The anatomical distribution and volume fractions of pancreatic A cells (glucagon), B cells (insulin) and D cells (somatostatin) were evaluated by an immunoperoxidase technique in 6 diabetic cats, 6 normoglycaemic glucose-intolerant cats and 6 normal control cats. Islets lacking A cells were observed in some sections from the right lobe of the pancreas which correlated with a significantly lower A cell volume fraction in the right pancreatic lobe. Endocrine cell volume fractions in normoglycaemic glucose-intolerant cats were not significantly different from controls. Thus, a reduction in B cell volume fraction was not necessary for the occurrence of impaired glucose tolerance in these cats. However, the reduction of B cell volume fraction in the 2 normoglycaemic glucose-intolerant cats with insular amyloidosis may in part explain the more severely impaired glucose tolerance previously observed in these cats. Insular amyloidosis in our feline diabetics, as in human type II diabetics, was associated with a significant decrease in A and B cell volume fractions. In both human type II and feline diabetes mellitus, however, the reduction in B cell mass does not appear sufficient alone to lead to diabetes mellitus. Therefore, amyloid replacement of functional endocrine cells does not appear to be the primary diabetogenic event in feline diabetes mellitus, but may contribute to progression of the condition due to loss of functional B cell reserves. We thus postulate that a B cell defect precedes deposition of islet amyloid and that these amyloid deposits may thus provide an important biochemical clue to specific B cell derangements occurring in adult-onset diabetics.