To determine the potential for differential release of islet amyloid polypeptide and insulin, we performed studies in rat islet monolayer cultures under conditions known to impair regulated beta-cell secretion. In inhibiting concentrations of epinephrine or the absence of calcium, islet amyloid polypeptide was secreted through a constitutive pathway while insulin was not. These findings suggest a mechanism for persistent islet amyloid polypeptide secretion and amyloid accumulation when regulated insulin release is impaired as in Type 2 (non-insulin-dependent) diabetes mellitus and insulinomas.