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physiological substrates, that is they are inactivated in vivo. The other issue about targets

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in vivo is that there are other enzymes present that inactivate those particular targets. So,

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the reason I guess what you are getting at is the reason why GLP-1 or GIP are the most

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important targets and therefore have the inhibiting DPP-4 has efficacy for type 2 diabetes,

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and it appears to be because as was mentioned at the start that GLP-1 is inactivated very

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rapidly by DPP-4, that's two to four minutes. So when you inactivate it, the next enzyme

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that comes along which is an endopeptidase which when activated, takes a whole lot

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longer, it takes 10 hours. So, that's apparently where the efficacy comes in. Now the

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other question about knockout mice, I have been breeding the knockout mice for more

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than 10 years without seeing any detrimental effects in them.

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enzyme. It's made by lymphocytes, endothelial cells, epithelial cells. So it’s throughout

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the body. It's on the surface of cells. It's released into the serum and extracellular, it's

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actual function has never been entirely clear. It appears to have a widespread function in

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inactivating small peptides by cleaving a small bit of the N-terminus, and the number of

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peptides is about two dozen that’s has been identified as being targets of this enzyme.

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DR. WOLF: We are not aware of any.

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DR. BURMAN: Thank you. Dr. Wyne, did you have a question?

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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

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or humans of elevating GLP-1 other than the ones you are talking about related to

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diabetes?

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DR. GARRELL: Okay. So the source of DPP-4 is it's a ubiquitous

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DR. BURMAN: One other quick question, I know the committee has one

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