Transgenic overproduction of islet amyloid polypeptide (amylin) is not sufficient for islet amyloid formation.
Islet amyloid polypeptide forms islet amyloid deposits in non-insulin-dependent diabetes mellitus. We have generated transgenic mice which express human islet amyloid polypeptide in their pancreatic beta cells yet do not develop islet amyloid deposits despite producing levels of the amyloidogenic human peptide 2 - 3 fold higher than the native (mouse) peptide. To determine whether marked overproduction of islet amyloid polypeptide is a potential cause of islet amyloid formation, we increased expression of this transgene by producing homozygous transgenic animals and by making heterozygous mice experimentally insulin resistant with nicotinic acid. Pancreatic content of islet amyloid polypeptide-like immunoreactivity in homozygous and nicotinic acid-treated mice was 2-fold (25 +/- 7 fmol/microg; n = 6) and 3.5-fold (47 +/- 20 fmol/microg; n = 3) higher, respectively, than that of untreated heterozygous animals (13+/-2 fmol/microg; n = 11; both p < 0.05). Despite this marked increase in production of islet amyloid polypeptide, neither group of mice developed gross islet amyloid deposits even after 16 months of age. We conclude that overproduction of islet amyloid polypeptide, even as produced by extreme insulin resistance, is not in itself sufficient for islet amyloid formation.
Verchere
C B
CB
Division of Metabolism, Endocrinology, and Nutrition, VA Puget Sound Health Care System and University of Washington, Seattle 98108, U.S.A.
D'Alessio
D A
DA
Wang
S
S
Andrikopoulos
S
S
Kahn
S E
SE
D000682:Amyloid / Q000096:biosynthesis*; D000818:Animals; D006801:Humans; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000166:cytology / Q000378:metabolism
D000682:Amyloid; D058228:Islet Amyloid Polypeptide