave de origen autoinmune. Arch Argent Pediatr 2019; 117: 388-391
• 156 Rivkees SA, Bode HH, Crawford JD. Long-term growth in juvenile acquired hypothyroidism: The failure to achieve normal adult stature. N Engl J Med 1988; 318: 599-602
• 157 Mohn A, Di Michele S, Di Luzio R. et al. The effect of subclinical hypothyroidism on metabolic control in children and adolescents with Type 1 diabetes mellitus. Diabet Med 2002; 19: 70-73
• 158 Felber J, Bläker H, Fischbach W. et al. Aktualisierte S2k-Leitlinie Zöliakie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS). Z Gastroenterol 2022; 60: 790-856
• 159 Kamrath C, Tittel SR, Dunstheimer D. et al. Early vs late histological confirmation of coeliac disease in children with new-onset type 1 diabetes. Diabetologia 2022; 65: 1108-1118
• 160 Pham-Short A, Donaghue KC, Ambler G. et al. Screening for Celiac Disease in Type 1 Diabetes: A Systematic Review. Pediatrics 2015; 136: e170-e176
• 161 Jansen MAE, Kiefte-de Jong JC, Gaillard R. et al. Growth trajectories and bone mineral density in anti-tissue transglutaminase antibody-positive children: The Generation R Study. Clin Gastroenterol Hepatol 2015; 13: 913-920.e5
• 162 Husby S, Koletzko S, Korponay-Szabó I. et al. European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020. J Pediatr Gastroenterol Nutr 2020; 70: 141-156
• 163 Hansen D, Brock-Jacobsen B, Lund E. et al. Clinical benefit of a glutenfree diet in type 1 diabetic children with screening-detected celiac disease: A population-based screening study with 2 yearsʼ follow-up. Diabetes Care 2006; 29: 2452-2456
• 164 Nagl K, Bollow E, Liptay S. et al. Lower HbA_1c in patients with type 1 diabetes and celiac disease who reached celiac-specific antibodynegativity-A multicenter DPV analysis. Pediatr Diabetes 2019; 20: 1100-1109
• 165 Weiman DI, Mahmud FH, Clarke ABM. et al. Impact of a Gluten-Free Diet on Quality of Life and Health Perception in Patients With Type 1 Diabetes and Asymptomatic Celiac Disease. J Clin Endocrinol Metab 2021; 106: e1984-e1992
• 166 Triolo TM, Armstrong TK, McFann K. et al. Additional autoimmune disease found in 33% of patients at type 1 diabetes onset. Diabetes Care 2011; 34: 1211-1213
• 167 Warncke K, Fröhlich-Reiterer EE, Thon A. et al. Polyendocrinopathy in children, adolescents, and young adults with type 1 diabetes: A multicenter analysis of 28,671 patients from the German/Austrian DPV-Wiss database. Diabetes Care. 2010; 33: 2010-2012
• 168 Bundesarbeitsgemeinschaft für Rehabilitation (BAR). Gemeinsames Rahmenkonzept der Gesetzlichen Krankenkassen und der Gesetzlichen Rentenversicherung für die Durchführung stationärer medizinischer Leistungen der Vorsorge und Rehabilitation für Kinder und Jugendliche. 2008. Zugriff am 16.10.2022 unter https://www.bar-frankfurt.de/fileadmin/dateiliste/_publikationen/reha_vereinbarungen/pdfs/Gemeinsames_Rahmenkonzept.pdf
• 169 Deutsche Rentenversicherung Bund. Leitlinien für die sozialmedizinische Begutachtung: Beurteilung der Rehabilitationsbedürftigkeit von Kindern und Jugendlichen für die Deutsche Rentenversicherung. Zu griff am 16.10.2022 unter https://www.deutsche-rentenversicherung.de/SharedDocs/Downloads/DE/Experten/infos_fuer_aerzte/begutachtung/leitlinie_rehabed-uerftigkeit_kiju_langfassung_pdf.html
• 170 Heinrich M, Boß K, Wendenburg J. et al. Unzureichende Versorgung gefährdet Inklusion von Kindern mit Diabetes mellitus Typ 1. Diabetol Stoffwechs 2019; 14: 380-387
• 171 Dehn-Hindenberg A, Lange K. Eltern von Kindern mit Typ-1-Diabetes: Folgen für Berufstätigkeit, psychosoziale Belastungen und Bedarf an Unterstützungsleistungen – Ergebnisse der AMBA-Studie. Diabetol Stoffwechs 2019; 14: S69
• 172 Cranston I, Lomas J, Maran A. et al. Restoration of hypoglycaemia awareness in patients with long-duration insulin-dependent diabetes. Lancet 1994; 344: 283-287
• 173 Guvener M, Pasaoglu I, Demircin M. et al. Perioperative hyperglycemia is a strong correlate of postoperative infection in type II diabetic patients after coronary artery bypass grafting. Endocr J 2002; 49: 531-537
• 174 Patterson CC, Karuranga S, Salpea P. et al. Worldwide estimates of incidence, prevalence and mortality of type 1 diabetes in children and adolescents: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract 2019; 157: 107842