Amyloid formation in response to beta cell stress occurs in vitro, but not in vivo, in islets of transgenic mice expressing human islet amyloid polypeptide.
BACKGROUND
Human, but not mouse, islet amyloid polypeptide (IAPP) is amyloidogenic. Transgenic mice overexpressing human IAPP in the beta cells of the islets of Langerhans should be useful in identifying factors important for the deposition of IAPP as insoluble amyloid fibrils.


METHODS
Transgenic mice expressing human IAPP were examined using several experimental models for the production of persistent hyperglycemia, as well as for the overstimulation and/or inhibition of beta cell secretion. Obesity was induced by aurothioglucose. Persistent hyperglycemia was produced by long-term administration of glucocorticosteroids or by partial pancreatectomy. Inhibition of normal beta cell exocytosis by diazoxide administration, with or without concurrent dexamethasone injections, was carried out to increase crinophagy of secretory granules. The human IAPP gene was also introduced into the ab and ob mouse models for diabetes. Finally, isolated islets cultivated in vitro at high glucose concentration were also examined.


RESULTS
No amyloid deposits were found in the pancreata of any of the animals, either by light microscopy after Congo red staining or by electron microscopy after immunogold labeling with antibodies specific for human IAPP. Aurothioglucose treatment resulted in increased numbers of granules in the beta cell and the appearance of large lysosomal bodies without amyloid. However, islets from db and ob mice expressing human IAPP cultivated in vitro in the presence of glucocorticosteroid and/or growth hormone, were found to contain extracellular amyloid deposits reacting with antibodies to human IAPP.


CONCLUSIONS
Oversecretion of human IAPP or increased crinophagy are not sufficient for amyloid formation. This indicates that other factors must influence amyloid deposition; one such factor may be the local clearance of IAPP.
Department of Pathology, Faculty of Health Sciences, Linköping University, Sweden.
G
G
Westermark
M B
MB
Arora
N
N
Fox
R
R
Carroll
S J
SJ
Chan
P
P
Westermark
D F
DF
Steiner
D000682:Amyloid / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D006051:Aurothioglucose / Q000008:administration & dosage / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D003348:Cortisone / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009765:Obesity / Q000378:metabolism; D010180:Pancreatectomy
D000682:Amyloid; D000959:Antihypertensive Agents; D001786:Blood Glucose; D058228:Islet Amyloid Polypeptide; D006051:Aurothioglucose; D003981:Diazoxide; D003348:Cortisone