Clinical Presentation and Natural History of T1D

Type 1 diabetes (T1D) is a slowly progressive disease. It may take months or even years before symptoms severe enough for diagnosis develop, and by then patients are typically in a clinical crisis. However, multiple autoantibodies may be detected from a few weeks up to 20 years before the onset of clinical disease.1 Indeed, 90% of children who develop T1D before puberty have islet autoantibodies (IAbs) by 5 or 6 years of age, and many have IAbs by 2 years of age.2

The most common presentation of T1D in children is absolute insulin deficiency, leading to diabetic ketoacidosis (DKA), which has higher rates in African American and Hispanic children.3

The rate of β-cell destruction can vary significantly on both an individual level and across populations and age groups, with significantly faster progression at younger ages.1,6

It also differs between individuals, with environmental, physiological, and genetic factors determining functional β-cell mass and C-peptide levels, a marker of endogenous insulin production.1,4 A model about T1D natural history, originally proposed in 1986, describes a somewhat linear concept of progression, from genetic predisposition to a progressive loss of insulin release and development of T1D, and is shown in black in the figure below.4 However, recent research suggests a heterogeneity of the natural history and progression of T1D, which is noted in blue in the figure below, and has improved our understanding of T1D progression and opportunities for asymptomatic screening, early detection, and early treatment.4

Based on the improved understanding of T1D progression and on the idea that once an individual develops more than 1 islet autoantibody, they have a near 100% lifetime risk of clinical disease T1D is classified into 3 stages.4 All 3 stages are characterized by the presence of multiple islet autoantibodies (≥ 2) and differ in symptoms and glycemic status, as shown below. Stages 1 and 2 are asymptomatic, with normoglycemia in stage 1 and dysglycemia in stage 2. Stage 3 marks the onset of symptoms and clinical disease, with diabetes being diagnosed by standard criteria.4 Another stage, stage 4, was recently added to denote long-standing T1D, as described in the 2022 guidelines from the International Society for Pediatric and Adolescent Diabetes (ISPAD).5 Progressive loss of functional β-cell mass occurs across all stages but, as noted above, this can be highly variable among individuals.4 The timing of progression across stages is still unclear.1-4

References

  1. Ilonen J, Lempainen J, Veijola R. The heterogeneous pathogenesis of type 1 diabetes mellitus. Nat Rev Endocrinol. 2019;15:635-650.
  2. Ziegler A-G. The countdown to type 1 diabetes: when, how and why does the clock start? Diabetologia. 2023;66:1169-1178.
  3. American Diabetes Association. 2. Diagnosis and classification of diabetes: standards of care in diabetes 2025. Diabetes Care. 2025;48(suppl 1):S27-S49.
  4. Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet. 2014;383:69-82.
  5. Besser REJ, Bell KJ, Couper JJ, et al. ISPAD clinical practice consensus guidelines 2022: stages of type 1 diabetes in children and adolescents. Pediatr Diabetes. 2022;23:1175-1187.
  6. Greenbaum CJ, Bean CA, Boulware D, et al. Fall in C-peptide during first 2 years from diagnosis: evidence of at least two distinct phases from composite Type 1 Diabetes TrialNet data. Diabetes. 2012;61(8):2066-2073.

Etiopathogenesis

Clinical Features & Natural History

Early Screening & Detection

Delaying T1D Progression

Patient Support & Practice Implications

Reading & Resources

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This activity is supported by an educational grant from Sanofi US.
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