The pathophysiology, presentation and classification of Type 1 diabetes

Abstract

Type 1 diabetes is characterised by the autoimmune destruction of pancreatic β-cells, leading to an absolute or near-absolute insulin deficiency. Although traditionally associated with childhood onset, it can manifest at any age, and it is increasingly recognised that there is significant heterogeneity in its clinical presentation. This review examines the intricate interplay between genetic susceptibility, environmental factors, and autoimmune mechanisms that contribute to the pathogenesis of type 1 diabetes. The role of clinical phenotype, along with diagnostic and clinical measurements of autoantibodies and C-peptide, in the classification of type 1 diabetes is discussed, alongside the challenges in diagnosing and classifying the disease. Emerging insights from studies into the heterogeneity of type 1 diabetes phenotypes and mechanistic endotypes underscore the need for refined diagnostic criteria, particularly in identifying autoimmunity in individuals initially diagnosed with type 2 diabetes. The impact of obesity and insulin resistance on disease progression and clinical management is also examined. Overall, this review aims to provide a comprehensive understanding of the evolving landscape of type 1 diabetes, highlighting critical areas for future research and potential therapeutic approaches tailored to individual patient profiles. PLAIN LANGUAGE SUMMARY: Type 1 diabetes is an autoimmune disease where the body does not produce insulin, leading to high blood sugar levels. Traditionally thought to start in children and young adults, type 1 diabetes can occur at any age. However, many factors contribute to when someone develops type 1 diabetes and how rapidly the disease progresses, including a person's combination of genetic factors, including specific genes that can either be protective or high-risk for the development of type 1 diabetes. Although it is widely assumed that a triggering event or events initiate the autoimmune process, the trigger or triggers remain unknown. However, it is this autoimmune process that causes progressive destruction of insulin-producing Β-cells in the pancreas that eventually leads to high blood sugar and the diagnosis of diabetes. Although we have several tools to diagnose and classify diabetes, including measuring autoimmune markers (antibodies) in the blood, there is significant variation in how individuals with type 1 diabetes can present, which can make recognizing and appropriately treating type 1 diabetes more challenging. Finding better ways to characterize the unique characteristics of each subgroup of individuals may provide new insights into how we can best tailor treatment to each of these patient groups.

Keywords: Type 1 diabetes; beta cell function; insulin resistance; islets.

FIGURE 1

Stages of type 1 diabetes with variability due to heterogeneity. This graph illustrates the functional β‐cell mass throughout the stages of type 1 diabetes (green curve), with influences from heterogeneity due to genetic, environmental, and developmental factors that can impact the establishment of β‐cell mass and functional maturation (blue curve). Genetic risk and potential environmental factors may influence susceptibility to the triggering event or events that initiate the β‐cell‐directed autoimmune process, with ongoing effects on the intensity of the autoimmune attack (grey curve) and contribution of insulin resistance (orange arrows) on timing of symptomatic presentation with dysglycaemia (blue dots) and hyperglycaemia (red dots). The blue, green, and grey shaded areas and curves represent the remaining insulin secretory capacity of β‐cells, with time on the x‐axis representing a broad range (which could be months or years, depending on the factors influencing the heterogeneity of the disease process and presentation). Refer to the text for a definition of the stages of type 1 diabetes.

FIGURE 2

Pancreas and islet changes during stages of type 1 diabetes disease progression. The progressive reduction in pancreas volume is illustrated at the top of the figure and occurs throughout the disease course, with changes noted even before the development of multiple autoantibodies (Stage 1) and continuing after diagnosis (Stage 3). Below the pancreas are schematics of pancreatic islets at each stage. Circulating islet autoantibodies that are markers of autoimmunity, but not cytotoxic, are present starting at Stage 1. However, negative seroconversions can occur, leading to decreased or undetectable antibodies by Stage 3 or in long‐standing type 1 diabetes. Cytotoxic immune cells can be present with scattered insulitis in Stages 1 and 2, leading to progressive loss of β‐cells. This insulitis is most prominent at Stage 3, but is not observed in long‐standing diabetes, despite some individuals retaining residual β‐cell function. C‐peptide levels also decrease throughout the stages, coinciding with the loss of β‐cells, and this leads to the development of dysglycaemia (Stage 2), which progresses to hyperglycaemia (Stage 3). Refer to the text for additional details.