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Diabetes in Humans
type 1, 2 and 3


Leo Rogier Verberne


10. The way juvenile diabetes develops

In juvenile diabetics, several gene-variants in the DNA code for different deviations in the immune system (2). Thus, there are various ways to develop T1D and at different speeds. But sooner or later T lymphocytes mistakenly detect insulin producing β cells in the pancreas as cancer cells or infected body cells and subsequently shut them down. Which is called an auto-immune reaction. It terminates monitoring of the blood glucose level and insulin production, leading to type 1 diabetes. So that auto-immune reaction in the pancreas is crucial, both to the development of T1D as well as to its cure.

Autopsy
The pancreas was examined in post mortems of 45 juvenile diabetic organ donors with various T1D durations, up to 56 years (1). Inflamed pancreatic islets appeared typically dominated by autoreactive CD8 T lymphocytes, causing CD8 insulitis in all T1D patients. Other leukocytes were more or less incidentally included. In 27 controls, derived from non-diabetics, T2D patients and gestational diabetics, no CD8 insulitis was found. So islet autoreactive (derailed) CD8 T cells are the key-evildoers in the shutdown of pancreatic β cells. Other leukocytes help to remove killed cells. Roep suggests that such CD8 T cells in type 1 diabetics might be suitable targets for immune intervention therapy in T1D (3).

Residual β cells
A second result of these post mortems on juvenile diabetics: many cases maintained a residual pool of functional β cells even after disease durations of more than 50 years (1). So, these residual β cells can restart insulin production, provided that all derailed CD8 T cells have been eliminated with efficient therapy. If the residual β cells sufficiently regenerate, then the supply of insulin will no longer be needed to keep the blood glucose concentration within normal limits. A supplementary provision of β cells by stem cells might be needed in some cases. Thus the effective elimination of autoreactive CD8 T cells will cure many of the juvenile diabetics.

Islet autoreactive CD8 T cells
CD8 T cells (Cluster of Differentiation 8) are part of the immune system. The prefix T refers to the thymus, a lymphoid organ that matures certain lymphocytes (6). It is situated inside the chest between the heart and the sternum. CD8 T cells are also known as cytotoxic T cells, cytotoxic T lymphocytes or killer T cells (4). They regularly shut down cancer cells, infected body cells (particularly with viruses) or cells that are damaged in other ways. However, if juvenile diabetic gene-variants in the DNA code for a derailed maturing of certain lymphocytes in the thymus, then islet autoreactive CD8 T cells develop, that shut down normal β cells in the pancreatic islets, as if they were cancer cells.

Thymus
The thymus enlarges during childhood, reaching its maximum weight (20 to 37 grams in humans) by one’s puberty (6). From then on it starts shrinking. At a later age, the residual thymus weight is only 6 grams, predominantly consisting of inactive, adipose tissue. So an individual’s supply of all kinds of T cells is built up early in life. That early shrinking of the thymus is an advantage for juvenile diabetics. Because, after a treatment that successfully eliminated the islet autoreactive CD8 T cells in the pancreas, the gene-variants in the DNA keep on coding for deviations in the immune system. But with increasing age, the thymus will hardly be able to respond to that coding and will stop producing islet autoreactive CD8 T cells. Thus the need for repeated elimination of those T cells in T1D patients will diminish after puberty.

Conclusions
1. In juvenile diabetes, several gene-variants in the DNA code for deviations in the maturing processes of lymphocytes in the thymus; which leads to the production of islet autoreactive CD8 T lymphocytes.
2. Islet autoreactive CD8 T cells mistakenly detect β cells in the pancreatic islets as cancer cells and shut them down; which is called an auto-immune reaction, leading to juvenile diabetes.
3. Elimination of islet autoreactive CD8 T cells will stop the auto-immune reaction in the pancreatic islets, thus stopping the shutdown of β cells.
4. Even after more than 50 years manifest juvenile diabetes, a residual pool of functional β cells is present in the pancreas; they will start to produce insulin again if all islet autoreactive CD8 T cells have been effectively eliminated.

References
1. Coppieters KT, Dotta F, Amirian N, Campbell PD, Kay TWH, Atkinson MA, Roep BO, von Herrath MG (2012) Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients
2. Hes FL en Breuning MH (2010) Klinische genetica In: Interne geneeskunde. eds. Stehouwer, Koopmans en van der Meer. 14e druk (2010); ISBN 978-90-313-7360-4; p 75-97
3. Roep BO (2008) Islet autoreactive CD8 T-cells in type 1 diabetes
4. Wikipedia.en (2016) Cytotoxic T cell
5. Wikipedia.en (2016) Immune system
6. Wikipedia.en (2016) Thymus

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© Leo Rogier Verberne
ISBN/EAN:978-90-825495-4-6
www.diabetesbook.org