Difference between revisions of "Team:Virginia/Project"

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<p>Welcome the University of Virginia iGEM 2015 Wiki! Use the navigation bar at the top of every page to move between pages. Please let us know if you have any comments or questions about our project by visiting the “Contact Us” page.</p>
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<h2>
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House of Carbs
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<h1>House of Carbs: The Project</h1>
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<p>A Novel Solution to Minimizing Postprandial Hyperglycemic Spikes</p>
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<p>(click a tab to reveal more information)</p>
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<h1>Project Overview</h1>
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<p>Project Background</p>
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<h3 id="h3-1">The Problem: Diabetes Mellitus and Hyperglycemia</h3>
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<h1>Problem Statement</h1>
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<p>Diabetes mellitus is a common metabolic disease that is characterized by long-term hyperglycemia, peripheral resistance to human insulin and general lack of insulin production (Kumar et al. 2005). Diabetes is fairly remarkable in its impact mostly due to its far-reaching epidemiological impact; that is, in 2012, nearly 6.9% of American adults had some form of diabetes, which is staggering because this represents a 147% increase in diagnoses over 31 years according to the Centers for Disease Control and Prevention (CDC) (ADA 2014) , (CDC 2014). In addition, there are predictions that by 2050 there will be 552 million cases of diabetes mellitus worldwide (Whiting et al., 2011). The umbrella term “diabetes” covers two distinct disease states, named Type-1 (or juvenile) diabetes mellitus and Type-2 (or acquired) diabetes mellitus. Type-2 diabetes tends to develop as a result of poor dietary habits, alcohol abuse, obesity, or genetic predisposition, and the increase in the incidence of diabetes mellitus as a whole is largely reflective of an increase of the incidence of Type-2 diabetes rather than an increase in juvenile diabetes (ADA 2014). </p>
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<p>SHOW MORE</p>
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<p>With regards to Type-2 diabetes (referred to as T2DM) specifically, a number of devastating consequences can arise from increased blood sugar levels on a regular basis, but many of the major complications of T2DM arise from drastic fluctuations in the blood glucose level (Ceriello et al., 2012). Postprandial (post-meal) blood sugar spikes specifically are one of the most damaging complications of diabetes. Many diabetics are able to effectively manage post-meal glycemic spikes with self-administered doses of insulin, but these incidents still kill more Americans per year than any other diabetes-related complications. Arguably, the gravest consequence of glycemic spikes in diabetes patients is the development of progressive macrovascular disease (MVD), which affects the large blood vessels of the body, hardening and blocking these vessels (Ceriello et al. 2012). MVD is the leading cause of death among T2DM patients in the United States, and thus it is a huge target for diabetes treatments research. MVD also frequently leads to other severe complications such as ischemia in the extremities and blindness (Haffner et al., 1998).</p>
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<p>Luckily for many T1DM and T2DM patients, it has been shown that the regular control and management of blood glucose levels has been shown to prevent many of the vascular complications of the disease, but most of the time control over glucose is difficult to attain because of the self-dosing insulin treatment system that a lot of moderately to severely sick diabetes patients use is often hard to calibrate and use. Many people with regular hyperglycemia that are not considered diabetic also suffer the risk associated with glycemic spikes and resulting MVD, but these individuals do not have an insulin regimen to regulate high blood sugar levels typically. </p>
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<p>From diabetes mellitus a number of devastating complications, such as amputations, blindness, crippling neuropathies, and many others, can arise from increased blood sugar levels on a regular basis, but many of  
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the major complications of diabetes arise from drastic fluctuations in the blood glucose  
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level (Ceriello et al., 2012). Up to two-thirds of people with diabetes die of
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cardiovascular disease (CVD) brought about by diabetes-related macrovascular diseases
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(Deshpande et al. 2008). In fact, the risk for cardiovascular disease mortality is 2 to 4
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times higher in people with diabetes than in people who do not have diabetes.
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Additionally, diabetic retinopathy is the most common microvascular complication
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among people with diabetes and results in more than 10,000 new cases of blindness per
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year. Retinopathy is associated with prolonged hyperglycemia; it is slow to develop, and
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there is some evidence that it can begin to develop as early as 7 years before clinical
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diagnosis of diabetes (Deshpande et al., 2008).
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</p>
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<p>Postprandial (post-meal) blood sugar spikes specifically are one of the most  
 +
damaging complications of diabetes (Parkin et al., 2002). Many diabetics are able to  
 +
effectively manage post-meal glycemic spikes with self-administered doses of insulin,  
 +
but these hyperglycemic incidents still kill more Americans per year than any other  
 +
diabetes-related complications (Parkin et al., 2002). Arguably, the gravest consequence of  
 +
glycemic spikes in diabetes patients is the development of progressive macrovascular  
 +
disease (MVD), which affects the large blood vessels of the body, hardening and  
 +
blocking these vessels (Ceriello et al., 2012). MVD is the leading cause of death among  
 +
T2DM patients in the United States, causing up to 65% of diabetes-related deaths, making it a huge target for diabetes treatments research (Deshpande et al., 2008). MVD  
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also frequently leads to other severe complications such as ischemia in the extremities  
 +
and blindness (Haffner et al., 1998).
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</p></div>
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<h3 id="h3-2">Controlling Hyperglycemic Spikes</h3><div id="des2">
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<p>SHOW LESS</p>
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<p>For many T1DM and T2DM patients, it has been shown that the regular  
 +
control and management of blood glucose levels prevents many of the vascular  
 +
complications of the disease, but most of the time control over glucose is difficult to  
 +
attain because the self-dosing insulin treatment system that a lot of moderately to  
 +
severely sick diabetes patients use is often hard to calibrate and use (Parkin et al., 2002).
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</p>
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<p>Compared to sucrose-rich food, starch-rich food has been found to create less
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fluctuation in blood glucose levels, and thus is beneficial to diabetes patients and
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hyperglycemia patients. There is evidence that this flatter response caused by a starch
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rich meal is associated with the slower rate of digestion of complex sugars versus simple
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sugars (Jenkins, Wolever, & Jenkins, 1988). Thus, if some of the simple sugars are first
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converted into complex saccharides inside the E. coli and then released back into small
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intestine, a similar flatter glycemic response will take place, which will be beneficial to
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the patients.
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</p></div>
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<h3 id="h3-3">Our Devices</h3><div id="des3">
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<p>SHOW LESS</p>
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<p style="margin-bottom:30px;"> We have assembled one plasmid with genes that dictate a controllable level of simple sugars uptake and one plasmid to produce glucan and fructan from simple sugars and then lyse to release the complex sugars back into the environment. In essence, this microbial device runs on two genetic devices -- an uptake circuit and a polymerization circuit. </p></div>
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<p style="font-style:italic; border-top:1px dotted #007bb6"> In order to learn more details, please visit the <a href="/Team:Virginia/Project">Project page.</a> </p>
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<a href="javascript:void(0);"><div id="ref-button">
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<p>Show References</p>
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<p>Hide References</p>
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<div id="ref-content">
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<h3>References</h3>
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<p>A. Ceriello, S. Colagiuri, (2011). Guideline for management of postmeal glucose in
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diabetes. International Diabetes Federation Guideline Development Group,
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http://www.idf.org/sites/default/files/postmeal%20glucose%20guidelines.pdf ,
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Accessed May. 6th, 2015
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</p>
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<p>American Diabetes Association (2014). National Diabetes Statistics Report.
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http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf
 +
Accessed May. 5th, 2015
 +
</p>
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<p>Anal, A. K., & Singh, H. (2007). Recent advances in microencapsulation of probiotics for
 +
industrial applications and targeted delivery. Trends in Food Science &
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Technology, 18(5), 240–251. http://doi.org/10.1016/j.tifs.2007.01.004
 +
</p>
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<p>Anan, F., Masaki, T., Eto, T., Fukunaga, N., Iwao, T., Kaneda, K., ... Yoshimatsu, H.
 +
(2008). Postchallenge Plasma Glucose and Glycemic Spikes Are Associated with
 +
Pulse Pressure in Patients with Impaired Glucose Tolerance and Essential
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Hypertension. Hypertension Research, 31(8), 1565–1571.
 +
http://doi.org/10.1291/hypres.31.1565
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</p>
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<p>AHFS Consumer Medication Information [Internet]. Bethesda (MD): American Society
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of Health-System Pharmacists, Inc.; ©2008. Acarbose; [revised 2015 Feb. 15;
 +
reviewed 2015 Apr. 28; cited 2015 May. 3]; Available from:
 +
http://www.nlm.nih.gov/medlineplus/druginfo/meds/ a696015.html
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</p>
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<p>AHFS Consumer Medication Information [Internet]. Bethesda (MD): American Society
 +
of Health-System Pharmacists, Inc.; ©2008. Pramlintide; [revised 2015 Feb. 15;
 +
reviewed 2015 Apr. 28; cited 2015 May. 3]; Available from:
 +
http://www.nlm.nih.gov/medlineplus/druginfo/meds/a605031.html
 +
</p>
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<p>Banguela, A., Arrieta, J. G., Rodríguez, R., Trujillo, L. E., Menéndez, C., & Hernández,
 +
L. (2011). High levan accumulation in transgenic tobacco plants expressing the
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Gluconacetobacter diazotrophicus levansucrase gene. Journal of Biotechnology,
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154(1), 93–98. http://doi.org/10.1016/j.jbiotec.2011.04.007
 +
</p>
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<p>Barr EL, Zimmet PZ, Welborn TA et al. (2007). "Risk of cardiovascular and all-cause
 +
mortality in individuals with diabetes mellitus, impaired fasting glucose, and
 +
impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study
 +
(AusDiab)". Circulation 116 (2): 151–7.
 +
</p>
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<p>Bernard, A. M., Anderson, L., Cook, C. B., & Phillips, L. S. (1999). What do internal
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medicine residents need to enhance their diabetes care? Diabetes Care, 22(5),
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661–666. http://doi.org/10.2337/diacare.22.5.661
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</p>
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<p>Boada C, Martínez-Moreno J. Pathophysiology of diabetes mellitus type 2: beyond the
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duo "insulin resistance-secretion deficit.". Nutricion Hospitalaria [serial online].
 +
March 2, 2013;28:78-87. Available from: Fuente Académica, Ipswich, MA.
 +
Accessed April 16, 2015.
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</p>
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<p>B. Göke, H. F. (1995). Voglibose (AO128) Is an Efficient α-Glucosidase Inhibitor and
 +
Mobilizes the Endogenous GLP-1 Reserve. Digestion, 56(6), 493–501.
 +
http://doi.org/10.1159/000201282
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</p>
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<p>Brown, J. B., Harris, S. B., Webster-Bogaert, S., Wetmore, S., Faulds, C., & Stewart, M.
 +
(2002). The role of patient, physician and systemic factors in the management of
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type 2 diabetes mellitus. Family Practice, 19(4), 344–349.
 +
http://doi.org/10.1093/fampra/19.4.344
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</p>
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<p>Butterworth, P. J., Warren, F. J., & Ellis, P. R. (2011). Human α-amylase and starch
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digestion: An interesting marriage. Starch - Stärke, 63(7), 395–405.
 +
http://doi.org/10.1002/star.201000150
 +
</p>
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<p>Centers for Disease Control and Prevention. (2014). National Diabetes Statistics Report.</p>
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<p>Chiasson, J.-L., Josse, R. G., Gomis, R., Hanefeld, M., Karasik, A., & Laakso, M. (2002).
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Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM
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randomised trial. The Lancet, 359(9323), 2072–2077.
 +
http://doi.org/10.1016/S0140-6736(02)08905-5
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</p>
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<p>Chiasson, J.-L., Josse, R. G., Hunt, J. A., Palmason, C., Rodger, N. W., Ross, S. A., ...
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Wolever*, T. M. S. (1994). The Efficacy of Acarbose in the Treatment of Patients
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with Non–Insulin-Dependent Diabetes Mellitus: A Multicenter, Controlled
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Clinical Trial. Annals of Internal Medicine, 121(12), 928–935.
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http://doi.org/10.7326/0003-4819-121-12-199412150-00004
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Crude and Age-Adjusted Rate per 100 of Civilian, Noninstitutionalized Population with
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Diagnosed Diabetes, United States, 1980–2011. (2014, September 5). Retrieved
 +
April 24, 2015, from
 +
http://www.cdc.gov/diabetes/statistics/prev/national/figage.htm
 +
</p>
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<p>Dedonder, R. 1966. Levansucrase from Bacillus subtilis. Methods Enzymol. 8:500–505.</p>
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<p>Deshpande, A. D., Harris-Hayes, M., & Schootman, M. (2008). Epidemiology of diabetes
 +
and diabetes-related complications. Physical therapy, 88(11), 1254-1264.
 +
</p>
 +
<p>D.M. Nathan, P.A. Cleary, J.Y. Backlund, S.M. Genuth, J.M. Lachin, T.J. Orchard, et al.,
 +
Intensive diabetes treatment and cardiovascular disease in patients with type 1
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diabetes, N Engl J Med, 353 (2005), pp. 2643–2653
 +
</p>
 +
<p>D.R. Whiting, L. Guariguata, C. Weil, J. Shaw, IDF diabetes atlas: global estimates of the
 +
prevalence of diabetes for 2011 and 2030 Diabetes Res Clin Pract, 94 (2011), pp.
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311–321
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</p>
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<p>Duncan, A. E. (2012). Hyperglycemia and Perioperative Glucose Management.Current
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Pharmaceutical Design, 18(38), 6195–6203.
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</p>
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<p>Edelman, P. S., Maier, H., & Wilhelm, K. (2012). Pramlintide in the Treatment of
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Diabetes Mellitus. BioDrugs, 22(6), 375–386. http://doi.org/10.2165/0063030-
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200822060-00004
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</p>
 +
<p>Ferraris, R. P., Yasharpour, S. A. S. A. N., Lloyd, K. C., Mirzayan, R. A. F. F. Y., &
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Diamond, J. M. (1990). Luminal glucose concentrations in the gut under normal
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conditions. American Journal of Physiology-Gastrointestinal and Liver
 +
Physiology, 259(5), G822-G837.
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</p>
 +
<p>Gay, P., Le Coq, D., Steinmetz, M., Ferrari, E., & Hoch, J. A. (1983). Cloning structural
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gene sacB, which codes for exoenzyme levansucrase of Bacillus subtilis:
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expression of the gene in Escherichia coli. Journal of bacteriology,153(3), 1424-
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1431.
 +
</p>
 +
<p>Gray, G. M., & Ingelfinger, F. J. (1966). Intestinal absorption of sucrose in man:
 +
interrelation of hydrolysis and monosaccharide product absorption. Journal of
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Clinical Investigation, 45(3), 388.
 +
</p>
 +
<p>Grant, R. W., Buse, J. B., & Meigs, J. B. (2005). Quality of Diabetes Care in U.S.
 +
Academic Medical Centers Low rates of medical regimen change. Diabetes Care,
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28(2), 337–442. http://doi.org/10.2337/diacare.28.2.337
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</p>
 +
<p>Grant, R. W., Pirraglia, P. A., Meigs, J. B., & Singer, D. E. (2004). Trends in complexity
 +
of diabetes care in the United States from 1991 to 2000. Archives of Internal
 +
Medicine, 164(10), 1134–1139. http://doi.org/10.1001/archinte.164.10.1134
 +
</p>
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<p>Halschou, K., Bukhave, K., & Rikardt, J. (2012). Intestinal Disaccharidase Activity and
 +
Uptake of Glucose from Sucrose. In S. Chackrewarthy (Ed.), Glucose Tolerance.
 +
InTech. Retrieved from http://www.intechopen.com/books/glucose-
 +
tolerance/intestinal-disaccharidase-activity-and-uptake-of-glucose-from-sucrose
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</p>
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<p>Hanahan, D. (1983). Studies on transformation of Escherichia coli with plasmids. Journal
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of Molecular Biology, 166(4), 557–580.
 +
</p>
 +
<p>Hoffmann, J., & Spengler, M. (1997). Efficacy of 24-Week Monotherapy With Acarbose,
 +
Metformin, or Placebo in Dietary-Treated NIDDM Patients: The Essen-II Study.
 +
The American Journal of Medicine, 103(6), 483–490.
 +
http://doi.org/10.1016/S0002-9343(97)00252-0
 +
Intensive blood-glucose control with sulphonylureas or insulin compared with
 +
conventional treatment and risk of complications in patients with type 2 diabetes
 +
(UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.
 +
</p>
 +
<p>Jenkins, D. J. A., Wolever, T. M. S., & Jenkins, A. L. (1988). Starchy Foods and
 +
Glycemic Index. Diabetes Care, 11(2), 149–159.
 +
http://doi.org/10.2337/diacare.11.2.149
 +
</p>
 +
<p>Jones, M. C. (2007). Therapies for diabetes: pramlintide and exenatide. American Family
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Physician, 75(12), 1831–1835.
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</p>
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<p>J Reizer, S. L. S. (1992). Functional interactions between proteins of the
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phosphoenolpyruvate:sugar phosphotransferase systems of Bacillus subtilis and
 +
Escherichia coli. The Journal of Biological Chemistry, 267(13), 9158–69.
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Jenkins, D. J., Wolever, T. M., & Jenkins, A. L. (1988). Starchy foods and glycemic
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index. Diabetes care, 11(2), 149-159.
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</p>
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<p>Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Cotran, Ramzi S. ; Robbins, Stanley L.
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(2005). Robbins and Cotran Pathologic Basis of Disease (7th ed.). Philadelphia,
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Pa.: Saunders. pp. 1194–1195. ISBN 0-7216-0187-1. Lancet. 1998 Sep 12;
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352(9131):837-53.
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</p>
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<p>Kundig, W., Ghosh, S., & Roseman, S. (1964). PHOSPHATE BOUND TO HISTIDINE
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IN A PROTEIN AS AN INTERMEDIATE IN A NOVEL PHOSPHO-
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TRANSFERASE SYSTEM. Proceedings of the National Academy of Sciences of
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the United States of America, 52, 1067–1074.
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</p>
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<p>Lebovitz, H. E. (1997). ALPHA-GLUCOSIDASE INHIBITORS. Endocrinology and
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Metabolism Clinics of North America, 26(3), 539–551.
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http://doi.org/10.1016/S0889-8529(05)70266-8
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</p>
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<p>Lourens-Hattingh, A., & Viljoen, B. C. (2001). Yogurt as probiotic carrier food.
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International Dairy Journal, 11(1–2), 1–17. http://doi.org/10.1016/S0958-
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6946(01)00036-X
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</p>
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<p>Malagelada, J. R., Bazzoli, F., Elewaut, A., Fried, M., Krabshuis, J. H., Lindberg, G., ...
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Vakil, N. (2007). World Gastroenterology Organisation Practice Guidelines.
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Dysphagia. Retrieved from http://almacen-
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gpc.dynalias.org/publico/Dysphagia%20WGO%202004%20Ingles.pdf
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</p>
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<p>Man, C. D., Camilleri, M., & Cobelli, C. (2006). A System Model of Oral Glucose
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Absorption: Validation on Gold Standard Data. IEEE Transactions on Biomedical
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Engineering, 53(12), 2472–2478. http://doi.org/10.1109/TBME.2006.883792
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</p>
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<p>Meigs, J. B., Nathan, D. M., Wilson, P. W., Cupples, L. A., & Singer, D. E. (1998).
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Metabolic risk factors worsen continuously across the spectrum of nondiabetic
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glucose tolerance. The Framingham Offspring Study. Annals of Internal Medicine,
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128(7), 524–533.
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</p>
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<p>Narimasa, S., Tatsuo, H., Mitsutaka, Y., & Toshio, I. (1979). Action of human pancreatic
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and salivary α-amylases on maltooligosaccharides: Evaluation of kinetic
 +
parameters. Clinica Chimica Acta, 97(2–3), 253–260.
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http://doi.org/10.1016/0009-8981(79)90423-6
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</p>
 +
<p>National Diabetes Data Group. (1979). Classification and Diagnosis of Diabetes Mellitus
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and Other Categories of Glucose Intolerance. Diabetes, 28(12), 1039–1057.
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http://doi.org/10.2337/diab.28.12.1039
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</p>
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<p>Nissle, A. (1959). [Explanations of the significance of colonic dysbacteria & the
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mechanism of action of E. coli therapy (mutaflor)]. Die Medizinische, 4(21),
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1017–1022.
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</p>
 +
<p>Parkin, C. G., & Brooks, N. (2002). Is postprandial glucose control important? Is it
 +
practical in primary care settings?. Clinical Diabetes, 20(2), 71-76.
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</p>
 +
<p>Patterson, Joan (2013). Many Schools Cutting Back on Physical Education. Las Vegas
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Review - Journal.
 +
Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S.
 +
adults. The Third National Health and Nutrition Examination Survey, 1988-1994.
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</p>
 +
<p>Peng, C.-K., Buldyrev, S. V., Havlin, S., Simons, M., Stanley, H. E., & Goldberger, A. L.
 +
(1994). Mosaic organization of DNA nucleotides. Physical Review E, 49(2),
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1685–1689. http://doi.org/10.1103/PhysRevE.49.1685
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</p>
 +
<p>Rathmann, W., & Giani, G. (2004). Global Prevalence of Diabetes: Estimates for the
 +
Year 2000 and Projections for 2030: Response to Wild et al. Diabetes Care, 2568-
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2569.
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</p>
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<p>Recorbet, G. H. I. S. L. A. I. N. E., Robert, C., Givaudan, A., Kudla, B., Normand, P., &
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Faurie, G. (1993). Conditional suicide system of Escherichia coli released into
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soil that uses the Bacillus subtilis sacB gene. Applied and environmental
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microbiology, 59(5), 1361-1366.
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</p>
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<p>Ried, J. L., and A. Collmer. 1987. An nptI-sacB-sacR cartridge for constructing directed,
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unmarked mutations in Gram-negative bacteria by marker exchange-eviction
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mutagenesis. Gene 57:239–246.
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</p>
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<p>Riddle, M., Frias, J., Zhang, B., Maier, H., Brown, C., Lutz, K., & Kolterman, O. (2007).
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Pramlintide Improved Glycemic Control and Reduced Weight in Patients With
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Type 2 Diabetes Using Basal Insulin. Diabetes Care, 30(11), 2794–2799.
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http://doi.org/10.2337/dc07-0589
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</p>
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<p>Saydah, S. H., Miret, M., Sung, J., Varas, C., Gause, D., & Brancati, F. L. (2001).
 +
Postchallenge Hyperglycemia and Mortality in a National Sample of U.S. Adults.
 +
Diabetes Care, 24(8), 1397–1402. http://doi.org/10.2337/diacare.24.8.1397
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</p>
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<p>Snelling, Anatasia; Korba, Casey; Burkey, Alyvia (2007). The National School Lunch
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and Competitive Food Offerings and Purchasing Behaviors of High School
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Students, 77(10), 701-705.
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</p>
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<p>Sonnenborn, Ulrich; Schulze, Jurgen. 2009. The Non-Pathogenic Escherichia coli strain
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Nissle 1917 - Features of a Versatile Probiotic. Microbial Ecology in Health and
 +
Disease, (21), 122-158.
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</p>
 +
<p>S.M. Haffner, S. Lehto, T. Ronnemaa, K. Pyorala, M. Laakso, Mortality from coronary
 +
heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and
 +
without prior myocardial infarction, N Engl J Med, 339 (1998), pp. 229–234
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</p>
 +
<p>Schultz, M. (2008). Clinical use of E. coli Nissle 1917 in inflammatory bowel disease.
 +
Inflammatory Bowel Diseases, 14(7), 1012–1018.
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http://doi.org/10.1002/ibd.20377
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</p>
 +
<p>Seifter, S., & Dayton, S. (1950). The estimation of glycogen with the anthrone reagent.
 +
Archives of Biochemistry, 25(1), 191–200.
 +
</p>
 +
<p>Shulman, N. B., Martinez, B., Brogan, D., Carr, A. A., & Miles, C. G. (1986). Financial
 +
cost as an obstacle to hypertension therapy. American Journal of Public Health,
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76(9), 1105–1108.
 +
</p>
 +
<p>Suwattee, P., Lynch, J. C., & Pendergrass, M. L. (2003). Quality of Care for Diabetic
 +
Patients in a Large Urban Public Hospital. Diabetes Care, 26(3), 563–568.
 +
http://doi.org/10.2337/diacare.26.3.563
 +
</p>
 +
<p>Temelkova-Kurktschiev, T. S., Koehler, C., Henkel, E., Leonhardt, W., Fuecker, K., &
 +
Hanefeld, M. (2000). Postchallenge plasma glucose and glycemic spikes are more
 +
strongly associated with atherosclerosis than fasting glucose or HbA1c level.
 +
</p>
 +
<p>Diabetes Care, 23(12), 1830–1834. http://doi.org/10.2337/diacare.23.12.1830
 +
What are normal blood glucose levels? Retrieved from Virginia Mason Medical Center
 +
website: https://www.virginiamason.org/whatarenormalbloodglucoselevels.
 +
Accessed: May. 5th ,2015
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Simple sugars cause a larger fluctuation in blood glucose, whether it be a sharper spike or even a depression below the homeostatic level, whereas complex sugars do not cause such a large fluctuation, thereby mitigating the spike and lessening the threat to the human body.
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Our solution involves engineering a genetically modified E.coli organism into the small intestine of a human where it can hydrolyze simple sugars into complex sugars, thereby mitigating hyperglycemic spikes that occur immediately after meals. Specifically, we studied the mitigation of two simple sugars, fructose and glucose, which constitute a majority of the average American diet in this research.
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This solution requires two different BioBricks, a polymerization circuit and an uptake circuit. The uptake circuit, containing the Enzyme-IIA membrane protein, transports glucose into the cytoplasm of the E.coli. The uptake circuit contains the GlgC gene, which codes for BLAH BLAH enzyme, that polymerizes glucose into glycogen. The same circuit contains the SacB gene, which codes for the levansucrase enzyme that hydrolyzes fructose into levan. Levansucrase also confers a fructose sensitivity to the chassis that causes it to lyse after two hours  in the presence of 5% sucrose. This releases the hydrolyzed sugars into the small intestine where they are broken down slowly and absorbed into the body, thereby mitigating the hyperglycemic spike.
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Synthetic biology is a better solution than existing chemicals, such as alpha-glucosidase inhibitors and analogs of amylin, that perform the same hydrolyses because a bacterium does not require dosage and can easily adapt to variable concentrations of simple sugars present. Therefore, the difficulties of dosage that remain a problem with drugs are not an issue with the bacteria.
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Limitations of this solution are mild gastrointestinal symptoms that already exist with chemical solutions due to the similar nature of treatment. Furthermore, the introduction of a probiotic into the body poses a risk of infection or gene transfer into other bacteria of the gut. However, the preferred strain of the E.coli chassis would be a probiotic-certified bacteria that would be biologically harnessed from colonizing the gut or performing horizontal gene transfer.</p>
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<p>Glucose and fructose are uptaken by different mechanisms into E.coli due to the nature of their polymerization. Glucose, polymerized into glycogen in the cytoplasm, requires to be transferred through the two outer membranes of E.coli. Glucose can diffuse through the outer membrane but requires the use of the Enzyme-IIA to pump it through the inner membrane to the cytoplasm. On the other hand, the levansucrase enzyme polymerizes fructose into levan between the two membranes of E.coli. Fructose, which easily dissolves through the outer membrane but is impermeable to the inner membrane, does not require a protein to transport it to the space between the two membranes where the levansucrase enzyme exists. Therefore, the sugar uptake cassette is only the Enzyme-IIA. </p>
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<p>The polymerization plasmid consists of the GlgC gene, which encodes for the protein BLAH that polymerizes glucose into glycogen, and the SacB gene, which encodes for the levansucrase protein that polymerizes fructose to levan and confers levan sensitivity to the chassis in the presence of 5% fructose. </p>
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<p> The uniqueness of this kill switch originates from the fact that it is not genetically based and instead relies on the toxic effect of fructose to the chassis. This type of kill-switch better serves our purpose because there is lessened risk of a genetic mutation in the kill-switch gene erasing the kill switch capability. It is less likely that mutations will erase the toxic effects of fructose on E.coli due to the SacB gene. </p>
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iGEM 2015

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University of Virginia iGEM 2015

House of Carbs

A Novel Solution to Minimizing Postprandial Hyperglycemic Spikes

Project Overview

The Problem: Diabetes Mellitus and Hyperglycemia

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From diabetes mellitus a number of devastating complications, such as amputations, blindness, crippling neuropathies, and many others, can arise from increased blood sugar levels on a regular basis, but many of the major complications of diabetes arise from drastic fluctuations in the blood glucose level (Ceriello et al., 2012). Up to two-thirds of people with diabetes die of cardiovascular disease (CVD) brought about by diabetes-related macrovascular diseases (Deshpande et al. 2008). In fact, the risk for cardiovascular disease mortality is 2 to 4 times higher in people with diabetes than in people who do not have diabetes. Additionally, diabetic retinopathy is the most common microvascular complication among people with diabetes and results in more than 10,000 new cases of blindness per year. Retinopathy is associated with prolonged hyperglycemia; it is slow to develop, and there is some evidence that it can begin to develop as early as 7 years before clinical diagnosis of diabetes (Deshpande et al., 2008).

Postprandial (post-meal) blood sugar spikes specifically are one of the most damaging complications of diabetes (Parkin et al., 2002). Many diabetics are able to effectively manage post-meal glycemic spikes with self-administered doses of insulin, but these hyperglycemic incidents still kill more Americans per year than any other diabetes-related complications (Parkin et al., 2002). Arguably, the gravest consequence of glycemic spikes in diabetes patients is the development of progressive macrovascular disease (MVD), which affects the large blood vessels of the body, hardening and blocking these vessels (Ceriello et al., 2012). MVD is the leading cause of death among T2DM patients in the United States, causing up to 65% of diabetes-related deaths, making it a huge target for diabetes treatments research (Deshpande et al., 2008). MVD also frequently leads to other severe complications such as ischemia in the extremities and blindness (Haffner et al., 1998).

Controlling Hyperglycemic Spikes

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For many T1DM and T2DM patients, it has been shown that the regular control and management of blood glucose levels prevents many of the vascular complications of the disease, but most of the time control over glucose is difficult to attain because the self-dosing insulin treatment system that a lot of moderately to severely sick diabetes patients use is often hard to calibrate and use (Parkin et al., 2002).

Compared to sucrose-rich food, starch-rich food has been found to create less fluctuation in blood glucose levels, and thus is beneficial to diabetes patients and hyperglycemia patients. There is evidence that this flatter response caused by a starch rich meal is associated with the slower rate of digestion of complex sugars versus simple sugars (Jenkins, Wolever, & Jenkins, 1988). Thus, if some of the simple sugars are first converted into complex saccharides inside the E. coli and then released back into small intestine, a similar flatter glycemic response will take place, which will be beneficial to the patients.

Our Devices

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We have assembled one plasmid with genes that dictate a controllable level of simple sugars uptake and one plasmid to produce glucan and fructan from simple sugars and then lyse to release the complex sugars back into the environment. In essence, this microbial device runs on two genetic devices -- an uptake circuit and a polymerization circuit.

In order to learn more details, please visit the Project page.

Show References

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References

A. Ceriello, S. Colagiuri, (2011). Guideline for management of postmeal glucose in diabetes. International Diabetes Federation Guideline Development Group, http://www.idf.org/sites/default/files/postmeal%20glucose%20guidelines.pdf , Accessed May. 6th, 2015

American Diabetes Association (2014). National Diabetes Statistics Report. http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf Accessed May. 5th, 2015

Anal, A. K., & Singh, H. (2007). Recent advances in microencapsulation of probiotics for industrial applications and targeted delivery. Trends in Food Science & Technology, 18(5), 240–251. http://doi.org/10.1016/j.tifs.2007.01.004

Anan, F., Masaki, T., Eto, T., Fukunaga, N., Iwao, T., Kaneda, K., ... Yoshimatsu, H. (2008). Postchallenge Plasma Glucose and Glycemic Spikes Are Associated with Pulse Pressure in Patients with Impaired Glucose Tolerance and Essential Hypertension. Hypertension Research, 31(8), 1565–1571. http://doi.org/10.1291/hypres.31.1565

AHFS Consumer Medication Information [Internet]. Bethesda (MD): American Society of Health-System Pharmacists, Inc.; ©2008. Acarbose; [revised 2015 Feb. 15; reviewed 2015 Apr. 28; cited 2015 May. 3]; Available from: http://www.nlm.nih.gov/medlineplus/druginfo/meds/ a696015.html

AHFS Consumer Medication Information [Internet]. Bethesda (MD): American Society of Health-System Pharmacists, Inc.; ©2008. Pramlintide; [revised 2015 Feb. 15; reviewed 2015 Apr. 28; cited 2015 May. 3]; Available from: http://www.nlm.nih.gov/medlineplus/druginfo/meds/a605031.html

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Bernard, A. M., Anderson, L., Cook, C. B., & Phillips, L. S. (1999). What do internal medicine residents need to enhance their diabetes care? Diabetes Care, 22(5), 661–666. http://doi.org/10.2337/diacare.22.5.661

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Brown, J. B., Harris, S. B., Webster-Bogaert, S., Wetmore, S., Faulds, C., & Stewart, M. (2002). The role of patient, physician and systemic factors in the management of type 2 diabetes mellitus. Family Practice, 19(4), 344–349. http://doi.org/10.1093/fampra/19.4.344

Butterworth, P. J., Warren, F. J., & Ellis, P. R. (2011). Human α-amylase and starch digestion: An interesting marriage. Starch - Stärke, 63(7), 395–405. http://doi.org/10.1002/star.201000150

Centers for Disease Control and Prevention. (2014). National Diabetes Statistics Report.

Chiasson, J.-L., Josse, R. G., Gomis, R., Hanefeld, M., Karasik, A., & Laakso, M. (2002). Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. The Lancet, 359(9323), 2072–2077. http://doi.org/10.1016/S0140-6736(02)08905-5

Chiasson, J.-L., Josse, R. G., Hunt, J. A., Palmason, C., Rodger, N. W., Ross, S. A., ... Wolever*, T. M. S. (1994). The Efficacy of Acarbose in the Treatment of Patients with Non–Insulin-Dependent Diabetes Mellitus: A Multicenter, Controlled Clinical Trial. Annals of Internal Medicine, 121(12), 928–935. http://doi.org/10.7326/0003-4819-121-12-199412150-00004 Crude and Age-Adjusted Rate per 100 of Civilian, Noninstitutionalized Population with Diagnosed Diabetes, United States, 1980–2011. (2014, September 5). Retrieved April 24, 2015, from http://www.cdc.gov/diabetes/statistics/prev/national/figage.htm

Dedonder, R. 1966. Levansucrase from Bacillus subtilis. Methods Enzymol. 8:500–505.

Deshpande, A. D., Harris-Hayes, M., & Schootman, M. (2008). Epidemiology of diabetes and diabetes-related complications. Physical therapy, 88(11), 1254-1264.

D.M. Nathan, P.A. Cleary, J.Y. Backlund, S.M. Genuth, J.M. Lachin, T.J. Orchard, et al., Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes, N Engl J Med, 353 (2005), pp. 2643–2653

D.R. Whiting, L. Guariguata, C. Weil, J. Shaw, IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030 Diabetes Res Clin Pract, 94 (2011), pp. 311–321

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Edelman, P. S., Maier, H., & Wilhelm, K. (2012). Pramlintide in the Treatment of Diabetes Mellitus. BioDrugs, 22(6), 375–386. http://doi.org/10.2165/0063030- 200822060-00004

Ferraris, R. P., Yasharpour, S. A. S. A. N., Lloyd, K. C., Mirzayan, R. A. F. F. Y., & Diamond, J. M. (1990). Luminal glucose concentrations in the gut under normal conditions. American Journal of Physiology-Gastrointestinal and Liver Physiology, 259(5), G822-G837.

Gay, P., Le Coq, D., Steinmetz, M., Ferrari, E., & Hoch, J. A. (1983). Cloning structural gene sacB, which codes for exoenzyme levansucrase of Bacillus subtilis: expression of the gene in Escherichia coli. Journal of bacteriology,153(3), 1424- 1431.

Gray, G. M., & Ingelfinger, F. J. (1966). Intestinal absorption of sucrose in man: interrelation of hydrolysis and monosaccharide product absorption. Journal of Clinical Investigation, 45(3), 388.

Grant, R. W., Buse, J. B., & Meigs, J. B. (2005). Quality of Diabetes Care in U.S. Academic Medical Centers Low rates of medical regimen change. Diabetes Care, 28(2), 337–442. http://doi.org/10.2337/diacare.28.2.337

Grant, R. W., Pirraglia, P. A., Meigs, J. B., & Singer, D. E. (2004). Trends in complexity of diabetes care in the United States from 1991 to 2000. Archives of Internal Medicine, 164(10), 1134–1139. http://doi.org/10.1001/archinte.164.10.1134

Halschou, K., Bukhave, K., & Rikardt, J. (2012). Intestinal Disaccharidase Activity and Uptake of Glucose from Sucrose. In S. Chackrewarthy (Ed.), Glucose Tolerance. InTech. Retrieved from http://www.intechopen.com/books/glucose- tolerance/intestinal-disaccharidase-activity-and-uptake-of-glucose-from-sucrose

Hanahan, D. (1983). Studies on transformation of Escherichia coli with plasmids. Journal of Molecular Biology, 166(4), 557–580.

Hoffmann, J., & Spengler, M. (1997). Efficacy of 24-Week Monotherapy With Acarbose, Metformin, or Placebo in Dietary-Treated NIDDM Patients: The Essen-II Study. The American Journal of Medicine, 103(6), 483–490. http://doi.org/10.1016/S0002-9343(97)00252-0 Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.

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