Type 2 diabetes mellitus in children: clinical guidelines

List of Abbreviations

GADA – Glutamic Acid Decarboxylase Autoantibodies

IAA – Insulin Autoantibodies

IA-2 – Insulinoma-Associated-2 Autoantibodies (autoantibodies to tyrosine phosphatase)

ICA – Islet Cell Cytoplasmic Autoantibodies

HbA1c – Hemoglobin A1c (glycated hemoglobin)

HLA – Human Leukocyte Antigens

ZnT8A – Zinc Transporter 8 (autoantibodies to zinc transporter 8)

AH – arterial hypertension

BP – blood pressure

ACE – angiotensin-converting enzyme

Abs – antibodies

ATC – Anatomical Therapeutic Chemical classification

HRV – heart rate variability

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 of insulin (and its analogs)

ICD-10 – International Classification of Diseases 10th Revision

INN – International Nonproprietary Name

CGM – continuous glucose monitoring

CSII – continuous subcutaneous insulin infusion (of insulin and its analogs)

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

Terms and Definitions

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

Autoimmunity – the appearance of antibodies in the body against its own structures and tissues

Biguanides – a class of hypoglycemic medications

Insulin analogs – a form of insulin in which certain modifications have been made to the human insulin molecule. An analog acts similarly to insulin, but with pharmacokinetic / pharmacodynamic differences that can provide advantages

Hyperglycemia – blood glucose level above the normal range

Hypoglycemia – blood glucose levels below normal values

Glycemia – blood glucose concentration

Glycated hemoglobin – an indicator reflecting the average blood glucose level over the past 2–3 months

Dyslipidemia – an abnormality in the physiological ratio of blood lipids manifested as elevated triglycerides and low-density lipoproteins, and decreased high-density lipoproteins

Insulin – a hormone secreted under physiological conditions by the pancreatic beta cells, regulating blood glucose levels by stimulating glucose uptake by tissues

Insulin resistance – impairment of the biological action of insulin and the response of insulin-sensitive tissues to insulin at the pre- and post-receptor levels, leading to chronic metabolic changes and accompanied initially by compensatory hyperinsulinemia.

Immunological markers of autoimmune insulitis: IAA – insulin autoantibodies, ICA – islet cell cytoplasmic autoantibodies, GADA – glutamic acid decarboxylase autoantibodies, IA2 – tyrosine phosphatase autoantibodies, ZnT8 – zinc transporter 8 autoantibodies.

Lipodystrophy – pathological alteration of adipose tissue at insulin injection sites

Metabolic syndrome – a combination of type 2 diabetes mellitus (T2DM) or impaired glucose tolerance (IGT) with insulin resistance along with two of the following features: abdominal obesity, arterial hypertension (AH), elevated plasma triglycerides and/or decreased high-density lipoproteins (HDL), microalbuminuria.

Impaired glucose tolerance (IGT) – an elevated blood glucose level during an oral glucose tolerance test at 2 hours post-load up to 7.8 and higher (but below 11.1) mmol/L

Obesity – elevated body mass index (above 2 SDS)

Oral glucose tolerance test (OGTT) – assessment of glycemia levels following a load of a dextrose solution** per os – fasting and 2 hours post-load

Prandial insulin is short-acting insulin administered with meals.

Self-monitoring of blood glucose – independent determination of blood glucose by patients at home using a glucometer or continuous glucose monitoring system

Bread unit (BU) – a method for estimating the amount of carbohydrates in food. One bread unit is equivalent to 10–12 grams of carbohydrates.

Insulin pen – a device for insulin injection

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Diabetes mellitus (DM) — a complex metabolic disorder 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 altered insulin effects on target tissues, which in turn causes disturbances in carbohydrate, lipid, and protein metabolism. The same patient may simultaneously exhibit impaired insulin secretion and impaired insulin action [1].

Type 2 diabetes mellitus (T2DM) – a polygenic disease resulting from a mismatch between insulin secretion and the level of insulin resistance, i.e., relative insulin deficiency. Typically, the development of T2DM is associated with other components of the metabolic syndrome (dyslipidemia, arterial hypertension, polycystic ovary syndrome, non-alcoholic fatty liver disease).

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

The development of T2DM is the result of a combination of genetic factors, environmental factors, and individual metabolic characteristics. Similarly to adults, the increasing incidence of T2DM in children is associated with the rising prevalence of overweight and obesity [2,3].

Specific risk factors for the development of T2DM in childhood currently include: intrauterine growth restriction followed by rapid weight gain in infancy, a positive family history of T2DM in first-degree relatives, maternal gestational diabetes during the child's prenatal development or in other pregnancies, and belonging to high-risk ethnic groups for T2DM.

The pathogenesis of T2DM is based on peripheral defects in insulin action and/or primary impairments in insulin secretion by b-cells. Pancreatic dysfunction at the onset of the disease is characterized by the loss of the first phase of insulin response to secretory stimuli. Elevated overall glycemia levels, in turn, increase the secretory workload on b-cells and cause hyperinsulinemia [4]. The gradual worsening of peripheral insulin resistance occurs simultaneously with primary changes in the pancreas. As a result, the workload on b-cells increases, leading to progressive hyperinsulinemia. This creates a "vicious circle" of changes followed by the exhaustion of b-cell function and the manifestation of diabetes. As the disease progresses, insulin secretion declines significantly, and absolute insulin deficiency may develop rapidly [1].

1.3 Epidemiology of the Disease or Condition

The total number of patients under 18 years old with T2DM in the Russian Federation as of December 31, 2022, was 697 individuals (2.3 per 100,000 child population), with an incidence of 177 individuals (0.6 per 100,000 child population). The prevalence of T2DM in 2022 among children was 1.18 per 100,000 child population, and among adolescents, 8.7 per 100,000 adolescent population. The incidence of T2DM in children in 2022 was 0.33 per 100,000 child population, and among adolescents, 2.07 per 100,000 adolescent population [5–10].

According to epidemiological studies, the incidence of T2DM in children and adolescents varies significantly. In the United States, among adolescents aged 12–19 years, the highest prevalence of T2DM was observed among American Indians (1.74 per 1,000), followed by African Americans (1.05 per 1,000), Asian/Pacific Islanders (0.54 per 1,000), Hispanics (0.48 per 1,000), and non-Hispanic whites (0.19 per 1,000). The increase in the incidence and prevalence of T2DM among youth in the U.S. and several other populations is evidently the result of a predominance of high-risk ethnic groups within them. Several studies in Europe show that T2DM in adolescents remains rare in European populations, accounting for only 1–2% of all diabetes cases [11].

1.4 Features of Coding the Disease or Condition

E11.2 - Type 2 diabetes mellitus: with renal complications;

E11.3 - Type 2 diabetes mellitus: with ophthalmic complications;

E11.4 - Type 2 diabetes mellitus: with neurological complications;

E11.5 - Type 2 diabetes mellitus: with peripheral circulatory complications;

E11.6 - Type 2 diabetes mellitus: with other specified complications;

E11.7 - Type 2 diabetes mellitus: with multiple complications;

E11.8 - Type 2 diabetes mellitus: with unspecified complications;

E11.9 - Type 2 diabetes mellitus: without complications.

R73.0 - Abnormal glucose tolerance test findings.

Example of diagnosis formulation: Type 2 diabetes mellitus with neurological complications (ICD-10 code: E11.4).

1.5 Classification of the disease or condition

The classification of DM is presented in Table 1.

Table 1 – Etiological classification of diabetes mellitus (ISPAD, 2022 [12])

^a Except for overt diabetes mellitus.

1.6 Clinical presentation of the disease or condition

Clinical features of type 2 diabetes mellitus in adolescence [13]:

• In most cases, type 2 diabetes mellitus develops in adolescents who are overweight or have varying degrees of obesity, up to morbid obesity. Severe obesity is frequently accompanied by sleep apnea.

• The age at diagnosis is mostly in the middle of puberty (mean age 13–14 years) — Tanner stage 3 and above.

• Girls are affected more often than boys, with a ratio of 1.2–1.7:1, depending on ethnicity.

• A positive family history of type 2 diabetes: 50–75% of patients have a parent with type 2 diabetes, and up to 90% have 1 to several first- or second-degree relatives with type 2 diabetes [4, 14].

• Ethnicity plays an important role in susceptibility to type 2 diabetes.

• A common and dominant feature is insulin resistance. Type 2 diabetes in adolescents is associated with other symptoms of "metabolic syndrome": abdominal obesity, arterial hypertension, dyslipidemia, microalbuminuria, acanthosis nigricans, and non-alcoholic fatty liver disease.

• The range of clinical manifestations of type 2 diabetes under the age of 18 is quite broad — from moderate asymptomatic hyperglycemia to severe ketoacidosis (extremely rare). In many patients, type 2 diabetes is diagnosed during routine laboratory screening, or during evaluation for obesity or a positive family history [14]. Up to 20% of adolescents with type 2 diabetes present with polyuria, polydipsia, and weight loss. Up to 25% of girls with type 2 diabetes present with a vaginal infection as their primary complaint.

Some adolescents with type 2 diabetes develop ketosis or diabetic ketoacidosis (DKA) at onset or during the course of the disease, the mechanism of which is not fully understood. It is hypothesized that insulin resistance combined with the adverse effects of chronic hyperglycemia on insulin secretion and action ("glucotoxicity") leads to relative insulin deficiency. When the deficiency becomes severe (due to prolonged hyperglycemia or an intercurrent illness), it enhances lipolytic processes, resulting in elevated free fatty acid levels, ketonemia, and ketonuria [4]. DKA is most commonly observed in African American and Hispanic patients. Studies have shown that baseline insulin sensitivity in these groups is lower than in their Caucasian peers, which may increase their susceptibility to developing relative insulin deficiency.

• Hyperglycemic hyperosmolar state in type 2 diabetes has been described mainly in African American patients with severe comorbid conditions. Precipitating factors include infectious diseases, medications, non-compliance, undiagnosed diabetes, substance abuse, and other chronic conditions. As in adults, this condition in adolescents is associated with high mortality. Causes of death included hypovolemic shock, multiorgan failure, massive pulmonary embolism, etc. In rare cases, complications such as pancreatic necrosis, extensive small bowel necrosis, and superior mesenteric artery thrombosis have been described in adolescents.

• The course of type 2 diabetes is usually undulating. Periods of deterioration alternate with periods of stabilization and improvement. Seasonal changes, emotional stress, weight changes, and other factors influence the course of the disease.

• Adolescents with type 2 diabetes are at a high risk of developing specific micro- and macrovascular complications, which significantly exceeds that of type 1 diabetes, as well as type 2 diabetes diagnosed at an older age.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

1) Blood glucose and/or glycated hemoglobin levels meeting the criteria for diabetes mellitus (Table 2) combined with the clinical presentation;

2) Absence of type 1 diabetes-associated autoantibodies and molecular genetic data indicating a monogenic form of diabetes;

3) Obesity or overweight, clinical and/or laboratory signs of insulin resistance — elevated fasting insulin and/or C-peptide levels and/or during an OGTT, positive insulin resistance indices, and other components of "metabolic syndrome" (dyslipidemia, arterial hypertension (AH), ovarian hyperandrogenism, etc.), with a positive family history of type 2 diabetes in first-degree relatives.

Table 2 – Diagnostic criteria for diabetes mellitus (ISPAD, 2018 [15])

^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 World Health Organization guidelines, adopted 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 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 entities, but are regarded as "prediabetes" [15, 16], reflecting a high risk of developing 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 [17]:

• 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.

2.1 Complaints and Anamnesis

The onset of type 2 diabetes in children occurs in the second decade of life, coinciding with puberty. The disease extremely rarely manifests in the prepubertal period. The clinical presentation of type 2 diabetes onset in children varies from asymptomatic hyperglycemia to pronounced clinical symptoms of diabetes.

Most adolescents at the onset of type 2 diabetes present with complaints of thirst, polyuria, fatigue, asthenia, and in some cases, weight loss, recurrent vulvitis, and balanitis. When ketosis develops, there is acetone breath, dry skin and mucous membranes, vomiting, and altered consciousness up to a comatose state in DKA. In some children, manifestations of hyperglycemia and dehydration are absent at the onset of type 2 diabetes, and the disease may be diagnosed incidentally during routine health check-ups or evaluation for obesity or other conditions [14].

The development of the disease in most children occurs against the background of overweight and obesity. Patients complain of elevated blood pressure, skin darkening in natural folds, sleep disturbances, snoring, daytime sleepiness; girls may experience menstrual irregularities and hirsutism [18].

2.2 Physical Examination

Physical examination includes inspecting the skin for darkening in natural folds (acanthosis nigricans) and signs of hirsutism (in girls), measuring weight and height with calculation of body mass index and BMI SDS, assessing the presence of subcutaneous adipose tissue redistribution in an abdominal pattern, and measuring peripheral blood pressure [14].

2.3 Laboratory Diagnostics

Comments:

o Blood glucose testing using glucometers is not recommended for the diagnosis of type 2 diabetes, as glucometers lack sufficient accuracy for a definitive diagnosis and may lead to diagnostic errors;

o In the absence of symptoms, the diagnosis of type 2 diabetes cannot be based solely on a single blood glucose measurement. If the diagnosis is in doubt, prolonged monitoring with fasting and/or postprandial blood glucose testing and/or an OGTT may be required;

o Hyperglycemia identified under stress conditions, during acute infection, trauma, surgery, respiratory dysfunction, circulatory problems, etc., may be transient and require treatment, but does not in itself indicate the presence of diabetes.

• In the absence of clinical symptoms of diabetes in patients with hyperglycemia, repeat laboratory blood glucose testing and/or an OGTT is recommended for the diagnosis of type 2 diabetes [15, 17].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: An OGTT should not be performed if diabetes can be diagnosed using fasting, postprandial, or random blood glucose levels.

Rules for conducting an OGTT:

OGTT should be performed in the morning after at least 3 days of unrestricted diet and normal physical activity. The test must be preceded by an 8–10 hour overnight fast (water is permitted). The last evening meal should contain 30–50 g of carbohydrates. After fasting blood sampling, the 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 [12]. Smoking is prohibited during the test. A repeat blood sample is taken after 2 hours.

To prevent glycolysis and erroneous results, glucose concentration must be determined immediately after blood collection, or the blood must be centrifuged immediately after collection, stored at 0–4°C, or collected in a vacuum tube containing sodium fluoride and EDTA.

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:

o The glycated hemoglobin assay must be performed using methods (equipment and kits) certified by the NGSP and standardized against the Diabetes Control and Complications Trial (DCCT);

o A significant discrepancy between glycated hemoglobin values and blood glucose levels may be due to the presence of various hemoglobin variants (hemoglobinopathy) in the patient, which affects the results obtained by certain methods; in such cases, an alternative method for determining glycated hemoglobin should be used.

o Under conditions affecting erythrocyte lifespan (iron deficiency anemia, sickle cell anemia, pregnancy, hemodialysis, recent blood loss or transfusion, or erythropoietin therapy, etc.), only blood plasma glucose determination should be used to diagnose type 2 diabetes mellitus.

Comments: If there is a significant elevation of ketones in blood or urine, treatment must be initiated immediately, and the child should be referred to a diabetes specialist on the same day due to the high risk of DKA development.

2.3.1 Laboratory diagnostic tests performed for differential diagnosis

Comments: The presence of one or more diabetes-associated autoantibodies (autoantibodies to glutamic acid decarboxylase – GADA; autoantibodies to tyrosine phosphatase – IA-2; autoantibodies to zinc transporter 8 – ZnT8) confirms the diagnosis of type 1 diabetes mellitus.

If islet autoantibody titers are negative, given the heterogeneity and overlap of clinical features of various types of DM in children, it is advisable to consider molecular genetic testing in the following cases:

• Family history of DM with an autosomal dominant inheritance pattern;

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

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

• Associated conditions such as deafness, optic atrophy, or syndromic forms (mitochondrial diseases, lipoatrophic diabetes, Rabson-Mendenhall syndrome, Alström syndrome).

Comments: elevated C-peptide/insulin levels are not characteristic of type 1 diabetes mellitus 12–14 months after disease onset; detectable C-peptide levels are not characteristic of type 1 diabetes mellitus 5 years after disease onset

2.4 Instrumental Diagnostics

No specific instrumental diagnostic tests are provided for diagnosing type 2 diabetes mellitus. Instrumental diagnostic tests for diagnosing complications and comorbidities of type 2 diabetes mellitus 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 2 diabetes mellitus in children consists of the following main components:

• glucose-lowering therapy;

• self-management education and home monitoring;

• nutrition;

• physical activity;

• psychological support.

3.1 Assessment and glycemic control targets

Comments:

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

o Regular HbA1c monitoring (4 times a year).

o Regular self-monitoring of blood glucose. The frequency of monitoring is individual, based on the degree of disease compensation and the type of glucose-lowering therapy used (ranging from fasting and postprandial glucose measurements several times a week in well-compensated cases, up to 6–10 times a day on an intensified insulin therapy regimen).

o Regular evaluation and adjustment of treatment.

o Due to the lack of systematic data in the "children and adolescents" age category, data have been extrapolated from the "adults and young adults" age category

3.2 Pharmacotherapy

Therapy for type 2 diabetes mellitus in children involves metformin** preparations and insulin and insulin analog preparations, either as monotherapy or in combination, depending on the severity of DM symptoms, the degree of hyperglycemia, and the presence or absence of ketosis/ketoacidosis. The use of liraglutide in type 2 diabetes mellitus in adolescents has demonstrated efficacy and safety in clinical trials. The goal of pharmacotherapy is to achieve and maintain optimal glycemic control, prevent acute and chronic complications, improve insulin sensitivity, and enhance endogenous insulin secretion [4,25].

Comments: When diagnosing type 2 diabetes mellitus, metformin** may be prescribed as monotherapy if glycated hemoglobin is <8.5% and there is no ketosis, or in combination with insulin therapy if glycated hemoglobin is ≥8.5% or ketosis/DKA is present (prescribed after ketosis resolution). In the second case, transition to metformin** monotherapy after type 2 DM manifestation is usually possible within 2–6 weeks. When adding metformin** preparations, the dose of insulin and its analogs is reduced by 30–50% with each increase in the metformin** dose (Appendix B).

The starting dose of metformin** is 500 mg per day. The dose is titrated once a week. The maximum daily dose is 1000 mg twice a day or 850 mg three times a day.

o The risk of hypoglycemia with metformin** monotherapy is extremely low.

o Gastrointestinal side effects (abdominal pain, diarrhea, nausea) may occur with metformin** use, but in most cases can be minimized by slow dose titration (over 3–4 weeks) and taking it with meals.

o The risk of lactic acidosis associated with metformin** use is extremely low. However, metformin** should not be prescribed to patients with ketoacidosis, renal, cardiovascular, or pulmonary failure. Metformin** therapy should be temporarily discontinued if radiocontrast agents are required, or in the event of gastrointestinal diseases.

Comments: long-acting insulins (and their injectable analogs)

are prescribed: 1) upon diagnosis of type 2 DM with a glycated hemoglobin level of ≥8.5% and/or ketosis/DKA as monotherapy or in combination with metformin** in children over 10 years of age (after DKA resolution), or 2) when HbA1c is above the target level during 3–4 months of metformin** monotherapy (Appendix B).

Long-acting insulins (and their injectable analogs) and their administration regimens are selected individually for each patient based on the drug action profile and individual tolerance. The initial dose of long-acting insulin (and its injectable analogs) is 0.25–0.5 IU/kg/day. Dose titration is performed based on glycemia indicators until target glycemic control goals are reached.

Table 3 – Types and action profiles of insulin preparations

Doses of insulin preparations and their analogues, as well as the administration regimen, are selected individually for each patient based on age, insulin action profile, individual tolerability, etc., using glycemic control data (glycemia indices and HbA1c levels).

Switching from one insulin preparation and its analogues to another occurs quite frequently. When switching a patient from one insulin to another, the following set of requirements must be followed to best ensure patient safety [44]:

1. In 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 self-monitoring of blood glucose, patient education, and dose adjustment of the newly prescribed insulin and its analogues.

• The switch can be made from one insulin preparation and its analogues to another 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 case of the same INN.

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

• 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.

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

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.

Comments: the addition of short-acting insulins and their analogues for injection is recommended when the target glycated hemoglobin level cannot be achieved with a combination of metformin** and long-acting insulins and their analogues for injection (at a maximum daily dose of 1.5 IU/kg/day) in order to optimize glycemic control.

Short-acting insulin and the administration regimen are selected individually for each patient based on the insulin action profile and individual tolerability. Titration of doses of insulin and its analogues is carried out according to glycemia indices.

Comments: in case of ineffectiveness of metformin** monotherapy or a combination of metformin** with insulins and their analogues (glycated hemoglobin level above the target level), therapy with

the glucagon-like peptide-1 (GLP-1) analogue liraglutide may be prescribed in addition to the ongoing therapy.

Comment: Children with type 2 diabetes and their parents must learn to independently inspect injection sites and recognize lipodystrophies.

3.3 Glucose self-monitoring

Comments:

Blood glucose monitoring is performed using blood glucose meters. Personal blood glucose meters are used at home. Currently, there are blood glucose meters with adjustable individual glycemic target ranges, as well as meters with wireless data transmission of glucose levels to medical specialists, relatives, or a special application installed on the patient's smartphone for use during remote monitoring.

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

In healthcare facilities, in addition to laboratory analyzers, professional-use blood glucose meters (multi-user, hospital-grade) must be used, which possess higher measurement accuracy compared to personal blood glucose meters and withstand multiple disinfection cycles in accordance with well-validated methods provided by the manufacturer.

Recommendations for the frequency of glycemic self-monitoring in children with type 2 diabetes are individual and depend on the glucose-lowering therapy used and the level of carbohydrate metabolism compensation.

o Blood glucose measurement at least 3–4 times a week in children on metformin** monotherapy. When achieving the target glycated hemoglobin level during metformin** monotherapy, several blood glucose measurements throughout the week are usually sufficient: fasting and postprandial.

o In case of an elevated glycated hemoglobin level, during an intercurrent illness, or upon the onset of symptoms of hyper- and hypoglycemia, the frequency of self-monitoring should be increased.

o Patients on insulin therapy need to perform glycemic self-monitoring more frequently, up to 6–10 times a day.

3.4 Education

Education is a necessary element of successful diabetes treatment and control and should be accessible to all children with type 2 diabetes and their parents.

Comments:

o Education should be tailored to each individual according to their lifestyle, learning capacity, etc.

o Education should be continuous to maintain the level of knowledge and motivation.

o The patient's family must understand the high importance of lifestyle modification for the effective treatment of a patient with type 2 diabetes.

o Potential uncertainty in the type of diabetes at the onset of the disease often causes anxiety for the adolescent and their family. Already at the time of diabetes diagnosis, the physician should emphasize the importance of normalizing glycemia using glucose-lowering therapy appropriate to the degree of carbohydrate metabolism impairment (including insulin therapy), regardless of the "type" of diabetes.

o Education should include contraceptive counseling to prevent unplanned pregnancy in diabetes.

o Adolescents with type 2 diabetes need regular education on the hazards of smoking and the consequences of alcohol abuse for individuals with diabetes, such as the development of fatty liver disease and severe hypoglycemia.

3.5 Diet therapy

Diet therapy is an element of type 2 diabetes treatment and is recommended for all children.

Comments: Dietary recommendations should be based on healthy eating principles and be suitable for all children with T2D and their families to improve diabetes control outcomes and reduce cardiovascular risks. Nutritional advice should be tailored to cultural, ethnic, and family traditions, while also taking into account the cognitive and psychosocial aspects of the child and family.

Priority dietary modifications in T2D include:

o Elimination of sugary drinks and juices.

o Increased consumption of fruits and vegetables.

o Reduction in the intake of 'ready-to-eat' convenience foods.

o Reduction in the consumption of products containing refined sugar and corn syrup.

o Portion size control.

o Reduction of meals eaten outside the home.

o In families with Asian dietary traditions – increasing the consumption of animal protein and fresh vegetables while decreasing high-carbohydrate foods (noodles, white rice, starches).

o Replacing foods with easily digestible carbohydrates with those having a lower glycemic index (replacing white rice and white flour with brown rice and whole grain flour).

3.8 Physical activity

Recommendations regarding the need for regular physical activity are an essential part of T2D management.

• In children with T2D, regular physical activity is recommended to improve glycemic control parameters, reduce excess weight, and enhance overall well-being [50,52–54].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comments: All adolescents with T2D are recommended to engage in regular physical activity lasting at least 60 minutes daily, which should include moderate-to-vigorous physical activity. The recommended level of physical activity is chosen individually. Screen time spent on computers, watching television, or playing video games should be reduced to a maximum of 2 hours per day [55,56]. 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 [57].

3.9 Psychological support

3.10 Pain management

Not applicable.

3.11 Other treatment

Not applicable.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Specific rehabilitation measures are not provided.

The list of rehabilitation measures for patients with T2D may include sessions with a medical psychologist, spa-resort treatment in specialized sanatoriums for children (including sanatoriums for children with parents) featuring medicinal mineral waters and a therapeutic climate, as well as social adaptation with the participation of specialists and social workers.

5. Prevention and Dispensary Observation

Comments: Prevention of overweight and obesity is one of the key strategies in the prevention of T2D.

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

• General health and well-being:

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

o Intercurrent illnesses, diabetes-related emergencies, and hospitalizations. During the initial visit, conduct a thorough inquiry regarding the onset of the first symptoms of the disease, types and doses of administered insulins, reasons for and duration of hospitalizations (including cases of diabetic ketoacidosis [DKA] and severe hypoglycemia), timing and diagnostic methods for specific complications if present, concomitant endocrine and systemic diseases, and family history.

• Glycemic control:

o Assessment of blood glycated hemoglobin levels over the past three months;

o Analysis of home blood glucose monitoring data (glucometer readings, continuous glucose monitoring [CGM], flash glucose monitoring [FGM]);

o Assessment of the frequency/severity of hypoglycemia, including determination of hypoglycemia awareness and the method used to treat hypoglycemia.

• Metformin**:

o Doses of the drug;

o Adjustment of therapy based on glucose levels, diet, and physical activity;

• Insulin therapy:

o Types and doses of the drug;

o Adjustment of insulin therapy taking into account glucose levels, diet, and physical activity;

o Injection technique.

• General examination:

o Height, weight, body mass index (BMI), and sexual development;

o Skin condition (acanthosis nigricans) and insulin injection/administration sites (if applicable), infusion sets/CGM sensors (lipodystrophy, local reactions);

o Oral mucosa and teeth (caries, gingivitis);

o Abdominal examination (hepatomegaly), foot examination (calluses, ingrown toenails, and other lesions);

o Blood pressure adjusted for age, sex, and height percentiles.

6. Organization of Medical Care

Indications for hospitalization in a medical organization:

1) Form: elective; setting: inpatient, day hospital:

a. At the initial presentation for persistent hyperglycemia without clinical manifestations of T2D and/or ketosis;

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

c. Comprehensive screening for complications and comorbid conditions when outpatient evaluation is not feasible;

d. Transition to multiple daily insulin injection (MDI) therapy.

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

a. At the initial presentation for hyperglycemia with clinical manifestations of T2D and/or ketosis;

b. Severe hypoglycemia;

c. DKA;

d. Acute development of specific complications.

Indications for patient discharge from a medical organization:

1) Form: elective; setting: inpatient, day hospital:

a. Achievement of individual target glucose levels with a time-in-range (TIR) of at least 50% according to CGM or self-monitoring of blood glucose (SMBG);

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

a. 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 time-in-range (TIR) of at least 50% according to CGM or SMBG;

7. Additional Information

T2D in children and adolescents is typically accompanied by obesity and insulin resistance. Risk factors for T2D and insulin resistance include premature adrenarche [60], low birth weight for gestational age, maternal obesity during pregnancy [61], as well as obesity and a sedentary lifestyle in early childhood.

7.1 Complications and comorbid conditions of T2DM

Specific microvascular complications of diabetes in adolescence include 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 nephropathy

Diabetic nephropathy (DN) is a specific renal complication of diabetes characterized by the development of nodular glomerulosclerosis, leading to end-stage renal disease (ESRD) requiring renal replacement therapy (dialysis, transplantation). Contributing factors for progression include the duration of T2D, glycated hemoglobin levels above the individual target, and elevated diastolic blood pressure [62].

Classification.

The diagnosis of DN is established in accordance with the chronic kidney disease (CKD) classification based on the stage of glomerular filtration rate (GFR) reduction and albuminuria level [63].

CKD stages in patients with diabetes

*GFR – glomerular filtration rate

Schwartz formula (Bedside modification) [64,65] for calculating GFR in children:

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

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

CKD classification by albuminuria category

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

Example of diagnosis formulation: Diabetic nephropathy, CKD G1A2.

When the GFR and urinary albumin levels are normal (stage C1A1), the diagnosis of CKD can be established only in the presence of other markers of renal injury [66,67].

Comments:

The presence of microalbuminuria is confirmed by the following: an albumin/creatinine ratio of 2.5 to 30 mmol/mg or 30 to 300 mg/g (single-void urine sample) in men, and 3.5 to 30 mmol/mg or 42 to 300 mg/g in women (due to decreased creatinine excretion).

A single-void urine sample for microalbuminuria is preferred due to known circadian fluctuations in albumin excretion and postural effects. Collecting 24-hour urine for microalbuminuria is difficult and has low informativeness.

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:

Table 4 – ACE Inhibitors

7.1.2 Diabetic retinopathy

Diabetic retinopathy (DR) is a specific late neuromicrovascular complication of diabetes, typically developing 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 a breakdown of the blood-retinal barriers and a mismatch between fluid transudation and the ability for its reabsorption. 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 one of the 3 features:

o venous abnormalities in 2 or more quadrants

o moderate IRMA in at least one quadrant

o multiple retinal hemorrhages in 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 by determining retinal visual acuity (visometry), fundus biomicroscopy, dilated ophthalmoscopy (examination of the peripheral fundus using a Goldmann three-mirror lens), and fundus biomicrophotography using a fundus camera [77].

Comments: Due to the potential worsening of DR in children with prolonged poor glycemic control upon its stable improvement, ophthalmological monitoring is recommended before starting 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 prior to therapy intensification, or if it progressed during treatment.

Comments: despite the lack of sufficient literature data confirming the efficacy and safety of panretinal laser photocoagulation of the retina and intravitreal administration of anti-angiogenic agents (anti-VEGF) in children with type 2 diabetes, these methods have proven efficacy in DR in adult patients with type 1 diabetes [77–80]. Therefore, there is no reason to assume that these data cannot be extended to children with type 2 diabetes.

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 type 2 diabetes. Diabetic distal symmetric polyneuropathy (DPN) 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 to sensory loss and later leads to motor function loss distributed in a stocking-and-glove pattern. Cardiovascular autonomic neuropathy (CAN) results from damage to the autonomic nervous system and can manifest as orthostatic hypotension, impaired adequate heart rate (HR) response, and Q-T interval prolongation. CAN is associated with the risk of sudden death and other cardiovascular risk factors [76,80–82].

Comments: Specific tests for diagnosing DPN include the assessment of general and vibratory sensitivity, and reflexes. Specific tests for diagnosing CAN may include performing cardiovascular tests and/or assessing HRV in the frequency or time domain over short or long periods [84,85].

7.1.4. Dyslipidemia

Comments: Elevated triglycerides and decreased HDL are characteristic of type 2 diabetes, obesity, and hyperinsulinism [87]. High LDL cholesterol is defined as values above 2.6 mmol/L, low HDL cholesterol as less than 0.91 mmol/L, and high triglycerides as more than 1.7 mmol/L. In these cases, children with type 2 diabetes are advised to improve metabolic control, make dietary changes (cholesterol-lowering diet), and increase physical activity.

• If dyslipidemia persists after 6 months, as well as when fasting triglyceride levels rise above 5.6 mmol/L, it is recommended to consult a pediatric cardiologist [21,86,87].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Elevated triglyceride levels increase the risk of pancreatitis.

7.1.5. Arterial hypertension

Hypertension in patients with type 2 diabetes is associated with endothelial dysfunction and an increased risk of cardiovascular and renal diseases. Its prevalence in young patients with type 2 diabetes ranges from 13.9% at 7 months after diabetes diagnosis to 33.8% at 3.9 years [87].

Comments: For a newly detected blood pressure elevation above the 95th percentile, weight loss, restriction of dietary sodium intake, and increased physical activity are recommended [21]. Maintaining BP within the target range in the UKPDS study in adult patients with type 2 diabetes showed a significant correlation with a reduced incidence of micro- and macrovascular complications to the same extent as the improvement in metabolic control.

Comments: despite the lack of sufficient literature data confirming the efficacy and safety of this therapy in children with type 2 diabetes mellitus and hypertension, it has proven efficacy in hypertension in children without diabetes [85] and in hypertension in young adult patients with type 2 diabetes [87]. Therefore, there is no reason to assume that these data cannot be extended to children with type 2 diabetes mellitus. The dosing regimen is determined in accordance with the instructions for medical use of a specific medicinal product of this pharmacological group.

7.1.6. Ovarian hyperandrogenism

The presence of hyperandrogenism in childhood is a risk factor for the development of polycystic ovary syndrome in adulthood

7.1.7. Non-alcoholic fatty liver disease (NAFLD)

Steatohepatitis is diagnosed in 25–50% of patients with type 2 diabetes; disease progression leads to liver cirrhosis and portal hypertension [91, 92].

7.1.8. Obstructive sleep apnea syndrome (OSAS)

Comments: If the aforementioned complaints are identified in children with type 2 diabetes, an evaluation (examination, consultation) by a neurologist (somnologist) is necessary for the timely diagnosis, confirmation of the diagnosis, and prescription of therapy for OSAS [21].

7.2. Diabetic ketoacidosis

Diabetic ketoacidosis in type 2 diabetes is very rare. Treatment is managed similarly to type 1 diabetes.

7.3 Hypoglycemia

Currently, the following classification of hypoglycemia is adopted [98]:

Level 1: plasma glucose levels from 3.0 to < 3.9 mmol/L (with or without symptoms) in patients with diabetes receiving glucose-lowering therapy indicate the risk of hypoglycemia and require the initiation of hypoglycemia-reversal 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:

- overdose of insulin and its analogues: patient error, malfunction of the insulin pen, insulin pump***, or glucometer, intentional overdose; physician error (excessively low target glycemic level, excessively high doses);

- alteration in the pharmacokinetics of insulin and its analogues: high titer of insulin antibodies, improper injection technique;

- increased sensitivity to insulin and its analogues: prolonged physical exertion, 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: Treatment of hypoglycemia should raise blood glucose levels by approximately 3-4 mmol/L. Depending on the circumstances (nighttime hypoglycemia, physical exertion, etc.), fast-acting carbohydrates should be followed by additional slow-acting carbohydrates to prevent recurrent hypoglycemia. Blood glucose levels should be re-measured 10-15 minutes after carbohydrate intake to ensure the target glucose level has been achieved. If blood glucose does not rise sufficiently, repeat the intake of fast-acting carbohydrates followed by another blood glucose measurement in 10–15 minutes.

7.3.1 Severe hypoglycemia

Severe hypoglycemia is defined as an event characterized by 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 to all patients, parents, and caregivers of children with type 2 diabetes mellitus receiving insulin therapy, especially when there is a high risk of severe hypoglycemia. These individuals must be properly trained in the injection technique of the drug [99].

[1] The method of administration (route of administration) has undergone clinical trials, but this route of administration is not listed in the drug's package leaflet in the Russian Federation at the time of publication of the clinical guidelines

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

LEADERS:

Valentina A. Peterkova – Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, Scientific Supervisor of the Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health, Head of the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health, Chief freelance pediatric specialist endocrinologist of the Russian Ministry of Health.

Olga B. Bezlepkina – Doctor of Medical Sciences, Deputy Director of the Center – Director of the Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health, Professor at the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

TEXT AUTHORS:

Laptev Dmitry Nikitich – Doctor of Medical Sciences, Professor of the RAS, Head of the Pediatric Diabetes Department, National Medical Research Center for Endocrinology of the Russian Ministry of Health, Professor at the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Eremina Irina Alexandrovna – Candidate of Medical Sciences, Senior Researcher at the Pediatric Diabetes Department, National Medical Research Center for Endocrinology of the Russian Ministry of Health, Associate Professor at the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Sechko Elena Alexandrovna – Candidate of Medical Sciences, Senior Researcher at the Pediatric Diabetes Department, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

EXPERTS:

Alimova Irina Leonidovna – Doctor of Medical Sciences, Professor, Head of the Department of Hospital Pediatrics with a Course in Neonatology, Faculty of Additional Professional Education, Smolensk State Medical University of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of the Smolensk Region.

Andrianova Ekaterina Andreevna – Candidate of Medical Sciences, Leading Researcher at the Pediatric Diabetes Department, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Bashnina Elena Borisovna — Doctor of Medical Sciences, Professor at the 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.

Bolotova Nina Viktorovna — Doctor of Medical Sciences, Professor at the Department of Propaedeutics of Childhood Diseases, Pediatric Endocrinology, and Diabetology, Saratov State Medical University named after V.I. Razumovsky of the Russian Ministry of Health.

Galkina Galina Aleksandrovna — Doctor of Medical Sciences, Head of the Pediatric Endocrinology Department, Research Institute of Obstetrics and Pediatrics, Rostov State Medical University of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of the Rostov Region, Chief freelance pediatric endocrinologist of the Southern Federal District.

Emelyanov Andrey Olegovich – PhD in Medical Sciences, Leading Researcher, Pediatric Diabetes Department, National Medical Research Center for Endocrinology of the Russian Ministry of Health; Associate Professor, Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Kiyaev Alexey Vasilievich — Doctor of Medical Sciences, Professor at the Department of Hospital Pediatrics, Ural State Medical University of the Russian Ministry of Health, Head of the Center for Pediatric Endocrinology, Regional Children's Clinical Hospital, Chief freelance pediatric endocrinologist of the Sverdlovsk Region, Chief freelance pediatric endocrinologist of the Ural Federal District.

Kostrova Irina Borisovna — Head of the Pediatric Endocrinology Department, Children's Republican Clinical Hospital named after N.M. Kuraev, Chief freelance pediatric endocrinologist of the Republic of Dagestan, Chief freelance pediatric endocrinologist of the North Caucasian Federal District.

Kuraeva Tamar Leonidovna – Doctor of Medical Sciences, Chief Researcher, Pediatric Diabetes Department, National Medical Research Center for Endocrinology of the Russian Ministry of Health; Associate Professor, Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Malievsky Oleg Arturovich, Doctor of Medical Sciences, Professor at the Department of Hospital Pediatrics, Bashkir State Medical University of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of the Volga Federal District.

Petryaikina Elena Efimovna — Doctor of Medical Sciences, Director of the Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of Moscow, Chief freelance pediatric endocrinologist of the Central Federal District.

Samsonova Lyubov Nikolaevna — Doctor of Medical Sciences, Head of the Department of Pediatric Endocrinology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health.

Svetlova Galina Nikolaevna – PhD in Medical Sciences, Deputy Chief Medical Officer, National Medical Research Center for Endocrinology of the Russian Ministry of Health; Pediatric Endocrinologist.

Taranushenko Tatyana Evgenievna — Doctor of Medical Sciences, Head of the Department of Pediatrics, Institute of Postgraduate Education, Krasnoyarsk State Medical University named after Professor V.F. Voyno-Yasenetsky of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of the Krasnoyarsk Territory, Chief freelance pediatric endocrinologist of the Siberian Federal District.

Titovich Elena Vitalievna – PhD in Medical Sciences, Leading Researcher, Pediatric Diabetes Department, National Medical Research Center for Endocrinology of the Russian Ministry of Health; Associate Professor, Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Khramova Elena Borisovna – Doctor of Medical Sciences, Professor, Head of the Department of Pediatric Diseases, Faculty of Pediatrics, Tyumen State Medical University of the Russian Ministry of Health; Chief freelance pediatric endocrinologist of the Tyumen Region.

Conflict of interest: the authors of the clinical guidelines declare no conflict of interest.

For final editing and quality control, the guidelines were re-analyzed by the working group members, who concluded that all expert comments and feedback had been taken into account and the risk of systematic bias in guideline development was minimized.

Appendix A2. Methodology for Developing Clinical Guidelines

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

Description of methods used for assessing the quality and strength of evidence: the evidence base for the guidelines included publications from the Cochrane Library, EMBASE, MEDLINE, and PubMed databases. Literature search depth was 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.

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.

Primary care physicians (pediatric endocrinologists) provided Comments regarding the clarity of these guidelines, as well as their assessment of the importance of the proposed recommendations as a tool for daily practice.

All Comments received from experts were thoroughly systematized and discussed by the working group members (authors of the guidelines). Each item was discussed separately.

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 final editing and quality control, the guidelines were re-analyzed by the working group members, who concluded that all expert remarks and Comments had been taken into account, and the risk of systematic bias in the development of the guidelines was minimized.

Key recommendations

The strength of recommendations (1–5) based on the corresponding levels of evidence (A–C) (Table P1 and Table P2) is provided alongside the text of the recommendations.

Target audience for these clinical guidelines:

1. Pediatric endocrinologists;

2. Pediatricians;

3. General practitioners (family physicians).

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grade of Recommendation (GoR) scale 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 medicine data on 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

Not used

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Bread unit table

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

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

* - foods such as pelmeni, blini, oladyi, pirozhki, syrniki, varenyky, and cutlets also contain carbohydrates, but the XE count depends on the size and recipe of the item.

Pasta 1 BU = ....

* - refers to uncooked pasta; in cooked form, 1 XE is contained in

2–4 tablespoons of the product (50 g) depending on the shape of the item.

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

* - refers to 1 tablespoon of dry groats; in cooked form (porridge), 1 XE is contained in 2 heaped tablespoons (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

Not applicable