J Korean Med Assoc.  2009 Jul;52(7):677-687. 10.5124/jkma.2009.52.7.677.

Type 1 Diabetes Mellitus

• Lee MS
• Kim KA

• KMID: 2188028
• DOI: http://doi.org/10.5124/jkma.2009.52.7.677

Abstract

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by selective autoimmune- mediated destruction of pancreatic islet beta- cells leading gradually to absolute insulin deficiency. T1D is under polygenic control. The HLA complex attributes 50% of the genetic risk for T1D while as many as 20 genes influence susceptibility to T1D. The autoimmune beta-cell destruction could be triggered by environmental factors. While the exact trigger of anti-islet autoimmunity remains elusive, it can lead to an imbalance between regulatory T cells and autoimmune effector T cells. During the initiation of insulitis, emerging evidences suggest that the infiltrating macrophages via toll-like receptor 2 (TLR2) activation lead to induction and amplification of insulitis. Following the priming of diabetogenic T-cells, autoreactive T effector cells destroy the beta cells by direct contact- dependent cytolysis or by soluble mediators secreted from macrophages or CD4 T effector cells. The hyperglycemia occurs late in its course after 80% of the beta cells have been destroyed. Although no current cure exists, refinement of genetic studies and islet autoantibodies has improved the ability to predict the risk of T1D and aid the establishment of rationally designed preventive therapies. Other strategies involve beta-cell replacement by islet transplantation. Extensive and long-term research on the efficacy of islet transplantation and preservation of beta-cell function is keenly needed.

Keyword

Pancreatic beta-cell; Type 1 diabetes mellitus; Innate and adaptive immunity; Insulitis; Apoptosis; Preventive trial

MeSH Terms

Apoptosis
Autoantibodies
Autoimmune Diseases
Autoimmunity
Diabetes Mellitus, Type 1
Hyperglycemia
Insulin
Islets of Langerhans
Islets of Langerhans Transplantation
Macrophages
T-Lymphocytes
T-Lymphocytes, Regulatory
Toll-Like Receptor 2
Autoantibodies
Insulin
Toll-Like Receptor 2

Figure

• 

  Figure 1. Overview of the natural history of T1D and intervention trials according to the disease stage. Also shown are the proposed roles for innate immunity in triggering of autoimmune diabetes. Accumulation of damaged β-cells can stimulate APCs via TLR2, thus allowing them to prime diabetogenic T cells in pancreatic lymph nodes (PLN). Once sensitized, autoreactive T cells may migrate to the PLNs and induce β-cell apoptosis by direct cytolysis or indirectly via soluble mediators such as IFN-γ, TNF-α or IL-1β. In IFN-γ/TNF-α synergism model for β-cell apoptosis, CD4+T cells act in collaboration with macrophages to induce β-cell death. NF-KB is activated by IL-1β or TNF-α. When activated by IL-1β, NF-KB plays a proapoptotic role by producing nitric oxide. In contrast, NF-KB activation by TNF-α plays an antiapoptotic role by inducing antiapoptotic molecules such as XIAP that inhibits caspases. STAT1 activated by IFN-γ inhibits translation of antiapoptotic proteins.

Reference

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