Type 1 Diabetes Mellitus

Myung-Shik Lee; Kyoung-Ah Kim

doi:10.5124/jkma.2009.52.7.677

J Korean Med Assoc > Volume 52(7); 2009 > Article

Lee and Kim: Type 1 Diabetes Mellitus

Focused Issue of This Month

J Korean Med Assoc 2009; 52(7): 677-687.

Published online: January 10, 2009

DOI: http://dx.doi.org/10.5124/jkma.2009.52.7.677

Type 1 Diabetes Mellitus

Myung-Shik Lee, MD, Kyoung-Ah Kim, MD

Department of Medicine, Sungkyunkwan University College of Medicine E-mail: mslee0923@skku.edu

Department of Medicine, Dongguk University College of Medicine E - mail: kyoung-ah.kim@duih.org

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.

Key words: Pancreatic beta-cell; Type1 diabetes mellitus; Innate and adaptive immunity; Insulitis; Apoptosis; Preventive trial

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.

Table 1.

Representative clinical trials for prevention of T1D

Agent/ Route	Study design	Results	Ref.
Primary Prevention:	To block autoimmunity	(at genetic risk)
TRIGR (Hydrolysed cow's milk)/Oral	- Test whether delayed exposure to intact food proteins will reduce the chances of developing T1D	Ongoing	(44) (45)
Oral insulin/Oral, Pre-POINT/ Intranasal insulin	- Dose finding in children with high genetic risk for T1D (Based on the beneficial effect of oral insulin (22))	Ongoing	(19, 20)
Secondary Prevention:	To block /S-cell destruction	(in prediabetes)
Insulin (DPT-1)/Parenteral (s.c. & i.v.)	- Low dose insulin injections in high-risk (50% over 5 years) 1^st-degree relatives of T1D patients	- No effect seen on disease prevention or delay the onset of disease	(21)
	-Screened 84,228 relatives for ICA - 3,152 ICA-positive - 372 relatives: risk projection for T1D > 50%(parenteral insulin group) - 388 relatives: risk projection for T1D of 26∼50% over 5 years (oral insulin group)
Insulin (DPT-1)/Oral insulin capsule	- In relatives at intermediate risk of T1D (ICA-and IAA-positive relatives with 25∼50% 5-year risk). - Based on the concept of oral tolerance	- No beneficial effect seen on disease progression - Post-hoc analysis; subgroup with confirmed IAA > 80 nU/mL showed a delay of diabetes of more than 4 years	(22)
The European Nicotinamide Diabetes Intervention Trial (ENDIT)/Oral	- ICA-positive, 1^st-degree relatives of individuals with T1D (projected 5-year risk of T1D was 40%). _st - Screened 35,000 1^st-degree relatives to identify eligible subjects. - Randomized 552 subjects	- No effect - 4 years of follow-up, 159 subjects developed T1D (82 in the nicotinamide group and 77 in the placebo group: P = 0.97).	(23)
Insulin (INIT I)/ Intranasal	- Older antibody-positive relatives	- No acceleration of loss of beta cell function - Show a skewing of the immune response consistent with tolerance induction	(46)
GAD-Alum Prevention Study	- Nondiabetic relatives of patients with T1D, age 3∼45, who are positive for GADA but not IAA	Ongoing	(20)
Tertiary Prevention:	To preserve S-cell function	(in overt T1D)
Insulin (DPT-1)/Oral Anti-CD3 mAb* (hOKT3r1 (Ala-Ala))/ i.v.	- Recent diabetes - At onset of type 1 diabetes (within 6 weeks of T1D diagnosis) - Age 8∼30, n= 24 or 42	- No difference in HbA1c, C peptide, insulin requirements - Significant preservation of C-peptide secretion for at least 1 year - Reduced insulin requirement & HbA1c	(47, 48) (17, 49)
Anti-CD3 mAb (ChAglyCD3 (TRX4))/ i.v.	- Newly diagnosed T1D - Age 12∼39, n=80	- Reduced insulin requirement out to 18 months (strongest effects in those with the greatest residual S-cell function at study entry)	(50)
rhGAD65 (alum)/s.c	- T1D and positive GADA (within 18 months of T1D diagnosis) - Age 10∼18, n=70	- After 15 months, preservation of residual insulin secretion, but did not change the insulin requirement	(18)

* mAb: monoclonal antibody, i.v.: intravenous, s.c.: subcutaneous

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