Insulin based analogs HLVEALYLV and LVEALYLV to inhibit the formation of amyloid fibrils in beta cells

<p>Human islet amyloid polypetide (hIAPP) is a 37 amino acid peptide, co-secreted along with insulin in the islets of Langerhans of pancreatic beta cells. Aggregation of hIAPP fibrils is believed to be toxic to beta cells and responsible for beta cell dysfunction and death associated with type 2 diabetes. Insulin has been found to act against the actions of hIAPP. The internal sequence of insulin, HLVEALYLV, recognizes and binds the 10-19 region of hIAPP. Since insulin reportedly blocks the formation of amyloid fibers, insulin analogs may protect cell membranes from damage. In an effort to study this effect, truncated analogs of insulin, namely HLVEALYLV and LVEALYLV, were synthesized and tested in the presence of hIAPP. Carboxyfluorescein-encapsulating vesicles that mimic the $-cell were created using a 7:3 ratio of the lipids 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-dioleoyl-sn-glycero-3- (phospho-L-serine) (DOPS), respectively, and the percent leakage of fluorescent dye from the vesicles in the presence of the peptides was calculated as compared to a 100% Triton-X detergent-treated control. The activity of the truncated analogs was compared to that of insulin under the same conditions. Whereas insulin was somewhat protective of the effects of hIAPP, the shorter analogs were found to increase the damage caused by hIAPP rather than reducing it, possibly by co-aggregating with the hIAPP.</p>

Name thesis:degree_name

Master of Science (MS)

Level thesis:degree_level

Open Access Thesis

Discipline thesis:degree_discipline

Chemistry

Year dc:date.available

2011

Author dc:creator

• Kurva, Balakrishna

Contributors dc:contributor

• Dr. Deborah Heyl-Clegg, PhD, Chair

• insulin-based inhibitors
• membrane disruption
• hIAPP
• Amyloid formation
• Chemistry

Repository record dc:identifier

https://commons.emich.edu/theses/323

OAI identifier oai:identifier

oai:commons.emich.edu:theses-1319