Genetics, pathogenesis and clinical interventions in type 1 diabetes

Abstract

Type 1 diabetes is an autoimmune disorder afflicting millions of people worldwide. Once diagnosed, patients require lifelong insulin treatment and can experience numerous disease-associated complications. The last decade has seen tremendous advances in elucidating the causes and treatment of the disease based on extensive research both in rodent models of spontaneous diabetes and in humans. Integrating these advances has led to the recognition that the balance between regulatory and effector T cells determines disease risk, timing of disease activation, and disease tempo. Here we describe current progress, the challenges ahead and the new interventions that are being tested to address the unmet need for preventative or curative therapies.

Figure 1. Markers of diabetes

a, Typical child followed from birth until development of diabetes in the DAISY (Diabetes Auto Immunity Study in the Young; http://www.uchsc.edu/misc/diabetes/Teddy/DAISY/DAISY_home.htm) study (M. Rewers, unpublished work), expressing multiple autoantibodies (GAD, the islet cell antibody ICA512 and low-level insulin autoantibodies). b, Islet invasion by lymphocytes of NOD mice is asynchronous during progression to diabetes, often with a mixture of normal islets, peri-insulitis, intra-islet insulitis, and complete β-cell destruction. c, Pathology of the pancreas in a long-term type 1 diabetic (the nPOD program, pancreas 6028, see http://www.jdrfnpod.org/). The section shows lobular areas in which all β-cells (insulin-producing) in all islets have been destroyed (pseudoatrophic islets in which only glucagon, somatostatin, and pancreatic polypeptide cells are present) juxtaposed with regions in which all islets contain insulin-containing β-cells.

Figure 2. Immunologic history of type 1 diabetes

An as-yet-undefined immunologic insult occurs in an individual with genetic predisposition and initiates a chronic low-grade immunologic process (priming). The initiating events involve infiltration of innate immune cells (such as monocytes and natural killer cells with autoreactive B cells) (orange ovals) into the pancreatic islets. The principal site of antigen presentation is thought to be the pancreatic lymph node where islet antigens are presented by antigen-presenting cells (white ovals) to T cells (brown dots). Blue ovals are antigen-presenting cells loaded with islet antigens. B cells (green dots) and dendritic cells may be among the early antigen-presenting cells. The cellular infiltration of islets ensues but the insulitis is uneven. Islets with infiltration may be situated near to islets without cells. The process specifically targets insulin-producing β-cells (light blue circles), while other endocrine cells (red circles) within the islet are spared. In the lymph nodes, the cycle of antigen presentation, activation of adaptive immune cells, licensing of effector T cells and epitope spreading continues with the loss of β-cells over time. There is evidence for a regenerative attempt of β-cells in the midst of the islet inflammation (dark blue circles). Tertiary lymphoid organs are thought to develop within the islets, which may lead to amplification of the adaptive immune response. Regulatory T cells (yellow dots) may arrest this process in its early and late stages but are not able to contain the amplified process in the late stages despite an increase in their numbers. With continued loss of β-cells, hyperglycaemia can be detected. The loss of metabolic function at presentation may be both functional and anatomic, because immune therapies can restore cells that have lost the capacity to produce insulin but have not been destroyed. Without intervention, however, β-cell loss continues.

Figure 3. Immune system balance is key to disease pathogenesis

This schematic illustrates the fine balance of immune regulation versus pathogenesis, highlighting a number of genes that are likely to influence the balance through effects on central and peripheral tolerance and the environmental factors that control immunity. The key cell types that affect the balance locally during immune responses are listed (with the regulatory cytokines and proteins given in parentheses). iNOS, inducible nitric oxide synthase. IDO, indoleamine-2,3 dioxygenase.

Figure 4. Targets of immune intervention in type 1 diabetes

This schematic provides an overview of the pathogenesis of type 1 diabetes, highlighting a number of key pathways that are being targeted by current therapeutics. Although not exhaustive (see Supplementary Table 1), this figure shows that both non-specific and antigen-specific therapies are being tested, which inhibit effector cells and antigen presentation as well as boost regulatory pathways. Purple and green dotted arrows indicate the therapeutics, black arrows are immune and metabolic pathways; a green dotted arrow indicates a positive effect and a purple dotted arrow indicates a negative effect. In addition, these immunotherapies are being combined with drugs that promote β-cell survival to potentially replenish insulin-producing β-cells. The figure has been redrawn after ref. , with permission.