Prolonged exposure of pancreatic beta cells to raised glucose concentrations results in increased cellular content of islet amyloid polypeptide precursors

Most non-insulin dependent diabetic patients have amyloid deposits in their pancreatic islets. It is not known whether chronic hyperglycaemia contribu tes to the formation of amyloid fibrils from the islet amyloid polypeptide that is produced by the pancreatic beta cells. Since islet amyloid exhibits islet amyloid polypeptide precursors immunoreactivity, we examined whether sustained in vitro exposure to raised glucose increases the abundance of t hese precursors in human beta cells. After 6 days stimulation with 20 mmol/ l glucose the cellular content of insulin but not islet amyloid polypeptide was decreased leading to an increase in the ratio of the latter over insul in (3.0 +/- 0.6 vs 1.8 +/- 0.3 after 6 mmol/l glucose culture, p < 0.05). S imilar changes occurred in rat beta cells cultured for 3 days in the presen ce of 20 mmol/l glucose plus 3-isobutyl-1-methylxanthine. Western blot anal ysis of cellular islet amyloid polypeptide after prolonged exposure to high glucose indicated the presence of higher proportions of its precursor- and intermediate forms. In human beta cells cultured in 20 mmol/l glucose, the major form corresponds to an intermediate species which exhibits an immuno reactivity for the N-flanking peptide, as is also the case in islet amyloid . We concluded that prolonged in vitro exposure of beta cells to raised glu cose concentrations increases the relative proportion of islet amyloid poly peptide over insulin, as well as of its precursors over the mature form of islet amyloid polypeptide.