• Luciani, Dan S.

    Titles
    Investigator, BC Children's Hospital

    Associate Professor, Department of Surgery, Faculty of Medicine, University of British Columbia

    Degrees / Designations
    PhD
    Primary Area of Research
    Childhood Diseases
    Secondary Area(s) of Research
    Diabetes
    Phone
    604-875-2000 ext. 6170
    Fax
    604-875-2373
    Lab Phone
    604-875-2000 ext. 7714
    Mailing Address
    BC Children's Hospital Research Institute

    Room A4-183
    950 West 28th Avenue
    Vancouver, BC V5Z 4H4

    Affiliate Websites
    Research Areas

    Pancreatic β-cell physiology and the mechanisms of β-cell failure and death in diabetes and islet transplantation.

    Keywords: Diabetes, insulin secretion, pancreatic β-cells, apoptosis and other types of cell death, autophagy, mitochondrial physiology, Bcl-2 family proteins, cellular signaling and stress, fluorescence microscopy, genetic mouse models, biological oscillations.

    Summary

    Diabetes develops when the pancreas does not release enough insulin to lower blood sugar (glucose) levels after a meal. This happens when the insulin producing β-cells in the pancreas are defective or if the number of β-cells is reduced. Accordingly, functional failure and ‘cellular suicide’ of β-cells promote both type 1 and type 2 diabetes. Moreover, the effectiveness of islet transplantation as a treatment for type 1 diabetes is limited by β-cell death both before and after transplantation.

    Our research group seeks to clarify the complex mechanisms that link β-cell function, β-cell failure and various pathways of β-cell death. Intriguing new findings, including our own recent studies, suggest that the cellular machinery that mediates cell ‘suicide’ also has important roles in normal β-cell function and can control if β-cells adapt or fail during the cellular stress associated with diabetes. We study these mechanisms from the level of genetic changes to the impact of these on single cell function and the progression of diabetes. In this way we hope to identify and characterize new targets for diabetes prevention and therapy.

    Current Projects

    Control of β-cell metabolic signaling by core anti-apoptosis proteins
    Elevated levels of free fatty acids and blood glucose promote the failure and loss of β-cells in type 2 diabetes. Mitochondrial stress and the mitochondrial formation of excess reactive oxygen species contribute to this β-cell demise. Mitochondria are also organelles of paramount importance for normal nutrient-stimulated insulin secretion. Consequently, our research aims to clarify the mechanisms of β-cell mitochondrial function, mitochondrial dysfunction and the connection of these processes to apoptotic β-cell death. Apoptosis is tightly controlled at the mitochondria by the Bcl-2 family of pro- and anti-apoptotic proteins. We have generated mice in which core anti-apoptotic members of this family can be inducibly and specifically deleted in the pancreatic islets, and we study these mice in combination with pharmacological approaches to determine the roles of these proteins for β-cell function as well as β-cell failure and death under diabetogenic stress conditions. In our work we are clarifying novel roles for pro-survival Bcl proteins in β-cell mitochondrial physiology, insulin secretion and in vivo glucose tolerance, thus demonstrating that Bcl proteins provide link between normal β-cell physiology and the processes of apoptotic β-cell death in diabetes.

    Mapping the parallel and interrelated pathways of β-cell death
    It is generally accepted that stressed β-cells can die by apoptosis. However, the extent to which β-cell death in diabetes and islet transplantation also occurs by the alternate pathways of autophagy and programmed necrosis is not known. In this project we will use a combination of pathway-specific inhibitors and knockout mice to determine the i) relative contributions, ii) the context-dependence and iii) the functional interrelations of β-cell apoptosis, autophagy and necrosis. The goal of this is to identify new ways to most effectively target and prevent β-cell loss in diabetes and islet graft failure.

    Selected Publications

    Aharoni-Simon M, Shumiatcher R, Yeung A, Shih AZ, Dolinsky VW, Doucette CA, Luciani DS. 2016. Bcl-2 Regulates Reactive Oxygen Species Signaling and a Redox-Sensitive Mitochondrial Proton Leak in Mouse Pancreatic β-Cells. Endocrinology 157(6):2270-81. PMID: 27070098. DOI: 10.1210/en.2015-1964.

    Rountree AM, Neal AS, Lisowski M, Rizzo N, Radtke J, White S, Luciani DS, Kim F, Hampe CS, Sweet IR. 2014. Control of insulin secretion by cytochrome C and calcium signaling in islets with impaired metabolism. J Biol Chem 289(27):19110-9. PMID: 24841202. PMCID: PMC4081948. DOI: 10.1074/jbc.M114.556050.

    Sun AC, Ou D, Luciani DS, Warnock GL. 2014. B7-H4 as a protective shield for pancreatic islet beta cells. World J Diabetes 5(6):739-46. PMID: 25512776. PMCID: PMC4265860. DOI: 10.4239/wjd.v5.i6.739.

    Pedersen M.G., Mosekilde E., Polonsky K.S. and Luciani D.S. (2013). Complex patterns of metabolic and Ca2+ entrainment in pancreatic islets by oscillatory glucose. Biophysical Journal 105(1):29-39. PMID: 23823221. PMCID: PMC3699738. DOI: 10.1016/j.bpj.2013.05.036.

    Luciani D.S., White S.A., Widenmaier S.B., Saran V.V., Taghizadeh F., Hu X., Allard M.F. and Johnson J.D. (2013). Bcl-2 and Bcl-xL suppress glucose signaling in pancreatic β-cells. Diabetes 62(1):170-82. PMID: 22933114. PMCID: PMC3526034. DOI: 10.2337/db11-1464.

    Johnson J.D., Bround M., White S.A. and Luciani D.S. (2012). Nanospaces between endoplasmic reticulum and mitochondria as control centers of pancreatic β-cell metabolism and survival. Protoplasma 249 Suppl 1:S49-58. PMID: 22105567.

    Johnson J.D. and Luciani D.S. (2010). Mechanisms of pancreatic beta-cell apoptosis in diabetes and its therapies. (2010). Advances in Experimental Medicine and Biology. 654:447-62. PMID: 20217509. DOI: 10.1007/s00709-011-0349-3.

    Luciani D.S., Gwiazda K., Yang T.-L. B., Kalynyak T.B., Bychkivska Y., Frey M.H.Z., Jeffrey K.D., Sampaio A.V., Underhill T.M., and Johnson J.D. (2009). Roles of IP3R and RyR Ca2+ channels in endoplasmic reticulum stress and β-cell death. Diabetes 58(2):422-32. PMID: 19033399. PMCID: PMC2628616. DOI: 10.2337/db07-1762.

    Jeffrey K.D., Alejandro E.U., Luciani D.S., Kalynyak T.B., Hu X. Li H., Lin Y., Townsend R.R., Polonsky K.S. and Johnson J.D. (2008). Carboxypeptidase E mediates palmitate-induced β-cell ER stress and apoptosis. Proceedings of the National Academy of Sciences USA, 105(24):8452-7. PMID: 18550819. PMCID:  PMC2448857. DOI: 10.1073/pnas.0711232105.

    Bertram R., Satin L.S., Pedersen M.G., Luciani D.S. and Sherman A. (2007). Interaction of glycolysis and mitochondrial respiration in metabolic oscillations of pancreatic islets. Biophysical Journal 92(5): 1544-55. PMID: 17172305. PMCID: PMC1796835.

    Luciani D.S., Misler S., and Polonsky K.S. (2006). Ca2+ controls slow NAD(P)H oscillations in glucose-stimulated mouse pancreatic islets. Journal of Physiology 572(Pt 2):379-92. PMID: 16455690. PMCID: PMC1779687.

    Grants
    Honours & Awards
    • Juvenile Diabetes Research Foundation (JDRF), Career Development Award, 2013-2018
    • Canadian Diabetes Association (CDA) Postdoctoral Fellowship, 2008-2009
    • Michael Smith Foundation for Health Research (MSFHR) Postdoctoral Fellowship, 2008-2009
    • Carlsberg Foundation Research Stipend, 2008 
    • Juvenile Diabetes Research Foundation (JDRF) Postdoctoral Fellowship, 2006-2007
    • Postdoctoral Researcher of the Year, Department of Cellular and Physiological Sciences, UBC, 2008
    Research Group Members
    • Peter Yuanjie Zou, PhD Student
    • Daniel Pasula, PhD Student
    • Rocky Shi, MSc Student
    • Mei Tang, Research Technician
    • Mitsu Komba, Research Technician
    • Emma Martin, Undergraduate Academic Research Assistant
    • Benny Tang, Undergraduate Academic Research Assistant