Over-expression of Human Amylin Leads to Oligomerization and beta-cell Dysfunction Associated with Mitochondrial Uncoupling, Activation of c-Jun and Decrease Expression of JNK Interacting Protein-1

Zhang, ShaopingLiu, HChuang, CLLi, XLAu, MZhang, LCooper, GJS2014-02-022012-06-10American Diabetes Association - 72nd Scientific Sessions. 10 Jun 2012http://hdl.handle.net/2292/21520Over-expression of human amylin (hA) in pancreatic β-cells has been shown to contribute to cytotoxic hA aggregation and islet amyloid formation that can lead to β-cell dysfunction in type-2 diabetes mellitus. We aimed to investigate the functional and molecular changes associated with hA oligomer formation and their relation to β-cell dysfunction and diabetes development using transgenic mouse model that over-expresses hA in their islet β-cells.We showed that both homozygous and hemizygous hA transgenic mice developed spontaneous diabetes with different elevated levels of hA and with different time frame of disease onset and death. Homozygous mice displayed hyperinsulinemia and self-limiting insulin resistance during the pre-diabetic state, whereas by contrast, hemizygous mice had a longer prediabetic phase without insulin resistance. Intracellular and extracellular oligomers were clearly detectable before onset of diabetes with strong correlation with the time of β-cell apoptosis occurred in homozygous but not in hemizygous mice, indicating a difference in the extent of cytotoxic oligomerization between these animals. In addition, RT-qPCR analysis demonstrated progressive decrease in β-cell expression of functional and key regulatory molecules such as insulin, amylin, Pdx1, MafA, Glut2 and GCK. We also detected changes in expression of the mitochondrial membrane protein UCP-2 which contributes to decreased mitochondrial function. Further molecular analysis demonstrated activation of c-Jun/JNK and decrease expression of JNK-interacting protein 1, suggesting their role in mediating beta-cell death/apoptosis. Our studies should lead to a better understanding of the role and regulation of hA-evoked β-cell dysfunction and β-cell death in diabetesItems in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htmOver-expression of Human Amylin Leads to Oligomerization and beta-cell Dysfunction Associated with Mitochondrial Uncoupling, Activation of c-Jun and Decrease Expression of JNK Interacting Protein-1Conference Posterhttp://purl.org/eprint/accessRights/RestrictedAccess