Embedded Files
History and FDA Approvals
History and FDA Approvals
Reynolds, M. (2023, June 12). What the scientists who pioneered Weight-Loss drugs want you to know. WIRED. https://www.wired.com/story/obesity-drugs-researcher-interview-ozempic-wegovy/
Research, C. F. D. E. A. (2020, August 20). Drug trial snapshot: Ozempic. U.S. Food And Drug Administration. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-ozempic
Office of the Commissioner & Office of the Commissioner. (2021, June 4). FDA approves new drug treatment for chronic weight management, first since 2014. U.S. Food And Drug Administration. https://web.archive.org/web/20210604235421/https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014
FDA approves heart protective benefits of Ozempic and confirms safety of Rybelsus. (2021, August 14). DiaTribe. https://diatribe.org/diabetes-medications/fda-approves-heart-protective-benefits-ozempic-and-confirms-safety-rybelsus
FDA. (2005). BYETTA exenatide injection. https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021773s004lbl.pdf
Novo Nordisk Inc. (2021). Highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215256s000lbl.pdf
Eli Lilly and Company. (2022). HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215866s000lbl.pdf
Novo Nordisk Inc. (2017). Highlights of prescribing information [Prescribing information]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf
➡️ Differences in amino acid sequence/structure between semaglutide and liraglutide.
Knudsen, L. B., & Lau, J. (2019). The discovery and development of liraglutide and semaglutide. Frontiers in Endocrinology, 10. https://doi.org/10.3389/fendo.2019.00155
Triplitt, C., & Chiquette, E. (2006). Exenatide: From the Gila Monster to The Pharmacy. Journal of the American Pharmacists Association, 46(1), 44–55. https://doi.org/10.1331/154434506775268698
Ozempic Mechanisms
Ozempic Mechanisms
Kommu, S., & Whitfield, P. (2024, February 11). Semaglutide. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK603723/
➡️ Ozempic proved to be very effective at lowering blood sugar compared to other drugs.
Mahapatra, M. K., Karuppasamy, M., & Sahoo, B. M. (2022). Semaglutide, a glucagon like peptide-1 receptor agonist with cardiovascular benefits for management of type 2 diabetes. Reviews in Endocrine and Metabolic Disorders, 23(3), 521–539. https://doi.org/10.1007/s11154-021-09699-1
Hughes, S., & Neumiller, J. J. (2019). Oral semaglutide. Clinical Diabetes, 38(1), 109–111. https://doi.org/10.2337/cd19-0079
Tamayo-Trujillo, R., Ruiz-Pozo, V. A., Cadena-Ullauri, S., Guevara-Ramírez, P., Paz-Cruz, E., Zambrano-Villacres, R., Simancas-Racines, D., & Zambrano, A. K. (2024). Molecular mechanisms of semaglutide and liraglutide as a therapeutic option for obesity. Frontiers in Nutrition, 11. https://doi.org/10.3389/fnut.2024.1398059
GLP-1 RA Mechanism of Action | Ozempic® (semaglutide) injection 0.5 mg, 1 mg, or 2 mg. (n.d.). novoMEDLINK. https://www.novomedlink.com/diabetes/products/treatments/ozempic/about/mechanism-of-action.html
GLP-1
GLP-1
⬅️ GLP-1 expression from proglucagon in different tissues.
Muller, T. D., Finan, B., Bloom, S. R., & Drucker, D. J. (2019). Glucagon-like peptide 1 (GLP-1). Mol. Metab., 30, 72–130. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812410/
Smith, N. K., Hackett, T. A., Galli, A., & Flynn, C. R. (2019). GLP-1: Molecular mechanisms and outcomes of a complex signaling system. Neurochemistry International, 128, 94–105. https://doi.org/10.1016/j.neuint.2019.04.010
⬅️ GLP-1 and its effects on reward and appetite in the brain.
Skibicka, K. P. (2013). The central GLP-1: implications for food and drug reward. Frontiers in Neuroscience, 7. https://doi.org/10.3389/fnins.2013.00181
Tissue expression of GLP1R - Summary - The Human Protein Atlas. (n.d.). https://www.proteinatlas.org/ENSG00000112164-GLP1R/tissue#rna_expression
Cabou, C., & Burcelin, R. (2011). GLP-1, the Gut-Brain, and Brain-Periphery axes. The Review of Diabetic Studies, 8(3), 418–431. https://doi.org/10.1900/rds.2011.8.418
Diz-Chaves, Y., Herrera-Pérez, S., González-Matías, L. C., Lamas, J. A., & Mallo, F. (2020). Glucagon-Like peptide-1 (GLP-1) in the integration of neural and endocrine responses to stress. Nutrients, 12(11), 3304. https://doi.org/10.3390/nu12113304
Baggio, L. L., & Drucker, D. J. (2014). Glucagon-like peptide-1 receptors in the brain: controlling food intake and body weight. Journal of Clinical Investigation, 124(10), 4223–4226. https://doi.org/10.1172/jci78371
Flint, A., Raben, A., Astrup, A., & Holst, J. J. (1998). Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J. Clin. Invest., 515–520. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC508592/pdf/1010515.pdf
⬅️ The perception of sweet taste leads to GLP-1 signaling and communication with parts of the brain that control appetite and satiety.
Jensterle, M., Rizzo, M., & Janez, A. (2021). Glucagon-Like peptide 1 and taste perception: From molecular mechanisms to potential clinical implications. International Journal of Molecular Sciences, 22(2), 902. https://doi.org/10.3390/ijms22020902
Shah, M., & Vella, A. (2014). Effects of GLP-1 on appetite and weight. Reviews in Endocrine and Metabolic Disorders, 15(3), 181–187. https://doi.org/10.1007/s11154-014-9289-5
Klausen, M. K., Thomsen, M., Wortwein, G., & Fink‐Jensen, A. (2021). The role of glucagon‐like peptide 1 (GLP‐1) in addictive disorders. British Journal of Pharmacology, 179(4), 625–641. https://doi.org/10.1111/bph.15677
Ramracheya, R., Chapman, C., Chibalina, M., Dou, H., Miranda, C., González, A., Moritoh, Y., Shigeto, M., Zhang, Q., Braun, M., Clark, A., Johnson, P. R., Rorsman, P., & Briant, L. J. B. (2018). GLP-1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition of P/Q-type Ca2+ channels. Physiological Reports, 6(17), e13852. https://doi.org/10.14814/phy2.13852
Shilleh, A. H., Viloria, K., Broichhagen, J., Campbell, J. E., & Hodson, D. J. (2024). GLP1R and GIPR expression and signaling in pancreatic alpha cells, beta cells and delta cells. Peptides, 171179. https://doi.org/10.1016/j.peptides.2024.171179
Ben-Shlomo, S., Zvibel, I., Shnell, M., Shlomai, A., Chepurko, E., Halpern, Z., Barzilai, N., Oren, R., & Fishman, S. (2010). Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase. Journal of Hepatology, 54(6), 1214–1223. https://doi.org/10.1016/j.jhep.2010.09.032
Péterfi, Z., Szilvásy-Szabó, A., Farkas, E., Ruska, Y., Pyke, C., Knudsen, L. B., & Fekete, C. (2020). Glucagon-Like Peptide-1 Regulates the Proopiomelanocortin Neurons of the Arcuate Nucleus both Directly and Indirectly via Presynaptic Action. Neuroendocrinology, 111(10), 986–997. https://doi.org/10.1159/000512806
Chen, X., Chen, L., Yang, W., & Xie, A. (2021). GLP-1 suppresses feeding behaviors and modulates neuronal electrophysiological properties in multiple brain regions. Frontiers in Molecular Neuroscience, 14. https://doi.org/10.3389/fnmol.2021.793004
Spreckley, E. (2015). The L-cell in nutritional sensing and the regulation of appetite. Frontiers in Nutrition, 2. https://doi.org/10.3389/fnut.2015.00023
⬅️ Some cells of the GI tract. L-cells release GLP-1
Drucker, D.J. (2016). Evolving Concepts and Translational Relevance of Enteroendocrine Cell Biology. The Journal of clinical endocrinology and metabolism, 101 3, 778-86 .
Systems Affected by GLP-1 Signaling
Systems Affected by GLP-1 Signaling
Insulin
Kulkarni, R. N. (2013). Insulin action in the islet Β-Cell. Madame Curie Bioscience Database - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK6554/
Le, T. K. C., Dao, X. D., Nguyen, D. V., Luu, D. H., Bui, T. M. H., Le, T. H., Nguyen, H. T., Le, T. N., Hosaka, T., & Nguyen, T. T. T. (2023). Insulin signaling and its application. Frontiers in Endocrinology, 14. https://doi.org/10.3389/fendo.2023.1226655
De Meyts, P. (2016, April 27). The insulin receptor and its signal transduction network. Endotext - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK378978/
⬅️ Graph of the relationship between blood glucose and insulin release throughout the day.
File:Suckale08 fig3 glucose insulin day.png - Wikimedia Commons. (n.d.). https://commons.wikimedia.org/wiki/File:Suckale08_fig3_glucose_insulin_day.png
De Koster, J., Nelli, R. K., Strieder-Barboza, C., De Souza, J., Lock, A. L., & Contreras, G. A. (2018). The contribution of hormone sensitive lipase to adipose tissue lipolysis and its regulation by insulin in periparturient dairy cows. Scientific Reports, 8(1). https://doi.org/10.1038/s41598-018-31582-4
Shin, A. C., Filatova, N., Lindtner, C., Chi, T., Degann, S., Oberlin, D., & Buettner, C. (2017). Insulin receptor signaling in POMC, but not AGRP, neurons controls adipose tissue insulin action. Diabetes, 66(6), 1560–1571. https://doi.org/10.2337/db16-1238
Wang, Q., Somwar, R., Bilan, P. J., Liu, Z., Jin, J., Woodgett, J. R., & Klip, A. (1999). Protein kinase B/AKt participates in GLUT4 translocation by insulin in L6 myoblasts. Molecular and Cellular Biology, 19(6), 4008–4018. https://doi.org/10.1128/mcb.19.6.4008
Krycer, J. R., Quek, L., Francis, D., Zadoorian, A., Weiss, F. C., Cooke, K. C., Nelson, M. E., Diaz-Vegas, A., Humphrey, S. J., Scalzo, R., Hirayama, A., Ikeda, S., Shoji, F., Suzuki, K., Huynh, K., Giles, C., Varney, B., Nagarajan, S. R., Hoy, A. J., . . . James, D. E. (2020). Insulin signaling requires glucose to promote lipid anabolism in adipocytes. Journal of Biological Chemistry, 295(38), 13250–13266. https://doi.org/10.1074/jbc.ra120.014907
Leptin
⬅️Leptin's effects on different populations of neurons within the ARC of the hypothalamus.
Olivier Lavoie, Natalie Jane Michael, Alexandre Caron. File:Classic leptin–melanocortin model.jpg - Wikimedia Commons. (n.d.). https://commons.wikimedia.org/wiki/File:Classic_leptin%E2%80%93melanocortin_model.jpg
Dornbush, S., & Aeddula, N. R. (2023, April 10). Physiology, Leptin. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK537038/
PMercer, A. J., Hentges, S. T., Meshul, C. K., & Low, M. J. (2013). Unraveling the central proopiomelanocortin neural circuits. Frontiers in Neuroscience, 7. https://doi.org/10.3389/fnins.2013.00019
Martínez-Sánchez, N. (2020). There and back again: leptin actions in white adipose tissue. International Journal of Molecular Sciences, 21(17), 6039. https://doi.org/10.3390/ijms21176039
Metabolism
⬅️ Glycolysis and gluconeogenesis are both tightly controlled by insulin.
Gluconeogenesis - Function - Control - TeachMePhysiology. (2024, April 8). TeachMePhysiology. https://teachmephysiology.com/biochemistry/atp-production/gluconeogenesis/
Melkonian, E. A., Asuka, E., & Schury, M. P. (2023, November 13). Physiology, gluconeogenesis. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK541119/
Zhang, X., Yang, S., Chen, J., & Su, Z. (2019). Unraveling the regulation of hepatic gluconeogenesis. Frontiers in Endocrinology, 9. https://doi.org/10.3389/fendo.2018.00802
Kersten, S. (2001). Mechanisms of nutritional and hormonal regulation of lipogenesis. EMBO Reports, 2(4), 282–286. https://doi.org/10.1093/embo-reports/kve071
Rotondo, F., Ho-Palma, A. C., Remesar, X., Fernández-López, J. A., Del Mar Romero, M., & Alemany, M. (2017). Glycerol is synthesized and secreted by adipocytes to dispose of excess glucose, via glycerogenesis and increased acyl-glycerol turnover. Scientific Reports, 7(1). https://doi.org/10.1038/s41598-017-09450-4
Wang, L., Li, J., & Di, L. (2021). Glycogen synthesis and beyond, a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases. Medicinal Research Reviews, 42(2), 946–982. https://doi.org/10.1002/med.21867
Dholariya, S. J., & Orrick, J. A. (2022, October 17). Biochemistry, fructose metabolism. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK576428/
Diabetes and Obesity
Diabetes and Obesity
Diabetes - Diagnosis and treatment - Mayo Clinic. (n.d.). https://www.mayoclinic.org/diseases-conditions/diabetes/diagnosis-treatment/drc-20371451
Freeman, A. M., Acevedo, L. A., & Pennings, N. (2023, August 17). Insulin resistance. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK507839/
Galicia-Garcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebal, A., Siddiqi, H., Uribe, K. B., Ostolaza, H., & Martín, C. (2020). Pathophysiology of Type 2 diabetes mellitus. International Journal of Molecular Sciences, 21(17), 6275. https://doi.org/10.3390/ijms21176275
Lewis, S. T., Greenway, F., Tucker, T. R., Alexander, M., Jackson, L. K., Hepford, S. A., Loveridge, B., & Lakey, J. R. T. (2023). A Receptor Story: Insulin Resistance Pathophysiology and Physiologic Insulin Resensitization’s role as a Treatment Modality. International Journal of Molecular Sciences, 24(13), 10927. https://doi.org/10.3390/ijms241310927
Kim, J. H., & Choi, J. (2013). Pathophysiology and clinical characteristics of hypothalamic obesity in children and adolescents. Annals of Pediatric Endocrinology & Metabolism, 18(4), 161. https://doi.org/10.6065/apem.2013.18.4.161
Swisa, A., Glaser, B., & Dor, Y. (2017). Metabolic stress and compromised identity of pancreatic beta cells. Frontiers in Genetics, 08. https://doi.org/10.3389/fgene.2017.00021
Chandrasekaran, P., & Weiskirchen, R. (2024). The Role of Obesity in Type 2 Diabetes Mellitus—An Overview. International Journal of Molecular Sciences, 25(3), 1882. https://doi.org/10.3390/ijms25031882
Caturano, A., D’Angelo, M., Mormone, A., Russo, V., Mollica, M. P., Salvatore, T., Galiero, R., Rinaldi, L., Vetrano, E., Marfella, R., Monda, M., Giordano, A., & Sasso, F. C. (2023). Oxidative Stress in Type 2 Diabetes: Impacts from Pathogenesis to Lifestyle Modifications. Current Issues in Molecular Biology, 45(8), 6651–6666. https://doi.org/10.3390/cimb45080420
Ormazabal, V., Nair, S., Elfeky, O., Aguayo, C., Salomon, C., & Zuñiga, F. A. (2018). Association between insulin resistance and the development of cardiovascular disease. Cardiovascular Diabetology, 17(1). https://doi.org/10.1186/s12933-018-0762-4
Fonseca, V. A., Capehorn, M. S., Garg, S. K., Gimeno, E. J., Hansen, O. H., Holst, A. G., Nayak, G., & Seufert, J. (2019). Reductions in Insulin Resistance are Mediated Primarily via Weight Loss in Subjects With Type 2 Diabetes on Semaglutide. The Journal of Clinical Endocrinology & Metabolism, 104(9), 4078–4086. https://doi.org/10.1210/jc.2018-02685
Bain, S. C., Mosenzon, O., Arechavaleta, R., Bogdański, P., Comlekci, A., Consoli, A., Deerochanawong, C., Dungan, K., Faingold, M. C., Farkouh, M. E., Franco, D. R., Gram, J., Guja, C., Joshi, P., Malek, R., Merino‐Torres, J. F., Nauck, M. A., Pedersen, S. D., Sheu, W. H. ‐., . . . Husain, M. (2018). Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial. Diabetes Obesity and Metabolism, 21(3), 499–508. https://doi.org/10.1111/dom.13553
Genetics
Genetics
⬅️ "Main" genes associated with obesity according to an archived CDC post. There are many more.
Genes and obesity | CDC. (n.d.). https://archive.cdc.gov/www_cdc_gov/genomics/resources/diseases/obesity/obesedit.htm
Tao, Y. (2010). The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocrine Reviews, 31(4), 506–543. https://doi.org/10.1210/er.2009-0037
HSD11B1 hydroxysteroid 11-beta dehydrogenase 1 [Homo sapiens (human)] - Gene - NCBI. (n.d.). https://www.ncbi.nlm.nih.gov/gene/3290
LEPR gene: MedlinePlus Genetics. (n.d.). https://medlineplus.gov/genetics/gene/lepr/#conditions
Thomas, L. (2019, February 27). Leptin mutations. https://www.news-medical.net/health/Leptin-Mutations.aspx
Hess, M. E., & Brüning, J. C. (2014). The fat mass and obesity-associated (FTO) gene: Obesity and beyond? Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease, 1842(10), 2039–2047. https://doi.org/10.1016/j.bbadis.2014.01.017
SLC30A8 solute carrier family 30 member 8 [Homo sapiens (human)] - Gene - NCBI. (n.d.). https://www.ncbi.nlm.nih.gov/gene/169026
Abraham, H., Covasa, M., & Hajnal, A. (2009). Cocaine- and amphetamine-regulated transcript peptide immunoreactivity in the brain of the CCK-1 receptor deficient obese OLETF rat. Experimental Brain Research, 196(4), 545–556. https://doi.org/10.1007/s00221-009-1885-3
Miscellaneous
Miscellaneous
Pugle, M. (2023, November 30). What happens to your body when you stop taking Ozempic? Health. https://www.health.com/what-happens-stop-taking-ozempic-8406764
Aguinaga, D., Casanovas, M., Rivas-Santisteban, R., Reyes-Resina, I., Navarro, G., & Franco, R. (2019). The sigma-1 receptor as key common factor in cocaine and food-seeking behaviors. Journal of Molecular Endocrinology, 63(4), R81–R92. https://doi.org/10.1530/jme-19-0138
Editorial Staff. (2024, July 31). Long-Term side effects of cocaine on the brain & body. American Addiction Centers. https://americanaddictioncenters.org/stimulants/cocaine/long-term-side-effects-of-abuse
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