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A Revolution for Diabetes Therapies

Incretins have been the main talk in the diabetic community for the last two years. Introduction of these molecules in the pool of Type 2 diabetes therapies not only improved the regulation of the disorder but also showed incredible results in the weight loss journey of the patients. Incretins are hormones that are naturally produced in the enteroendocrine cells in the gut. In the last few years, they are being used as therapies for the regulation of Type 2 diabetes. This article analyses the molecular background of incretin therapies and explains why their action is so effective.


Insulin and Diabetes Mellitus

Before going into incretins, it is important to explain the main characteristics of insulin and diabetes. Insulin is a hormone crucial for the human organism. It is produced in the β-cells of Langerhans islets in the pancreas. The main role of insulin is that it enables the uptake of glucose from heart, skeletal muscle and adipose cells. Glucose is then saved in the form of energy (Sims, Carr, Oram, DiMeglio, & Evans-Molina, 2021). Diabetes is a long-term illness that affects both children and adults. Approximately 5-10% of the patients suffer from Type 1 diabetes whereas 90-95% of the patients suffer from Type 2 diabetes.


Type 1 diabetes is thought to be an autoimmune reaction. The immune system attacks the β-cells of the Langerhans islets of the pancreas and destroys them. These cells cannot produce insulin and thus glucose cannot enter the muscle and adipose tissue. This leads to a wide range of symptoms including weight loss, thirst, frequent urination, fatigue, hunger and sometimes blurred vision. Type 1 diabetes is usually diagnosed in the early years of life and is mainly treated by administration of insulin (DiMeglio, Evans-Molina, & Oram, 2018).


Type 2 diabetes, also known as adult-onset diabetes, is the result of genetic and environmental factors, especially weight-gain. Type 2 patients produce insulin but their cells are unable to uptake it, a condition called “insulin resistance”. Even though the pancreas makes more and more insulin in order to support the cells, it is not able to keep up and glucose remains in the blood stream. Symptoms are similar to those of Type 1 diabetes. Type 2 diabetes is mostly seen in adults but in the last few years more and more children and teenagers are diagnosed with Type 1 diabetes, due to Western lifestyle. The first step towards managing Type 2 diabetes is change of lifestyle. A balanced nutrition and exercise plan can lead to loss of weight, an important aspect that can help prevent onset of Type 2 diabetes. Other drugs such as metformin, SGLT2s and incretins are also administered to the patients, depending on their profile. If needed, Type 2 diabetes patients are also administered insulin (Tinajero & Malik, 2021).


Figure 1: Life with Diabetes (Rohra, 2022)

Incretins and Their Natural Function In The Human Organism

Incretins are a class of hormone that play a crucial role in regulating blood sugar levels in the body. They are primarily involved in the control of glucose metabolism and are secreted by specific cells in the gastrointestinal tract in response to food intake. Incretins act by stimulating the release of insulin from the pancreas which helps to lower blood sugar levels (Nauck, Quast, Wefers, & Pfeiffer, 2021). The two most well-known incretin hormones are the glucose-dependent insulinotropic peptide (GIP) and the glucagon-like peptide 1 (GLP-1). GLP-1 is produced by the L-cells in the intestines, while GIP is released by the K-cells in the upper small intestine. Both hormones are rapidly inactivated by an enzyme called dipeptidyl peptidase-4 (DPP-4), which limits their duration of action (Baggio & Drucker, 2007).


The natural function of incretins is to enhance insulin secretion in response to elevated blood sugar levels. When we eat a meal, GLP-1 and GIP are released into the bloodstream. They then bind to specific receptors on the beta cells of the pancreas, triggering the release of insulin. Incretins also suppress the release of glucagon, a hormone that increases blood sugar level by promoting the breakdown of stored glucose (Mayendraraj, Rosenkilde, & Gasbjerg, 2022).


Figure 2: The Effects of GIP and GLP-1 in Human Tissues (Nauck et al., 2021)

Incretins For The Fight Against Diabetes

Research on insulins and diabetes therapies led to the discovery of a revolutionary event: The incretin effect. It was found that when glucose was administered to individuals orally, the insulin response was much higher compared to what happened when glucose was administered intravenously. Moreover, not only the level of insulin was higher, but the individual had a decreased level of hunger, leading often to weight loss. To address this, pharmaceutical companies have developed medications that mimic the actions of incretin hormones or inhibit the enzyme responsible for their breakdown (Nauck & Meier, 2016).


GLP-1 receptor agonists are medications that mimic the effects of GLP-1. They bind to the GLP-1 receptors on pancreatic beta cells, promoting insulin secretion and suppressing glucagon release. By mimicking the actions of GLP-1, these medications help to lower sugar levels, improve glucose control, and reduce the risk of hypoglycaemia (Nauck, Quast, Wefers, & Meier, 2021).


DPP-4 inhibitors, on the other hand, work by blocking the enzyme DPP-4, which breaks down incretin hormones. By inhibiting DPP-4, these medications increase the levels of GLP-1 and GIP in the bloodstream, prolonging their action. This results in increased insulin secretion and reduced glucagon release, leading to improved blood sugar control (Gilbert & Pratley, 2020).


Both GLP-1 receptor agonists and DPP-4 inhibitors are used as medications for Type 2 diabetes. They are typically prescribed as an adjunct to diet and exercise when lifestyle modifications alone are not sufficient to control blood sugar levels. These medications have shown efficacy in lowering hemoglobin A1c, a measure of average blood sugar levels over time, promoting weight loss, and reducing the risk of cardiovascular events.


It is important to note that incretin-based therapies are not without potential side effects. Common side effects include nausea, vomiting, diarrhoea and abdominal discomfort. However, these side effects are usually transient and tend to improve over time (Stonehouse, Darsow, & Maggs, 2012).


Figure 3: Weight loss is important in diabetes treatment (Kelley - Hedgepeth, 2020)

Conclusion

Diabetes therapies are becoming more and more viable over time. Medications that mimic incretin hormones or inhibit their breakdown are used to treat Type 2 diabetes, helping to improved glucose control and reduce the risk of complications associated with the disease. Incretins have revolutionized the therapeutic approaches of Type 2 diabetes and have offered a new view towards fighting obesity.


Bibliographical References

Baggio, L. L., & Drucker, D. J. (2007). Biology of incretins: GLP-1 and gip. Gastroenterology, 132(6), 2131–2157. doi:10.1053/j.gastro.2007.03.054

https://doi.org/10.1053/j.gastro.2007.03.054


DiMeglio, L. A., Evans-Molina, C., & Oram, R. A. (2018). Type 1 diabetes. The Lancet, 391(10138), 2449–2462. doi:10.1016/s0140-6736(18)31320-5

https://doi.org/10.1016/S0140-6736(18)31320-5


Gilbert, M. P., & Pratley, R. E. (2020). GLP-1 analogs and DPP-4 inhibitors in type 2 diabetes therapy: Review of head-to-head clinical trials. Frontiers in Endocrinology, 11. doi:10.3389/fendo.2020.00178

https://doi.org/10.3389/fendo.2020.00178


Mayendraraj, A., Rosenkilde, M. M., & Gasbjerg, L. S. (2022). GLP-1 and GIP receptor signaling in beta cells – a review of receptor interactions and co-stimulation. Peptides, 151, 170749. doi:10.1016/j.peptides.2022.170749

https://doi.org/10.1016/j.peptides.2022.170749


Nauck, M. A., & Meier, J. J. (2016). The incretin effect in healthy individuals and those with type 2 diabetes: Physiology, pathophysiology, and response to therapeutic interventions. The Lancet Diabetes & Endocrinology, 4(6), 525–536. doi:10.1016/s2213-8587(15)00482-9

https://doi.org/10.1016/S2213-8587(15)00482-9


Nauck, M. A., Quast, D. R., Wefers, J., & Meier, J. J. (2021). GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art. Molecular Metabolism, 46, 101102. doi:10.1016/j.molmet.2020.101102

https://doi.org/10.1016/j.molmet.2020.101102


Nauck, M. A., Quast, D. R., Wefers, J., & Pfeiffer, A. F. (2021). The evolving story of Incretins in metabolic and cardiovascular disease: A pathophysiological update. Diabetes, Obesity and Metabolism, 23(S3), 5–29. doi:10.1111/dom.14496

https://doi.org/10.1111/dom.14496


Sims, E. K., Carr, A. L., Oram, R. A., DiMeglio, L. A., & Evans-Molina, C. (2021). 100 years of insulin: Celebrating the past, present and future of diabetes therapy. Nature Medicine, 27(7), 1154–1164. doi:10.1038/s41591-021-01418-2

https://doi.org/10.1038/s41591-021-01418-2


Stonehouse, A. H., Darsow, T., & Maggs, D. G. (2012). Incretin-based therapies. Journal of Diabetes, 4(1), 55–67. doi:10.1111/j.1753-0407.2011.00143.x

https://doi.org/10.1111/j.1753-0407.2011.00143.x


Tinajero, M. G., & Malik, V. S. (2021). An update on the epidemiology of type 2 diabetes. Endocrinology and Metabolism Clinics of North America, 50(3), 337–355. doi:10.1016/j.ecl.2021.05.013

https://doi.org/10.1016/j.ecl.2021.05.013



Visual Sources

Figure 1: Rohra D. (2022). Type 2 Diabetes - Its Symptoms and Causes. [Image]. Redcliffe Labs.

https://redcliffelabs.com/myhealth/diabetes/type-2-diabetes-its-symptoms-and-causes/


Figure 2: Nauck M. et al. (2021). The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update. [Diagram]. Diabetes, Obesity and Metabolism.

https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.14496#


Figure 3: Kelley-Hedgepeth A. (2020). Good News for Those with Type 2 Diabetes: Healthy Lifestyle Matters. Harvard Health Publishing.

https://www.health.harvard.edu/blog/good-news-for-those-with-type-2-diabetes-healthy-lifestyle-matters-2020021718827





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Matina Laskou

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