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 e xpress 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 incre ased expression of this transgene by producing homozygous transgenic a nimals and by making heterozygous mice experimentally insulin resistan t with nicotinic acid. Pancreatic content of islet amyloid polypeptide -like immunoreactivity in homozygous and nicotinic acid-treated mice w as 2-fold (25 +/- 7 fmol/mu g; n = 6) and 3.5-fold (47 +/- 20 fmol/mu g; n = 3) higher, respectively, than that of untreated heterozygous an imals (13 +/- 2 fmol/mu g; 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 a ge. We conclude that overproduction of islet amyloid polypeptide, even as produced by extreme insulin resistance, is not in itself sufficien t for islet amyloid formation.