Redefining type 1 diabetes: Early identification, staging, and clinical implications for pediatric care

Abstract

For over 100 years, type 1 diabetes (T1D) has traditionally been diagnosed and treated at the onset of symptomatic hyperglycemia, often accompanied by severe disease, including life-threatening diabetic ketoacidosis (DKA). However, advances in understanding the natural history of T1D have revealed a prolonged presymptomatic phase characterized by progressive autoimmune destruction of insulin-producing pancreatic beta cells. The staging classification system endorsed by the American Diabetes Association (ADA) and the International Society for Pediatric and Adolescent Diabetes (ISPAD) delineates three distinct stages of T1D based on autoantibody status, glycemic parameters, and clinical symptoms. This framework has transformed T1D from an acute-onset condition to a chronic autoimmune process with opportunities for early intervention to include a disease-modifying therapy. This review examines the current evidence supporting T1D staging, discusses clinical monitoring recommendations, and explores the emerging role of disease-modifying therapies in both asymptomatic and symptomatic disease.

The 3-stage classification and teplizumab redefine type 1 diabetes as a predictable and actionable disease process

Type 1 diabetes (T1D) is a chronic, immune-mediated disease characterized by the progressive destruction of insulin-producing pancreatic beta cells, culminating in absolute insulin deficiency and lifelong dependence on exogenous insulin therapy. Historically, T1D diagnosis occurred clinically at the onset of overt hyperglycemia, when approximately 80% to 90% of beta cell mass had already been destroyed.¹ This reactive symptom-based diagnostic approach often results in severe metabolic decompensation requiring intensive care with diabetic ketoacidosis (DKA) presenting in up to 40% to 60% of newly diagnosed children.²

The recognition that islet autoimmunity precedes clinical diabetes by months to years has fundamentally reshaped our conceptual framework for diagnosing type 1 diabetes (T1D). Population-based studies and natural history cohorts have demonstrated that individuals with confirmed multiple diabetes specific autoantibodies face a near-certain lifetime risk of developing clinical diabetes requiring exogenous insulin for survival.³ The relatively recent 3-stage classification system for T1D, endorsed by both the ADA and ISPAD, provides a structured approach to identifying and monitoring individuals before the onset of symptomatic disease.⁴ With the higher incidence of T1D versus T2D in children compared to adults, autoantibodies (AAbs) are routinely checked with a new diagnosis of diabetes. However, even recent ADA guidelines recommend diabetes specific autoantibody testing in adults with a new diabetes presentation, as ~40% of adults with clinical T1D are initially misdiagnosed as having T2D, resulting in delayed insulin initiation and increased risk of metabolic decompensation. In 2024, the CDC approved new ICD-10 codes for T1D staging (E10.A1, E10.1), supporting standardized documentation and surveillance.⁵

This T1D staging paradigm has gained clinical relevance with the recent approval of teplizumab, the first disease-modifying therapy capable of delaying progression to Stage 3 T1D in individuals with Stage 2 disease.⁶ As screening programs expand and therapeutic options emerge, understanding the clinical characteristics, progression risk, and monitoring recommendations for each stage has become essential for pediatric specialists caring for children.

Type 1 diabetes in U.S. children continues to rise, intensifying health and economic strain

The burden of disease in pediatric patients in the United States is overwhelming, not only to the patients, their families, and communities, but also to society and financially to healthcare systems. According to the most recent CDC surveillance data through 2019, the incidence of type 1 diabetes among US children and adolescents under 20 years has continued to increase, with the largest proportional rises observed in non-Hispanic Asian or Pacific Islander, Hispanic, and non-Hispanic Black populations, while non-Hispanic White youth have maintained the highest incidence across all reporting years.⁷ Hospitalizations for diabetes rank as the third leading cause among children aged 10 to 14 years and the fourth among adolescents aged 15 to 18 years, surpassing hospitalization rates for asthma. This accounts for approximately $425 million in annual hospital care in the United States.⁸

Children diagnosed with Stage 3 before age 10 may lose up to 16 years of life expectancy.⁹ Beyond the immediate costs of diagnosis and hospitalization, the lifetime economic burden of T1D is staggering. Each person with T1D incurs an additional lifetime healthcare cost of roughly $500,000.

These statistics highlight why early detection and prevention strategies represent not merely incremental improvements in diabetes care, but potentially transformative interventions with substantial individual, societal, and economic implications.

Early detection of type 1 diabetes enables timely intervention across progressive stages of autoimmunity and dysglycemia

Stage 1 T1D: Asymptomatic autoimmunity with normoglycemia

Stage 1 T1D is defined by the presence of 2 or more diabetes specific autoantibodies in the context of normoglycemia and absence of diabetes symptoms. There are 4 diabetes specific autoantibodies, including autoantibodies against insulin (IAA), glutamic acid decarboxylase (GAD65), insulinoma-associated protein 2 (IA-2), and zinc transporter 8 (ZnT8).

The presence of multiple autoantibodies carries profound prognostic significance. Longitudinal studies have demonstrated that individuals with two or more autoantibodies have an approximately 44% risk of progressing to clinical diabetes requiring exogenous insulin within 5 years, with lifetime progression risk approaching 100%.³

From a clinical standpoint, Stage 1 represents a window of opportunity for metabolic monitoring, family education, and potential therapeutic intervention. Individuals identified at this stage can be given expectations to prepare to manage the disease, and most importantly, counseled about recognizing symptoms, which reduces the likelihood of a severe presentation like DKA at the time of clinical diagnosis.¹⁰ (Figure 1)

Stage 2 T1D: Asymptomatic autoimmunity with dysglycemia

Stage 2 T1D is characterized by the presence of two or more diabetes specific autoantibodies accompanied by dysglycemia—defined as impaired fasting glucose, impaired glucose tolerance on oral glucose tolerance testing (OGTT), or elevated HbA1c that does not meet diagnostic criteria for overt hyperglycemia. About 75% of patients in stage 2 will be insulin dependent within 5 years.¹¹

The identification of Stage 2 T1D has gained particular clinical importance following FDA approval of teplizumab for delaying the onset of Stage 3 disease. In the pivotal TN-10 trial, teplizumab delayed the median time to Stage 3 diagnosis by approximately 2 years with evidence of preserved beta cell function in relatives of T1D patients and Stage 2 disease compared to placebo after only one 14-day course of therapy.^6,12The disease-modifying effect was further demonstrated in an extended median follow-up of 6.7 years, where 36% of participants remained free of clinical diabetes compared to 12.5% of the placebo treated group, indicating a durable immune response consistent with operational tolerance.¹³

Stage 3 T1D: Symptomatic diabetes

Stage 3 T1D represents the traditional clinical diagnosis of T1D, characterized by overt hyperglycemia meeting standard diagnostic criteria (fasting plasma glucose ≥ 126 mg/dL, random glucose ≥ 200 mg/dL with symptoms, or HbA_1c ≥ 6.5%) and the presence of classic diabetes symptoms, including polyuria, polydipsia, polyphagia, and weight loss. At Stage 3, beta cell mass has declined to the point where endogenous insulin production is insufficient to maintain normoglycemia.

Early detection of type 1 diabetes (T1D) in children through diabetes specific AAb screening and subsequent metabolic monitoring is associated with improved clinical outcomes at diagnosis, most notably a reduction in the risk of diabetic ketoacidosis (DKA). (Figure 2)

Population-based autoantibody screening dramatically reduces DKA at type 1 diabetes diagnosis in children

The Autoimmunity Screening for Kids (ASK) study in Colorado provides compelling evidence for the impact of general population AAb screening and metabolic monitoring. In this cohort, ~60% of children diagnosed with T1D in the general population presented in DKA. Among those who underwent AAb screening and received counseling and metabolic monitoring, the rate of DKA at diagnosis was reduced by 93%, with DKA occurring in only about 5% of cases.²

Preventing DKA at diagnosis improves long-term glycemic control, beta cell preservation, and overall outcomes in type 1 diabetes

The prevention of DKA at diagnosis has significant implications for long-term glycemic control. Multiple large cohort studies have demonstrated that children who present with DKA at the onset of T1D have persistently higher HbA_1c levels for years after diagnosis, independent of demographic and socioeconomic factors or access to care. For example, DKA at diagnosis predicts a long-term mean increase in HbA_1c from 0.9% (mild/moderate DKA) to 1.4% (severe DKA) compared to those without DKA, with this difference persisting for up to 15 years.¹⁴

Early glycemic control and beta cell preservation are critical for long-term outcomes in type 1 diabetes

Mechanistically, DKA at diagnosis is associated with a greater loss of residual beta cell function, as evidenced by lower C-peptide levels and higher insulin requirements in the years following diagnosis.¹⁵ The acute metabolic stress and systemic inflammation of DKA are thought to exacerbate autoimmune destruction of pancreatic islets, leading to diminished endogenous insulin secretion and impaired glycemic regulation.¹⁶

Importantly, early and sustained glycemic control is a key determinant of long-term outcomes in clinical T1D. The Diabetes Control and Complications Trial (DCCT) and subsequent studies have established that even modest reductions in HbA1c translate into substantial reductions in the risk of microvascular complications, including retinopathy, nephropathy, and neuropathy.¹⁷ For example, a 1.4% difference in HbA_1c, as observed between children with and without DKA at diagnosis, is associated with an approximately 50% reduction in the risk of retinopathy.¹⁸ Furthermore, better preservation of beta cell function is associated with a lower risk of severe pathological hypoglycemia and improved metabolic stability.

Early autoantibody screening reduces health care costs and eases the psychosocial burden of type 1 diabetes diagnosis

AAb screening is cost-effective in settings with high DKA rates, as it leads to improved long-term glycemic control (as measured by HbA_1c) and reduces acute care costs.¹⁹ The prevention of DKA episodes not only avoids immediate life-threatening complications but also reduces the substantial healthcare expenditures associated with intensive care unit admissions, emergency department visits, and prolonged hospitalizations.²⁰

Early identification of earlier stages of asymptomatic T1D allows children and their families more time to receive education, counseling, and support before the onset of symptoms and the need for insulin therapy, which can reduce the psychological burden and anxiety experienced at the time of this life-changing diagnosis.

Autoantibody screening enhances diagnostic accuracy and enables timely intervention in pediatric diabetes

Race, ethnicity, gender, age, and BMI are not accurate predictors of type 1 diabetes. AAb screening serves as an important diagnostic tool in pediatrics, helping to distinguish autoimmune T1D from monogenic diabetes caused by genetic abnormalities, and type 2 diabetes with insulin resistance, ensuring timely and appropriate intervention.

Growing global and U.S. support for universal early screening to identify type 1 diabetes before symptom onset

Current ADA and ISPAD recommendations support diabetes-specific autoantibody screening primarily for individuals at increased risk, such as first-degree relatives of those with T1D. However, because only about 10% of newly diagnosed children have an affected family member, this approach misses the majority who remain at risk for severe disease, including DKA at presentation, due to delayed recognition.

Population-based screening initiatives, including the Fr1da study in Bavaria, Germany, and the ASK program in Colorado, have demonstrated that large-scale screening for type 1 diabetes is both feasible and well accepted.

The European Association for the Study of Diabetes (EASD) panel recommends that, where policy and infrastructure are in place, screening using commercially available AAb assays should be offered to the general population. Screening should begin with children aged 2-4 years.²¹ If the AAb is negative, it should be repeated between ages 6-8 years and again at ages 10-15 years. Barbara Davis Center recommends universal screening for T1D in 3 age groups: 1 to 3 years, 4 to 6 years, and 9 to 11 years, aligning these time points with routine pediatric capillary and serum blood draws for other standard screenings. (Table 1)

National advocacy efforts are advancing universal early screening for type 1 diabetes in pediatric care

The momentum toward broader general population screening is gaining traction in the United States. Breakthrough T1D, formerly JDRF, has submitted an application to the U.S. Preventive Services Task Force (USPSTF) advocating for universal screening for early-stage type 1 diabetes to be incorporated into routine pediatric care visits.²² Additionally, a policy statement is under review by the American Academy of Pediatrics (AAP) that would endorse ISPAD and ADA guidelines for early T1D screening and staging. (Table 2)

Structured monitoring and early intervention protocols optimize outcomes across stages of type 1 diabetes progression

Comprehensive monitoring and family education are essential for managing stage 1 type 1 diabetes

For individuals with Stage 1 T1D, monitoring recommendations typically include periodic assessment of glycemic status through HbA_1c measurement and/or oral glucose tolerance testing at intervals ranging from age 3 to 12 months, depending on risk factors and local protocols. More frequent monitoring is recommended for younger children or individuals with additional risk factors concerning rapid progression.

Beyond metabolic monitoring, clinical care for Stage 1 individuals should include comprehensive education about T1D symptoms, guidance on when to seek medical attention, and psychosocial support for families navigating the uncertainty of presymptomatic disease and anticipating the need for exogenous insulin. (Table 3)

More intensive monitoring and early intervention are central to managing stage 2 type 1 diabetes

Stage 2 T1D warrants more intensive monitoring given the substantially higher short-term progression risk. Ongoing surveillance for metabolic decompensation in the clinic should include some form of glucose monitoring, including HbA_1c measurements. Most protocols incorporate home blood glucose monitoring to include continuous glucose monitoring (CGM) to detect evolving hyperglycemia between clinic visits. Clinic visit frequency depends on the patient’s age.

For individuals identified with Stage 2, discussion of the disease-modifying therapy, teplizumab, should be a key element of clinical management and patient counseling. The family should also be supported within a collaborative model of care that offers access to a pediatric diabetologist for early consultation. The Ask the Experts program, led by specialists at the Barbara Davis Center, was created for this consultation without charge, supported by a grant provided by the Helmsley Charitable Trust.

Targeted monitoring strategies guide care for individuals outside the standard type 1 diabetes staging framework

• Dysglycemia with negative AAbs - Hemoglobin A_1c every 3 months (American Academy of Pediatrics) and repeat AAb every 6 to 12 months times 3 (author's practice), depending on risk.
• One Positive AAb and normoglycemia - Repeat HbA_1c, random glucose, and AAbs every 6-12 months for ~3 years, dependent on age⁴
• One Positive AAb and dysglycemia - Repeat HbA_1c, random glucose every 3 months, and AAbs as needed for diagnosis or treatment eligibility. (K.M. Simmons, Barbara Davis Center, written and oral communication, October 2025)

Teplizumab marks a turning point in type 1 diabetes care, expanding therapeutic focus from prevention to early intervention

The approval of teplizumab for delaying the onset of Stage 3 T1D in individuals with Stage 2 disease represents a watershed moment in T1D care, transforming presymptomatic staging from a primarily observational framework to an actionable clinical paradigm. Recent evidence and FDA prioritization efforts suggest that teplizumab’s role may soon extend into early Stage 3 disease, where preserving residual β-cell function at the time of symptomatic presentation could alter the standard of care. This expansion would require pediatricians, pediatric endocrinologists, and emergency physicians to consider immune therapy alongside insulin initiation, reflecting a fundamental shift in early management strategy.²³

Beyond teplizumab, numerous immunomodulatory and beta-cell protective therapies are under investigation for both the prevention or delay of T1D but also for beta-cell preservation at clinical diagnosis. These include antigen-specific immunotherapies, combination immunomodulatory approaches, and other agents targeting beta-cell stress and inflammation. The inclusion of Stage 3 patients in emerging trials underscores a broader transition toward intervention at clinical diagnosis when symptoms present rather than prevention alone in an asymptomatic stage.

Presymptomatic staging and emerging immunotherapies are redefining the standard of care in type 1 diabetes

The three-stage classification system for T1D represents a paradigm shift from reactive diagnosis at symptomatic presentation to proactive identification and monitoring of asymptomatic disease. Stage 1 and Stage 2 T1D define actionable clinical entities characterized by islet autoimmunity with or without dysglycemia, respectively, preceding the onset of Stage 3 symptomatic diabetes. Pediatric clinicians must recognize these early stages, enabling metabolic monitoring, family education, and an opportunity to discuss disease-modifying intervention.

The approval of teplizumab for Stage 2 T1D validates this approach and establishes presymptomatic staging as a clinically actionable framework rather than solely a research classification. Moreover, the prevention of DKA at diagnosis has profound implications for long-term glycemic control and preservation of residual beta cell function, with benefits extending years beyond initial diagnosis.

With the FDA Commissioner’s National Priority Voucher (CNPV) pilot program and recent prioritization of teplizumab, the treatment paradigm is shifting beyond prevention into early intervention at Stage 3.²⁴ Clinicians will soon be challenged to decide not only how quickly to initiate insulin, but whether to begin immune-modifying therapy in the same clinical window. Hospitals and clinics may need to adapt workflows for rapid antibody confirmation, family counseling, and therapy initiation, while payers and policymakers prepare for early-stage treatment adoption. This evolution redefines “standard of care” for T1D, transitioning from crisis stabilization to immune preservation. It marks a genuine step forward from tertiary prevention (managing complications) to secondary prevention (reducing DKA at diagnosis) and now to early intervention (altering disease trajectory at or soon after diagnosis).

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