Human islet amyloid polypeptide transgenic mice: in vivo and ex vivo models for the role of hIAPP in type 2 diabetes mellitus.
Human islet amyloid polypeptide (hIAPP), a pancreatic islet protein of 37 amino acids, is the main component of islet amyloid, seen at autopsy in patients with type 2 diabetes mellitus (DM2). To investigate the roles of hIAPP and islet amyloid in DM2, we generated transgenic mice expressing hIAPP in their islet beta cells. In this study, we found that after a long-term, high-fat diet challenge islet amyloid was observed in only 4 of 19 hIAPP transgenic mice. hIAPP transgenic females exhibited severe glucose intolerance, which was associated with a downregulation of GLUT-2 mRNA expression. In isolated islets from hIAPP males cultured for 3 weeks on high-glucose medium, the percentage of amyloid containing islets increased from 5.5% to 70%. This ex vivo system will allow a more rapid, convenient, and specific study of factors influencing islet amyloidosis as well as of therapeutic strategies to interfere with this pathological process.
Höppener
J W M
JW
Division of Biomedical Genetics, Department of Metabolic and Endocrine Diseases, University Medical Center Utrecht, P.O. Box 85090, 3508 AB Utrecht, The Netherlands. j.w.m.hoeppener@umcutrecht.nl
Jacobs
H M
HM
Wierup
N
N
Sotthewes
G
G
Sprong
M
M
de Vos
P
P
Berger
R
R
Sundler
F
F
Ahrén
B
B
D000682:Amyloid / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000686:Amyloidosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001835:Body Weight; D002470:Cell Survival; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004041:Dietary Fats / Q000009:adverse effects; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D018149:Glucose Intolerance / Q000378:metabolism; D005951:Glucose Tolerance Test; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D046509:Tissue Culture Techniques
D000682:Amyloid; D004041:Dietary Fats; D051273:Glucose Transporter Type 2; D058228:Islet Amyloid Polypeptide; D012333:RNA, Messenger; C495682:Slc2a2 protein, mouse