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

2 Type 1 Diabetes and Its Etiology
The pancreas consists of an exocrine gland and an endocrine gland, of which only the
endocrine gland is of any concern to us. The endocrine part consists of between 5×10 5 -
1 × 10 6 islets of Langerhans, which in turn are constituted by different cell types. The
cells of the pancreas we are interested in are the β-cells. They make up around 75%
of the total number of cells in the islets of Langerhans which comes to about 500-1000
β-cells per islet Verchere (2009).
Postcibal 1 the β-cells are stimulated to secrete insulin, to maintain homeostasis of the
blood glucose level (Seeley et al., 2008, p.632-639). Much has been unveiled in the field
of autoimmune diabetes during the past 20 years. These advances owe a great deal
to what in the field of medicine is known simply as models. These are essentially animal
models, i.e. an animal in which the development of diabetes resembles, or can be
made to resemble, that of the human development. From here on we call these models
bio-models so as not to confuse them with mathematical models. One such bio-model
that is particularly suitable, and also the most extensively used in T1D-research, is the
diabetes prone NOD mouse. This is because the development of diabetes in NOD-mice
resembles the human development in some key aspects (Höglund et al. (1999))(Cantor
and Haskins, 2006, p.381), such as presence of autoantibodies in the pancreas and autoreactive
T cells (Anderson and Bluestone (2005)).
The use of bio-models has led to the consensus of today which is that: T1D arises
when β-cells fall prey to an autoimmune response (Höglund et al. (1999), Green and
Flavell (1999), Yoon and Yun (2001), Notkins and Åke Lernmark (2001), Beyan et al.
(2002), Cantor and Haskins (2006) to name a few). This depletion leads to a lack of
endogenous insulin, which has a detrimental impact on the homeostasis of blood glucose,
and inevitably results in constant hyperglycemia, leaving the subject dependent
on exogenous administered insulin. Clinical symptoms of T1D, in humans, become
apparent when 60-90% of the β-cells have been depleted (Notkins and Åke Lernmark,
2001, p.1247)(Seeley et al., 2008, p.636). In the NOD-mouse strain about 80% of female
and 20% of male NOD-mice develop overt hyperglycemia, this happens at 30 weeks of
age (Sreenan et al., 1999, p.989).
The autoimmune response induces β-cell death either by apoptosis or necrosis. Apoptosis
is commonly described as “programmed cell death”. It entails an organized shuttingdown
of the cell (like the regulated shutting-down of a computer), where the cell shrinks,
and no or little cell-debris is spilled (Steer et al., 2006, p.254-257). The result of this
“quiet” death is that no inflammation ensues. Necrosis on the other hand is associated
with inflammation, and entails loss of cell-membrane integrity which implies spillage of
cell-debris (Steer et al., 2006, p.254).
1 After ingestion of nutrients.
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