Associate Professor Melkam Kebede
Melkam Kebede was awarded her Ph.D. in 2007 from the University of Melbourne. During this period, she studied the metabolic consequences of pancreatic β-cell specific overexpression of fructose- 1,6-bisphosphatase using a transgenic mouse model, under the supervision of Professor Joseph Proietto and A/Prof Sof Andrikopoulos. In 2007 Melkam moved to Canada to undertake postdoctoral training at Montreal Diabetes Research Centre where she worked to characterize and understand the regulation and role of the G protein coupled receptor, GPR40 in pancreatic β-cells - under the mentorship of Professor Vincent Poitout. In Montreal, Melkam was supported by a post-doctoral fellowship from the Canadian Diabetes Association. In 2012 Melkam joined Professor Alan Attie’s laboratory at the University of Wisconsin, Madison for her second post-doctoral fellowship. In the Attie laboratory Melkam studied the involvement of VPS10 family of proteins, specifically Sorcs1, in the formation and stability of insulin containing secretory granules in pancreatic β-cells. Her research at the University of Wisconsin was supported by the American Diabetes Association mentor based post-doctoral fellowship. In 2015, Melkam returned to Australia to establish her own independent career as a Laboratory Head at the Charles Perkins Centre, University of Sydney funded by a Philanthropic Fellowship from the University of Sydney. Her lab aims to understand the mechanisms of β-cell failure in the pathogenesis of type 2 diabetes. Her research in Sydney has been funded by Diabetes Australia Research Trust and the NHMRC project and Ideas grants.
Type 2 diabetes occurs when the pancreatic beta-cells are not able to produce and secrete enough insulin to meet the increased demand for insulin brought about by insulin resistance. The molecular mechanisms that control pancreatic beta-cell failure during the progression to type 2 diabetes remain poorly understood. Therefore, the Kebede lab aims to understand the mechanisms of beta-cell failure in the pathogenesis of type 2 diabetes. The current projects in the lab focus on understanding the mechanisms behind insulin secretory granules biogenesis, maturation, stability and targeting for secretion. We use a combination of mass spectrometry, flow cytometry, microscopy, cell and molecular biology approaches to help us understand these processes in cell and animal models of type 2 diabetes.
Unit coordinator: PHSI3009/PHSI3909: Frontiers in Cellular Physiology
Project 1: A common characteristic of this failure is a reduction in glucose stimulated mature insulin secretion and increased proinsulin secretion. This can be due to defects in proinsulin sorting into secretory vesicles prior to its processing to mature insulin. The mechanism of proinsulin sorting into secretory vesicles is poorly understood and this project aims to study a candidate Golgi resident protein that may be responsible for this process. We show that this protein is expressed in beta-cells and not glucagon producing alpha-cells, and that its expression is increased in models of beta-cell compensation and decreased in type 2 diabetic models. Insights from this work could lead to the development of novel therapeutic approaches aimed at proper trafficking of proinsulin resulting in efficient processing to insulin and hence availability of insulin for secretion.
Project 2: Insulin secretory granules (SGs) exist in at least two functional distinct pools; newly synthesized younger SGs that are preferentially secreted upon stimulation, and older, SGs that are less mobile preferentially targeted for degradation. A detailed understanding of the various insulin secretory granules pools and how these contribute to healthy and disease is essential. Current therapies that increase insulin secretion do not consider the existence of these distinct pools of SGs. Accordingly, these approaches are only effective for a relatively short period, with the worsening of the diabetes associated with continued decline in β-cell function. In this project, we propose an entirely unique strategy to increase insulin secretion by elucidating and targeting mechanisms that limit old SG mobilization. Findings from this study will serve as a prerequisite for developing novel therapies aimed at preserving the functionality and increasing secretion of insulin SGs.
Project 3: Unveiling changes in a proteome through pathogenesis of diseases can provide unparalleled insights into the mechanisms underpinning disease. In this project, using flow cytometry and liquid chromatography mass spectrometry/mass spectrometry. We aim to characterise the deep proteome of both whole islets and individual islet cell types; alpha, beta, gamma, delta and epsilon from mice and humans at variable states of health and disease. By characterising the proteomes of the individual islet cell types, we can observe the communication between the islet cells, the regulation within islets and how this ultimately impacts on the regulation of blood glucose in the whole body. This can be further used to complement whole islet proteomics data of different stages of disease and attribute changes in the proteins specific to a cell type, furthering our understanding of how the cells within islets communicate.
Australian Diabetes Association.
Publications
Journals
- Hao, H., Yuan, Y., Ito, A., Eberand, B., Tjondro, H., Cielesh, M., Norris, N., Moreno, C., Maxwell, J., Neely, G., Payne, R., Kebede, M., Larance, M., et al (2025). FUT10 and FUT11 are protein O-fucosyltransferases that modify protein EMI domains. Nature Chemical Biology. [More Information]
- Diaz Vegas, A., Cooke, K., Cutler, H., Yau, B., Masson, S., Harney, D., Fuller, O., Potter, M., Madsen, S., Craw, N., Zhang, Y., Moreno, C., Kebede, M., Neely, G., Stoeckli, J., Burchfield, J., James, D. (2024). Deletion of miPEP in adipocytes protects against obesity and insulin resistance by boosting muscle metabolism. Molecular Metabolism, 86. [More Information]
- Yau, B., Madsen, S., Nelson, M., Cooke, K., Fritzen, A., Thorius, I., Stoeckli, J., James, D., Kebede, M. (2024). Genetics and diet shape the relationship between islet function and whole body metabolism. American Journal of Physiology - Endocrinology and Metabolism, 326(5), E663-E672. [More Information]
2025
- Hao, H., Yuan, Y., Ito, A., Eberand, B., Tjondro, H., Cielesh, M., Norris, N., Moreno, C., Maxwell, J., Neely, G., Payne, R., Kebede, M., Larance, M., et al (2025). FUT10 and FUT11 are protein O-fucosyltransferases that modify protein EMI domains. Nature Chemical Biology. [More Information]
2024
- Diaz Vegas, A., Cooke, K., Cutler, H., Yau, B., Masson, S., Harney, D., Fuller, O., Potter, M., Madsen, S., Craw, N., Zhang, Y., Moreno, C., Kebede, M., Neely, G., Stoeckli, J., Burchfield, J., James, D. (2024). Deletion of miPEP in adipocytes protects against obesity and insulin resistance by boosting muscle metabolism. Molecular Metabolism, 86. [More Information]
- Yau, B., Madsen, S., Nelson, M., Cooke, K., Fritzen, A., Thorius, I., Stoeckli, J., James, D., Kebede, M. (2024). Genetics and diet shape the relationship between islet function and whole body metabolism. American Journal of Physiology - Endocrinology and Metabolism, 326(5), E663-E672. [More Information]
- Thillainadesan, S., Jiang, B., Kebede, M., Morahan, G., James, D., Madsen, S., Hocking, S., Lambert, A., Cooke, K., Stoeckli, J., Yau, B., Masson, S., Howell, A., Potter, M., Fuller, O. (2024). The metabolic consequences of ‘yo-yo’ dieting are markedly influenced by genetic diversity. International Journal of Obesity, 48(8), 1170-1179. [More Information]
2023
- Thai, L., O'Reilly, L., Reibe-Pal, S., Sue, N., Holliday, H., Small, L., Schmitz-Peiffer, C., Dhenni, R., Wang-Wei Tsai, V., Norris, N., Kebede, M., Cooney, G., et al (2023). β-cell function is regulated by metabolic and epigenetic programming of islet-associated macrophages, involving Axl, Mertk, and TGFβ receptor signaling. iScience, 26(4). [More Information]
- Keller, M., Hudkins, K., Shalev, A., Bhatnagar, S., Kebede, M., Merrins, M., Davis, D., Alpers, C., Kimple, M., Attie, A. (2023). What the BTBR/J mouse has taught us about diabetes and diabetic complications. iScience, 26(7), 107036. [More Information]
2022
- Brandon, A., Small, L., Nguyen, T., Suryana, E., Gong, H., Yassmin, C., Hancock, S., Pulpitel, T., Stonehouse, S., Prescott, L., Kebede, M., Yau, B., Quek, L., Cooney, G., et al (2022). Insulin sensitivity is preserved in mice made obese by feeding a high starch diet. eLife, 11, Article e79250-19 pages. [More Information]
2021
- Singh, R., Cottle, L., Loudovaris, T., Yang, P., Thomas, H., Kebede, M., Thorn, P. (2021). Enhanced structure and function of human pluripotent stem cell-derived beta-cells cultured on extracellular matrix. Stem Cells Translational Medicine, 10(3), 492-505. [More Information]
- Wali, J., Milner, A., Luk, A., Pulpitel, T., Dodgson, T., Facey, H., Wahl, D., Kebede, M., Senior, A., Sullivan, M., Brandon, A., Yau, B., Lockwood, G., Koay, Y., Ribeiro, R., Solon-Biet, S., Bell-Anderson, K., O'Sullivan, J., Macia, L., Cooney, G., Cogger, V., Holmes, A., Raubenheimer, D., Le Couteur, D., Simpson, S., et al (2021). Impact of dietary carbohydrate type and protein–carbohydrate interaction on metabolic health. Nature Metabolism, 3(6), 810-828. [More Information]
- Germanos, M., Gao, A., Taper, M., Yau, B., Kebede, M. (2021). Inside the Insulin Secretory Granule. Metabolites, 11(8), 515-1-515-32. [More Information]
2020
- Yau, B., Hays, L., Liang, C., Laybutt, D., Thomas, H., Gunton, J., Williams, L., Hawthorne, W., Thorn, P., Rhodes, C., Kebede, M. (2020). A fluorescent timer reporter enables sorting of insulin secretory granules by age. Journal of Biological Chemistry, 295(27), 8901-8911. [More Information]
- Ma, W., Chang, J., Tong, J., Ho, U., Yau, B., Kebede, M., Thorn, P. (2020). Arp2/3 nucleates F-actin coating of fusing insulin granules in pancreatic b cells to control insulin secretion. Journal of Cell Science, 133(6), 1-11. [More Information]
2019
- Stoeckli, J., Zadoorian, A., Cooke, K., Deshpande, V., Yau, B., Kebede, M., Humphrey, S., James, D. (2019). ABHD15 regulates adipose tissue lipolysis and hepatic lipid accumulation. Molecular Metabolism, 25, 83-94. [More Information]
- Solon-Biet, S., Cogger, V., Pulpitel, T., Wahl, D., Clark, X., Bagley, E., Gregoriou, G., Senior, A., Wang, Q., Brandon, A., Perks, R., O'Sullivan, J., Koay, Y., Bell-Anderson, K., Kebede, M., Yau, B., Atkinson, C., Dodgson, T., Wali, J., Raubenheimer, D., Cooney, G., Le Couteur, D., Simpson, S., et al (2019). Branched-chain amino acids impact health and lifespan indirectly via amino acid balance and appetite control. Nature Metabolism, 1(5), 532-545. [More Information]
- Wali, J., Milner, A., Pulpitel, T., Koay, Y., Brandon, A., Kebede, M., Dodgson, T., O'Sullivan, M., Wahl, D., Yau, B., O'Sullivan, J., Solon-Biet, S., Cooney, G., Cogger, V., Le Couteur, D., Simpson, S., et al (2019). Determining the metabolic impact of dietary carbohydrate composition in the setting of low, medium and high protein diets. Obesity Research & Clinical Practice, 13(3), 296. [More Information]
2018
- Burchfield, J., Kebede, M., Meoli, C., Stoeckli, J., Whitworth, P., Wright, A., Hoffman, N., Minard, A., Ma, X., Krycer, J., Nelson, M., Yau, B., Cooke, K., Cooney, G., James, D., Fazakerley, D., et al (2018). High dietary fat and sucrose results in an extensive and time-dependent deterioration in health of multiple physiological systems in mice. Journal of Biological Chemistry, 293(15), 5731-5745. [More Information]
2016
- Ghislain, J., Fontés, G., Tremblay, C., Kebede, M., Poitout, V. (2016). Dual-reporter β-cell-specific male transgenic rats for the analysis of β-cell functional mass and enrichment by flow cytometry. Endocrinology, 157(3), 1299-1306. [More Information]
- Keller, M., Paul, P., Rabaglia, M., Stapleton, D., Schueler, K., Broman, A., Ye, S., Leng, N., Brandon, C., Kebede, M., et al (2016). The Transcription Factor Nfatc2 Regulates B-Cell Proliferation and Genes Associated with Type 2 Diabetes in Mouse and Human Islets. PLoS Genetics, 12(12), e1006466. [More Information]
2014
- Kebede, M., Attie, A. (2014). Insights into obesity and diabetes at the intersection of mouse and human genetics. Trends in Endocrinology and Metabolism, 25(10), 493-501. [More Information]
- Kebede, M., Oler, A., Gregg, T., Balloon, A., Johnson, A., Mitok, K., Rabaglia, M., Schueler, K., Stapleton, D., et al (2014). SORCS1 is necessary for normal insulin secretory granule biogenesis in metabolically stressed β cells. Journal of Clinical Investigation, 124(10), 4240-4256. [More Information]
2013
- O'Halloran, T., Kebede, M., Phillips, S., Attie, A. (2013). Zinc, insulin, and the liver: a menage a trois. Journal of Clinical Investigation, 123(10), 4136-4139. [More Information]
2012
- Ferdaoussi, M., Bergeron, V., Kebede, M., Mancini, A., Alquier, T., Poitout, V. (2012). Free Fatty Acid Receptor 1: A New Drug Target for Type 2 Diabetes? Canadian Journal of Diabetes, 36(5), 275-280. [More Information]
- Kebede, M., Ferdaoussi, M., Mancini, A., Alquier, T., Kulkarni, R., Walker, M., Poitout, V. (2012). Glucose activates free fatty acid receptor 1 gene transcription via phosphatidylinositol-3-kinase-dependent O-GlcNAcylation of pancreas-duodenum homeobox-1. Proceedings of the National Academy of Sciences of the United States of America, 109(7), 2376-2381. [More Information]
2009
- Alquier, T., Peyot, M., Latour, M., Kebede, M., Sorensen, C., Gesta, S., Kahn, C., Smith, R., Jetton, T., Metz, T., et al (2009). Deletion of GPR40 impairs glucose-induced insulin secretion in vivo in mice without affecting intracellular fuel metabolism in islets. Diabetes, 58(11), 2607-2615. [More Information]
- Kebede, M. (2009). Lipid receptors and islet function: therapeutic implications? Diabetes, Obesity and Metabolism, 11(Suppl 4), 10-20. [More Information]
2008
- Kebede, M., Favaloro, J., Gunton, J., Laybutt, D., Shaw, M., Wong, N., Fam, B., Aston-Mourney, K., Rantzau, C., Zulli, A., et al (2008). Fructose-1,6-bisphosphatase overexpression in pancreatic beta-cells results in reduced insulin secretion: a new mechanism for fat-induced impairment of beta-cell function. Diabetes, 57(7), 1887-1895. [More Information]
- Kebede, M., Tremblay, J. (2008). The fatty acid receptor GPR40 plays a role in insulin secretion in vivo after high-fat feeding. Diabetes, 57(9), 2432-2437. [More Information]
Selected Grants
2024
- Research ancillary support, Kebede M, Charles Perkins Centre/CPC Research Funding Award
2019
- Proinsulin sorting at the trans-Golgi-network, Kebede M, Asensio C, von Blume J, National Health and Medical Research Council (NHMRC)/Ideas Grant
- The role of Cab45 in proinsulin sorting at the Trans-Golgi Network, Kebede M, Diabetes Australia/Diabetes Research Grant Program