nr. 477 - 2011 - Institut for Natur, Systemer og Modeller (NSM)

8 Type 1 Diabetes and Its Etiology
This much is understood and well documented today, but the exact etiology of T1D in
humans as well as NOD-mice is still a Nobel Prize away. In the following we shed light
on mechanisms, at a cellular level, that recent research has identified as crucial to the
development of diabetes. 2 Some of the findings are still a matter of debate, and to the
uninitiated it sometimes seems as though the ones who are “right” are the ones who
are most respected or are the most cited; e.g. Andrew C. Ivy’s rejection of the incretin
concept. We try to explain things without venturing too deep into the field of advanced
cellular biology – when it is necessary to use technical terms, these will be accompanied
by an explanatory footnote.
2.1 Prediction and Detection Using Autoantigens
Just as the old saying goes: there is no smoke without a fire, so there are no autoantibodies
without diabetes. 3 This may be an overstatement but there is some truth to
it, since 70-80 % of newly diagnosed patients have autoantibodies to the autoantigen 4
known as glutamic acid decarboxylase (GAD), approximately the same number are positive
for antibodies to another autoantigen called tyrosine phosphatase (IA-2) (Wong and
Jr., 1999, p.643)(Notkins and Åke Lernmark, 2001, p.1249), the remaining cases that
are not associated with antibodies for these two autoantigens can be ascribed to insulin
autoantibodies, and to a lesser extent autoantigens that are less frequent (Notkins and
Åke Lernmark, 2001, p.1248-1249). In total over 90 % of newly diagnosed T1D patients
are positive for autoantibodies (Pociot (2009)).
Insulin has been shown to be an autoantigen for the pathogenic T cells 5 CD4 + and
CD8 + (Wong and Jr., 1999, p.645) while GAD is an autoantigen to CD4 + but not
CD8 + in NOD-mice (Wong and Jr., 1999, p.644). Though the exact interaction between
autoantigens and immune cells is not fully understood (Yoon and Yun (2001)),
there are results that indicate a clear connection between GAD as well as insulin and
diabetes in NOD-mice (Yoon and Yun, 2001, p.202). Furthermore Notkins and Åke
Lernmark (2001) report of the presence of autoantibodies in humans long before the
onset of diabetes (Notkins and Åke Lernmark, 2001, p.1249), and further lists a number
of articles (e.g. Leslie et al. (1999)) that provide results that indicate how the presence
of one or more autoantibodies in a healthy person can be used to asses how likely said
person is to develop diabetes. This relation between autoantibodies and the risk of
developing diabetes is shown in figure 2.1. The y-axis represents the risk of developing
2 Though scientific evidence has been gathered that indicates that environmental factors also play
a part (Notkins and Åke Lernmark, 2001, p.1250)(Gianani and Eisenbarth, 2005, p.233)(Onengut-
Gumuscu and Concannon, 2006, p.634)(Yu and Eisenbarth (2006)) we omit these results, because they
are of no importance to the aim of this project.
3 Antibodies are proteins that can attach themselves to antigens (see next footnote) and cause them to
self-destruct (Seeley et al., 2008, p.661). Autoantibodies have the same function, but for autoantigens.
4 An antigen can be a virus, a bacteria or even drugs just to name a few; i.e. substances that cause
the immune system to react. An autoantigen, sometimes called a self-antigen, is an antigen produced
by the body itself (Seeley et al., 2008, p.798).
5 When an immature T cell is presented with an antigen it matures into either a helper T cell, also
called a CD4, or a cytotoxic T cell, also called a CD8. The respective cells are called so because they
“express” CD4 and CD8 (Seeley et al., 2008, p.802), for the same reason they are sometimes called
CD4 + and CD8 + T cells.