Cell Bio Task 4

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Diabetes Mellitus Type 2: An in-depth analysis of the disease and it’s mechanisms ASSESSMENT 4 – BMS241 OVERVLIET, GABRIEL - 11716504 2021

1 Introduction – 180 words Glucose is an essential energy source for cells in the body. Glucose can either be sourced from dietary absorption or generated within the body, Glucose is then transported to the target cells to be distributed for consumption or storage. There are several different glucoregulatory hormones which regulate glucose levels within the body with insulin and glucagon being the two key regulators. Insulin is a regulatory hormone formed by beta-cells in the pancreas, which is essential to the metabolism of glucose in the body. Glucagon is the other key regulatory hormone formed by alpha cells in the pancreas and is essential to the catabolism of glucose in the body. Type 2 Diabetes Mellitus is often caused due to an increase in insulin resistance restricting the metabolism of glucose in the body. Glucose homeostasis – 540 words When examining Type 2 Diabetes Mellitus it is important to look at the mechanisms which maintain and manage blood glucose levels as well as how glucose is transported and distributed through the cellular membrane. Glucose homeostasis is a process that manages the balance of insulin and glucagon within the body. Insulin signalling which increases the absorption of glucose in the cells and inhibits glucose production in the liver, gluconeogenesis and glycogenesis, and glucose cell membrane transporters are all essential mechanisms in glucose homeostasis. There are two main states to look at with glucose homeostasis, the fasting and non-fasting states, which have a big effect on the way glucose is formed and how glucagon and insulin are balanced. In the fasting state blood glucose levels are maintained by glucagon stimulating gluconeogenesis which converts non- carbohydrate sources into glucose and glycogenolysis which converts glycogen into glucose in the liver. Glycogenolysis is primarily responsible for the generation of glucose during the early stages of fasting with gluconeogenesis only contributing after several hours of fasting occurs. Insulin levels are decreased as the need for disposal of glucose is minimal and no limitation on glucagon induced gluconeogenesis and glycogenolysis is required. However, in the non-fasting state glucose is generated from the digestion of nutrients and therefore glucagon levels are supressed in order to reduce the stimulation of gluconeogenesis and glycogenesis and insulin signalling increases in response to dietary action which increases disposal of glucose and limit glucose generation from gluconeogenesis and glycogenesis. This system is depicted in Figure 1 which shows how blood glucose levels are maintained within the body in the fasting and non-fasting states. DIABETES MELLITUS TYPE 2: AN IN-DEPTH ANALYSIS OF THE DISEASE AND IT’S MECHANISMS OVERVLIET, GABRIEL - 11716504

2 Figure 1 – Glucose Homeostasis. Pathways of glucose generation in non- diabetic fasting and non-fasting states. Reprinted from: Aronoff et al., 2004. The process of cell transportation through the cellular membrane is another essential aspect of glucose homeostasis and any interference in the mechanisms which take place can have detrimental effects on the balance between insulin and glucagon. Cell membranes are made up phospholipid bilayers ( Figure 2) and have proteins which allow for specific actions to occur such as glucose transport. The phospholipid bilayers are formed with the polar head on the outside due to the hydrophobic tail wanting to escape the water molecules in the extracellular fluid (Alberts et al., 2002). Figure 2 – Phospholipid Bilayer. This depicts the composition of a cell membrane. Reprinted from: Cooper, 2000. Glucose molecules unlike other smaller molecules cannot traverse through the cellular lipid membrane by itself. This is also due to the non-polar nature of glucose being incompatible with the polar nature of the cell membrane. ( Figure 3) DIABETES MELLITUS TYPE 2: AN IN-DEPTH ANALYSIS OF THE DISEASE AND IT’S MECHANISMS OVERVLIET, GABRIEL - 11716504

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3 Figure 3 – Permeability of phospholipid bilayers. This figure depicts different molecule’s reaction to the lipid cell membrane. Reprinted from Cooper, 2000. Due to the glucose molecules size, it requires transport proteins in order to form a passage for the molecules to pass through. There are two main classes of glucose transport proteins which are used to facilitate glucose transport through the cell membrane, Sodium-glucose linked transporters (SGLTs) and facilitated diffusion glucose transporters (GLUT). SGLTs many have different sub-classes, but the main three which focus on glucose transport are: SGLT1, SGLT2, and SGLT3 which assist in glucose transport in the gastrointestinal, renal, and cardiothoracic systems. GLUT also has many different sub-classes as can be seen in Table 1 below but have 5 major sub-classes GLUT1 – 5 which facilitate glucose transport all around the body and have various different functions (Litwack, 2018). DIABETES MELLITUS TYPE 2: AN IN-DEPTH ANALYSIS OF THE DISEASE AND IT’S MECHANISMS OVERVLIET, GABRIEL - 11716504

4 Table 1 – Classes of Facilitated Diffusion Glucose Transporters and their properties. Reprinted from Litwack, 2018. A key difference between these two classes of glucose transporters is the mechanisms they use to facilitate glucose traversal across the cell membrane, SGLTs use an active transport mechanism which uses energy from a sodium ion gradient created by a sodium/potassium ATPase pump to facilitate glucose transport whereas GLUTs use a passive mechanism in order to facilitate glucose transport (Navale & Paranjape, 2016). Diabetes Mellitus Type 2 – 720 words Type 2 Diabetes Mellitus is an adult-onset form of diabetes and normally occurs later in life as a result of excessive weight gain and overall lack of physical activity. It is statistically the most common instance of diabetes accounting for around 90% of all cases of Diabetes mellitus (Zheng et al., 2017). This form of diabetes is distinguished by a variety of factors such as high blood glucose content, low levels of insulin due to beta cell malfunctions in the pancreas, or resistance to insulin causing an imbalance in glucose homeostasis. The development of Type 2 Diabetes Mellitus involves physiological changes in multiple different organs causing severe consequences on the mechanisms which work to maintain glucose homeostasis. Some examples of the physiological changes which affect the development of type 2 diabetes are, defective pancreatic beta cells causing impaired insulin production and defective pancreatic alpha cells causing increased glucagon secretion. Increased production of glucose in the hepatic system as well as increased absorption in the gastrointestinal and renal systems can also contribute to the development of Type 2 Diabetes Mellitus. Glucose homeostasis is one of the key processes when looking at Type 2 Diabetes Mellitus. Unlike in a non-diabetic individual, the insulin has increased resistance preventing effective insulin signalling. As seen below in Figure 4 in contrast with the non-diabetic system shown in Figure 1, direct injection of insulin into the system accounts for the influence on the rate that glucose is disposed of and has little effect on the rate at which gluconeogenesis and glycogenesis occurs. The glucose homeostasis system in diabetic and non- diabetic patients is similar in most regards with glucagon induced gluconeogenesis and glycogenesis occurring in the fasting state and disposal of glucose due to insulin signalling still occurring. However, it is when digestive glucose production occurs that the system differs the most. As can be seen in Figure 4 below, the insulin resistance increase is too strong for external insulin injection to overcome and therefore is overwhelmed. As insulin signalling is responsible for controlling both hepatic generation of glucose and the disposal of glucose, having an increased resistance to insulin makes controlling these mechanisms ineffective. Due to the ineffective control over these mechanisms glucose production from both the hepatic system and digestive system are both producing glucose and sending it throughout the circulatory system resulting in hyperglycaemia. DIABETES MELLITUS TYPE 2: AN IN-DEPTH ANALYSIS OF THE DISEASE AND IT’S MECHANISMS OVERVLIET, GABRIEL - 11716504

5 Figure 4 – Glucose Homeostasis. Pathways of glucose generation in diabetic fasting and non-fasting states. Reprinted from Aronoff et al., 2004. As with glucose homeostasis in a normal patient the glucose transport proteins play a key role in the development of diabetes mellitus type 2. It is when any one of the numerous transport proteins becomes defective, that issues begin to arise in the glucose homeostasis system. Facilitated diffusion glucose transporters such as GLUT2 which facilitates the transport of glucose into the pancreatic beta cells signalling insulin release, and GLUT4 which absorbs insulin in the blood stream to reduce blood glucose levels, both contribute to type 2 diabetes when defective. When GLUT 2 is defective it causes insufficient signalling to the beta cells to produce insulin and when GLUT4 is defective glucose dispersal through the muscle and adipose tissue is limited. Whereas sodium coupled glucose transport proteins such as, SGLT1, and SGLT2 are responsible for glucose absorption in the gastrointestinal, renal, and cardiovascular systems and if defective would limit the dispersion of glucose throughout those systems (Litwack, 2018). It is also important to look at cellular membrane composition in type 2 diabetes mellitus as there are a number of factors to consider such as phospholipid composition and the effect it has on membrane fluidity. In patients with diabetes mellitus type 2, it has been observed that the cellular membrane is abnormally rigid meaning membrane fluidity has decreased. The phospholipid bilayer composition of the cellular membrane is known to have a major effect on the overall properties of the membrane. Changes in the composition of the phospholipid bilayer such as the increased level of lipids such as cholesterol and other fatty acids which are often found in diabetic patients, contribute to the decreased fluidity of the cellular membrane (Pilon, 2016) . Diabetes mellitus type 2 therapy – 180 words There are a few areas of the glucose homeostasis system that can be targeted for possible treatment of Diabetes mellitus type 2. Two of these areas are targeting the cellular membrane components and targeting specific glucose transport proteins. Glycoprotein which can be found in the composition of the cell membrane is a suitable target for treatment as a decrease in metabolism contributes to type 2 diabetes. Glycoproteins essentially provide regulatory DIABETES MELLITUS TYPE 2: AN IN-DEPTH ANALYSIS OF THE DISEASE AND IT’S MECHANISMS OVERVLIET, GABRIEL - 11716504

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6 mechanisms to the cell membrane by forming hydrogen bonds with water molecules outside of the membrane affecting fluidity (Naseri et al., 2020). It was found that there are compounds that can assist in the metabolization of excess glycoproteins found in the cell membrane as seen in Figure 5 below. Figure 5 – Glycoprotein regulation. This figure shows compounds which assist in the metabolization and regulation of glycoproteins. Reprinted from Naseri et al., 2020. Another potential target for treatment of diabetes mellitus type 2 is any of the numerous glucose transport proteins such as GLUT4 or SGLT1. However, there have been a number of studies which examine the role of the facilitated diffusion glucose transporter, GLUT4. This is a key transport protein in glucose homeostasis as if defective it would affect the passage of glucose through the cell membrane effectively impeding cellular energy production. Specific treatment options have been studied in order to effectively decrease the impact of a defective GLUT4 protein such as diet and exercise and compounds which initiate the specific GLUT4 signalling pathways (Alam et al., 2016). Conclusion – 180 words Glucose homeostasis is an essential system throughout the body which works to provide a constant source of glucose to cells in the body and maintain a healthy blood glucose level. However, any factors which may impede this system from functioning to its fullest extent can have detrimental effects of the human body such as Diabetes Mellitus Type 2. It is through the study of the disease and the processes surrounding it that we can gain further insights into these complex intertwining systems within the human body and unlock further potential treatment pathways and understanding of the disease as a whole. DIABETES MELLITUS TYPE 2: AN IN-DEPTH ANALYSIS OF THE DISEASE AND IT’S MECHANISMS OVERVLIET, GABRIEL - 11716504

7 Reference List Abbott, S. K., Else, P. L., Atkins, T. A., & Hulbert, A. (2012). Fatty acid composition of membrane bilayers: Importance of diet polyunsaturated fat balance. Biochimica et Biophysica Acta (BBA) - Biomembranes , 1818 (5), 1309–1317. https://doi.org/10.1016/j.bbamem.2012.01.011 Alam, F., Asiful Islam, M., Ibrahim Khalil, M., & Hua Gan, S. (2016). Metabolic Control of Type 2 Diabetes by Targeting the GLUT4 Glucose Transporter: Intervention Approaches. Current Pharmaceutical Design , 22 (20), 3034–3049. https://doi.org/10.2174/1381612822666160307145801 Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2002). Molecular Biology of the Cell, Fourth Edition (4th ed.). Garland Science. https://www.ncbi.nlm.nih.gov/books/NBK26871/ Aronoff, S. L., Berkowitz, K., Shreiner, B., & Want, L. (2004). Glucose Metabolism and Regulation: Beyond Insulin and Glucagon. Diabetes Spectrum , 17 (3), 183–190. https://doi.org/10.2337/diaspect.17.3.183 Boden, G. (1996). Fatty Acids and Insulin Resistance. Diabetes Care , 19 (4), 394–395. https://doi.org/10.2337/diacare.19.4.394 Boucher, J., Kleinridders, A., & Kahn, C. R. (2014). Insulin Receptor Signaling in Normal and Insulin-Resistant States. Cold Spring Harbor Perspectives in Biology , 6 (1), a009191. https://doi.org/10.1101/cshperspect.a009191 Chatterjee, S., Khunti, K., & Davies, M. J. (2017). Type 2 diabetes. The Lancet , 389 (10085), 2239–2251. https://doi.org/10.1016/s0140-6736(17)30058-2 Cooper, G. (2000). The Cell: A Molecular Approach (2nd ed.). Sinauer Associates Inc. https://www.ncbi.nlm.nih.gov/books/NBK9928/ DIABETES MELLITUS TYPE 2: AN IN-DEPTH ANALYSIS OF THE DISEASE AND IT’S MECHANISMS OVERVLIET, GABRIEL - 11716504

8 Czech, A., Piątkiewicz, P., & Tatoń, J. (2009). Cellular glucose transport and glucotransporter 4 expression as a therapeutic target: clinical and experimental studies. Archivum Immunologiae et Therapiae Experimentalis , 57 (6). https://doi.org/10.1007/s00005-009-0052-7 DeFronzo, R. A., Ferrannini, E., Groop, L., Henry, R. R., Herman, W. H., Holst, J. J., Hu, F. B., Kahn, C. R., Raz, I., Shulman, G. I., Simonson, D. C., Testa, M. A., & Weiss, R. (2015). Type 2 diabetes mellitus. Nature Reviews Disease Primers , 1 (1). https://doi.org/10.1038/nrdp.2015.19 Fu, Z., R. Gilbert, E., & Liu, D. (2012). Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes. Current Diabetes Reviews , 9 (1), 25–53. https://doi.org/10.2174/1573399811309010025 Kapogiannis, D., & Avgerinos, K. I. (2020). Brain glucose and ketone utilization in brain aging and neurodegenerative diseases. International Review of Neurobiology , 79–110. https://doi.org/10.1016/bs.irn.2020.03.015 Khan, M. A. B., Hashim, M. J., King, J. K., Govender, R. D., Mustafa, H., & al Kaabi, J. (2019). Epidemiology of Type 2 Diabetes – Global Burden of Disease and Forecasted Trends. Journal of Epidemiology and Global Health , 10 (1), 107. https://doi.org/10.2991/jegh.k.191028.001 Litwack, G. (2018). Insulin and Sugars. Human Biochemistry , 131–160. https://doi.org/10.1016/b978-0-12-383864-3.00006-5 Maulucci, G., Cordelli, E., Rizzi, A., de Leva, F., Papi, M., Ciasca, G., Samengo, D., Pani, G., Pitocco, D., Soda, P., Ghirlanda, G., Iannello, G., & de Spirito, M. (2017). Phase separation of the plasma membrane in human DIABETES MELLITUS TYPE 2: AN IN-DEPTH ANALYSIS OF THE DISEASE AND IT’S MECHANISMS OVERVLIET, GABRIEL - 11716504

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9 red blood cells as a potential tool for diagnosis and progression monitoring of type 1 diabetes mellitus. PLOS ONE , 12 (9), e0184109. https://doi.org/10.1371/journal.pone.0184109 Naseri, R., Navabi, S. J., Samimi, Z., Mishra, A. P., Nigam, M., Chandra, H., Olatunde, A., Tijjani, H., Morais-Urano, R. P., & Farzaei, M. H. (2020). Targeting Glycoproteins as a therapeutic strategy for diabetes mellitus and its complications. DARU Journal of Pharmaceutical Sciences , 28 (1), 333–358. https://doi.org/10.1007/s40199-020-00327-y Navale, A. M., & Paranjape, A. N. (2016). Glucose transporters: physiological and pathological roles. Biophysical Reviews , 8 (1), 5–9. https://doi.org/10.1007/s12551-015-0186-2 N.M. Weijers, R. (2012). Lipid Composition of Cell Membranes and Its Relevance in Type 2 Diabetes Mellitus. Current Diabetes Reviews , 8 (5), 390–400. https://doi.org/10.2174/157339912802083531 Pilon, M. (2016). Revisiting the membrane-centric view of diabetes. Lipids in Health and Disease , 15 (1). https://doi.org/10.1186/s12944-016-0342-0 Saha, S. (2020). Association between the membrane transporter proteins and type 2 diabetes mellitus. Expert Review of Clinical Pharmacology , 13 (3), 287–297. https://doi.org/10.1080/17512433.2020.1729125 Song, P., Onishi, A., Koepsell, H., & Vallon, V. (2016). Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus. Expert Opinion on Therapeutic Targets , 20 (9), 1109–1125. https://doi.org/10.1517/14728222.2016.1168808 DIABETES MELLITUS TYPE 2: AN IN-DEPTH ANALYSIS OF THE DISEASE AND IT’S MECHANISMS OVERVLIET, GABRIEL - 11716504

10 The Lancet. (2017). Diabetes: a dynamic disease. The Lancet , 389 (10085), 2163. https://doi.org/10.1016/s0140-6736(17)31537-4 Zheng, Y., Ley, S. H., & Hu, F. B. (2017). Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nature Reviews Endocrinology , 14 (2), 88–98. https://doi.org/10.1038/nrendo.2017.151 DIABETES MELLITUS TYPE 2: AN IN-DEPTH ANALYSIS OF THE DISEASE AND IT’S MECHANISMS OVERVLIET, GABRIEL - 11716504

Cell Bio Task 4

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