Type 1 diabetes

Abstract

Type 1 diabetes is a chronic autoimmune disease characterised by insulin deficiency and resultant hyperglycaemia. Knowledge of type 1 diabetes has rapidly increased over the past 25 years, resulting in a broad understanding about many aspects of the disease, including its genetics, epidemiology, immune and β-cell phenotypes, and disease burden. Interventions to preserve β cells have been tested, and several methods to improve clinical disease management have been assessed. However, wide gaps still exist in our understanding of type 1 diabetes and our ability to standardise clinical care and decrease disease-associated complications and burden. This Seminar gives an overview of the current understanding of the disease and potential future directions for research and care.

Figure 1:. Challenges to the Eisenbarth model of the natural history of type 1 diabetes

Key events of the Eisenbarth model over the course of the disease (measured in years) are shown by dotted lines at different time points. Challenges to this model, taking into account the increasing complexity of type 1 diabetes, include the following: precipitating immune events that might occur prenatally (A); large variation in starting β-cell mass and function, defects in one or both could be developmentally programmed (B); initiation of autoimmunity is measured by autoantibodies, but other immunological abnormalities probably precede the presence of detectable pancreatic antibodies (C); the patient’s environment could affect their entire disease course (D); β-cell loss could relapse or remit (E); dysglycaemia occurs before clinical diagnosis (F); decline in β-cell function might not mirror decline in β-cell mass—methods to measure β-cell mass have not been established (G); and residual C-peptide is detectable in many people who have long duration type 1 diabetes (H). Furthermore, progression through stages A–C is heterogeneous, and will be affected by immune, genetic, environment, and key demographic features (ie, age, body-mass index). Adapted from Atkinson et al.

Figure 2:. Factors contributing and disease progression to type 1 diabetes

(A) The probability of developing diabetes in childhood stratified by the number of islet antibodies. In a study by Zeigler and colleagues, 13 377 children were identified as at risk in the newborn or infant period on the basis of high-risk HLA genotypes or having a relative with type 1 diabetes, or both, and were followed-up regularly. The numbers at risk are the number of children receiving follow-up at ages 0, 5, 10, 15, and 20 years. Adapted from Ziegler et al with permission of the American Medical Association. (B) Type 1 diabetes progression and stages of type 1 diabetes. Stage 1 is the start of type 1 diabetes, marked by individuals having two or more diabetes-related autoantibodies and normal blood sugar concentrations. In stage 2, individuals have dysglycaemia without symptoms. Stage 3 is the time of clinical diagnosis. Reproduced from Greenbaum et al, with permission from the American Diabetes Association. T1D=type 1 diabetes.

Figure 3:. The immunopathogenesis of type 1 diabetes

The development of type 1 diabetes is thought to be initiated by the presentation of β-cell peptides by antigen-presenting cell (APCs). APCs bearing these autoantigens migrate to the pancreatic lymph nodes where they interact with autoreactive CD4+ T lymphocytes, which in turn mediate the activation of autoreactive CD8+T cells (A). These activated CD8+ T cells return to the islet and lyse β cells expressing immunogenic self-antigens on major histocompatibility complex class I surface molecules (B). β-cell destruction is further exacerbated by the release of proinflammatory cytokines and reactive oxygen species from innate immune cells (macrophages, natural killer cells, and neutrophils; C). This entire process is amplified by defects in regulatory T lymphocytes, which do not effectively suppress autoimmunity (D). Activated T cells within the pancreatic lymph node also stimulate B lymphocytes to produce autoantibodies against β-cell proteins. These autoantibodies can be measured in circulation and are considered a defining biomarker of type 1 diabetes (E).

Figure 4:. Pancreatic and islet abnormalities in type 1 diabetes

(A) Type 1 diabetes is characterised by a variety of abnormalities that involve both the islet and the exocrine pancreas. The hallmark of type 1 diabetes is loss of insulin-producing β cells and immune infiltration of islets. However, the presence of insulitis, even within an individual pancreas, can be highly variable. (B) Immunofluorescent image of an insulitic islet from a cadaveric donor with long-term type 1 diabetes. Insulin is shown in blue and CD8+ T cells surrounding the islet are shown in yellow. (C) Haematoxylin and eosin staining of an islet from a cadaveric donor that exhibits a classic pattern of insulitis. The islet is circled with a yellow dotted line. The infiltrating immune cells are circled in red and indicated by arrows. (D) Haematoxylin and eosin staining of an islet, circled in yellow dotted line, from a cadaveric donor with long-term type 1 diabetes without any discernible immune infiltrate. By contrast with the islet in (C), this islet has evidence of peri-islet fibrosis as shown circled in red and indicated by arrows. Images B–D courtesy of M Campbell-Thompson, University of Florida, Gainesville, FL, USA.

Figure 5:. Glucose concentrations in patients with type 1 diabetes with a hybrid closed-loop system, before and after use, over 24 h

Sensor glucose profiles from 124 people with type 1 diabetes, of which 30 were adolescents (14–21 years; A) and 94 were adults (22–75 years; B), before (during run-in phase) and during the study phase using the Medtronic MiniMed 670 g hybrid closed-loop system (Medtronic, Northridge CA, USA) under clinical trial conditions. Median and IQR of sensor glucose values are given as a green line and band for the run-in phase, and a pink line and band for the study phase, respectively. In the run-in phase, the hybrid closed-loop system was in manual mode, with participants making all treatment decisions except for the pump automatically suspending before senor glucose concentrations became too low. In the study phase, the hybrid closed-loop system was in auto mode. Participants had less variability in their blood glucose concentration during auto mode. Reproduced from Garg et al, with permission from Mary Ann Liebert.