Matrix Metalloproteinase-9 Reduces Islet Amyloid Formation by Degrading Islet Amyloid Polypeptide

Deposition of islet amyloid polypeptide ( IAPP) as amyloid is a pathological hallmark of the islet in type 2 diabetes, which is toxic to beta-cells. We previously showed that the enzyme neprilysin reduces islet amyloid deposition and thereby reduces beta-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, A beta, the constituent of amyloid deposits in Alzheimer 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 nontransgenic islets do not, a broad spectrum MMP inhibitor ( GM6001) and an MMP-2/9 inhibitor increased amyloid formation and the resultant beta-cell apoptosis. In contrast, a specific MMP-2 inhibitor had no effect on either amyloid deposition or beta-cell apoptosis. Mass spectrometry demonstrated that MMP-9 degraded amyloidogenic hIAPP but not nonamyloidogenic mouse IAPP. Thus, MMP-9 constitutes an endogenous islet protease that limits islet amyloid deposition and its toxic effects via degradation of hIAPP. Because 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 beta-cell loss. Approaches to increase islet MMP-9 activity could reduce or prevent amyloid deposition and its toxic effects in type 2 diabetes.