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48. Diabetes Mellitus in Children
1. Bugubaeva Makhabat Mitalipovna
2. Veliyathuparambil Baiju Aparna (aparnaappu5.1.2003@gmail.com)
(1. HOD Clinical Disciplines-2, Associate Professor, International Medical Faculty, Osh State University, Osh, Kyrgyzstan.
2. Student, International Medical Faculty, Osh State University, Osh, Kyrgyzstan.)
Abstract
Diabetes mellitus in the pediatric population represents a heterogeneous and increasingly prevalent chronic condition, dominated historically by Type 1 Diabetes (T1D) but experiencing a dramatic rise in childhood-onset Type 2 Diabetes (T2D). This expert-level review synthesizes current clinical knowledge, focusing on the distinct epidemiological trends, nuanced differential diagnosis protocols (including Monogenic Diabetes of the Young, MODY), and modern, technology-driven therapeutic strategies guided by international consensus guidelines, particularly those established by the International Society for Pediatric and Adolescent Diabetes (ISPAD) and the World Health Organization (WHO). T1D management centers on intensive insulin therapy, enhanced by Continuous Glucose Monitoring (CGM) and Advanced Hybrid Closed-Loop (AHCL) systems, which prioritize metrics like Time in Range (TIR). Diagnosis relies on strict glucose and HbA1c criteria (greater than or equal to 6.5%). The report details the critical importance of accurate classification, given the high rate of MODY misdiagnosis, and reviews the severe, accelerated risk of microvascular and macrovascular complications associated particularly with childhood-onset T2D. Successful outcomes are intrinsically linked to robust psychosocial support, comprehensive diabetes education (including carbohydrate counting), and individualized care that adapts to developmental stages, highlighting the crucial role of multidisciplinary teams in mitigating long-term mortality and morbidity.
Type 1 diabetes, Type 2 diabetes, Monogenic diabetes, Pediatric, ISPAD Guidelines, Continuous Glucose Monitoring, Time in Range, Childhood Diabetes, Glycemic Control, Carbohydrate Counting.
Diabetes mellitus stands as one of the most common and complex chronic diseases encountered in childhood, posing immense challenges to clinical care and public health systems globally. The overall prevalence of diabetes is undergoing a profound global surge, having risen from an estimated 200 million people in 1990 to 830 million in 2022.1 This upward trend is observed across all income levels, though prevalence rates are increasing more rapidly in low- and middle-income countries.2
Type 1 Diabetes (T1D), characterized by the autoimmune destruction of pancreatic beta-cells 4, remains the dominant etiology in the pediatric cohort, accounting for approximately two-thirds of new diagnoses across all racial and ethnic backgrounds.6 The incidence of T1D continues to increase worldwide, with annual growth rates reported between 2% and 5%.6 While T1D can manifest at any age, diagnosis commonly clusters around two major peaks: between four and six years, and again between 10 and 14 years of age.6 Notably, recent epidemiological data suggest that the trend of increasing incidence in the youngest demographic (children under age five) has stabilized, with greater proportionate increases now being documented in the older age group of 10 to 19 years.6
In stark contrast, Type 2 Diabetes (T2D), which was once considered exceptionally rare or nonexistent in children, has experienced a dramatic increase in frequency worldwide.6 This surge in childhood-onset T2D directly mirrors the global epidemic of childhood obesity.6 T2D in this population is generally diagnosed later than T1D, typically presenting after the onset of puberty, with the highest documented rates occurring between 15 and 19 years of age.6 Clinical studies consistently indicate that approximately 80% of children diagnosed with T2D present with co-existing obesity, underscoring the critical etiologic role of metabolic stress and lifestyle factors in the expression of this complex disease in young individuals.6
The management of pediatric diabetes is complex, requiring clinicians to navigate distinct autoimmune, lifestyle-related, and genetically determined forms of the disease. The inherent heterogeneity, coupled with the rapid evolution of diagnostic criteria and therapeutic technologies, mandates a unified, expert-level clinical resource. International consensus guidelines, such as those issued by the International Society for Pediatric and Adolescent Diabetes (ISPAD), provide comprehensive clinical recommendations for children globally, even offering specific chapters dedicated to limited care settings. This review aims to synthesize these core recommendations, integrating the current standards of classification and diagnosis with emerging evidence regarding advanced technological management, particularly the utilization of Continuous Glucose Monitoring (CGM) and Automated Insulin Delivery (AID) systems.8
The underlying pathology of T1D involves a complex interplay between genetic susceptibility and various environmental factors, which ultimately lead to a T cell-mediated autoimmune assault on the insulin-producing pancreatic beta-cells.4 This destruction results in a severe deficiency or absolute absence of endogenous insulin, culminating in the defining characteristic of chronic hyperglycemia.4
The natural history of T1D is now clinically defined by three distinct stages, a framework crucial for identifying individuals who may benefit from future preventative interventions.5 Stage 1 is defined by the presence of two or more diabetes-related autoantibodies but with normoglycemia and an asymptomatic state. Stage 2 involves the progression to dysglycemia, evidenced by elevated glucose levels, though the patient remains clinically asymptomatic. Stage 3 marks the symptomatic clinical onset, requiring immediate diagnosis and initiation of insulin replacement therapy.5
T2DM in children is fundamentally a disorder rooted in peripheral insulin resistance.6 While the pancreas may initially maintain some insulin production, the body’s cells fail to utilize the hormone effectively. This resistance is closely linked to excess adiposity and the resulting cascade of inflammation and metabolic perturbation. Given the gradual and often subtle nature of T2D symptoms, such as generalized fatigue or mild polyuria, the diagnosis may be delayed by several years after the onset of the underlying pathophysiology, frequently leading to the detection of complications even at the time of initial presentation.
Monogenic diabetes syndromes, the most common of which is Maturity-Onset Diabetes of the Young (MODY), are forms of diabetes arising from single-gene defects. Although MODY is relatively less prevalent than T1D or T2D, accurate identification is critical because management protocols differ significantly from the autoimmune or lifestyle-driven forms.
MODY accounts for an estimated 1% to 5% of all diabetes cases, although precise prevalence figures vary depending on the population studied and the diagnostic criteria applied. A significant and ongoing clinical challenge is the high rate of misclassification. Studies confirm that greater than 90% of MODY cases are misdiagnosed, frequently confused with T1D (36%) or T2D (51%).9 This diagnostic failure results in the systematic underreporting of monogenic diabetes prevalence.
The clinical implications of this misclassification are substantial. If a patient with a sulfonylurea-responsive form of MODY (e.g., HNF1A-MODY) is misdiagnosed with T1D, they are unnecessarily subjected to intensive, life-long insulin therapy based on the basal-bolus regimen.1 For many MODY subtypes, management can be achieved effectively and less burdensomely using oral medications. The persistence of high misdiagnosis rates, even with the availability of biomarkers, indicates that clinical practice must aggressively incorporate differential diagnostic testing early in the course of disease, particularly in children who present with atypical features for T1D, such as older age, a strong family history, or a non-ketotic presentation.9 Systematic screening using negative autoantibodies and the presence of C-peptide can reliably identify appropriate candidates, even within overweight or obese cohorts, who warrant genetic testing to secure the correct diagnosis and prevent the initiation of suboptimal, excessive therapy.9
The definitive diagnosis of diabetes mellitus relies upon clinical assessment combined with rigorous, standardized laboratory measurement of plasma glucose levels.14 Classical symptoms often include polyuria, polydipsia, and unexplained weight loss, which may be accompanied by polyphagia, fatigue, or acute changes like blurred vision or behavioral disturbances.
A critical element of initial triage is the recognition of potential acute metabolic crises. The presence of significant ketones, detected in blood or urine, mandates urgent same-day referral to a diabetes specialist to prevent the progression to life-threatening diabetic ketoacidosis (DKA).5 Furthermore, guidelines emphasize that a definitive diagnosis of diabetes must not be based on a single plasma blood glucose level in the absence of unequivocal, overt symptoms. Diagnosis based on elevated fasting, random, or post-load glucose or HbA1c values, when symptoms are ambiguous or absent, must be confirmed by repeat testing.14 It is also explicitly stated that capillary blood glucose monitors are insufficient for the purpose of definitive diagnosis.4
The diagnosis of diabetes is confirmed upon meeting specific threshold criteria for glucose levels or HbA1c, established by international bodies.
Table 1. Diagnostic Criteria for Diabetes Mellitus in Children
Reliability Constraints of HbA1c Testing
While HbA1c is accepted for diagnosis, its reliability is contingent upon stringent laboratory quality assurance and standardization (NGSP certification and alignment to international reference values).14 Furthermore, several clinical conditions compromise the validity of HbA1c as a measure of average glucose. Conditions that affect normal red blood cell turnover—including hemoglobinopathies, specific forms of anemia (such as iron deficiency), hemolysis, and cystic fibrosis—significantly complicate interpretation.14 In patients presenting with abnormal red cell turnover, the diagnosis of diabetes must rely exclusively on plasma glucose criteria.14 Clinicians must remain aware that in geographical areas with high rates of iron deficiency and anemia, diabetes prevalence estimates based solely on HbA1c may lead to diagnostic inaccuracy, resulting in underestimations in certain populations and overestimations in others.14
3.3 Targeted Screening Protocols for Type 2 Diabetes in Childhood
The increasing prevalence and often insidious onset of T2D mandate a protocol for targeted screening in children who possess specific risk factors. Screening efforts should be considered after the onset of puberty or after 10 years of age, who have a BMI at or above the 85th percentile for age and sex, plus one or more additional risk factors.3
Table 2. Targeted Screening Recommendations for Childhood-Onset Type 2 Diabetes
If initial screening tests (FPG, HbA1c, or OGTT) yield results within the normal range, rescreening is recommended every two to three years.3 However, annual rescreening is essential if the patient's BMI continues to increase, if their cardiometabolic risk profile deteriorates, or if they are diagnosed with conditions closely associated with heightened insulin resistance, such as PCOS or metabolic dysfunction-associated steatotic liver disease (MASLD).3
The highly granular nature of these screening recommendations is a direct clinical response to the recognition that childhood-onset T2D is inextricably linked to systemic metabolic comorbidities, including hypertension, dyslipidemia, and fatty liver disease.3 Identifying these high-risk individuals early—especially those presenting with definitive markers of insulin resistance, such as acanthosis nigricans—provides a critical window for primary intervention. The establishment of this aggressive targeted screening protocol is essential for delaying or preventing the severe, accelerated cardiovascular and microvascular complications documented in individuals who develop T2D during childhood.
Diabetic Ketoacidosis (DKA) is the most common acute, life-threatening complication of T1D, often marking the initial presentation, but it can also occur in established T1D due to intercurrent illness or non-adherence, and occasionally in T2D. DKA management follows strict ISPAD consensus guidelines focused on three therapeutic pillars: rehydration through careful fluid replacement, timely initiation and meticulous titration of intravenous insulin, and intensive monitoring for life-threatening secondary complications.5 Particular attention must be paid to monitoring and correcting electrolyte disturbances, especially potassium and phosphate, and vigilantly watching for signs of cerebral edema, a rare but devastating complication, typically managed by controlled fluid and glucose lowering rates.
The Hyperglycemic Hyperosmolar State (HHS) is characterized by extreme hyperglycemia and dehydration leading to hyperosmolarity, typically without the profound ketosis or acidosis seen in DKA. Although HHS is less common in children than in adults, it carries a high mortality risk. Management centers on correcting the severe dehydration through cautious fluid replacement and gradually lowering glucose levels. Excessive or rapid osmotic shifts must be avoided during treatment to prevent cerebral injury.
Long-term management aims to optimize glycemic control to minimize chronic complications while maintaining an acceptable quality of life and avoiding severe hypoglycemia. Glycated hemoglobin (HbA1c) remains the standard measure of average control and must be measured every three months.10
The recommended optimal HbA1c target for most children is stringent, set at less than 6.5% (48 mmol/L).10 This strict goal acknowledges the long-term risk profile, particularly for childhood-onset T2D, which is highly hazardous. However, clinical flexibility is crucial; a slightly relaxed target of less than 7.0% (53 mmol/mol) may be justified. This higher target may be considered at the initiation of therapy or in situations where the standard goal is assessed as detrimental to the overall well-being of the person or their caregivers—for example, due to frequent or significant hypoglycemic episodes.10 In addition to HbA1c targets, specific glucose goals are established: Fasting Plasma Glucose (FPG) targets are between 70 and 110 mg/dL (4 and 6 mmol/L), and postprandial targets are between 70 and 140 mg/dL (4 and 8 mmol/L).10
Intensive insulin treatment is the established standard of care for T1D, recognized as necessary to facilitate optimal glucose control.11 The current approach is based on the basal-bolus paradigm, utilizing modern long-acting insulin analogs for basal needs and rapid-acting analogs for mealtime boluses and corrections.
Insulin delivery systems include multiple daily injections (MDI) or Continuous Subcutaneous Insulin Infusion (CSII).11 The choice between MDI and CSII must be individualized based on family preference, lifestyle, and the ability to maintain adherence.17 The intensive regimen necessitates refined calculations for both basal substitution and prandial boluses, leveraging modern devices and insulin analogs to improve outcomes.17
Table 3: MDI vs. CSII
Nutritional guidance is foundational to diabetes care and must be individualized, considering the family's cultural background and traditions. Comprehensive education, monitoring, and support should be provided by a pediatric diabetes dietitian, beginning at diagnosis and continuing at regular intervals.
Carbohydrate Counting (CC) is a core meal-planning strategy for patients utilizing intensive insulin regimens.1 CC involves understanding the carbohydrate content of food and calculating the required bolus insulin dose using a predetermined insulin-to-carbohydrate ratio.1 Evidence suggests that CC positively affects metabolic control, resulting in lower glycosylated hemoglobin concentration (HbA1c) and potentially reducing the frequency of hypoglycemic events. Moreover, CC improves quality of life by providing flexibility in meal and snack choices, allowing children to integrate their diabetes management more effectively into their daily routines. CC may be further refined by incorporating fat and protein counting to calculate the insulin bolus dose with even greater accuracy.1 For preschoolers, mealtime management is frequently cited by caregivers as one of the most challenging aspects of care, highlighting the need for specialized nutritional support and consistent monitoring.
Recent breakthroughs in diabetes technology have ushered in a new era of T1D management, dramatically transforming clinical care for children.8
Continuous Glucose Monitoring (CGM) systems are now recognized as essential tools, providing dynamic glucose trends that allow for proactive adjustments to insulin delivery and lifestyle. Integrating CGM data with insulin pumps forms the basis of Automated Insulin Delivery (AID) systems, particularly Advanced Hybrid Closed-Loop (AHCL) systems.8 These systems, which automate basal insulin delivery based on sensor readings, have been shown to offer superior glycemic control and facilitate greater personalization of treatment compared to traditional manual injection or pumping regimens.8 Beyond physiological benefits, internet applications, videoconferencing for virtual visits, mobile apps, text message reminders, and interactive gaming provide psychosocial support, encouraging adherence to complex lifestyle and treatment regimens.18
The availability of CGM data has led to the emergence of new metrics, such as Time in Range (TIR, defined as 70 to 180 mg/dL), which provide a more nuanced assessment of glucose control than HbA1c alone.8 TIR and glycemic variability measurements are critical because they highlight the frequency and severity of acute glucose fluctuations, offering a dynamic picture of control.8
This clinical shift toward prioritizing TIR reflects the understanding that reducing acute glucose fluctuations is as vital as reducing the overall glucose average. Given the established link between poor glycemic control early in life and the subsequent development of microvascular disease , achieving a high TIR—ideally greater than 70% 8—with AHCL technology offers the most effective available strategy to mitigate this long-term damage during the vulnerable formative years, when neurodevelopment and growth are highly sensitive to glycemic disruption. The predictive value of TIR, Time in Tight Range, and glycemic variability regarding complication risk is subject to ongoing research.8
Table 4. Recommended Glycemic Targets and Performance Metrics (ISPAD Consensus)
Effective T1D management requires continuous adjustment to the child’s evolving developmental stage. Children encounter a myriad of age-specific obstacles—including neurological, physiological, behavioral, psychological, and social factors—that complicate the consistent execution of effective care. These factors contribute significantly to the risk of poor metabolic control and adverse health outcomes.
Regardless of the child’s age, primary caregivers retain the paramount responsibility for maintaining optimal glycemic control, overseeing diet, daily activity, and insulin administration. The management demands continuous adjustment as the child progresses through developmental stages; the period encompassing adolescence is often cited as the most challenging, marked by a drive for autonomy, increased risk-taking, and issues of adherence that require intense, targeted psychosocial intervention.
Successful diabetes management necessitates the integration of clinical demands into the child's broader life context, or "ecosystem." Optimal glycemic control is crucial, as it provides the child with the best opportunity to concentrate, participate, and learn in school.
Consequently, diabetes education must extend beyond the family unit to include staff within the child's school and preschool environments. This ensures that protocols are in place to promote the child’s safe and equal participation in all educational activities. The recognized difficulty caregivers face in managing mealtimes, particularly for preschoolers, and the heavy reliance on the primary caregiver for daily management underscore a critical need for integrated care. The multidisciplinary team (composed of endocrinologists, nurse educators, dietitians, social workers, and psychologists) must function as a system integrator, bridging the gap between clinical complexity and the child’s social and educational existence. When comprehensive, holistic psychosocial support is lacking, high-fidelity adherence often fails, demonstrating that advanced technology alone cannot overcome the behavioral and social demands of chronic disease management.18
Sustained, high-level glycemic control is the primary mechanism for reducing the risk of both microvascular and macrovascular complications. Evidence strongly correlates poor glycemic control experienced early in life with the subsequent development of microvascular disease, highlighting the long-lasting detrimental "legacy effect" of early hyperglycemia.
A significant concern emerging from long-term follow-up studies is the aggressive complication profile of childhood-onset T2D. Data suggest that T2D diagnosed in children is associated with an earlier onset of both microvascular (nephropathy, retinopathy, neuropathy) and macrovascular (cardiac, cerebrovascular, peripheral vascular) diseases and is ultimately considered more hazardous and lethal than T1D. This finding elevates the clinical urgency for both accurate early diagnosis and sustained, stringent management of T2D in children.
Prevention efforts require both strict glycemic targets and aggressive management of all associated risk factors.
Microvascular Risks: These complications include retinopathy, nephropathy, and neuropathy. Prevention involves intensive glucose management, early screening for microalbuminuria (a marker of nephropathy) 19, and annual comprehensive ophthalmology examinations. The focus on maintaining a stable HbA1c trajectory, rather than just an isolated low value, is essential for mitigating the development of vascular disease.
Macrovascular Risks: The risk of cardiovascular events is significantly increased in childhood-onset diabetes, particularly T2D, due to its strong association with metabolic syndrome components.3 Prevention necessitates aggressive identification and treatment of comorbidities, including hypertension, dyslipidemia, and obesity.3
Screening for chronic complications must be initiated in a timely manner, dictated by the diabetes type and duration. For T1D, standard recommendations typically suggest initiating microvascular screening five years after diagnosis or at the onset of puberty. However, given the high prevalence of comorbidities and the often-delayed recognition of T2D, screening for complications in childhood-onset T2D must generally begin immediately upon diagnosis, regardless of disease duration.19 Prevention relies on sustained vigilance in maintaining optimal glycemic metrics (high TIR) and ensuring that multidisciplinary care addresses both the acute metabolic demands and the long-term cardiometabolic risk profile.
Diabetes mellitus in the child population demands a high degree of diagnostic acuity, personalized therapeutic planning, and robust technological integration. The rising burden of T2D and the chronic challenge of MODY misdiagnosis necessitate standardized algorithms that aggressively pursue differential diagnosis using clinical presentation, biomarkers, and genetic testing where indicated. Modern care for T1D is optimized by Automated Insulin Delivery systems, which achieve superior outcomes by focusing on dynamic metrics like Time in Range (TIR), thereby offering the best prospect for mitigating microvascular complications linked to early poor control. Crucially, the severe and accelerated long-term morbidity associated with childhood-onset T2D demands immediate and highly aggressive management of all cardiometabolic risk factors upon diagnosis. Ultimately, sustained success relies not only on technology but on the foundational element of holistic, individualized care, ensuring that comprehensive psychosocial and educational support is continuously adapted to the child’s developmental stage within their environment.
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