Fibrillar islet amyloid polypeptide (amylin) is internalised by macrophages but resists proteolytic degradation.
Pancreatic islet amyloid, formed from islet amyloid polypeptide, is found in 96% of Type II (non-insulin-dependent) diabetic patients. Islet amyloidosis is progressive and apparently irreversible. Fibrils immunoreactive for islet amyloid polypeptide are found in macrophages associated with amyloid, suggesting that deposits can be phagocytosed. To determine the mechanism for the recognition and internalisation of fibrils, mouse peritoneal macrophages were cultured with fibrillar synthetic human islet amyloid polypeptide. Fibrils did not exert a cytotoxic effect over 72 h of culture. The uptake and degradation of fibrils was analysed by quantitative light-and electron-microscopic immunocytochemistry and immunoreactivity was detectable in 86+/-3% cells within 6 h of culture. Neither polyinosinic acid (200 microg/ml) nor nocodazole (10 microg/ml) inhibited fibril uptake, suggesting that internalisation is not blocked by poly-ions and is independent of microtubule assembly. Inhibition of pseudopodia formation by cytochalasin B blocked fibriI uptake. Fibril aggregates became condensed in lysosomes to form protofilaments and were resistant to intracellular proteolysis. Fibrils can be phagocytosed by macrophages in vitro but amyloid-associated factors may block the recognition of fibrils in vivo preventing the removal of islet amyloid in diabetes.
Badman
M K
MK
Laboratory of Cellular Endocrinology, Department of Human Anatomy, Oxford University, Oxford, UK.
Pryce
R A
RA
Chargé
S B
SB
Morris
J F
JF
Clark
A
A
D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003571:Cytochalasin B / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D058228:Islet Amyloid Polypeptide; D008247:Lysosomes / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008870:Microtubules / Q000187:drug effects / Q000502:physiology; D015739:Nocodazole / Q000494:pharmacology; D010179:Pancreas / Q000378:metabolism; D011069:Poly I / Q000494:pharmacology
D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D011069:Poly I; D003571:Cytochalasin B; D010450:Endopeptidases; D015739:Nocodazole