Dr Melkam Kebede

Research Fellow
School of Life and Environmental Sciences
Head - Islet Biology and Metabolism Laboratory

D17 - Charles Perkins Centre
The University of Sydney

Telephone +61 2 8627 0164

Website Room 5217 - D17 Charles Perkins Centre

Biographical details

Melkam Kebede was awarded her Ph.D. in2007 from the University of Melbourne. During this period, she studied the metabolic consequences of pancreatic beta-cell specific overexpression of one of the gluconeogenic enzymes, fructose- 1,6-bisphosphatase, using a transgenic mouse model, under the mentorship of Professor Joseph Proietto andA/Prof Sof Andrikopoulos.In 2007 Melkam moved to Montreal, 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 inpancreatic beta-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 Melkamstudied the involvement of VPS10 family of proteins, specifically Sorcs1, in the formation and stability of insulin containing secretory granules in pancreatic beta-cells.Her research at the University of Wisconsin wassupported by the American Diabetes Association mentor based post-doctoral fellowship.Melkam was the recipient ofthe 2014 Paul D. Boyer Postdoctoral Excellence Award in Biochemistry, University of Wisconsin.In 2015, Melkam returned to Australia to establish her own independent career as a Laboratory Headat the Charles Perkins Centre, Sydney Universityfunded by a Philanthropic Fellowship from the University of Sydney. Her labaims tounderstand the mechanisms ofβ-cellfailure in the pathogenesis ofT2D. Her research in Sydney has been funded by Diabetes Australia Research Trust and the NHMRC projects grants.

Research interests

The obesity epidemic is bringing a parallel epidemic in metabolic diseases such as type 2 diabetes (T2D). It is well established that obesity causes insulin resistance; an inability of insulin to elicit its normal physiological response. In the early stages of insulin resistance, thepancreaticb-cellsproduce and secrete more insulin in order to compensate for the insulin resistance. T2Doccurs when theb-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 β-cell failure during the progression toT2Dremain poorly understood. Therefore, our lab aims tounderstand the mechanisms ofβ-cellfailure in the pathogenesis ofT2D. The current projects in the lab focus on understanding the mechanisms behind insulin 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 T2D.

Teaching and supervision

Supervision – University of Sydney

  • Primary Supervision of PhD students Sheyda Naghiloo (started 2016), Jason Tong (Started 2017)and Mark Germanos (started 2018).
  • Supervision of Honours Students Zachary Blood (2016) and Mark Germanos (2017).
  • Supervision of University of Bath placement Students Ian Mathew (2016-2017) and Amy Watson (2017-2018).
  • Co-supervision of a post-doctoral fellow Dr Reena Singh (started 2017).

Teaching

  • Design and teach a “Pancreatic beta-cells and Type 2 Diabetes” Practical class as part of Nutrition and Metabolism (NUTM3001) course. (2016 – Present)
  • Designed and taught an advanced Biochemistry Course with a team of four others for postgraduate students. University of Wisconsin, Madison, USA. (2015)

Current research students

Project title Research student
A Cab for Insulin � Characterizing Cab45 in Pancreatic Beta Cells Mark GERMANOS
Pancreatic Islet Cell Atlas Sheyda NAGHILOO
Synthetic encapsulation and implantation of pancreatic beta cells to treat type 1 diabetes Jason TONG

Current projects

Project 1: High amounts of circulating proinsulin levels and reduced insulin response to a glucose challenge are important features of T2D. Insulin is produced as a precursor, proinsulin, which is processed to mature insulin. Under normal conditions, only mature insulin is secreted into the blood stream in response to a rise in blood glucose levels. In patients with T2D, an increased demand for insulin (usually from insulin resistance) confronts a failure of β-cells to meet this demand. 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 β-cells and not glucagon producing a-cells, and that its expression is increased in models of β-cell compensation and decreased in models of β-cell failure. 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:Blunted glucose stimulated insulin secretion is the hallmark of pancreatic β-cell failure associated with T2D. In β-cells, mature insulin is packaged and stored in secretory granules (SGs). Upon stimulation, these granules mobilize and fuse with the plasma membrane, delivering insulin to the bloodstream. These insulin 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 our 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 spectrometrywe 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.

Associations

Australian Diabetes Association.

Themes

Biochemistry and metabolism

Selected grants

2018

  • The preferential release of young insulin secretory granules.; Kebede M, Thorn P, Larance M; National Health and Medical Research Council (NHMRC)/Project Grants.

2017

  • Bio-functionalization of capsules to maintain insulin secretion, enhance angiogensis and inhibit fibrosis.; Thorn P, Porrello D, Weiss A, Kebede M, Hudson J, Bilek M; Juvenile Diabetes Research Foundation International (JDRF)/Strategic Research Agreement (SRA).
  • Growing better beta cells; Thorn P, Kebede M, Weiss A, Bilek M, Porrello D, Hudson J; Juvenile Diabetes Research Foundation (Australia)/Australian Type 1 Diabetes Clinical Research Network: Innovation Award.
  • A multidisciplinary, regenerative medicine approach to cure type 1 diabetes; Thorn P, Kebede M, Bilek M, Weiss A; DVC Research/Sydney Research Excellence Initiative 2020 (SREI).
  • Investigating the interplay between Sorcs1 and Sortilin in the regulation of insulin degrdation in pancreatic beta-cells; Kebede M; Diabetes Australia/Research Grant.
  • Enhancing insulin secretion from stem cells; Thorn P, Hudson D, Porrello D, Kebede M; Diabetes Australia/Research Grant.
  • Biogenesis of endocrine secretory granules; Kebede M; American Diabetes Association/Research Support.

2016

  • Understanding the Role of a Single Nucleotide Polymorphism (SNP) in the pro-domain of Sorcs1 on Pancreatic Beta-cells Insulin Content; Kebede M; Diabetes Australia/Diabetes Research Grant Program.

Selected publications

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Journals

  • Burchfield, J., Kebede, M., Meoli, C., Stoeckli, J., Whitworth, P., Wright, A., Hoffman, N., Minard, A., Ma, X., Krycer, J., Healy, M., Yau, B., Thomas, 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]
  • Ghislain, J., Font�s, 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), 1-26. [More Information]
  • 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]
  • 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]
  • 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]
  • 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]
  • 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]

2018

  • Burchfield, J., Kebede, M., Meoli, C., Stoeckli, J., Whitworth, P., Wright, A., Hoffman, N., Minard, A., Ma, X., Krycer, J., Healy, M., Yau, B., Thomas, 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., Font�s, 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), 1-26. [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]

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