Matrix metalloproteinase-9 reduces islet amyloid formation by degrading islet amyloid polypeptide

VA Puget Sound Health Care System and University of Washington, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 12/2012; 288(5). DOI: 10.1074/jbc.M112.438457
Source: PubMed

ABSTRACT Deposition of islet amyloid polypeptide (IAPP) as amyloid is a pathological hallmark of the islet in type 2 diabetes, which is toxic to β cells. We previously showed that the enzyme neprilysin reduces islet amyloid deposition, and thereby reduces β-cell apoptosis, by inhibiting fibril formation. Two other enzymes, matrix metalloproteinase (MMP)-2 and MMP-9, are extracellular gelatinases capable of degrading another amyloidogenic peptide, Aβ, the constituent of amyloid deposits in Alzheimers disease. We therefore investigated whether MMP-2 and MMP-9 play a role in reducing islet amyloid deposition. MMP-2 and MMP-9 mRNA were present in mouse islets but only MMP-9 activity was detectable. In an islet culture model where human IAPP (hIAPP) transgenic mouse islets develop amyloid but non-transgenic islets do not, a broad-spectrum MMP inhibitor (GM6001) and an MMP-2/9 inhibitor increased amyloid formation and the resultant β-cell apoptosis. In contrast, a specific MMP-2 inhibitor had no effect on either amyloid deposition or β-cell apoptosis. Mass spectrometry demonstrated that MMP-9 degraded amyloidogenic hIAPP but not non-amyloidogenic mouse IAPP. Thus, MMP-9 constitutes an endogenous islet protease that limits islet amyloid deposition and its toxic effects via degradation of hIAPP. As islet MMP-9 mRNA levels are decreased in type 2 diabetic subjects, islet MMP-9 activity may also be decreased in human type 2 diabetes, thereby contributing to increased islet amyloid deposition and β-cell loss. Approaches to increase islet MMP-9 activity could reduce or prevent amyloid deposition and its toxic effects in type 2 diabetes.

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    • "[24] Moreover, it was found that metal ion-induced aggregation of IAPP depends also on the origin of the peptide, i.e. if it is hu- man [18] [22] or murine (m-IAPP), [25] and mass spectrometry (MS) has also been applied to elucidate the structure of copper(II)–IAPP complexes and the putative binding sites. [26] On the other hand, IAPP homeostasis seems to be regulated also by the action of some metalloproteases which have been found to be able to degrade [27] [28] [29] this hormone and/or to impede its aggre- gation. [30] In particular, more than 10 years ago, insulin-degrading enzyme (IDE) was suggested to have an important role in the regulation of IAPP homeostasis and aggregation. "
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