Islet amyloid (IA) represents a substantial and uniform morphologic marker for adult-onset diabetes mellitus (DM) in humans and cats, and is associated with impaired glucose tolerance when present in normoglycemic cats. The common occurrence of IA and its immunoreactivity with antiserum to insulin B-chain, together with the demonstration of amyloid with identical immunohistochemical characteristics adjacent to B-cells within pancreatic ganglia and nerves of diabetic cats, supports a significant etiopathologic relationship between DM and IA. This common occurrence of IA with adult-onset DM (which is especially significant considering the complexity and heterogeneity of potential islet and extraislet defects which contribute to the development of this form of DM) provides an opportunity to utilize isolated/purified IA and insulin from diabetic cats as dual probes for the analysis of primary or secondary B-cell defects occurring in adult-onset diabetes. Utilizing the spontaneous cat model which so closely resembles Type 2 DM in humans, our experimental protocol is designed to elucidate the etiopathogenic relationship of IA to DM, and to determine mechanisms of IA formation that may be linked to B-cell secretion or degradation defects. This will be achieved through: 1) Confirmation of the chemical nature (i.e., insulin-relatedness) of IA through isolation, purification, and amino acid sequence analysis of IA from diabetic cats (using procedures established in our laboratory); 2) Amino acid sequence analysis of normal cat insulin (not previously done) as a base of comparison for possible amino acid substitutions present in insulin or insulin-related IA isolated from diabetic cats; and 3) Determination of whether IA is an unusual (i.e., fibrillar) accumulation of normal insulin, or if IA represents qualitatively abnormal insulin or insulin-related product. Comparison of IA sequences of insulin isolated from pancrease of IA-negative versus IA-positive cats will provide further opportunity to confirm insulin sequence variations linked to amyloidogenesis, versus variations independently or simultaneously linked to modified insulin function and DM.
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