Matrix Metalloproteinase-9 Protects Islets from Amyloid-induced Toxicity.
Deposition of human islet amyloid polypeptide (hIAPP, also known as amylin) as islet amyloid is a characteristic feature of the pancreas in type 2 diabetes, contributing to increased β-cell apoptosis and reduced β-cell mass. Matrix metalloproteinase-9 (MMP-9) is active in islets and cleaves hIAPP. We investigated whether hIAPP fragments arising from MMP-9 cleavage retain the potential to aggregate and cause toxicity, and whether overexpressing MMP-9 in amyloid-prone islets reduces amyloid burden and the resulting β-cell toxicity. Synthetic hIAPP was incubated with MMP-9 and the major hIAPP fragments observed by MS comprised residues 1-15, 1-25, 16-37, 16-25, and 26-37. The fragments 1-15, 1-25, and 26-37 did not form amyloid fibrils in vitro and they were not cytotoxic when incubated with β cells. Mixtures of these fragments with full-length hIAPP did not modulate the kinetics of fibril formation by full-length hIAPP. In contrast, the 16-37 fragment formed fibrils more rapidly than full-length hIAPP but was less cytotoxic. Co-incubation of MMP-9 and fragment 16-37 ablated amyloidogenicity, suggesting that MMP-9 cleaves hIAPP 16-37 into non-amyloidogenic fragments. Consistent with MMP-9 cleavage resulting in largely non-amyloidogenic degradation products, adenoviral overexpression of MMP-9 in amyloid-prone islets reduced amyloid deposition and β-cell apoptosis. These findings suggest that increasing islet MMP-9 activity might be a strategy to limit β-cell loss in type 2 diabetes.
From the VA Puget Sound Health Care System and University of Washington, Seattle, Washington 98108.
Daniel T
DT
Meier
Genomic Research Center, Academia Sinica, Taipei, Taiwan, Department of Chemistry, Stony Brook University, Stony Brook, New York 11794, and.
Ling-Hsien
LH
Tu
From the VA Puget Sound Health Care System and University of Washington, Seattle, Washington 98108.
Sakeneh
S
Zraika
From the VA Puget Sound Health Care System and University of Washington, Seattle, Washington 98108.
Meghan F
MF
Hogan
From the VA Puget Sound Health Care System and University of Washington, Seattle, Washington 98108.
Andrew T
AT
Templin
From the VA Puget Sound Health Care System and University of Washington, Seattle, Washington 98108.
Rebecca L
RL
Hull
Department of Chemistry, Stony Brook University, Stony Brook, New York 11794, and Department of Structural and Molecular Biology, University College London, London WC1E 6BT, United Kingdom.
Daniel P
DP
Raleigh
From the VA Puget Sound Health Care System and University of Washington, Seattle, Washington 98108, skahn@uw.edu.
Steven E
SE
Kahn
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000473:pathology; D058228:Islet Amyloid Polypeptide / Q000633:toxicity*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000633:toxicity*
D058228:Islet Amyloid Polypeptide; D010455:Peptides; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
amyloid; apoptosis; diabetes; islet amyloid polypeptide; mass spectrometry (MS); matrix metalloproteinase-9; pancreatic islet