Team:Bilkent-UNAMBG/Description
Project Description & Inspiration
A summer full of work and fun has to be described and inspired
THE PROBLEM
Diabetes Mellitus or more commonly known as diabetes is a group of metabolic disorders resulting in hyperglycemia or high blood sugar levels due to defects in insulin secretion or insulin action or both. Insulin is a hormone that is made by the pancreas, which promotes glucose uptake in cells. Currently, there is no known cure for diabetes. The widely used treatment for diabetes is the injection of insulin externally. Patients have to inject insulin at least 2 - 3 times per day. Without adequate amounts of insulin, diabetic patients will result in dehydration, fatigue, weight loss and in extreme cases, death [1].
The Magnitude
Figure 1: A map that shows the numbers of diabetic people and predicts how much they will increase until 2045 [6].
South and Central America
2 out of 5 people with diabetes were undiagnosed. Only 4% of global healthcare expenditure for diabetes spent in this religion.
North America & Carribbean
Half of the global diabetes healthcare spending occurs in tihs region. 1 in 7 adults in this region is at risk of type 2 diabetes.
Europe
USD 1 of every USD 4 of the global diabetes healthcare spending occurs in this region. 1 in 6 live births is effected by hyperglycemia in pregnancy.
Middle East & North Africa
1 in 5 live births is affected by hyperglycemia in pregnancy. 1 out of 2 deaths due to diabetes were people in under age of 60.
OUR SOLUTION
Designing constructs with single chain insulin analogs that will be optimized.
Our aim is to create a probiotic E. coli which we can be orally administrable. Since wild-type E. coli strains lack machinery for post-translational modifications to mature proinsulin, the recombinant production of active insulin is not possible. Therefore, we decided to use single chain insulin analogs, SCIs, in our probiotic strain. The SCI polypeptides have short linker sequences instead of C chain, and have similar binding affinity to human insulin receptors [8]. In our project, we will mutate the A and B chains to increase the stability of insulin [9]. Moreover, different linker sequences will be incorporated between insulin chains. To secrete the full SCI chain with the S-S bridge from E. coli, polypeptides incorporated with a site specific protease site will be displayed on the outer membrane with autotransporter proteins. The secretion will be accomplished upon display of the site-specific protease [10]. To increase the permeability of insulin through the intestinal cell wall, cell penetrating peptides will be used [11] InsulinInsulinInsulinInsulinInsulinInsulin.
OUR INSPIRATION
This year is our 4th year entering the iGEM competition as the Bilkent UNAMBG team. When we gathered this year’s team we didn’t have a project topic ready. Although we didn’t have a project subject we were unanimous on designing a project about human health, either in the diagnostics or therapeutics tracks. While we were brainstorming, we came up with a list of diseases which humankind suffers from today and will probably suffer from in the next decade. We did research on the diseases on the list and we talked about what everyone found. Out of the diseases on this list we discovered the statistics mentioned above, in the section about the magnitude of diabetes. We were aware of diabetes like most of the world, yet as we delved into the literature and gained more and more knowledge, we were shocked by the monumental problem that diabetes is becoming. Unhealthy food consumption is a big contributor to the increase in diabetic patients [5]. The junk and fast food industries show no signs of slowing down their production capacity, so we can only assume that diabetes and obesity will only grow. In Turkey, the diabetic population is also growing very rapidly. In fact, some of our team members have diabetic patients in their families, they see the hardships of diabetes.
References
Diagnosis and Classification of Diabetes Mellitus American Diabetes Association Diabetes Care Jan 2013, 36 (Supplement 1) S67-S74; DOI: 10.2337/dc13-S067 Diabetes. (2018). Who.int. Retrieved 17 June 2019, from https://www.who.int/news-room/fact-sheets/detail/diabetes
Hua X, Carvalho N, Tew M, Huang ES, Herman WH, Clarke P. Expenditures and Prices of Antihyperglycemic Medications in the United States: 2002-2013. JAMA. 2016;315(13):1400–1402. doi:10.1001/jama.2016.0126
Herkert D, Vijayakumar P, Luo J, et al. Cost-Related Insulin Underuse Among Patients With Diabetes. JAMA Intern Med. 2019;179(1):112–114. doi:10.1001/jamainternmed.2018.5008
Joel Gittelsohn, Thomas M. S. Wolever, Stewart B. Harris, Robert Harris-Giraldo, Anthony J. G. Hanley, Bernard Zinman, Specific Patterns of Food Consumption and Preparation Are Associated with Diabetes and Obesity in a Native Canadian Community, The Journal of Nutrition, Volume 128, Issue 3, March 1998, Pages 541–547, https://doi.org/10.1093/jn/128.3.541
International Diabetes Federation. IDF Diabetes Atlas, 8th edn. Brussels, Belgium: International Diabetes Federation, 2017. http://www.diabetesatlas.org
Wilcox G. (2005). Insulin and insulin resistance. The Clinical biochemist. Reviews, 26(2), 19–39.
Rajpal, G., Liu, M., Zhang, Y., & Arvan, P. (2009). Single-Chain Insulins as Receptor Agonists. The Journal of Clinical Endocrinology & Metabolism, 94(4), 1474-1474. doi:10.1210/jcem.94.4.9995
Ronald Eugene Chance, Richard Dennis Dimarchi James Arthur Hoffmann, Harlan Beall Long, Anne Reifel Miller (1996). Single chain insulin with high bioactivity. EP0741188A2.
Ahan, R. E., Kırpat, B. M., Saltepe, B., & Şeker, U. Ö. (2019). A Self-Actuated Cellular Protein Delivery Machine. ACS Synthetic Biology, 8(4), 686-696. doi:10.1021/acssynbio.9b00062
Yang, L., Li, M., Sun, Y., & Zhang, L. (2018). A cell-penetrating peptide conjugated carboxymethyl-β-cyclodextrin to improve intestinal absorption of insulin. International Journal of Biological Macromolecules,111, 685-695. doi:10.1016/j.ijbiomac.2018.01.077"