benzyloxycarbonylleucyl-leucyl-leucine-aldehyde and Insulinoma

Human islet amyloid polypeptide (hIAPP) is the principal constituent of amyloid deposits and toxic oligomers in the pancreatic islets. Together with hyperglycemia, hIAPP-derived oligomers and aggregates are important culprits in type 2 diabetes mellitus (T2DM). Here, we explored the role of the cell's main proteolytic complex, the proteasome, in hIAPP turnover in normal and stressed β-cells evoked by chronic hyperglycemia. Moderate inhibition (10-35%) of proteasome activity/function in cultured human islets by the proteasome inhibitor lactacystin enhanced intracellular accumulation of hIAPP. Unexpectedly, prolonged (>1 h) and marked (>50%) impairment of proteasome activity/function had a strong inhibitory effect on hIAPP transcription and secretion from normal and stressed β-cells. This negative compensatory feedback mechanism for controlling IAPP turnover was also observed in the lactacystin-treated rat insulinoma β-cell line (INS 832/13), demonstrating the presence of an evolutionarily conserved mechanism for IAPP production. In line with these

Topics: Acetylcysteine; Animals; Cell Line, Tumor; Diabetes Mellitus, Type 2; Down-Regulation; Hepatocyte Nuclear Factor 3-beta; Humans; Insulin-Secreting Cells; Insulinoma; Islet Amyloid Polypeptide; Leupeptins; Mice; Oligopeptides; Promoter Regions, Genetic; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Rats