1. Amylin/Islet Amyloid Polypeptide (IAAP) Molly Cook 3/18/15 Proteopathy presentation

2. Type II Diabetes Mellitus Chronic disease that usually does not appear until age 40 or later, but is increasingly being found in younger people and children Occurs when the body is resistant to insulin and makes it in smaller amounts that required Risk factors Genetic propensity Being overweight History of hypertension, high cholesterol, gestational diabetes (a temporary diabetes that can occur during pregnancy), and/or polycystic ovarian syndrome (PCOS), which can affect insulin resistance

3. Insulin and diabetes Insulin is a hormone that is normally created by the pancreas Pancreatic Islets of Langerhans have β-cells that produce insulin Production is triggered after eating and blood sugar levels rise Insulin moves the glucose from the bloodstream into cells where it can be converted into energy or stored In diabetes, a lack of or resistance to insulin leads to glucose not being stored and building up in the bloodstream, which causes problems

4. Symptoms Abnormal thirst and frequent urination Increased hunger Weight loss Fatigue Blurred vision Inability to heal normally Increased susceptibility to infection Acanthosis nigricans, or dark patches on skin

5. Further complications If left untreated, type II diabetes can lead to Heart and blood vessel diseases including heart attack and stroke Nerve damage Kidney damage Eye damage Foot damage Hearing impairment Various skin conditions There is also a correlation between type II diabetes and Alzheimer’s disease, although the reason for this connection in unknown

6. Amylin/IAPP Disulfide bridge between cysteines at 2 and 7 Only 37 amino acids long once active Has 2 alpha helices, no beta sheets on its own Sequence from 20-29 is key in forming amyloid fibrils (SNNFGAILSS)

7. Mutation in humans is possible at 20, making it more likely to form amyloid fibrils with other IAPP’s

8. Amylin and Type II Diabetes Amylin, or Islet Amyloid Polypeptide, is a hormone that is stored along with insulin in the β-cells and released when blood sugar levels increase Normally, it is believed to slow down the amount of glucose in blood by slowing rate of stomach emptying and increasing satiety (fullness) Amylin causes problems when it is allowed to form amyloids/fibrillation It is more likely to form amyloids when there is a higher concentration of amylin Low pH in the storage granules of the β-cells keep fibrillation from occurring before amylin is released, even though there is a high concentration together here ProIAPP is formed before it is cleaved and activated When too much proIAPP is formed due to response to high blood sugar, there are not enough enzymes available to cleave all of the proIAPP to make IAPP, therefore proIAPP accumulates ProIAPP can collect IAPP inside islet β-cells When amyloid is released, it collects more IAPP outside cell Initiates apoptosis cascade and kills beta cells Exact mechanism is unknown Amyloids are believed to disrupt the membrane of β-cells and cause leakage and cell death Without β-cells, insulin is not produced and diabetes is aggravated

9. Amyloid fibrillation There are some mutations that make fibrillation more likely (S->G at position 20, found more commonly in Asian populations), but fibrillation depends mostly on environment Normal amylin structure:Possible Prefibrillated structure:

10. Amyloid fibrillation When ProIAPP accumulates enough amyloids, they form beta sheets Aggregation of amylin and formation of fibrils is irreversible In storage in granules (in beta cells of pancreas), this is probably prevented by the low pH of the environment Amyloid formation must depend on 20-29 sequence, as this is not the same in a similar polypeptide that does not aggregate into beta sheets Rat IAPP has more proline residues, and these disrupt beta sheets and discourage formation of amyloids This is not the only area that affects amyloid formation, as when rat residues were replaced there was only a weak tendency

11. Suggested models of fibrillation:

12. Interfering with membranes Exact mechanism is not known May be multiple overlapping pathways for causing β-cell apoptosis IAPP fibrils accumulate extracellularly, then disrupt membranes of beta cells Possibly by creating ion channels that allow toxic amount of leakage through membrane

13. Treatment No known cure Most common treatment is diet and exercise regulation Can use insulin injections to help compensate Other medications are also available Can increase sensitivity to insulin or encourage production of more insulin For patients with high BMIs, weight loss surgery can help mitigate the affect of the disease Future treatments affecting the amylin protein are not likely to be available soon, but they may involve modifying the protein to be more like rat IAPP or other modifications that inhibit fibril formation

14. Works Cited Type 2 Diabetes Mellitus. (n.d.). Retrieved March 11, 2015, from http://emedicine.medscape.com/article/117853http://emedicine.medscape.com/article/117853 Type 2 Diabetes. (n.d.). Retrieved March 11, 2015, from http://www.mayoclinic.org/diseases-conditions/type-2- diabetes http://www.mayoclinic.org/diseases-conditions/type-2- diabetes Cao, P., Marek, P., Noor, H., Patsalo, V., Tu, L.-H., Wang, H., … Raleigh, D. P. (2013). Islet amyloid: From fundamental biophysics to mechanisms of cytotoxicity. FEBS Letters, 587(8), 1106–1118. Gurlo, T., Ryazantsev, S., Huang, C., Yeh, M. W., Reber, H. A., Hines, O. J., … Butler, P. C. (2010). Evidence for Proteotoxicity in β Cells in Type 2 Diabetes : Toxic Islet Amyloid Polypeptide Oligomers Form Intracellularly in the Secretory Pathway. The American Journal of Pathology, 176(2), 861–869. Cao, P., Abedini, A., & Raleigh, D. P. (2013). Aggregation of islet amyloid polypeptide: from physical chemistry to cell biology. Current Opinion in Structural Biology, 23(1), 82–89. Wiltzius, J. J. W., Sievers, S. A., Sawaya, M. R., Cascio, D., Popov, D., Riekel, C., & Eisenberg, D. (2008). Atomic structure of the cross-β spine of islet amyloid polypeptide (amylin). Protein Science : A Publication of the Protein Society, 17(9), 1467–1474. Patil, S.M., Xu, S., Sheftic, S.R., Alexandrescu, A.T. (2009). Dynamic alpha-helix structure of micelle- bound human amylin. J. Biol. Chem. 284, 11982-11991. Lee, C. (n.d.). Modeling Amyloid Fibrillation. Retrieved March 10, 2015, from http://web.mit.edu/mcraegroup/wwwfiles/ChuangChuang/t hesis_files/Chapter 3_Modeling Amyloid Fibrillation.pdf http://web.mit.edu/mcraegroup/wwwfiles/ChuangChuang/t hesis_files/Chapter 3_Modeling Amyloid Fibrillation.pdf Krampert, M., Bernhagen, J., Schmucker, J., Horn, A., Schmauder, A., Brunner, H.,... Kapurniotu, A. (n.d.). Amyloidogenicity of recombinant human pro-islet amyloid polypeptide (ProIAPP). Chemistry & Biology, 855-871. Paulsson, J., & Westermark, G. (2005). Aberrant Processing of Human Proislet Amyloid Polypeptide Results in Increased Amyloid Formation. Diabetes, 2117-2125.