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Altered immunoreactivity of islet amyloid polypeptide (IAPP) may reflect major modifications of the IAPP molecule in amyloidogenesis
Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
Ludwig Institute of Cancer Research, Uppsala Branch, Uppsala, Sweden.
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1997 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 40, no 7, 793-801 p.Article in journal (Refereed) Published
Abstract [en]

We have developed a mouse monoclonal antibody against rat/mouse islet amyloid polypeptide (IAPP). The antibody recognises an epitope in the N-terminal part of the molecule, which is conserved between different species. The antibody immunohistochemically labelled beta cells in normal islets of most different mammalian species including man and in one avian species. Previous immunohistochemical studies of human pancreatic tissue from individuals with non-insulin-dependent diabetes mellitus (NIDDM) have revealed a paradoxical and unexplained lack of IAPP immunoreactivity in beta cells close to amyloid in spite of the presence of IAPP mRNA. In contrast to these findings we show that the newly developed monoclonal IAPP antibody strongly labels such beta cells while islet amyloid deposits which are labelled by polyclonal antisera do not bind the monoclonal antibody. These findings with the polyclonal antisera and the monoclonal antibody indicate that IAPP undergoes one or several structural changes during the amyloidogenesis. Knowledge of these structural changes that may include abnormal folding or chemical modification of IAPP is probably important for the understanding of the amyloidogenesis and the pathogenesis of the islet lesion in NIDDM.

Place, publisher, year, edition, pages
1997. Vol. 40, no 7, 793-801 p.
Keyword [en]
islet amyloid polypeptide, monoclonal antibody, non-insulin-dependent diabetes mellitus, immunohistochemistry, deposits.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-80001DOI: 10.1007/s001250050751OAI: oai:DiVA.org:liu-80001DiVA: diva2:545008
Available from: 2012-08-17 Created: 2012-08-17 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Islet amyloid polypeptide (IAPP): Mechanisms of Amyloidogenesis in the Pancreatic Islets and Potential Roles in Diabetes Mellitus
Open this publication in new window or tab >>Islet amyloid polypeptide (IAPP): Mechanisms of Amyloidogenesis in the Pancreatic Islets and Potential Roles in Diabetes Mellitus
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Islet amyloid is the most common characteristic feature of the islets in type 2 diabetes, being found in up to 90% of diabetic patients at post-mortem. lt has as its unique component the islet beta-cell peptide islet amyloid polypeptide (IAPP), which is eo-secreted with insulin. Because all human subjects produce and secrete the amyloidogenic form of IAPP, yet not all develop islet amyloid, some other factors must be involved in islet amyloid formation. The aim of the research presented in this thesis was to study factors of importance for the IAPP amyloidogenesis in type 2 diabetes. We developed a mouse monoclonal antibody to raVmouse IAPP (MAb4A5). MAb4A5 shows reactivity with IAPP in different species without detecting its close relative CGRP. In the pancreatic islets from patients with type 2 diabetes and diabetic cat, MAb4A5 labels immunohistochemically cellular IAPP but not IAPP in islet amyloid deposits. In contrast to MAb4A5 polyclonal rabbitiAPP antisera label beta cells close to amyloid only weakly, but label strongly IAPP in its amyloid form. The varying findings of IAPP immunoreactivity in pancreatic islets indicate that IAPP undergoes structural changes (impaired cleavage of proiAPP, conformational change, or post-transitional modifications) during the amyloidogenesis. A potentially important finding was the increased IAPP immunoreactivity in beta cells in islets of impaired glucose tolerant cats, irrespective of presence of amyloid in these islets. The finding may indicate that the formation of first islet amyloid occurs before Type 2 diabetes is manifest. Given the immunohistochemical results with MAb 4A5, we investigated whether the altered immunoreactivity of IAPP in association with the amyloidogenesis is due to a modification of IAPP (e.g. non-enzymatic glycation). We used synthetic IAPP fibrils glycated in vitro to study if non-enzymatic glycation may result in loss of an antigenic epitope. The results showed that a possible explanation of the lack of immunoreactivity of islet amyloid with MAb 4A5 actually is an nonenzymatic glycation. Association of an IAPP gene mutation with Type 2 diabetes has been found in the Japanese and Chinese population. We studied the possible enhanced fibril formation capacity of the mutant IAPP in vitro. Full-length and truncated IAPPS20G can form more amyloid-like fibrils and do this faster compared to wild type IAPP in vitro. We concluded that mutant (S20G) IAPP is a more amyloidogenic IAPP molecule and may be associated with an increased islet amyloid formation in vivo.

Based on the reports on the occurrence of islet amyloid in transgenic mice fed high fat diet, we investigated effects of free fatty acids on IAPP amyloid formation in isolated islets from transgenic mice expressing the gene for human IAPP but deficient of endogenous murine IAPP, and effects of FFAs on polymerization of IAPP in vitro. We found free fatty acids accelerate and increase polymerization of IAPP in vitro and promote amyloid like aggregation occurring in cultivated transgenic mouse isolated islets. All these results indicate that the pathogenesis of the islet amyloid may be a complex process involving many different mechanisms.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2001. 70 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 655
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-28607 (URN)13762 (Local ID)91-7219-756-0 (ISBN)13762 (Archive number)13762 (OAI)
Public defence
2001-01-12, Berzeliussalen, Universitetssjukhuset, Linköping, 13:30 (Swedish)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-08-17Bibliographically approved

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Westermark, Gunilla

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