Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide.
The islet in non-insulin-dependent diabetes mellitus (NIDDM) is characterized by loss of beta cells and large local deposits of amyloid derived from the 37-amino acid protein, islet amyloid polypeptide (IAPP). We have hypothesized that IAPP amyloid forms intracellularly causing beta-cell destruction under conditions of high rates of expression. To test this we developed a homozygous transgenic mouse model with high rates of expression of human IAPP. Male transgenic mice spontaneously developed diabetes mellitus by 8 weeks of age, which was associated with selective beta-cell death and impaired insulin secretion. Small intra- and extracellular amorphous IAPP aggregates were present in islets of transgenic mice during the development of diabetes mellitus. However, IAPP derived amyloid deposits were found in only a minority of islets at approximately 20 weeks of age, notably after development of diabetes mellitus in male transgenic mice. Approximately 20% of female transgenic mice spontaneously developed diabetes mellitus at 30+ weeks of age, when beta-cell degeneration and both amorphous and amyloid deposits of IAPP were present. We conclude that overexpression of human IAPP causes beta-cell death, impaired insulin secretion, and diabetes mellitus. Large deposits of IAPP derived amyloid do not appear to be important in this cytotoxicity, but early, small amorphous intra- and extracellular aggregates of human IAPP were consistently present at the time of beta-cell death and therefore may be the most cytotoxic form of IAPP.
Janson
J
J
Endocrine Research Unit, Mayo Clinic, Rochester, MN 55905, USA.
Soeller
W C
WC
Roche
P C
PC
Nelson
R T
RT
Torchia
A J
AJ
Kreutter
D K
DK
Butler
P C
PC
D000375:Aging; D000682:Amyloid / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D005934:Glucagon / Q000032:analysis; D006801:Humans; D007328:Insulin / Q000032:analysis / Q000235:genetics; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D011401:Promoter Regions, Genetic; D051381:Rats; D012727:Sex Characteristics
D000682:Amyloid; D001786:Blood Glucose; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D005934:Glucagon