physiological substrates, that is they are inactivated in vivo. The other issue about targets
in vivo is that there are other enzymes present that inactivate those particular targets. So,
the reason I guess what you are getting at is the reason why GLP-1 or GIP are the most
important targets and therefore have the inhibiting DPP-4 has efficacy for type 2 diabetes,
and it appears to be because as was mentioned at the start that GLP-1 is inactivated very
rapidly by DPP-4, that's two to four minutes. So when you inactivate it, the next enzyme
that comes along which is an endopeptidase which when activated, takes a whole lot
longer, it takes 10 hours. So, that's apparently where the efficacy comes in. Now the
other question about knockout mice, I have been breeding the knockout mice for more
than 10 years without seeing any detrimental effects in them.
enzyme. It's made by lymphocytes, endothelial cells, epithelial cells. So it’s throughout
the body. It's on the surface of cells. It's released into the serum and extracellular, it's
actual function has never been entirely clear. It appears to have a widespread function in
inactivating small peptides by cleaving a small bit of the N-terminus, and the number of
peptides is about two dozen that’s has been identified as being targets of this enzyme.
DR. WOLF: We are not aware of any.
DR. BURMAN: Thank you. Dr. Wyne, did you have a question?
What happens in vivo is that namely four peptides have been found to be
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as well, and that relates to are there any other adverse pathophysiologic effects in animals
or humans of elevating GLP-1 other than the ones you are talking about related to
DR. GARRELL: Okay. So the source of DPP-4 is it's a ubiquitous