Earlier identification of patients at risk of type 1 diabetes (T1D)

An estimated 2.07 million Americans have T1D, including nearly 300,000 children and adolescents.¹ While T1D has traditionally been thought of as a childhood disease, ≥50% of T1D cases are diagnosed during adulthood,² prompting the need for increased education and screening for this condition.

While T1D arises through an interaction of genetic and nongenetic factors, 90% of T1D patients do not have a family history of the disease.³ This adds to the challenge of detecting risk in the presymptomatic stages.

To support earlier diagnosis and intervention, the American Diabetes Association supports screening for T1D using autoantibody testing for individuals at risk for T1D. Autoantibody testing can enable physicians to identify T1D earlier, even before symptoms develop. This gives physicians the opportunity to provide more timely, effective interventions, increasing the possibility of preventing complications.

In this article:

Clinical challenge | Why it matters | Ordering recommendations | Supporting resources

Clinical challenge: Identifying T1D before complications including diabetic ketoacidosis (DKA)

T1D is characterized by autoimmune destruction of insulin-producing pancreatic β cells, progression to hyperglycemia, ketoacidosis, and a need for exogenous insulin (stage 3). T1D was historically known as “juvenile diabetes,” but epidemiological data shows that adult-onset T1D is more common than childhood-onset T1D.²

The most frequent clinical presentation consists of increased thirst, frequent urination, and weight loss,⁴ but up to 30% of all children diagnosed with T1D present with diabetic ketoacidosis (DKA).⁵ This number goes up to 50% in children with poor socioeconomic backgrounds.⁶ This advanced-stage presentation is a medical emergency requiring ICU hospitalization, and it predisposes patients to poorer health consequences—including higher lifetime HbA1C and adverse impacts on memory and IQ. Because 90% of T1D patients do not have a family history,³ patients and their families may not recognize the severity of the situation until urgent hospitalization is required.

Clinical presentation of T1D may vary with age and differ from T2D. Adults tend to have more gradual onset of symptoms, making it hard to differentiate T1D from T2D.² Because of this, up to 40% of adults diagnosed with T1D were originally misdiagnosed as T2D.² This can lead to years of mistreatment and even multiple incidences of DKA.⁷ Adult-onset T1D is usually distinguished from T2D by leaner body mass, family history of diabetes, more rapid progression to insulin dependence, and comorbidities (eg, cancer treatment with immune checkpoint inhibitors or a triggering infection, such as COVID-19).⁸ However, because insulin resistance, obesity, and other metabolic abnormalities are becoming increasingly more common in the general population, they alone are not enough to rule out T1D.⁸

A hallmark of T1D is its association with autoantibodies (also called islet autoantibodies or IAbs) targeting insulin, tyrosine phosphatase-related islet antigen 2 (IA-2), zinc transporter 8 (ZnT8), and glutamic acid decarboxylase-65 (GAD). Using these four antibodies together (Table 1),^9-12 T1D can be diagnosed in 93% to 98% of symptomatic patients.^13-15 On this basis, the American Diabetes Association recommends screening for T1D using these markers, especially among patients who are at risk (eg, family history of T1D).⁸

Why it matters: Earlier identification of autoantibodies can increase opportunities to prevent T1D complications

Autoantibody screening over the past few decades has helped identify individuals at high risk of developing T1D, and such monitoring has been shown to significantly reduce the incidence of DKA at T1D diagnosis.^16-21 The introduction of islet autoantibody (IAb) screening for T1D has also helped researchers understand that immune system–mediated destruction of β cells begins long before the onset of symptoms and abnormal blood sugar levels.

Early identification and regular follow-up of individuals who test positive for autoantibodies are associated with lower rates of DKA (2%-3% vs 18%-29%).^22,23 Early identification is also associated with lower long-term HbA1c levels and risk of complications.²⁴ In addition, these advances and the positive results of the TN10 prevention trial with teplizumab have created opportunities to prevent T1D and its complications.²⁵

Ordering recommendations: Autoantibody panel

The American Diabetes Association supports using autoantibody (AAb) screening to diagnose T1D.⁸ T1D autoantibodies are markers of ongoing damage to insulin-producing beta cells. The four AAbs used in clinical practice to diagnose T1D are: AAbs against insulin (IAA), tyrosine phosphatase IA₂ (IA₂A), glutamic acid decarboxylase (GAD65), and zinc transporter 8 (ZnT8). Numerous clinical trials demonstrate important clinical benefits associated with detecting T1D using an AAb screening approach.²⁶

The recommendation is to use all 4 IAbs (ie, IA₂, GAD65, IAA, and ZnT8) for T1D screening, diagnosis, and differential diagnosis from other types of diabetes mellitus. Testing all 4 IAbs at once provides the highest sensitivity for detecting the presence of at least two positive autoantibodies,²⁷ which is associated with the eventual development of T1D.²⁸ The American Diabetes Association and European Association for the Study of Diabetes have recently published guidelines for monitoring individuals with islet autoantibody‑positive pre‑stage 3 T1D.²⁹ Besides discussing modalities to manage clinically iAb+ patients, these guidelines give particular emphasis to providing these patients with educational and psychological support.

Recommended test: Diabetes Type 1 Autoantibody Panel

Test code: 13621

Panel components may be ordered separately: Glutamic Acid Decarboxylase-65 Antibody (34878), Insulin Autoantibody (36178), IA-2 Antibody (37933), Zinc Transporter 8 (ZnT8) Antibody (93022).

Clinical use

• Diagnose type 1 diabetes (T1D) in symptomatic children and adults
• Differentially diagnose T1D vs type 2 diabetes (T2D)
• Screen and assess risk for development of T1D in presymptomatic individuals
• Determine eligibility for teplizumab therapy or clinical trials for new therapies that delay onset of clinical diabetes

Individuals suitable for testing

• Patients with diabetes of uncertain etiology
  • Younger patients (< 35 years) with atypical diabetes
  • Patients with ketosis-prone diabetes that is not clearly type 1 diabetes
  • Patients suspected of having maturity-onset diabetes of the young (MODY)
  • Patients with gestational diabetes (helps clarify risk of future diabetes)
• Obese patients with acute-onset diabetes with ketoacidosis
• Lean patients with nonketotic diabetes
• Presymptomatic patients who are at risk of T1D (eg, based on family history of autoimmune diabetes) or who have previously had a positive test result for ≥1 T1D autoantibody
• Patients ≥ 8 years old being considered for teplizumab therapy

Supporting resources