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

14 Prospects for Therapy – A Mini Review
third stage of T1D, at which point antigen therapy looses its applicability. Regeneration,
neogenesis and proliferation of β-cells are defining aspects of potential treatment
strategies.
Total depletion of β-cells delineates the fourth stage. Future possible courses of action
at this stage is to insert “immune-blind” β-cells and use intermittent immunotherapy,
i.e. stopping the autoimmune process.
Besides this brief introduction to the different strategies applicable to different stages
of the disease the following sections are reserved solely for strategies directed at autoimmunity
and β-cell destruction. We choose to do so because these are the most realistic
stages to aim at today, and they are the most relevant stages of the model of Marée
et al. (2006). Furthermore GLP-1 will be commented on most extensively simply because
articles on GLP-1 were most abundant.
Though different promising ideas for therapy have been proposed since the mid-eighties,
it is necessary to be cautious (Marée et al. (2006)) – the final section of this chapter is
reserved for a brief note on this.
3.2 Glucagon-Like Peptide 1
GLP-1 is an incretin peptide, i.e. it meets the criteria given in the introduction.
GLP-1 was interesting for T2D-patients from the point of its discovery (Nauck (1998)),
because it
• enhances glucose-stimulated postcibal insulin secretion,
• inhibits glucagon release and
• inhibits gastric emptying, and food intake (Brubaker and Drucker (2004)),
while it was not until the beginning of the 1990’s, that results emerged that suggested
that GLP-1 also had an effect in patients with T1D (Nauck, 1998, p.125). Since then
an abundance of articles on GLP-1 has appeared – and continue to appear. A search
for GLP-1 and diabetes on the scholar version of google as of June 2009 returns 14300
results. Accordingly we are not able to give a full overview, and have chosen to confine
ourselves to some recent results.
Suarez-Pinzon et al. (2008) found that a combination of GLP-1 and gastrin (we will
return to gastrin in section 3.3) restored normoglycemia in NOD-mice through an increase
in β-cell mass and downregulation of the autoimmune response (Suarez-Pinzon
et al., 2008, p.3281), while GLP-1 or gastrin alone did not induce such an effect. The
downregulation of the autoimmune response arises when the cytokines change their
expression from cytotoxic to benign, thus sparing the β-cells from further cytokineinduced
apoptosis. Beside this intermittence of autoimmunity Suarez-Pinzon et al.
(2008) also observed an increase in β-cell replication of duct cells, but not from the
pancreatic β-cells (Suarez-Pinzon et al., 2008, p.3284). The results of Suarez-Pinzon
et al. (2008) suggests that combination therapy with GLP-1 and gastrin can be used at
the third stage of T1D.
Besides these positive results obtained by the combination of GLP-1 and gastrin,
Urusova et al. (2004) gives a summary of recent data that shows that GLP-1 on its
own has an anti-apoptotic effect on β-cells. Urusova et al. (2004) also reports that
GLP-1 regulates the differentiation of progenitor cells as well as induces β-cell prolif-