Inhibition of Insulin-Degrading Enzyme Does Not Increase Islet Amyloid Deposition in Vitro

Islet amyloid deposition in human type 2 diabetes results in β-cell loss. These amyloid deposits contain the unique amyloidogenic peptide human islet amyloid polypeptide (hIAPP), which is also a known substrate of the protease insulin-degrading enzyme (IDE). Whereas IDE inhibition has recently been...

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Bibliographic Details
Published in:Endocrinology (Philadelphia) 2016-09, Vol.157 (9), p.3462-3468
Main Authors: Hogan, Meghan F, Meier, Daniel T, Zraika, Sakeneh, Templin, Andrew T, Mellati, Mahnaz, Hull, Rebecca L, Leissring, Malcolm A, Kahn, Steven E
Format: Article
Language:English
Subjects:
Amylin
Amyloid - metabolism
Amyloidogenesis
Animals
Apoptosis
Beta cells
Cell death
Deposition
Diabetes
Diabetes mellitus (non-insulin dependent)
Diabetes Mellitus, Type 2 - metabolism
Enzymes
Female
Glucose
Glucose metabolism
Humans
Insulin
Insulin - metabolism
Insulysin
Insulysin - antagonists & inhibitors
Insulysin - metabolism
Islet Amyloid Polypeptide - metabolism
Islets of Langerhans - metabolism
Male
Metabolism
Mice, Inbred C57BL
Mice, Transgenic
Original Research
Polypeptides
Substrate inhibition
Transgenic mice
β-Amyloid
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Summary:Islet amyloid deposition in human type 2 diabetes results in β-cell loss. These amyloid deposits contain the unique amyloidogenic peptide human islet amyloid polypeptide (hIAPP), which is also a known substrate of the protease insulin-degrading enzyme (IDE). Whereas IDE inhibition has recently been demonstrated to improve glucose metabolism in mice, inhibiting it has also been shown to increase cell death when synthetic hIAPP is applied exogenously to a β-cell line. Thus, we wanted to determine whether a similar deleterious effect is observed when hIAPP is endogenously produced and secreted from islets. To address this issue, we cultured hIAPP transgenic mouse islets that have the propensity to form amyloid for 48 and 144 hours in 16.7 mM glucose in the presence and absence of the IDE inhibitor 1. At neither time interval did IDE inhibition increase amyloid formation or β-cell loss. Thus, the inhibition of IDE may represent an approach to improve glucose metabolism in human type 2 diabetes, without inducing amyloid deposition and its deleterious effects.
ISSN:0013-7227
1945-7170
DOI:10.1210/en.2016-1410