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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK036734-02
Application #
3235225
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1986-02-01
Project End
1989-01-31
Budget Start
1987-02-01
Budget End
1988-01-31
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Veterinary Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Jordan, K; O'Brien, S J; Johnson, K H et al. (1995) Assignment of islet amyloid polypeptide (IAPP) gene to feline chromosome B4 using the polymerase chain reaction technique on feline-rodent hybrid cell lines. Vet Pathol 32:195-7
O'Brien, T D; Butler, A E; Roche, P C et al. (1994) Islet amyloid polypeptide in human insulinomas. Evidence for intracellular amyloidogenesis. Diabetes 43:329-36
O'Brien, T D; Butler, P C; Westermark, P et al. (1993) Islet amyloid polypeptide: a review of its biology and potential roles in the pathogenesis of diabetes mellitus. Vet Pathol 30:317-32
Johnson, K H; O'Brien, T D; Betsholtz, C et al. (1992) Islet amyloid polypeptide: mechanisms of amyloidogenesis in the pancreatic islets and potential roles in diabetes mellitus. Lab Invest 66:522-35
Johnson, K H; Sletten, K; Hayden, D W et al. (1992) Pulmonary vascular amyloidosis in aged dogs. A new form of spontaneously occurring amyloidosis derived from apolipoprotein AI. Am J Pathol 141:1013-9
O'Brien, T D; Westermark, P; Johnson, K H (1991) Islet amyloid polypeptide and insulin secretion from isolated perfused pancreas of fed, fasted, glucose-treated, and dexamethasone-treated rats. Diabetes 40:1701-6
Johnson, K H; O'Brien, T D; Westermark, P (1991) Newly identified pancreatic protein islet amyloid polypeptide. What is its relationship to diabetes? Diabetes 40:310-4
Galeazza, M T; O'Brien, T D; Johnson, K H et al. (1991) Islet amyloid polypeptide (IAPP) competes for two binding sites of CGRP. Peptides 12:585-91
Johnson, K H; Wernstedt, C; O'Brien, T D et al. (1991) Amyloid in the pancreatic islets of the cougar (Felis concolor) is derived from islet amyloid polypeptide (IAPP). Comp Biochem Physiol B 98:115-9

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