Amylin/Islet Amyloid Polypeptide (IAAP)

Molly Cook3/18/15

Proteopathy presentation

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

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

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

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

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)

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

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

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:

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

Suggested models of fibrillation:

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

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

Works Cited• Type 2 Diabetes Mellitus. (n.d.). Retrieved March 11, 2015, from

http://emedicine.medscape.com/article/117853• Type 2 Diabetes. (n.d.). Retrieved March 11, 2015, from

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/thesis_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.