Abstract Number: 2537-PO
Authors: XIUJU WU, ANDREW HUANG, LEENA HAATAJA, PETER C. BUTLER.
Institutions: Los Angeles, CA.
Results: The islet in type 2 diabetes is characterized by a deficit in beta cell number, increased beta cell apoptosis and islet amyloid derived from islet amyloid polypeptide (IAPP). While the mechanism underlying the increased beta cell apoptosis remains unresolved, one hypothesis for neurodegenerative diseases (Alzheimer's, Parkinson's, Prion related disease) with amyloid derived from locally expressed proteins is that misfolding of amyloidogenic proteins leads to toxic protein oligomers and apoptosis. This circumstance may occur when chaperone protein folding fails, either because of excessive synthesis of amyloidogenic proteins or dysfunctional chaperone proteins; so called chaperonopathies. Experimental Plan. In order to establish the major chaperone proteins (also called heat shock proteins; hsp's) that traffic and fold human IAPP through the beta cell secretory pathway we (1) established the most abundant hsp's in lysates of human islets, (2) performed cross linking studies for these hsp's and IAPP in protein lysates of human islets Results. BiP, hsp70, PDI and hsp27 are highly expressed in human islets. Hsp70 and BiP bind most abundantly to IAPP based on cross-linking. PDI did not cross link with IAPP. Conclusion. IAPP is trafficked through the endoplasmic reticulum and golgi in human beta cells by the chaperone proteins BiP and Hsp70. Since misfolding of IAPP is a characteristic of the islet in type 2 diabetes, these data suggest that efforts to understand the impact of common polymorphisms in these chaperone proteins on IAPP folding and trafficking may provide insights into the basis for formation of misfolded IAPP, IAPP oligomers and increased beta cell apoptosis in Type 2 diabetes.
Category: Islet Biology - Apoptosis