Type 1 diabetes mellitus in children: clinical guidelines

List of Abbreviations

GADA – Glutamic Acid Decarboxylase Autoantibodies

IAA – Insulin Autoantibodies

IA-2A – Insulinoma-Associated-2 Autoantibodies

ICA – Islet Cell Cytoplasmic Autoantibodies

HbA1c – glycated hemoglobin

HLA – Human Leukocyte Antigens

ZnT8A – Zinc Transporter 8 Autoantibodies

AH – arterial hypertension

BP – blood pressure

ACE – angiotensin-converting enzyme

Abs – antibodies

ATC – Anatomical Therapeutic Chemical classification

HRV – heart rate variability

TAR – time above range

TBR – time below range

TIR – time in range

BG – blood glucose

ONH – optic nerve head

DKA – diabetic ketoacidosis

DME – diabetic macular edema

DNA – deoxyribonucleic acid

DN – diabetic nephropathy

DPPN – diabetic peripheral polyneuropathy

DR – diabetic retinopathy

BMI – body mass index

LAI – long-acting insulin (long-acting insulins and their injectable analogs)

RAI – rapid-acting insulin (short-acting insulins and their injectable analogs)

UAI – ultra-rapid-acting insulin (short-acting insulins and their injectable analogs)

Uulai – ultra-long-acting insulin (long-acting insulins and their injectable analogs)

Urai – ultra-short-acting insulin (short-acting insulins and their injectable analogs)

CAN – cardiovascular autonomic neuropathy

HDL – high-density lipoproteins

LDL – low-density lipoproteins

MDI – multiple daily injections

ICD-10 – International Classification of Diseases 10th Revision

INN – International Nonproprietary Name

CGM – continuous glucose monitoring

CSII – continuous subcutaneous insulin infusion

NPH – Neutral Protamine Hagedorn

ND – neonatal diabetes mellitus

OGTT – oral glucose tolerance test

eGFR – estimated glomerular filtration rate

DM – diabetes mellitus

T1D – type 1 diabetes mellitus

T2D – type 2 diabetes mellitus

GFR – glomerular filtration rate

LCE – level of confidence of evidence

GRS – grade of recommendation strength

FGM – flash glucose monitoring

HR – heart rate

CKD – chronic kidney disease

XE – bread unit

ECG – electrocardiography

** – the medicinal product is included in the list of vital and essential drugs for medical use

*** – included in the list of medical devices provided during the provision of medical care under the state guarantee program for free medical care to citizens

# – a medicinal product used off-label (contrary to the indications, contraindications, routes of administration, and dosages contained in the package leaflet)

Terms and Definitions

C-peptide – a 31-amino acid polypeptide formed during the cleavage of proinsulin by peptidases.

Autoimmunity – the development of antibodies in the body directed against its own structures and tissues.

Insulin analogs – a form of insulin featuring specific modifications to the human insulin molecule. An analog acts similarly to insulin but possesses pharmacokinetic/pharmacodynamic differences that can offer clinical advantages.

Basal insulin regimen – continuous insulin delivery by an insulin pump at a user-defined rate (constant or varying throughout the day) or administration of long-acting insulin.

Insulin boluses – discrete doses of insulin administered by an insulin pump user, required to maintain glycemic control after meals and to correct hyperglycemia.

Glycemic variability – a measure of the frequency, duration, and amplitude of blood glucose fluctuations over a given period of time.

Hyperglycemia – blood glucose levels above normal values.

Hypoglycemia – blood glucose levels below normal values.

Glycemia – blood glucose concentration.

Glycated hemoglobin – an indicator that reflects the average blood glucose level over the past 2–3 months.

Dyslipidemia – an alteration in the physiological ratio of blood lipids manifested by elevated triglyceride and low-density lipoprotein levels, and decreased high-density lipoprotein levels.

Insulin – a hormone physiologically secreted by pancreatic beta cells that regulates blood glucose levels by stimulating glucose uptake by tissues.

Insulin pump is a device for continuous subcutaneous insulin infusion. Insulin pumps include the following medical devices: ambulatory insulin infusion pump***, ambulatory insulin infusion pump with an integrated blood glucose meter***.

Infusion set is a single-use set of medical devices used for insulin infusion, consisting of an insulin reservoir, a subcutaneously placed cannula (teflon or steel), and a catheter connecting the reservoir and the cannula.

Bolus calculator is a mathematical algorithm that enables an insulin pump to calculate the meal and/or blood glucose correction bolus dose based on user-entered parameters (carbohydrate amount in food, blood glucose level) and pre-set individual coefficients (carbohydrate ratio, insulin sensitivity factor, target blood glucose, insulin action time, etc.).

Lipodystrophy is a pathological alteration of adipose tissue at insulin injection sites.

Ambulatory insulin infusion pump*** – see insulin pump.

Ambulatory insulin infusion pump with an integrated blood glucose meter*** – see insulin pump.

Continuous subcutaneous insulin infusion (CSII) therapy is a method of insulin therapy delivered via continuous subcutaneous insulin infusion using an insulin pump.

Prandial insulin is short-acting insulin administered with meals.

Self-monitoring of blood glucose (SMBG) is the independent determination of blood glucose by patients at home using a blood glucose meter or a continuous glucose monitoring system.

Carbohydrate choice (Bread unit) is an amount of food containing 10–12 grams of carbohydrates.

Insulin pen is a device for insulin injections.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Diabetes mellitus (DM) is a large group of complex metabolic disorders characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Impaired insulin secretion and/or reduced tissue response to insulin as part of complex hormonal processes lead to impaired insulin action on target tissues, which in turn causes disturbances in carbohydrate, lipid, and protein metabolism. The same patient may simultaneously exhibit both impaired insulin secretion and impaired insulin action [1].

Type 1 diabetes mellitus (T1DM) is a disease resulting from autoimmune destruction of insulin-producing pancreatic β-cells, followed by the development of absolute insulin deficiency.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

T1DM is characterized by chronic, immune-mediated destruction of pancreatic islet β-cells, which leads, in most cases, to absolute insulin deficiency. The destruction of β-cells occurs at a variable rate and becomes clinically significant when approximately 70–90% of β-cells are destroyed.

T1DM is a multifactorial disease; however, the specific mechanisms of interaction between genetic predisposition, environmental factors, and immune system status underlying T1DM remain unclear.

Autoimmune β-cell destruction is a complex, multistage process involving the activation of both cellular and humoral branches of the immunity. In response to primary β-cell injury and antigen release, the islets are infiltrated by autoreactive T lymphocytes, triggering autoimmune activation and further β-cell damage. As the autoimmune process progresses, the islets of Langerhans are infiltrated by monocytes and macrophages, which release pro-inflammatory cytokines (IL-1, IL-6, TNF-α), reactive oxygen species, nitric oxide, and hydroxyl radicals. Cytokines induce apoptosis—programmed cell death of transformed or healthy cells. Nitric oxide and other radicals damage the deoxyribonucleic acid (DNA) of β-cells. Given the low antioxidant enzyme defense of β-cells, free radicals cause protein denaturation and β-cell destruction.

T1DM-associated autoantibodies (AAb) are serological markers of autoimmune β-cell destruction. These include autoantibodies to glutamic acid decarboxylase (GADA), tyrosine phosphatase (IA-2A), insulin (IAA), and zinc transporter 8 (ZnT8A). There is an age-related dissociation in the appearance of these autoantibodies: IAA and GADA are more frequently detected in children under 10 years of age, whereas IA-2A and ZnT8A are found in older age groups. The clinical utility of islet cell antibody (ICA) testing, both for predicting T1DM and for differential diagnosis with other types of diabetes, has diminished with the advent of biochemical autoantibodies, given the complexity of test standardization and performance [2].

Susceptibility to autoimmune T1DM is determined by multiple genes: genome-wide association studies have identified more than 75 loci associated with the development of T1DM. Of these, the major histocompatibility complex (HLA) accounts for about 50% of all participating genetic systems [3]. In the Russian Federation, the strongest predisposing HLA-DR and DQ gene haplotypes are [4–6]: DRB1*04-DQA1*03:01-DQB1*03:02, DRB1*04-DQA1*03:01-DQB1*03:04; moderate-risk haplotypes include DRB1*17(03)-DQA1*05:01-DQB1*02:01, DRB1*01-DQA1*01:01-DQB1*05:01, DRB1*16-DQA1*01:02-DQB1*05:02/4; and protective haplotypes include DRB1*15-DQA1*01:02-DQB1*06:02/8, DRB1*13-DQA1*01:03-DQB1*06:02/8. There are genetic differences in T1DM risk across various populations, including within the Russian Federation [7]. With the rising incidence of T1DM in a number of countries, a decrease in the relative contribution of the strongest HLA genotypes to T1DM development has been observed, indicating an increasing role of environmental factors.

Among other genes, the INS, PTPN22, and IL2RA genes make the highest contribution to susceptibility to T1DM. All of them are involved in the development of islet β-cell autoimmunity.

Environmental triggers (infectious, dietary, or chemical) initiating β-cell destruction remain unknown. There is evidence regarding the potential impact of enterovirus (Coxsackie virus) and rotavirus infections, early introduction of gluten and whole cow's milk-based formulas, etc., on the onset of islet autoimmunity and/or T1DM. However, current data are insufficient to formulate definitive preventive recommendations.

1.3 Epidemiology of the Disease or Condition

According to the International Diabetes Federation (IDF) data for 2021, the total number of children and adolescents (under 19 years of age) with T1DM worldwide is over 1.2 million, of whom more than half (54%) are children under 15 years of age. The incidence of T1DM is growing every year, with over 108,000 children aged 0 to 14 years and over 41,000 adolescents aged 15 to 19 years diagnosed annually [8].

T1D is the most common type of diabetes in children, accounting for up to 90% of all diabetes cases in children in most countries, while among all age groups the prevalence of T1D ranges from 5 to 10% [9].

The incidence of T1D in children varies significantly across countries [9], ranging from over 50 per 100,000 children in Finland to 2–3 cases per 100,000 children in Southeast Asian countries.

The peak incidence occurs during early puberty, manifesting 1–2 years earlier in girls than in boys. By the end of puberty, the incidence decreases for both sexes.

The total number of patients with T1D under the age of 18 in the Russian Federation as of December 31, 2023, was 61,318 individuals (208 per 100,000 children), with an incidence of 8,009 (28 per 100,000 children). The prevalence of T1D in children in 2023 was 177 per 100,000 children, and in adolescents, 376 per 100,000 adolescents. The incidence of T1D in children in 2022 was 27 per 100,000 children, and in adolescents, 36 per 100,000 adolescents [10–15].

In most countries, including Russia, an increasing incidence of T1D in childhood is registered, especially in developing countries and countries with high economic growth. In a number of countries, there is a disproportionately high increase in the incidence of T1D in children under the age of 5 years.

1.4 Features of Coding the Disease or Condition

E10.1 – Insulin-dependent diabetes mellitus: with ketoacidosis;

E10.2 – Insulin-dependent diabetes mellitus: with renal complications;

E10.3 – Insulin-dependent diabetes mellitus: with ophthalmic complications;

E10.4 – Insulin-dependent diabetes mellitus: with neurological complications;

E10.5 – Insulin-dependent diabetes mellitus: with peripheral circulatory complications;

E10.6 – Insulin-dependent diabetes mellitus: with other specified complications;

E10.7 – Insulin-dependent diabetes mellitus: with multiple complications;

E10.8 – Insulin-dependent diabetes mellitus: with unspecified complications;

E10.9 – Insulin-dependent diabetes mellitus: without complications.

Example of diagnosis formulation: Type 1 diabetes mellitus: without complications (ICD-10 code: E10.9).

1.5 Classification of the disease or condition

The classification of diabetes is presented in Table 1.

Table 1. Etiological classification of diabetes mellitus (ISPAD, 2022[16])

^a Except for overt diabetes mellitus.

Unlike the ICD-10 classification approved in the Russian Federation, domestic and foreign practice uses the terms type 1 DM (instead of insulin-dependent DM) and type 2 DM (instead of non-insulin-dependent DM).

In 2019, WHO published a new classification of diabetes, which introduced hybrid forms of diabetes and unclassified diabetes [17]. Currently, the Russian Association of Endocrinologists recommends continuing to use the 2018 ISPAD classification, taking into account potential ICD-10 coding difficulties.

The concept of diabetes severity is excluded from the diagnosis formulation. The severity of diabetes is determined by the presence of complications, the characteristics of which are indicated in the diagnosis.

Due to the introduction of individualized treatment targets, the concepts of compensation, subcompensation, and decompensation are inappropriate in the diagnosis formulation for patients with diabetes. Following the complete diagnosis formulation, the individual target level of glycemic control should be indicated (see Section 3.1 Assessment and Target Goals of Glycemic Control).

1.6 Clinical presentation of the disease or condition

Clinical Manifestations of T1D

The clinical presentation of diabetes ranges from non-urgent manifestations to severe dehydration and DKA, up to the development of a comatose state (Table 2). The rate of progression from the first clinical manifestations to the development of DKA varies among patients, ranging from a few days in infants to several months in adolescents.

Following diagnosis and the initiation of insulin therapy, T1D has a chronic course with periods of carbohydrate metabolism compensation and phases of decompensation with or without ketosis/DKA. Disease decompensation can be caused by patient-related management failures (infrequent glycemic monitoring, non-compliance with diet and insulin therapy regimens), interruption of insulin delivery when using an insulin pump (insulin pumps include the following medical devices: ambulatory continuous subcutaneous insulin infusion pump***, ambulatory continuous subcutaneous insulin infusion pump with built-in blood glucose meter***) due to various reasons, or as a result of intercurrent illnesses. In T1D, there is a high risk of developing specific micro- and macrovascular complications.

In approximately 80% of children with T1D, shortly after the initiation of insulin therapy, a partial remission of T1D or "honeymoon phase" is observed, lasting from a few weeks to six months, rarely up to a year or more. Diabetes remission is temporary and does not signify a cure for T1D. Complete remission is the cessation of insulin administration without deterioration of glycemic parameters. Partial remission is defined as an insulin requirement of less than 0.5 IU/kg of body weight and a glycated hemoglobin (HbA1c) level in the blood of less than 7%.

Table 2. Clinical manifestations of diabetes mellitus

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition: The diagnosis of T1D is established based on pathognomonic findings:

1) anamnesis and complaints: polyuria, polydipsia, weight loss, etc., see Table 2 (may be absent at the preclinical stage);

2) laboratory tests:

a. Glycemia and/or HbA1c levels corresponding to the criteria for diabetes (Table 3). Meanwhile, the preclinical stage is characterized by normal glycemic parameters or initial carbohydrate metabolism disorders (see "Stages of T1D");

b. DKA and/or elevated blood/urine ketone levels (may be absent at the preclinical stage);

c. The presence of one or more islet autoantibodies associated with type 1 diabetes confirms the diagnosis of type 1 diabetes. At the same time, the complete absence of autoantibodies does not rule out type 1 diabetes (idiopathic).

Table 3. Criteria for diagnosing diabetes mellitus (ISPAD, 2022 [16]).

^a In the absence of overt hyperglycemia, a diagnosis of diabetes mellitus made on the basis of these criteria must be confirmed by repeat tests.

^b A level of less than 6.5% does not exclude the possibility of diagnosing diabetes mellitus based on glucose levels. The role of HbA1c itself in the diagnosis of type 1 diabetes in children remains incompletely understood.

In accordance with the recommendations of the World Health Organization, supported by the Russian Association of Endocrinologists, the normal fasting venous plasma glucose level is <6.1 mmol/L, and 2 hours after a load during an OGTT, it is <7.8 mmol/L. The intermediate stages in the progression of carbohydrate metabolism disorders from normal glucose homeostasis to clinical type 1 diabetes are impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). These conditions are not independent nosological units, but are regarded as "prediabetes" [16,18], which reflects a high risk of developing the clinical stage of diabetes.

IGT and IFG are not interchangeable concepts, as they represent different levels of impaired glucose regulation: basal metabolism and the dynamic response to a standardized glucose load.

Diagnostic criteria for IGT and IFG [19]:

• IFG is defined as a fasting venous plasma glucose level of ≥6.1 and <7.0 mmol/L;

• IGT is defined as a venous plasma glucose level 2 hours after a load of ≥7.8 and <11.1 mmol/L during an OGTT.

Stages of Type 1 Diabetes

The results of prospective studies in individuals at increased risk for type 1 diabetes have shown that the disease is a continuous process that sequentially progresses through various identifiable stages before the appearance of clinical symptoms, which has made it possible to distinguish several stages of type 1 diabetes [20] (Table 4):

Stage 1: Autoimmune process / Normoglycemia / Absence of clinical manifestations. The first stage is characterized by signs of a β-cell autoimmune process, determined by the presence of two or more autoantibodies. At the same time, glycemic parameters do not exceed the norm, and clinical manifestations of diabetes are absent. The duration of the first stage can range from months to years. In prospective studies among children at high risk for type 1 diabetes, the 5-year risk of symptomatic disease is approximately 44%, and the 10- and 15-year risks are 70% and 85%, respectively [21].

Stage 2: Autoimmune process / Dysglycemia / Absence of clinical manifestations. In the second stage of type 1 diabetes, carbohydrate metabolism disorders are added to the signs of a β-cell autoimmune process, determined by the presence of two or more positive autoantibody titers. At this stage, the 5-year risk of developing clinical type 1 diabetes is approximately 75%, and the lifetime risk approaches 100% [3].

Stage 3: Autoimmune process / Hyperglycemia / Clinical Type 1 Diabetes. The third stage represents the manifestation of type 1 diabetes with a characteristic glycemic level and a classical clinical picture, which may include polyuria, polydipsia, weight loss, etc. Sometimes stage 3 is divided into stages 3 and 4, depending on the presence or absence of clinical manifestations of type 1 diabetes.

To date, the presence of multiple islet autoantibodies (two or more) is considered an absolute sign of the eventual onset of the clinical stage of type 1 diabetes.

Table 4. Criteria for the stages of type 1 diabetes mellitus [22,23].

2.1 Complaints and Anamnesis

Symptoms characteristic of type 1 diabetes at disease onset include thirst, frequent urination with nocturnal and diurnal enuresis in young children, weight loss or unexplained failure to gain weight (in infants), weakness, fatigue, recurrent skin infections, and inflammatory diseases of the external genitalia.

When these complaints appear, the development of DKA can occur within a timeframe ranging from a few days to a few months. Clinical symptoms of DKA include dry skin and mucous membranes, the smell of acetone in the breath, vomiting, impaired consciousness up to a comatose state, and uniform rare breathing with a deep noisy inspiration and enhanced expiration (Kussmaul breathing) [24].

2.2 Physical Examination

No special physical examination is required to diagnose type 1 diabetes. Physical examination for diagnosing complications of type 1 diabetes is presented in the relevant section.

2.3 Laboratory Diagnostics

Comments:

• It is not recommended to test blood glucose levels using glucometers for the diagnosis of type 1 diabetes, as glucometers do not have sufficient accuracy for a definitive diagnosis and may lead to diagnostic errors;

• In the absence of symptoms, the diagnosis of type 1 diabetes cannot be based solely on a single glycemic measurement. If there are doubts about the diagnosis, prolonged monitoring with fasting blood glucose testing and/or 2-hour postprandial blood glucose testing and/or performing an OGTT may be required;

• Hyperglycemia determined under stress conditions, against the background of acute infection, trauma, surgery, respiratory dysfunction, circulatory problems, etc., may be transient and require treatment, but by itself does not indicate the presence of diabetes.

Comments: An OGTT should not be performed if type 1 diabetes can be diagnosed using fasting, postprandial, or random daily glycemic parameters.

Rules for conducting an OGTT:

The OGTT should be performed in the morning against the background of at least 3 days of unrestricted diet and normal physical activity. The test must be preceded by an overnight fast of 8–10 hours (drinking water is allowed). The last evening meal should contain 30–50 g of carbohydrates. After fasting blood collection, the test subject should drink a #dextrose** solution within no more than 5 minutes, calculated as 1.75 g of anhydrous #dextrose** (1.925 g of #dextrose** monohydrate) per kg of body weight, but not exceeding 75 g (82.5 g), dissolved in 250–300 ml of water [16]. Smoking is not allowed during the test. A repeat blood collection is performed 2 hours later.

To prevent glycolysis and erroneous results, glucose concentration determination should be performed immediately after blood collection, or blood must be centrifuged immediately after collection, stored at 0–4°C, or collected in a tube containing a preservative (sodium fluoride).

An OGTT is not performed:

• against the background of an acute illness;

• against the background of short-term intake of medications that increase glycemia levels.

Comments:

• The HbA1c test should be performed using methods (equipment and kits) certified by the NGSP and standardized according to the Diabetes Control and Complications Trial (DCCT);

• A significant discrepancy between HbA1c values and blood glucose levels may be due to the presence of various hemoglobin variants (hemoglobinopathy) in the patient, which affects the result obtained by a number of methods, and in this case, an alternative method for determining HbA1c should be used.

• Under conditions that affect erythrocyte lifespan (iron deficiency anemia, sickle cell anemia, pregnancy, hemodialysis, recent blood loss or transfusion, or erythropoietin therapy, etc.), only plasma glucose testing should be used to diagnose type 1 diabetes.

Comments: If there is a significant increase in blood or urine ketone bodies, urgent treatment may be required, and the child should be referred to a pediatric endocrinologist on the same day due to the high risk of developing DKA.

Comments: Islet autoantibody testing is a highly sensitive and specific marker of the autoimmune process in type 1 diabetes [20,25]. Early diagnosis helps prevent acute manifestation of type 1 diabetes, reduces the risk of DKA (by up to 90%), and improves metabolic outcomes at manifestation and in the long term.

At the same time, to date, there are no uniform recommendations and approaches for the early detection (screening) of type 1 diabetes regarding the target population, timing, and frequency of its implementation. The determination of blood autoantibodies to pancreatic islet cell antigens may be considered in individuals at high risk for type 1 diabetes: first-degree relatives of patients with type 1 diabetes (siblings, parents, children). This is especially relevant in the presence of several close relatives with type 1 diabetes, where the risk of the disease can reach 50%. High sensitivity (80%) can be achieved by screening children aged 2 and 6 years.

Depending on the degree of carbohydrate metabolism disorders, the stage of type 1 diabetes can be determined (see section 1.6). In the presence of a pre-clinical stage of type 1 diabetes (stages 1 and 2), it is advisable to consider patient follow-up by a pediatric endocrinologist with an assessment of the severity of carbohydrate metabolism disorders based on OGTT, HbA1c, or fasting blood glucose testing every 6–12 months, depending on the stage, age, and autoantibody level. The disease progresses faster in younger children and in the presence of higher levels or a greater number of autoantibodies, which may require more frequent monitoring.

• To diagnose type 1 diabetes at preclinical stages and prevent DKA in children who have a first-degree relative with type 1 diabetes, it is recommended to determine the blood levels of autoantibodies to pancreatic islet cell antigens (autoantibodies to glutamic acid decarboxylase – GADA; autoantibodies to tyrosine phosphatase – IA-2A; autoantibodies to zinc transporter 8 – ZnT8, autoantibodies to insulin – IAA, autoantibodies to islet cell structures – ICA) [26–29].

GCR ALEL 3Grade of Recommendation A (Level of Evidence – 3)

Comment: Identification and monitoring of children with preclinical stages of type 1 diabetes helps reduce the risk of developing DKA. Acute consequences of DKA include an increased risk of death, development of complications, and hospitalization, which leads to significant negative consequences for patients, their families, and the healthcare system [30,31]. DKA at the onset of stage 3 type 1 diabetes can have long-term consequences, including neurocognitive deficit, increased risk of DKA relapse and hypoglycemia risk, unsatisfactory glycemic control (according to studies over 15 years), which increases the risk of microvascular and macrovascular complications, mortality, and decreased life expectancy [26,32,33]. In addition, diagnosis of preclinical stages of type 1 diabetes gives children and/or their parents more time to acquire knowledge and skills about living with the disease, and can also reduce anxiety and stress associated with the onset of clinical manifestations of type 1 diabetes [26,29]. Another aspect of early detection of type 1 diabetes is the potential for disease prevention. To date, several immunotherapy drugs have shown efficacy in preserving (slowing the decline of) residual C-peptide secretion. However, considering that the clinical stage of type 1 diabetes is characterized by a significant decrease in beta-cell functional reserves, efforts are underway aimed at earlier treatment of the disease—at stages 1 and 2 of type 1 diabetes. In particular, to date, the drug teplizumab (anti-CD3 monoclonal antibodies) has been approved by the regulatory authority (FDA, USA) for use to delay the progression of type 1 diabetes to the clinical stage (stage 3) [34,35].

2.3.1 Laboratory diagnostic tests performed for differential diagnosis

Comments: The presence of one or more islet autoantibodies confirms the diagnosis of type 1 diabetes. The absence of autoantibodies does not completely exclude type 1 diabetes (so-called idiopathic type 1 diabetes), but may serve as a basis for further evaluation. Given the possibility of other types of diabetes, it is necessary to consider molecular genetic testing in children in the absence of autoantibodies associated with type 1 diabetes and [16]:

• Presence of diabetes mellitus in the family with an autosomal dominant inheritance pattern;

• Age of manifestation less than 12 months and especially the first 6 months of life;

• Moderate fasting hyperglycemia (5.5–8.5 mmol/L), especially at a younger age, without obesity, asymptomatic;

• Prolonged "honeymoon period" of over 1 year or unusually low insulin requirement (less than 0.5 IU/kg/day) with a diabetes duration of more than a year;

• Associated conditions such as deafness, optic atrophy, or syndromic forms (mitochondrial diseases).

For the differential diagnosis of type 1 diabetes with monogenic forms of diabetes, specialized risk assessment algorithms ("risk calculators") can be used to decide on the feasibility of genetic testing [38].

Comments: An elevated C-peptide/insulin level is not characteristic of type 1 diabetes 12–14 months after disease onset, and a detectable C-peptide level is not characteristic of type 1 diabetes 5 years after onset.

2.4 Instrumental Diagnostics

No special instrumental diagnostic tests are provided for diagnosing type 1 diabetes. Instrumental diagnostic tests for diagnosing complications and comorbid pathology of type 1 diabetes are presented in the relevant section.

2.5 Other Procedures

Not applicable.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The treatment of type 1 diabetes in children consists of the following main components:

• insulin therapy;

• self-management education and home monitoring;

• nutrition;

• physical activity;

• psychological support.

3.1 Assessment and glycemic control targets

Comments:

Table 5. Standardized continuous glucose monitoring metrics for clinical use in children with type 1 diabetes mellitus

^a Including values >13.9 mmol/L.

^b Including values <3.0 mmol/L.

Comments:

Table 6. Target HbA1c and glycemia levels in children and adolescents with type 1 diabetes mellitus (adapt. from ISPAD 2024 [45,46])

* – if necessary, higher levels within the 4.0–10.0 mmol/L range may be set at bedtime and overnight; ** – 1–2 hours after the start of a meal.

Recent data indicate that lowering the target HbA1c level at the individual and population level leads to a decrease in mean HbA1c without increasing the frequency of severe hypoglycemia and hypoglycemic coma, even in children with HbA1c less than 7% [47].

Comments: The choice of the HbA1c target should always be viewed as a compromise between the risk of hypo- and hyperglycemia and their consequences, the expected benefit of risk reduction regarding T1D-related acute and chronic complications, patient preferences, and treatment adherence.

Target glucose and HbA1c levels must be individualized for each patient [50]:

• HbA1c <6.5% (<48 mmol/mol) is recommended during partial remission (honeymoon phase) and when using CGM or automated insulin delivery systems combined with the necessary level of education and monitoring. Such a target level is appropriate only in the absence of an undue risk of severe hypoglycemia and a decrease in the quality of life of the child and parents;

• A higher HbA1c level (<7.5%) is appropriate in children who are unable to report symptoms of hypoglycemia, those with impaired awareness of hypoglycemia, or those with a history of severe hypoglycemia.

The necessary conditions for achieving the target level of glycemic control are:

• Regular testing (monitoring) of glycated hemoglobin (HbA1c) levels in the blood;

• Use of CGM or regular blood glucose monitoring at least 6 times daily;

• Regular evaluation and adjustment of treatment.

3.2 Insulin therapy

Insulin replacement therapy is currently the main and integral component and the sole pharmacological method of treating T1D in children.

In all age groups, the primary goal of insulin therapy is to achieve and maintain near-physiological insulinemia levels and optimal glycemic control.

Comment:

Table 7. Types and action profiles of insulin preparations

Insulin doses and the administration regimen are selected individually for each patient based on age, insulin action profile, individual tolerability, etc., relying on glycemic control data (glycemia indices and HbA1c levels). Insulin doses and their administration regimens may vary significantly among T1D patients; specifically, during remission periods, insulin doses can be minimal up to complete discontinuation (complete T1D remission) for a certain period, however, the final decision on the regimen and doses depends strictly on glycemia indices and HbA1c levels.

In clinical practice, switching from one insulin preparation or its analogues to another occurs quite frequently. When switching a patient from one insulin to another, the following set of requirements must be observed to best ensure patient safety [68]:

1. In the case of different INNs.

   • Switching from one insulin preparation and its analogues to another must be carried out strictly according to medical indications, only under the supervision of a physician, and requires more frequent blood glucose self-monitoring, patient education, and adjustment of the newly prescribed insulin dose.

   • The switch from one insulin preparation and its analogues to another can be carried out either within the same ATC classification group or with a change in the ATC group (e.g., switching from human insulin to an insulin analogue and vice versa).

2. In the case of the same INN.

   • Switching patients from one insulin and its analogues to another with proven interchangeability (i.e., proven bioequivalence in terms of pharmacokinetics, pharmacodynamics, and safety profile) generally does not require more frequent blood glucose self-monitoring, patient education, and adjustment of the newly prescribed insulin dose.

   • Switching patients from one insulin and its analogues to another within the same INN, but with different pharmacokinetics and pharmacodynamics, must be carried out according to the rules specified for preparations with different INNs.

3. In the event of adverse events occurring either upon the initiation of insulin therapy or when switching from one insulin preparation and its analogues to another, which include worsening of glycemic control, a substantial change in insulin requirement/dose, or the development of allergic reactions, reporting to the Federal Service for Surveillance in Healthcare is mandatory.

4. The decision to switch from one preparation of insulin and its analogues to another is made by the physician taking into account the current instructions for use.

Comment: If clinical manifestations of DKA are present, diagnostic and therapeutic measures must be performed in accordance with the Diabetic Ketoacidosis section.

Comments: Despite the fact that data on the efficacy of intensified insulin therapy regarding the risk of micro- and macrovascular complications of T1D were obtained in adolescents and adults, there is no reason to assume that these data cannot be extended to children.

Comment: Regardless of the insulin therapy method and insulin injection regimen, the patient and family members must undergo training appropriate to the child's and family's age, maturity, and individual needs.

Comments: Insulin injections with 4-mm pen needles should be given at a 90° angle, regardless of age, gender, or BMI. In children aged 6 years and younger, as well as when using pen needles >4 mm in length or insulin syringes, a skin fold and/or a 45° angle of insertion must be used to avoid intramuscular injection.

Comments: According to the instructions for insulin pen injectors, needles must be used only once.

Comment: T1D patients and their parents must learn to independently inspect injection sites and recognize lipodystrophies.

3.2.1 Insulin pump therapy

Pump insulin therapy or CSII is a modern method of insulin therapy that best mimics the physiological insulinemia profile. In the CSII mode, insulin is administered subcutaneously and continuously via a pre-programmed basal rate and delivery of individual boluses for meals and in case of hyperglycemia.

Comments: The use of CSII contributes to the effective and safe achievement of the target HbA1c level, a reduction in the frequency of hypoglycemia, and a decrease in glycemic variability [84–86]. The use of additional functions and capabilities, such as an automatic bolus calculator, temporary basal rate, and insulin pump data downloading, contributes to better glycemic parameters [87–92]. At the same time, pump insulin therapy supplemented with CGM has the greatest efficacy regarding the reduction of HbA1c levels without increasing the frequency of hypoglycemic episodes compared to MDI and traditional self-monitoring [86, 93]. In addition, insulin pumps with the function of stopping (including predictive stopping) insulin delivery in the event of hypoglycemia currently exist, which helps to reduce the frequency, duration, and severity of hypoglycemic episodes [94–96].

It should be noted that CSII using an insulin pump is an alternative method of insulin administration, and if necessary (presence of contraindications, lack of availability, etc.), insulin therapy can be carried out in the MDI regimen.

The use of pump insulin therapy may be considered in patients with:

• HbA1c above the individual target level despite intensified insulin therapy;

• Severe hypoglycemia (≥1 time over the past year), including due to impaired awareness of hypoglycemia;

• Frequent episodes of mild hypoglycemia;

• High glycemic variability regardless of the HbA1c level;

• Pronounced "dawn phenomenon";

• Presence of microvascular complications or risk factors for their development;

• Need for small insulin doses;

• Significant decrease in quality of life due to the need for/fear of insulin injections.

Comments: Pump insulin therapy is inappropriate under the following conditions:

• Refusal of the patient and/or legal representative from CSII;

• Inability/incapacity of the patient or legal representative to perform procedures related to T1D control and the insulin pump, including: regular blood glucose self-monitoring, dietary carbohydrate estimation, insulin administration, regular replacement of the infusion set, etc.;

• Presence of psychosocial problems in the patient's family that hinder education or could lead to inappropriate device handling, including drug addiction and alcoholism;

• Failure to achieve individual target goals of glycemic control and/or lack of a significant (more than 0.5%) reduction in HbA1c levels within one year after the initiation of pump insulin therapy;

• Increased frequency of DKA and severe hypoglycemia against the background of CSII;

• Individual poor tolerance to CSII: severe skin reactions, frequent occlusions of the infusion system, or other adverse events associated with the method and hindering its use.

Comments: The use of pump insulin therapy is advisable subject to the following conditions:

• Before transferring the patient to CSII, a specialist consultation is required to discuss the main aspects of pump insulin therapy, the patient's readiness, and the choice of an insulin pump;

• The patient possesses sufficient skills in intensified insulin therapy and is trained in self-monitoring principles;

• For effective and safe use, the initiation of CSII, patient education, and subsequent follow-up should be carried out in healthcare facilities staffed with necessary qualified specialists possessing sufficient experience and skills in pump insulin therapy;

• Periodic downloading of data from insulin pumps for the structured presentation and analysis of the obtained data.

Comments: The use of bolus calculators helps determine the necessary insulin doses for meals and glycemic correction, which contributes to improved glycemic control parameters and therefore should be recommended to patients for use.

3.3 Glucose monitoring

Comments: Blood glucose monitoring is performed using blood glucose meters or CGM systems (see section 3.3.1). Individual blood glucose meters are used at home. Currently, there are blood glucose meters with the setting of an individual target glycemic range, as well as blood glucose meters with the function of wireless transmission of blood glucose data to medical specialists, relatives, or to a special application installed on the patient's smartphone for use in remote monitoring.

Individual blood glucose meters must comply with GOST R ISO 15197-2015 regarding analytical and clinical accuracy. At a blood plasma glucose level of <5.6 mmol/L, 95% of measurements must deviate from the reference analyzer by no more than ±0.8 mmol/L; at a blood plasma glucose level of ≥5.6 mmol/L, 95% of measurements must deviate from the reference analyzer by no more than ±15%.

In medical organizations, in addition to laboratory analyzers, it is necessary to use blood glucose control systems and blood glucose meters (glucometers) for professional use (according to the instructions for use – multi-user, hospital-grade), which have higher measurement accuracy compared to individual blood glucose meters and can withstand multiple disinfection cycles in accordance with well-validated methods provided by the manufacturer.

Comments: Patients with T1D may be recommended to independently measure BG at the following times:

• before main meals and 2–3 hours after eating;

• before bed, upon awakening, and at night;

• during physical activity;

• when hypoglycemia is suspected and after its correction;

• during intercurrent illnesses.

The recommended time and frequency of BG measurement with a blood glucose meter should be individualized for each patient to achieve optimal glycemic control.

Comments: The increase in measurement accuracy in modern CGM systems makes it possible to significantly reduce the frequency of traditional self-monitoring with a blood glucose meter in favor of using CGM data (see section 3.3.1).

Comments: Patients or legal representatives should be advised to record data in self-monitoring diaries indicating the date and time of BG values, insulin doses, carbohydrate intake, episodes of hypo- and hyperglycemia, and other conditions (illness, physical activity, etc.). Self-monitoring data must be regularly analyzed by patients and parents, and are also necessary during visits to the attending physician for timely assessment and adjustment of ongoing treatment.

Taking into account the large amount of information accumulated during use and the difficulties that arise in their intuitive interpretation by specialists, periodic downloading of data from medical devices (CGM, insulin pumps, blood glucose meters) followed by analysis using specialized software contributes to better glycemic control [92].

3.3.1 Continuous glucose monitoring

Continuous glucose monitoring (CGM) systems record interstitial fluid glucose levels continuously at 5–15 minute intervals using subcutaneously placed electrodes (sensors). Currently available CGM systems can be roughly divided into four categories: 1) "blind" or professional CGM; 2) real-time CGM (rtCGM); 3) intermittently scanned CGM (isCGM, or flash glucose monitoring [FGM]); 4) combined CGM (second-generation FGM).

A distinctive feature of "blind" CGM systems is the retrospective nature of data obtained over a short period. The primary purpose of this method is the objective assessment of CGM metrics (time in range), identification of hidden episodes of hypo- and hyperglycemia to adjust ongoing treatment, and patient education. Currently, "blind" CGM systems are not available in the Russian Federation.

A key feature of real-time CGM systems is the presence of alarms that are triggered when glucose threshold values are reached, predicted, or when the rate of change in glucose levels reaches a threshold.

First-generation FGM systems do not display glucose data automatically, but only upon "scanning"—bringing a scanner or smartphone into close proximity to the system sensor. FGM provides information on current glucose levels, glucose trends (direction and rate of change), and a glucose graph for recent and previous periods. Combined CGM (second-generation FGM) is a real-time monitoring system with automatic glucose data display and data updates on the patient's smartphone once per minute, without the need for routine blood glucose meter use by patients for calibrations and decision-making (e.g., calculating insulin doses), and is also supplemented with FGM capability allowing patients to scan the sensor in case of connection loss.

Most CGM systems transmit glucose data directly to a smartphone, from where they can be saved to an internet server and used for remote monitoring. Remote monitoring can be performed by parents/relatives of the child or by medical professionals as part of telemedicine consultations and follow-up, and has a positive impact on quality of life, psychosocial parameters, and glycemic control [111–113].

Certain CGM systems require calibration, i.e., entering capillary blood glucose data. At the same time, newer systems already feature "factory calibration," eliminating the need for manual calibration (measuring glucose with a glucometer).

Certain CGM systems can be recommended for non-adjuvant (standalone) use, meaning for making therapeutic decisions (e.g., calculating insulin doses, treating hypoglycemia, etc.) without the need for confirmation using a glucometer. When using such systems, the need for a glucometer is lower compared to systems without such indications [106–110]. First-generation FGM can be used instead of a glucometer for clinical decision-making, except in certain cases (hypoglycemia, rapid blood glucose changes, or if symptoms do not match system readings). Second-generation FGM systems can be used instead of a glucometer for clinical decision-making, except in situations where symptoms do not match system readings or expectations.

At the same time, patients using CGM must have access to blood glucose self-monitoring for calibration (if necessary), during sensor startup, in case of loss of CGM connection, and in any situations recommended by the CGM system manufacturer. Thus, glycemic self-monitoring remains essential in the management of T1D.

The benefits of real-time CGM and FGM include reduced HbA1c and increased time in range (TIR), reduced frequency of hypoglycemia and time below range (TBR), and reduced glucose variability [103,104,107,114,115]. The effectiveness of CGM is largely determined by the frequency of sensor use, with a minimum required usage time (or active sensor time) of at least 60% [116]. When using FGM, efficacy regarding glycemic control (HbA1c and TIR) is also determined by the regularity of sensor scanning, with an optimal frequency of 11–15 times per day [117–119].

Comments: The choice of a CGM system may be determined by individual patient preferences, as well as the capabilities or limitations of a specific system (need for calibration, sensor wear duration, alarms, etc.).

The use of CGM should be considered in patients under the following circumstances:

• HbA1c and/or TIR is above the individual target range;

• Frequent episodes of mild hypoglycemia;

• Severe hypoglycemia (≥1 episode in the past year);

• High glycemic variability regardless of the HbA1c level;

• Impaired quality of life due to the need for regular blood glucose self-monitoring;

Comments: The use of real-time CGM or FGM is inappropriate under the following conditions:

• Refusal of CGM by the patient or legal representative;

• Inability and lack of capacity of the patient and/or legal representative to actively use CGM, perform regular self-monitoring, and follow the attending physician's recommendations;

• Individual intolerance to CGM: severe skin reactions or other adverse events associated with the method that preclude its use;

• Insufficient CGM usage (<60% of the time and/or scanning frequency less than 6 times per day).

Comments: The use of CGM is advisable under the following conditions:

• Before transitioning a patient to CGM, a specialist consultation is necessary to discuss the key aspects of CGM, patient readiness, and selection of the CGM system;

• The patient possesses sufficient skills in intensified insulin therapy and is trained in self-monitoring principles;

• For effective and safe use, CGM initiation, patient education, and ongoing follow-up must be conducted in healthcare facilities staffed by necessary qualified specialists with sufficient experience and skills in CGM;

• Periodic downloading of data from CGM systems and glucometers for structured analysis of the obtained data, including the use of the ambulatory glucose profile.

Comments: CGM is a useful tool to facilitate real-time data sharing in the context of telemedicine. The healthcare professional can easily review and interpret glucose data to adjust therapy during telemedicine consultations.

3.4 Insulin pump therapy with continuous glucose monitoring

Integrating CGM and an insulin pump into a single system allows automatic adjustment of insulin delivery based on sensor data—a method also known as "closed-loop insulin pump therapy." Various options for controlling insulin delivery based on CGM data are possible, which can be used individually or complement each other: insulin suspension immediately upon reaching the hypoglycemia threshold, predictive low glucose management (PLGM) prior to reaching the hypoglycemia threshold, automated basal insulin dosing, automated bolus insulin dosing for hyperglycemia, etc.

Systems comprising an insulin pump, CGM, and a control algorithm that automatically manage basal and bolus insulin delivery (fully or partially) are called "automated insulin delivery systems" or "closed-loop systems."

Comments: Insulin pump suspension occurs automatically when the lower glycemic threshold (set by the physician or patient) is reached or predicted to be reached based on CGM data. Insulin delivery automatically resumes after 120 minutes or if glucose levels rise. Compared to conventional pump therapy and CGM-augmented pump therapy, predictive low-glucose management reduces the risk of hypoglycemia by 30–50%.

Comments: Automated insulin delivery systems help increase TIR by 10–15% (3.9–10 mmol/L) and lower HbA1c by 0.3–0.7% compared to conventional pump therapy, CGM-augmented pump therapy, and pump therapy with predictive low-glucose management.

3.5 Patient education

Education is an essential element of successful diabetes treatment and management, which should be accessible to all children with type 1 diabetes and their parents [98].

Comments: The goals and objectives of education must be specified in accordance with the patient's current condition. Education should be tailored to each individual regarding age, duration of diabetes, lifestyle, learning capacity, etc. Education must be ongoing; patients who have not previously undergone training (primary course) or who have already completed training (refresher courses) are referred to the "Diabetes Education School" to maintain knowledge and motivation or when new therapeutic goals and technologies emerge.

Comments: Education can be conducted both individually and in patient groups. The content of educational programs must comply with accepted standards for the diagnosis and treatment of diabetes, and their structure must take into account basic pedagogical principles. The programs imply a strictly practical focus and accessibility for comprehension. Mandatory sections of educational programs include:

• general information about diabetes;

• insulin therapy;

• nutrition;

• glycemic self-monitoring;

• physical activity;

• hypoglycemia.

The content and delivery of structured programs need regular revision to meet the needs of patients with type 1 diabetes, current clinical practice, and to account for changes in technology and approaches to type 1 diabetes management.

Comments: If available, participation of a medical psychologist and a clinical dietitian is desirable.

3.6 Nutritional Therapy

Dietary therapy is one of the elements of type 1 diabetes treatment and is recommended for all children and adolescents.

Comments: Dietary recommendations should be based on healthy eating principles and be suitable for all children, adolescents with type 1 diabetes, and their families to improve diabetes management outcomes and reduce cardiovascular risks. Nutritional recommendations should be adapted to cultural, ethnic, and family traditions, as well as take into account the cognitive and psychosocial aspects of the child and family. Patients should be provided with dietary recommendations for managing both regular and unplanned physical activity, and for achieving individual goals in competitive sports.

Comments: Prevention of overweight and obesity in type 1 diabetes is one of the key strategies for monitoring patient health and should include a family-based approach.

Comments: There are several methods for carbohydrate quantification:

• carb counting using bread units (XE), where 1 XE corresponds to 10, 12, or 15 grams of carbohydrates

• counting the exact number of grams of carbohydrates.

There is no conclusive evidence that one specific method is superior to another. In the Russian Federation, the carbohydrate estimation method using XE is more commonly used, where 1 XE corresponds to 10 g of carbohydrates.

Comments: Dietary fats and proteins affect early and delayed postprandial glycemia.

3.7 Physical activity

Recommendations regarding the need for regular physical exercise are an integral part of type 1 diabetes management. It is necessary to provide ongoing education to the patient and their family on behavior before, during, and after physical activity, depending on glycemic levels, preceding insulin doses, and the anticipated level and duration of physical activity.

Comments:

Physical activity in children and adolescents with diabetes mellitus has numerous positive effects on physical health and psychological well-being, including [144,146–148]:

• Increased insulin sensitivity, better glycemic control (lower glycated hemoglobin), and a longer remission period in children with newly diagnosed diabetes mellitus

• Improved cardiometabolic health and reduced risk of cardiovascular diseases

• Increased muscle mass and bone mineral density

• Enhanced quality of life and improved well-being

• Body weight control – reduction of subcutaneous adipose tissue

All children and adolescents with diabetes mellitus aged 5 to 17 years are recommended to engage in regular physical activity lasting 60 minutes or more daily, which should include: 1) moderate-to-vigorous aerobic activity; 2) muscle-strengthening exercises; and 3) bone-strengthening exercises.

The recommended level of physical activity is selected individually. Patients with proliferative retinopathy and diabetic nephropathy should be prescribed types of physical activity that do not lead to a significant increase in blood pressure [149].

Absolute contraindications to physical activity in children with type 1 diabetes are:

• Diabetes complications (nephropathy, retinopathy) – heavy resistance training and anaerobic exercise.

Temporary contraindications to physical activity in children with type 1 diabetes are:

• Blood ketone elevation ≥1.5 mmol/L (++ in urine)

• Blood glucose >15 mmol/L and blood or urine ketones >0.5–1.5 mmol/L

• Severe hypoglycemia within the past 24 hours or recurrent episodes of mild hypoglycemia during previous physical activity

• Previous episodes of hypoglycemia – exercise associated with a high risk of injury (alpine skiing, rock climbing, scuba diving, etc.)

• Unstable glycemic control – intensive exercise

• Trauma and infections

3.8 Psychological support

Comments: Young people with newly diagnosed type 1 diabetes appear to have a higher incidence of depression, anxiety, psychological disorders, and eating disorders compared to their peers without diabetes and need psychological support.

Comments: Children with recurrent DKA are more likely to have mental disorders than children with good glycemic control. Poor glycemic control is also associated with a number of other psychosocial problems, including anxiety and low self-esteem.

3.9 Pain management

Not applicable.

3.10 Other treatment

Not applicable.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: Sanatorium-resort organizations may be recommended – sanatoriums for children, including for children with parents, featuring medicinal mineral waters and a therapeutic climate. Caution should be exercised in the presence of CKD stage 4 or proliferative diabetic retinopathy.

5. Prevention and Dispensary Observation

Comments: Outpatient visits should include periodic evaluation and recording of the following:

• General health and well-being:

  • Complaints, with special attention to symptoms associated with complications and comorbid conditions. If symptoms or signs are present, additional examination may be required;

  • Intercurrent illnesses, medical emergencies associated with diabetes, hospitalizations. During the initial visit, conduct a thorough inquiry regarding the time of onset of the first symptoms of the disease, types and doses of administered insulins, reasons for and duration of hospitalizations, including cases of DKA and severe hypoglycemia, timing and diagnostic methods for specific complications if present, concomitant endocrine and systemic diseases, and family history.

• Glycemic control:

  • Assessing glycated hemoglobin (HbA1c) levels over the past three months;

  • Analyzing home glucose monitoring data (glucometer readings, CGM, FGM);

  • Assessing the frequency/degree of hypoglycemia, including the determination of hypoglycemia awareness and the method of hypoglycemia treatment.

• Insulin therapy:

  • Types and doses of insulin;

  • Correction of insulin therapy taking into account glucose levels, nutrition, and physical activity;

  • Injection technique.

• General examination:

  • Measurement of height, body weight, and sexual development;

  • Skin condition (lipoid necrobiosis, acanthosis) and insulin injection sites / infusion set insertion sites / CGM sensors (lipodystrophy, local reactions);

  • Oral mucosa and teeth (caries, gingivitis);

  • Presence of joint mobility restriction;

  • Examination of the thyroid gland, chest and abdominal organs (hepatomegaly), feet (calluses, ingrown toenails, and other lesions);

  • Measurement of blood pressure (BP) on peripheral arteries, taking into account age-appropriate values.

• Acute and chronic complications of type 1 diabetes and comorbid pathology:

  • Diabetic retinopathy;

  • Diabetic nephropathy;

  • Diabetic neuropathy;

  • Macrovascular complications;

  • Diabetic ketoacidosis;

  • Severe hypoglycemia (glucagon** must be available for all patients, parents, and caregivers of children with type 1 diabetes).

• Comorbidities:

  • Hypo- and hyperthyroidism;

  • Celiac disease;

  • Menstrual irregularities;

  • Other diseases and conditions

6. Organization of Medical Care

Indications for hospital admission to a medical organization:

1) Form – scheduled; setting – inpatient, day hospital:

a. Upon initial presentation for persistent hyperglycemia without clinical manifestations of diabetes and/or ketosis;

b. Decompensation of glycemic control, high glycemic variability, frequent episodes of mild hypoglycemia;

c. Comprehensive screening for complications, in the absence of the possibility of outpatient examination;

d. Transition to CSII.

2) Form – emergency, urgent; setting – inpatient:

a. Upon initial presentation for hyperglycemia in the presence of clinical manifestations of diabetes and/or ketosis;

b. Severe hypoglycemia;

c. DKA;

d. Acute development of specific complications.

Indications for patient discharge from a medical organization

1) Form – scheduled; setting – inpatient, day hospital:

a. Achievement of individual target glucose levels with a frequency of measurements (time) in the target range of at least 50% according to CGM or SMBG data;

2) Form – emergency, urgent; setting – inpatient:

Absence of clinically significant metabolic abnormalities (acid-base balance parameters, blood and/or urine ketones within normal limits), absence of acute neurological symptoms combined with the achievement of individual target glucose levels with a frequency of measurements (time) in the target range of at least 50% according to CGM or SMBG data

7. Additional Information

7.1 Complications

Specific complications of DM in childhood and adolescence include microvascular disorders: diabetic retinopathy (DR), diabetic nephropathy (DN), and neuropathy.

Risk factors:

• long disease duration, older age, and puberty;

• smoking;

• hypertension;

• dyslipidemia;

• family history burdened by the development of complications;

• obesity;

• sedentary lifestyle.

The pathogenesis of specific DM complications is complex: disorders of microcirculation, blood coagulation and fibrinolytic systems, antioxidant defense system, metabolism of vascular wall protein components, and vascular permeability. Chronic hyperglycemia activates non-enzymatic protein glycation, the polyol pathway of glucose metabolism, and direct glucose toxicity.

7.1.1 Diabetic retinopathy

Diabetic retinopathy (DR) is a specific late neuromicrovascular complication of DM that typically develops sequentially from changes associated with increased permeability and occlusion of retinal vessels to the appearance of neovascularization and fibroglial tissue.

Diabetic macular edema (DME) – retinal thickening associated with fluid accumulation in the intercellular space of the neuroepithelium due to breakdown of the blood-retinal barriers and a mismatch between fluid transudation and its resorption capacity. DME can develop at any stage of DR.

The classification of DR identifies three main stages of the disease:

1. Non-proliferative: microaneurysms, small intraretinal hemorrhages, soft («cotton-wool») exudates.

2. Pre-proliferative: presence of at least 1 of the 3 features:

   • - venous loops/beading in 2 or more quadrants

   • - moderate IRMA in at least one quadrant

   • - multiple retinal hemorrhages in all 4 quadrants of the fundus.

3. Proliferative (rare in children): neovascularization (and/or fibrous proliferation) of the optic disc and/or retina, preretinal and/or vitreous hemorrhages (hemophthalmos), tractional (or traction-rhegmatogenous) retinal detachment, neovascular glaucoma.

Comments: Screening for DR is performed using retinal visual acuity testing (visometry), fundus biomicroscopy, dilated ophthalmoscopy (examination of the peripheral fundus using a Goldmann three-mirror lens), and digital fundus photography using a fundus camera [159,160].

Comments: Due to the potential worsening of DR in patients with prolonged poor glycemic control upon its stable improvement, ophthalmological monitoring is recommended before initiating intensive treatment and every three months for 6–12 months after its initiation, especially if DR was at a moderate non-proliferative stage or worse before the intensification of therapy, or if progression occurred during treatment.

Comments: Although there is insufficient data confirming the efficacy and safety of panretinal photocoagulation and intravitreal anti-VEGF agents in children with T1D, these methods have proven efficacy in DR in adult patients with T1D [162] and in retinopathy of prematurity [163]. Therefore, there is no reason to assume that these findings cannot be extrapolated to children with T1D.

7.1.2 Diabetic nephropathy

Diabetic nephropathy (DN) is a specific kidney lesion in DM accompanied by the development of nodular glomerulosclerosis, leading to end-stage renal disease requiring renal replacement therapy (dialysis, transplantation).

Chronic kidney disease (CKD) is a persistent organ lesion lasting for three months or more due to various etiological factors, anatomically characterized by the replacement of normal structures with fibrosis, leading to organ dysfunction [164].

DN is the result of metabolic (hyperglycemia, hyperlipidemia) and hemodynamic (hypertension, intraglomerular hypertension) factors affecting renal microcirculation, modulated by genetic factors [164].

DN develops in 20–40% of patients with type 1 diabetes [165]; it typically develops after a disease duration of more than 10 years, although earlier onset is possible in the presence of unfavorable factors. DN significantly increases the risk of cardiovascular events and treatment costs [166].

Classification.

According to the CKD concept, the stage of renal pathology is assessed by the GFR value, recognized as the most accurate reflection of the number and total workload of nephrons, including non-excretory functions (Table 8). In addition, there are three categories of albuminuria (see Table 9) [167].8) [142].

The diagnosis of DN is established in accordance with CKD based on the stage of glomerular filtration rate reduction and the level of albuminuria [168].

Table 8. Stages of chronic kidney disease by glomerular filtration rate level

eGFR – estimated glomerular filtration rate

Schwartz formula (Bedside modification) [169,170] for calculating GFR in children:

eGFR (mL/min/1.73 m²) = (36.2 × Height(cm)) / Plasma creatinine (µmol/L)

• The Schwartz formula was updated in 2009 and is currently considered the best method for estimating GFR in children.

• Methods with isotope-dilution mass spectrometry (IDMS) calibration must be used to determine serum creatinine.

• Using the original Schwartz formula leads to an overestimation of GFR by 20–40%.

Table 9. Classification of chronic kidney disease by albuminuria category

Note: A/C – albumin-to-creatinine ratio, AER – albumin excretion rate, *including nephrotic syndrome (albumin excretion >2200 mg/24 hours [A/C >2200 mg/g; >220 mg/mmol])

Example of diagnosis formulation:

Formulation of diabetic nephropathy (DN) diagnosis in accordance with the CKD classification:

1) Diabetic nephropathy, CKD G1 (2, 3, 4, or 5) A2

2) Diabetic nephropathy, CKD G1 (2, 3, 4, or 5) A3

3) Diabetic nephropathy, CKD G3 (4, or 5) A1 (i.e. regardless of the albuminuria level)

4) Diabetic nephropathy, CKD G5 (treated with renal replacement therapy)

With normal eGFR and urine albumin levels (stage G1A1), a diagnosis of CKD can only be made if other markers of kidney damage are present [171, 172].

If albuminuria normalizes during nephroprotective therapy in patients with preserved eGFR ≥60 mL/min/1.73 m², the diagnosis of DN and CKD is retained with the following formulation: DN, CKD G1-2 A1 (regression of albuminuria during nephroprotective therapy).

Specific symptoms of DN at CKD stages G1-3a A1-2 are absent in the majority of patients with T1D (episodes of elevated blood pressure are rarely noted). At CKD stages G4-5, patients experience weakness, drowsiness, fatigue, pronounced persistent edema, stably elevated blood pressure, nausea, and sometimes vomiting without relief. At CKD stages G3-5 A3, edema of the feet, lower legs, and occasionally thighs and face, decreased appetite, and worsening, persistently elevated blood pressure are noted.

Comments: The presence of microalbuminuria is confirmed by an albumin-to-creatinine ratio of 3 to 30 mmol/mg or 30 to 300 mg/g (spot urine sample).

A spot urine sample for microalbuminuria is preferred due to known diurnal variations in albumin excretion and postural effects. Collecting 24-hour urine for microalbuminuria is difficult and has low diagnostic value.

Due to biological variability, two out of three positive morning urine samples for microalbuminuria must be used to confirm it. Persistent albuminuria (proteinuria) is defined by the presence of abnormalities in two or all three samples over a period of 3 to 6 months.

Factors that can cause false-positive results include the following: prior physical exercise, infections, elevated body temperature, menstrual bleeding, kidney disease, fever, and marked hyperglycemia. Abnormal (false-positive) test results must be rechecked, as microalbuminuria can be transient.

Comments: The appropriateness of assessing eGFR initially at the onset of T1D and repeatedly as needed based on clinical status, age, T1D duration, and therapy should also be considered.

Comments:

Table 10. Angiotensin-converting enzyme inhibitors

7.1.3 Diabetic neuropathy

Diabetic neuropathy is a complex of clinical and subclinical syndromes, each characterized by diffuse or focal involvement of peripheral and/or autonomic nerve fibers resulting from T1D. Diabetic distal symmetric polyneuropathy (DSPN) is the most common generalized form, characterized by diffuse damage to all peripheral motor and sensory nerve fibers. Such damage appears asymptomatically, but then progresses, initially leading to a decrease in sensory functions and later resulting in the loss of motor function with a stocking-and-glove distribution. Cardiovascular autonomic neuropathy (CAN) arises from damage to the autonomic nervous system and may manifest as orthostatic hypotension, impaired adequate heart rate response, and QT interval prolongation. CAN is associated with the risk of sudden death and other cardiovascular risk factors.

Comments: Specific tests for diagnosing DSPN include the assessment of general and vibratory sensitivity, and reflexes. Specific tests for diagnosing CAN may include cardiovascular tests and/or heart rate variability (HRV) assessment in the frequency or time domain over short or long time intervals.

7.1.4 Macrovascular complications

Comments: High LDL cholesterol is defined by values above 2.6 mmol/L. In such cases, patients with T1D are recommended to improve metabolic control, make dietary changes (low-cholesterol diet), and increase physical activity. If there is a family history of hypercholesterolemia, early cardiovascular disease, or if family history is unknown, screening is recommended starting from age 2.

Comments: In children with T1D under 13 years of age, arterial hypertension is defined as a mean systolic BP and/or diastolic BP >95th percentile for sex, age, and height. In children with T1D aged 13 years and older, arterial hypertension is defined as a mean systolic BP >130 mm Hg and/or diastolic BP >80 mm Hg. Elevated blood pressure must be confirmed by measurements on 3 different days. If blood pressure is elevated, a consultation with a pediatric cardiologist is required for the diagnosis, confirmation, and prescription of antihypertensive therapy.

Comments: Although there is insufficient literature data confirming the efficacy and safety of this therapy in children with T1D and hypertension, it has proven efficacy in hypertension in children without diabetes [176] and in hypertension in adult patients with T1D [177]. Therefore, there is no reason to assume that these data cannot be extended to children with T1D.

7.2 Diabetic ketoacidosis

Diabetic ketoacidosis (DKA) is an acute metabolic decompensation in diabetes, manifested by a sharp increase in blood glucose and ketone body concentrations, their appearance in the urine, and the development of metabolic acidosis, accompanied by varying degrees of impaired consciousness or occurring without it, and requiring emergency hospitalization of the patient. The development of DKA in T1D without treatment is life-threatening and, in the absence of timely care, rapidly leads to a fatal outcome. Patients require immediate treatment and specialized care.

Risk factors for the development of DKA in newly diagnosed patients include younger age, later diagnosis of diabetes mellitus, lower socioeconomic status, and living in a region with a low prevalence of type 1 diabetes. Risk factors for DKA in previously diagnosed patients include insulin deficiency due to various causes, limited access to medical services, and unrecognized insulin delivery failure in patients using an insulin pump.

Biochemical criteria for diagnosing DKA are:

• Hyperglycemia (blood plasma glucose level >11 mmol/L);

• pH <7.3 in venous blood or serum bicarbonate <18 mmol/L;

• Ketonemia (blood beta-hydroxybutyrate ≥3 mmol/L) or moderate to significant ketonuria (≥2+).

The severity of DKA is determined by the degree of acidosis:

• Mild: venous blood pH <7.3 or serum bicarbonate <18 mmol/L;

• Moderate: venous blood pH <7.2, serum bicarbonate <10 mmol/L;

• Severe: venous blood pH <7.1, serum bicarbonate <5 mmol/L.

Clinical signs of DKA include: dehydration, tachycardia, tachypnea, Kussmaul breathing, acetone odor on breath, nausea and/or vomiting, abdominal pain, visual impairment, confusion, drowsiness, progressive decrease in the level of consciousness, and ultimately coma.

Management of DKA depends on the severity of the condition. In mild DKA with minimal signs of dehydration (absence of pronounced blood electrolyte changes), patients are prescribed abundant oral fluid intake and subcutaneous insulin administration until glycemia normalizes.

In cases of dehydration exceeding 5%, nausea and vomiting, deep breathing, but without loss of consciousness:

• Administer a bolus of 0.9% NaCl solution at 10–20 mL/kg. Subsequently, to compensate for the estimated deficit and physiological requirements, infusion therapy is carried out using 0.45–0.9% NaCl solution or a balanced salt solution until dehydration symptoms resolve.

• If blood potassium levels are below 5.3 mmol/L, KCl is added to the solution at 40 mmol per liter of fluid until electrolyte disturbances normalize. Electrocardiographic monitoring is performed until T-waves normalize, along with blood pressure measurement (control) in peripheral arteries.

• Administer short-acting insulin or a rapid-acting human insulin analog intravenously at a dose of 0.05–0.1 IU/kg/h.

• When glycemia drops below 17 mmol/L or decreases by more than 5 mmol/L per hour, a 5% dextrose solution is added to the infusion therapy.

• It may be necessary to use a 10% or even 12.5% dextrose solution to prevent hypoglycemia while continuing insulin infusion to correct metabolic acidosis. Such glucose concentrations are often required to prevent hypoglycemia during insulin infusion at a rate of 0.1 IU/kg/h.

• Mandatory hourly blood glucose testing, measurement of urine volume to monitor fluid intake and output, hourly neurological status assessment, electrolyte checks every 2 hours, detection of ketone bodies in urine or blood, and electrocardiographic monitoring.

The goals of treatment are to correct dehydration, acidosis, and ketosis, gradually restore hyperosmolality and glycemia to near-normal levels, monitor and treat complications of DKA, and identify and treat concomitant pathology.

Comment: Management of DKA includes: rehydration, administration of insulin and its analogs, correction of electrolyte disturbances, management of acidosis, general supportive measures, and treatment of the underlying conditions that triggered DKA.

Comment: Assessment of the degree of dehydration is imprecise and should be based on a combination of all physical signs. Mild DKA corresponds to an estimated 5% dehydration, moderate to 7%, and severe to 10%. The most useful signs for determining 5% dehydration in young children aged 1 month to 5 years are:

• prolonged capillary refill time (normal capillary refill is ≤1.5–2 seconds)

• decreased skin turgor (inelastic skin)

Other useful signs in assessing the degree of dehydration include: dry mucous membranes, sunken eyes, absence of tears, weak pulse, and cool extremities. A greater number of dehydration signs generally correlates with more severe dehydration.

Dehydration of ≥10% is confirmed by the presence of a weak or non-palpable peripheral pulse, hypotension, and oliguria.

Comment: In cases of pronounced peripheral circulation impairment, the initial bolus is administered faster (e.g., over 15–30 minutes), and a second bolus may be required to ensure adequate tissue perfusion.

Comment: Subsequent infusion therapy (deficit replacement) can be performed using 0.45% to 0.9% sodium chloride** solution or a balanced salt solution.

It is necessary to calculate the subsequent fluid infusion rate, accounting for maintenance volumes, to replace the estimated deficit over 24–48 hours. Infusion therapy is continued until pH normalizes to >7.3.

Table 11. Solutions for infusion therapy

Comment: 1 mL of 7.5% KCl solution contains 1 mmol/L of K+, and 1 mL of 4% KCl solution contains 0.5 mmol/L of K+.

Comment: Intravenous insulin administration is carried out until metabolic ketoacidosis is resolved. At a pH level >7.15, an insulin dose of 0.05 IU/kg/h can be used. With an adequate insulin dose, the B-hydroxybutyrate level decreases by 0.5 mmol/L per hour. If intravenous insulin administration is not feasible in mild and moderate DKA without peripheral circulation impairment, subcutaneous administration of short-acting insulin analogues (0.1–0.15 IU/kg every two hours) is recommended.

Comment: In patients with multiple risk factors for cerebral edema (elevated serum blood urea nitrogen concentration, severe acidosis, severe hypocapnia), mannitol or hypertonic saline solution with calculated dosages should be prepared in advance.

7.3 Hypoglycemia

The following classification of hypoglycemia is currently accepted [180]:

Level 1: plasma glucose values from 3.0 to <3.9 mmol/L (with or without symptoms) in patients with diabetes mellitus receiving glucose-lowering therapy indicate the risk of hypoglycemia and require initiating hypoglycemia correction measures regardless of the presence or absence of symptoms.

Level 2: plasma glucose values <3.0 mmol/L, with or without symptoms — clinically significant hypoglycemia requiring immediate correction.

Level 3: severe hypoglycemia — hypoglycemia within the above range with such cognitive impairment (including loss of consciousness, i.e., hypoglycemic coma) that requires the assistance of another person for correction.

Comments: The main cause of hypoglycemia: excess insulin in the body relative to the intake of carbohydrates from outside (with food) or from endogenous sources (hepatic glucose production), as well as during accelerated carbohydrate utilization (muscle work).

Triggering factors:

- insulin overdose: patient error, malfunction of the insulin pen, insulin pump, glucometer, intentional overdose; physician error (too low glycemic target, excessively high doses);

- changes in insulin pharmacokinetics: high titer of insulin antibodies, incorrect injection technique;

- increased insulin sensitivity: prolonged physical activity, early postpartum period, adrenal or pituitary insufficiency;

- skipped meal or insufficient amount of bread units (XE), alcohol, dietary restriction for weight loss (without a corresponding reduction in insulin dose); delayed gastric emptying (in autonomic neuropathy), vomiting, malabsorption syndrome;

Comments: Hypoglycemia treatment should increase blood glucose by approximately 3–4 mmol/L. To correct hypoglycemia, the following products are recommended: glucose tablets, gels or drinks, fruit juice, honey, sweet carbonated beverages, etc. In pump insulin therapy at a glucose level <3.0 mmol/L, it is additionally recommended to stop insulin delivery. After carbohydrate intake, blood glucose should be re-tested in 10–15 minutes to ensure that the target glucose level has been reached. If there is no sufficient increase in glucose level, it is necessary to repeat the intake of fast-acting carbohydrates followed by blood glucose measurement in another 10–15 minutes. If glucose levels rise >3.9 mmol/L, resume basal insulin delivery on the pump if it was previously turned off. Depending on the circumstances (nighttime hypoglycemia, physical activity, etc.), additional slow-acting carbohydrates should be taken after fast-acting carbohydrates to prevent recurrent hypoglycemia.

7.3.1 Severe hypoglycemia

Severe hypoglycemia is defined as an event with severe cognitive impairment (including coma and seizures) requiring the assistance of another person for the active administration of carbohydrates, glucagon, or other corrective actions. Hypoglycemic coma is a type of severe hypoglycemia that leads to loss of consciousness (coma) and seizures. Severe hypoglycemia requires prompt treatment.

Comments: Glucagon** should be available for all patients, parents, and caregivers of children with type 1 diabetes mellitus, especially when there is a high risk of severe hypoglycemia. These individuals must be properly trained in the injection technique of the drug [181]. In prolonged fasting, glucagon may be ineffective due to insufficient glycogen stores in the liver. Nausea and vomiting may occur after glucagon administration.

In young children with type 1 diabetes mellitus refusing to eat, subcutaneous mini-doses of glucagon (0.02–0.15 mg) can be effective and safe to prevent pronounced or impending hypoglycemia.

7.4 Comorbidities

Comments: A higher frequency of thyroid function assessment may be recommended for a patient with type 1 diabetes mellitus in the presence of clinical manifestations of hypothyroidism or thyrotoxicosis, autoantibodies, and an enlarged thyroid gland.

Comments: Monitoring of growth and physical development using appropriate charts: percentiles, growth curves taking into account parental height, is key in the management of children and adolescents with type 1 diabetes mellitus. Patients with type 1 diabetes mellitus with poor self-control show a decrease in growth rates and physical development. Mauriac syndrome may develop, characterized by delayed physical and sexual development, hepatopathy, and steatosis.

Comments: A higher frequency of celiac disease screening may be recommended for patients with T1D if they present with clinical manifestations (intermittent or chronic diarrhea and/or constipation, abdominal pain, dyspeptic symptoms, etc.) or if a parent or sibling has been diagnosed with celiac disease. If autoantibodies are detected, referral to a gastroenterologist is recommended to determine further management.

Comments: Girls with T1D during puberty are at risk of excessive weight gain, which may be associated with the development of hyperandrogenism, hirsutism, and absent and/or irregular menstruation. Ultimately, this can lead to polycystic ovary syndrome, which correspondingly worsens the course of T1D, leads to infertility, and contributes to the development of micro- and macrovascular complications.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Authors

1. Peterkova Valentina Alexandrovna – MD, PhD, Professor, Academician of the Russian Academy of Sciences, Scientific Director of the Institute of Pediatric Endocrinology, Head of the Department of Pediatric Endocrinology and Diabetology at the National Medical Research Center for Endocrinology of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of the Russian Ministry of Health.

   Conflict of interest is absent.

2. Bezlepkina Olga Borisovna – MD, PhD, Director of the Institute of Pediatric Endocrinology, Professor at the Department of Pediatric Endocrinology and Diabetology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

   Conflict of interest is absent.

3. Laptev Dmitry Nikitich – MD, PhD, Professor of the Russian Academy of Sciences, Head of the Pediatric Diabetes Department, Associate Professor at the Department of Pediatric Endocrinology and Diabetology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

   Conflict of interest is absent.

4. Kuraeva Tamara Leonidovna – MD, PhD, Professor, Chief Researcher at the Pediatric Diabetes Department, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

   Conflict of interest is absent.

5. Eremina Irina Alexandrovna – PhD, Researcher at the Pediatric Diabetes Department, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

   Conflict of interest is absent.

6. Titovich Elena Vitalievna – PhD, Leading Researcher at the Pediatric Diabetes Department, Associate Professor at the Department of Pediatric Endocrinology and Diabetology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

   Conflict of interest is absent.

7. Emelyanov Andrey Olegovich – PhD, Leading Researcher at the Pediatric Diabetes Department, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

   Conflict of interest is absent.

8. Svetlova Galina Nikolaevna – Candidate of Medical Sciences, Leading Researcher, Pediatric Diabetes Department, National Medical Research Center for Endocrinology, Russian Ministry of Health.

   Conflict of interest is absent.

Expert group

1. Alimova Irina Leonidovna – Doctor of Medical Sciences, Professor, Head of the Department of Hospital Pediatrics with a Course in Neonatology, Faculty of Postgraduate Education, Smolensk State Medical University, Russian Ministry of Health, Chief Freelance Pediatric Endocrinologist (Smolensk Oblast).

   Conflict of interest is absent.

2. Bashnina Elena Borisovna – Doctor of Medical Sciences, Professor, Department of Endocrinology named after Academician V.G. Baranov, North-Western State Medical University named after I.I. Mechnikov, Chief Freelance Pediatric Endocrinologist of the North-Western Federal District.

   Conflict of interest is absent.

3. Bolotova Nina Viktorovna – Doctor of Medical Sciences, Professor, Department of Propaedeutics of Children's Diseases, Pediatric Endocrinology and Diabetology, Saratov State Medical University named after V.I. Razumovsky, Russian Ministry of Health.

   Conflict of interest is absent.

4. Galkina Galina Aleksandrovna – Doctor of Medical Sciences, Professor, Head of the Pediatric Endocrinology Department, Research Institute of Obstetrics and Pediatrics, Rostov State Medical University, Russian Ministry of Health, Chief Freelance Pediatric Endocrinologist (Rostov Oblast), Chief Freelance Pediatric Endocrinologist of the Southern Federal District.

   Conflict of interest is absent.

5. Kiyaev Aleksey Vasilyevich – Doctor of Medical Sciences, Professor, Department of Hospital Pediatrics, Ural State Medical University, Russian Ministry of Health, Head of the Regional Center for Pediatric Endocrinology, Regional Children's Clinical Hospital, Chief Freelance Pediatric Endocrinologist of the Russian Ministry of Health in the Ural Federal District, Chief Freelance Pediatric Endocrinologist of the Ministry of Health of Sverdlovsk Oblast, Yekaterinburg

   Conflict of interest is absent.

6. Kostrova Irina Borisovna – Candidate of Medical Sciences, Head of the Pediatric Endocrinology Department, N.M. Kuraev Children's Republican Clinical Hospital, Chief Freelance Pediatric Endocrinologist (Republic of Dagestan), Chief Freelance Pediatric Endocrinologist of the North Caucasian Federal District.

   Conflict of interest is absent.

7. Malievsky Oleg Arturovich – Doctor of Medical Sciences, Professor, Department of Hospital Pediatrics, Bashkir State Medical University, Russian Ministry of Health, Chief Freelance Pediatric Endocrinologist (Republic of Bashkortostan), Chief Freelance Pediatric Endocrinologist of the Volga Federal District.

   Conflict of interest is absent.

8. Petryaikina Elena Efimovna – Doctor of Medical Sciences, Director, Professor, Department of Faculty Pediatrics, Pediatric Faculty, Russian Children's Clinical Hospital, Pirogovo Russian National Research Medical University, Russian Ministry of Health, Professor, Department of Evidence-Based Medicine, Medical Institute of RUDN University, Chief Freelance Pediatric Endocrinologist of the Moscow Healthcare Department, Chief Freelance Pediatric Endocrinologist of the Central Federal District.

   Conflict of interest is absent.

9. Samsonova Lyubov Nikolayevna – Doctor of Medical Sciences, Professor, Head of the Department of Pediatric Endocrinology, Russian Medical Academy of Continuous Professional Education, Russian Ministry of Health.

   Conflict of interest is absent.

10. Khramova Elena Borisovna – Doctor of Medical Sciences, Professor, Head of the Department of Children's Diseases, Pediatric Faculty, Tyumen State Medical University, Russian Ministry of Health, Chief Freelance Pediatric Endocrinologist (Tyumen Oblast).

    Conflict of interest is absent.

Appendix A2. Methodology for Developing Clinical Guidelines

Methods used for evidence collection/selection: electronic database search.

Description of methods used to assess the quality and strength of evidence: the evidentiary base for the guidelines included publications from the Cochrane Library, EMBASE, MEDLINE, and PubMed databases. Search depth – 15 years.

Methods used to assess the quality and strength of evidence:

expert consensus;

assessment of significance in accordance with the rating scheme.

Methods used for evidence analysis:

reviews of published meta-analyses;

systematic reviews with evidence tables.

Description of methods used for evidence analysis

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its validity. The result of this examination affects the level of evidence assigned to the publication, which in turn affects the strength of the recommendations.

To minimize potential bias, each study was evaluated independently. Any discrepancies in evaluations were discussed by the full panel of authors. If a consensus could not be reached, an independent expert was involved.

Evidence tables: compiled by the authors of the clinical guidelines.

Methods used to formulate the recommendations: expert consensus.

Recommended good clinical practice is based on the clinical experience of the authors of these guidelines.

Economic analysis

Cost analysis was not performed, and pharmacoeconomic publications were not analyzed.

Recommendation validation method

External expert review.

Internal expert review.

Description of the recommendation validation method

The draft of these recommendations was reviewed by independent experts who were primarily asked to comment on how comprehensible the interpretation of the evidence underlying the recommendations is.

Feedback was obtained from primary care physicians (pediatric endocrinologists) regarding the clarity of the presentation of these guidelines and their assessment of the importance of the proposed recommendations as a tool for daily practice.

All comments received from the experts were thoroughly systematized and discussed by the members of the working group (authors of the recommendations). Each item was discussed individually.

Consultation and peer review

The draft recommendations were reviewed by independent experts who were primarily asked to comment on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

Working Group

For the final revision and quality control, the recommendations were re-evaluated by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account and the risk of bias in the development of the recommendations was minimized.

Key recommendations

The strength of recommendations (1–5) based on the corresponding levels of evidence (A–C) (Tables 1–3) is provided throughout the text of the recommendations.

Target audience for these clinical guidelines:

1. Pediatric endocrinologists;

2. Pediatricians;

3. General practitioners (family physicians)

Table 1. Scale for grading levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for grading levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Injection and Infusion Technique in Diabetes Treatment. Methodological Guide https://apicr.minzdrav.gov.ru/static/МР102.PDF

Appendix B. Physician Action Algorithms

Abbreviations: CSII – continuous subcutaneous insulin infusion; CGM – continuous glucose monitoring.

Note: sections and subsections of the clinical guidelines are indicated in parentheses.

Appendix C. Patient Information

Bread unit table

(1 BU = amount of food containing 10–12 g of carbohydrates)

Bread and bakery products* 1 BU = ....

* – foods such as dumplings, pancakes, fritters, small pies, cottage cheese pancakes, vareniki, cutlets also contain carbohydrates, but the number of BUs depends on the size and recipe of the item.

Pasta 1 BU = ....

* – refers to uncooked pasta; in cooked form, 1 BU is contained

in 2–4 tbsp of the product (50 g) depending on the shape of the product.

Cereals, corn, flour 1 BU = ....

* – refers to 1 tbsp of dry grain; when cooked (porridge), 1 XE is contained in 2 heaping tbsp (50 g).

Potato 1 XE = ....

Milk and liquid dairy products 1 XE = ....

Fruits and berries (with pits and skin) 1 XE = ....

Vegetables, legumes, nuts 1 XE = ....

* – depending on the type.

Other foods 1 XE = ....

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Russian name: Glasgow Coma Scale.

Original name: The Glasgow Coma Scale, GCS

Source: Teasdale G., Jennett B. ASSESSMENT OF COMA AND IMPAIRED CONSCIOUSNESS // The Lancet. 1974. Vol. 304, № 7872. P. 81–84. [189]

Type: rating scale

Purpose: Designed to assess the severity of impaired consciousness and coma. The scale consists of three tests evaluating eye opening (E), verbal (V), and motor (M) responses.

Contents:

Key (interpretation):

• 15 points – clear consciousness

• 10–14 points – moderate and deep obtundation

• 8–10 points – stupor

• 6–7 points – moderate coma

• 4–5 points – terminal coma

• 3 points – brain death

Notes: none