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Exendin-4 increases islet amyloid deposition but offsets the resultant beta cell toxicity in human islet amyloid polypeptide transgenic mouse islets
journal contribution
posted on 2011-01-01, 00:00 authored by Kathryn Aston-MourneyKathryn Aston-Mourney, R Hull, S Zraika, J Udayasankar, S Subramanian, S KahnAims/hypothesis In type 2 diabetes, aggregation of islet amyloid polypeptide (IAPP) into amyloid is associated with beta cell loss. As IAPP is co-secreted with insulin, we hypothesised that IAPP secretion is necessary for amyloid formation and that treatments that increase insulin (and IAPP) secretion would thereby increase amyloid formation and toxicity. We also hypothesised that the unique properties of the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 to maintain or increase beta cell mass would offset the amyloid-induced toxicity.
Methods Islets from amyloid-forming human IAPP transgenic and control non-transgenic mice were cultured for 48 h in 16.7 mmol/l glucose alone (control) or with exendin-4, potassium chloride (KCl), diazoxide or somatostatin. Human IAPP and insulin release, amyloid deposition, beta cell area/islet area, apoptosis and AKT phosphorylation levels were determined.
Results In control human IAPP transgenic islets, amyloid formation was associated with increased beta cell apoptosis and beta cell loss. Increasing human IAPP release with exendin-4 or KCl increased amyloid deposition. However, while KCl further increased beta cell apoptosis and beta cell loss, exendin-4 did not. Conversely, decreasing human IAPP release with diazoxide or somatostatin limited amyloid formation and its toxic effects. Treatment with exendin-4 was associated with an increase in AKT phosphorylation compared with control and KCl-treated islets.
Conclusions/interpretation IAPP release is necessary for islet amyloid formation and its toxic effects. Thus, use of insulin secretagogues to treat type 2 diabetes may result in increased islet amyloidogenesis and beta cell death. However, the AKT-associated anti-apoptotic effects of GLP-1 receptor agonists such as exendin-4 may limit the toxic effects of increased islet amyloid.
Methods Islets from amyloid-forming human IAPP transgenic and control non-transgenic mice were cultured for 48 h in 16.7 mmol/l glucose alone (control) or with exendin-4, potassium chloride (KCl), diazoxide or somatostatin. Human IAPP and insulin release, amyloid deposition, beta cell area/islet area, apoptosis and AKT phosphorylation levels were determined.
Results In control human IAPP transgenic islets, amyloid formation was associated with increased beta cell apoptosis and beta cell loss. Increasing human IAPP release with exendin-4 or KCl increased amyloid deposition. However, while KCl further increased beta cell apoptosis and beta cell loss, exendin-4 did not. Conversely, decreasing human IAPP release with diazoxide or somatostatin limited amyloid formation and its toxic effects. Treatment with exendin-4 was associated with an increase in AKT phosphorylation compared with control and KCl-treated islets.
Conclusions/interpretation IAPP release is necessary for islet amyloid formation and its toxic effects. Thus, use of insulin secretagogues to treat type 2 diabetes may result in increased islet amyloidogenesis and beta cell death. However, the AKT-associated anti-apoptotic effects of GLP-1 receptor agonists such as exendin-4 may limit the toxic effects of increased islet amyloid.
History
Journal
DiabetologiaVolume
54Issue
7Pagination
1756 - 1765Publisher
SpringerLocation
Heidelberg, GermanyPublisher DOI
Link to full text
ISSN
0012-186XeISSN
1432-0428Language
engPublication classification
C1.1 Refereed article in a scholarly journalCopyright notice
2011, Springer-VerlagUsage metrics
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beta cell apoptosisbeta cell areabeta cell proliferationExendin-4GLP-1 receptor agonistIAPPinsulin secretionIslet amyloidScience & TechnologyLife Sciences & BiomedicineEndocrinology & MetabolismGLUCAGON-LIKE PEPTIDE-1IN-VITROGLUCOSE-HOMEOSTASISPANCREATIC-ISLETSFIBRIL FORMATIONGLYCEMIC CONTROLDIABETIC-RATSMICEMETFORMINAPOPTOSIS
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