Overview

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 ß-cells in the pancreas are defective or if the number of ß-cells is reduced. Accordingly, functional failure and ‘cellular suicide’ of ß-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 ß-cell death both before and after transplantation.

Our research group seeks to clarify the complex mechanisms that link ß-cell function, ß-cell failure and various pathways of ß-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 ß-cell function and can control if ß-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.

Publications

Bcl-2 Regulates Reactive Oxygen Species Signaling and a Redox-Sensitive Mitochondrial Proton Leak in Mouse Pancreatic ß-Cells.
Aharoni-Simon M, Shumiatcher R, Yeung A, Shih AZ, Dolinsky VW, Doucette CA, Luciani DS
DOI: 10.1210/en.2015-1964
PubMed: 27070098
06/2016

Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor.
MacDonald KG, Hoeppli RE, Huang Q, Gillies J, Luciani DS, Orban PC, Broady R, Levings MK
DOI: 10.1172/JCI82771
PubMed: 26999600
04/2016

Myt3 Mediates Laminin-V/Integrin-ß1-Induced Islet-Cell Migration via Tgfbi.
Tennant BR, Chen J, Shih AZ, Luciani DS, Hoffman BG
DOI: 10.1210/ME.2014-1387
PubMed: 26177052
09/2015

B7-H4 as a protective shield for pancreatic islet beta cells.
Sun AC, Ou D, Luciani DS, Warnock GL
DOI: 10.4239/wjd.v5.i6.739
PubMed: 25512776
12/2014

Control of insulin secretion by cytochrome C and calcium signaling in islets with impaired metabolism.
Rountree AM, Neal AS, Lisowski M, Rizzo N, Radtke J, White S, Luciani DS, Kim F, Hampe CS, Sweet IR
DOI: 10.1074/jbc.M114.556050
PubMed: 24841202
07/2014

Complex patterns of metabolic and Ca²¿ entrainment in pancreatic islets by oscillatory glucose.
Pedersen MG, Mosekilde E, Polonsky KS, Luciani DS
DOI: 10.1016/j.bpj.2013.05.036
PubMed: 23823221
07/2013

Cardiomyocyte ATP production, metabolic flexibility, and survival require calcium flux through cardiac ryanodine receptors in vivo.
Bround MJ, Wambolt R, Luciani DS, Kulpa JE, Rodrigues B, Brownsey RW, Allard MF, Johnson JD
DOI: 10.1074/jbc.M112.427062
PubMed: 23678000
06/2013

Bcl-2 and Bcl-xL suppress glucose signaling in pancreatic ß-cells.
Luciani DS, White SA, Widenmaier SB, Saran VV, Taghizadeh F, Hu X, Allard MF, Johnson JD
DOI: 10.2337/db11-1464
PubMed: 22933114
01/2013

Nanospaces between endoplasmic reticulum and mitochondria as control centres of pancreatic ß-cell metabolism and survival.
Johnson JD, Bround MJ, White SA, Luciani DS
DOI: 10.1007/s00709-011-0349-3
PubMed: 22105567
02/2012

MISC-1/OGC links mitochondrial metabolism, apoptosis and insulin secretion.
Gallo M, Park D, Luciani DS, Kida K, Palmieri F, Blacque OE, Johnson JD, Riddle DL
DOI: 10.1371/journal.pone.0017827
PubMed: 21448454
2011

Glucose-induced endothelial heparanase secretion requires cortical and stress actin reorganization.
Wang F, Wang Y, Kim MS, Puthanveetil P, Ghosh S, Luciani DS, Johnson JD, Abrahani A, Rodrigues B
DOI: 10.1093/cvr/cvq051
PubMed: 20164120
07/2010

Mechanisms of pancreatic beta-cell apoptosis in diabetes and its therapies.
Johnson JD, Luciani DS
DOI: 10.1007/978-90-481-3271-3_19
PubMed: 20217509
2010

A multi-parameter, high-content, high-throughput screening platform to identify natural compounds that modulate insulin and Pdx1 expression.
Hill JA, Szabat M, Hoesli CA, Gage BK, Yang YH, Williams DE, Riedel MJ, Luciani DS, Kalynyak TB, Tsai K, Ao Z, Andersen RJ, Warnock GL, Piret JM, Kieffer TJ, Johnson JD
DOI: 10.1371/journal.pone.0012958
PubMed: 20886041
2010

AMP-activated protein kinase confers protection against TNF-{alpha}-induced cardiac cell death.
Kewalramani G, Puthanveetil P, Wang F, Kim MS, Deppe S, Abrahani A, Luciani DS, Johnson JD, Rodrigues B
DOI: 10.1093/cvr/cvp166
PubMed: 19477967
10/2009

Maturation of adult beta-cells revealed using a Pdx1/insulin dual-reporter lentivirus.
Szabat M, Luciani DS, Piret JM, Johnson JD
DOI: 10.1210/en.2008-1224
PubMed: 19095744
04/2009

Roles of IP3R and RyR Ca2+ channels in endoplasmic reticulum stress and beta-cell death.
Luciani DS, Gwiazda KS, Yang TL, Kalynyak TB, Bychkivska Y, Frey MH, Jeffrey KD, Sampaio AV, Underhill TM, Johnson JD
DOI: 10.2337/db07-1762
PubMed: 19033399
02/2009

Pancreatic Beta-cell Apoptosis
Modern Insights Into Disease From Molecules to Man: APOPTOSIS.
2009

Rheb activates protein synthesis and growth in adult rat ventricular cardiomyocytes.
Wang Y, Huang BP, Luciani DS, Wang X, Johnson JD, Proud CG
DOI: 10.1016/j.yjmcc.2008.07.016
PubMed: 18722381
12/2008

Carboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis.
Jeffrey KD, Alejandro EU, Luciani DS, Kalynyak TB, Hu X, Li H, Lin Y, Townsend RR, Polonsky KS, Johnson JD
DOI: 10.1073/pnas.0711232105
PubMed: 18550819
06/2008

Glucose and endoplasmic reticulum calcium channels regulate HIF-1beta via presenilin in pancreatic beta-cells.
Dror V, Kalynyak TB, Bychkivska Y, Frey MH, Tee M, Jeffrey KD, Nguyen V, Luciani DS, Johnson JD
DOI: 10.1074/jbc.M710601200
PubMed: 18174159
04/2008

Voltage-gated Ca(2+) influx and insulin secretion in human and mouse beta-cells are impaired by the mitochondrial Na(+)/Ca(2+) exchange inhibitor CGP-37157.
Luciani DS, Ao P, Hu X, Warnock GL, Johnson JD
DOI: 10.1016/j.ejphar.2007.07.055
PubMed: 17719029
12/2007

Interaction of glycolysis and mitochondrial respiration in metabolic oscillations of pancreatic islets.
Bertram R, Satin LS, Pedersen MG, Luciani DS, Sherman A
DOI: 10.1529/biophysj.106.097154
PubMed: 17172305
03/2007

A simplified model for mitochondrial ATP production.
Bertram R, Gram Pedersen M, Luciani DS, Sherman A
DOI: 10.1016/j.jtbi.2006.07.019
PubMed: 16945388
12/2006

Suppressed insulin signaling and increased apoptosis in CD38-null islets.
Johnson JD, Ford EL, Bernal-Mizrachi E, Kusser KL, Luciani DS, Han Z, Tran H, Randall TD, Lund FE, Polonsky KS
DOI: 10.2337/db05-1455
PubMed: 17003338
10/2006

Ca2+ controls slow NAD(P)H oscillations in glucose-stimulated mouse pancreatic islets.
Luciani DS, Misler S, Polonsky KS
DOI: 10.1113/jphysiol.2005.101766
PubMed: 16455690
04/2006

Acute effects of insulin on beta-cells from transplantable human islets.
Luciani DS, Johnson JD
DOI: 10.1016/j.mce.2005.06.006
PubMed: 16099589
09/2005

Reduced expression of the insulin receptor in mouse insulinoma (MIN6) cells reveals multiple roles of insulin signaling in gene expression, proliferation, insulin content, and secretion.
Ohsugi M, Cras-Méneur C, Zhou Y, Bernal-Mizrachi E, Johnson JD, Luciani DS, Polonsky KS, Permutt MA
DOI: 10.1074/jbc.M411727200
PubMed: 15546857
02/2005

Increased islet apoptosis in Pdx1+/- mice.
Johnson JD, Ahmed NT, Luciani DS, Han Z, Tran H, Fujita J, Misler S, Edlund H, Polonsky KS
DOI: 10.1172/JCI200316537
PubMed: 12697734
04/2003

Research

Mapping the parallel and interrelated pathways of ß-cell death
It is generally accepted that stressed ß-cells can die by apoptosis. However, the extent to which ß-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 ß-cell apoptosis, autophagy and necrosis. The goal of this is to identify new ways to most effectively target and prevent ß-cell loss in diabetes and islet graft failure.

Control of ß-cell metabolic signaling by core anti-apoptosis proteins
Elevated levels of free fatty acids and blood glucose promote the failure and loss of ß-cells in type 2 diabetes. Mitochondrial stress and the mitochondrial formation of excess reactive oxygen species contribute to this ß-cell demise. Mitochondria are also organelles of paramount importance for normal nutrient-stimulated insulin secretion. Consequently, our research aims to clarify the mechanisms of ß-cell mitochondrial function, mitochondrial dysfunction and the connection of these processes to apoptotic ß-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 ß-cell function as well as ß-cell failure and death under diabetogenic stress conditions. In our work we are clarifying novel roles for pro-survival Bcl proteins in ß-cell mitochondrial physiology, insulin secretion and in vivo glucose tolerance, thus demonstrating that Bcl proteins provide link between normal ß-cell physiology and the processes of apoptotic ß-cell death in diabetes.

Honours & Awards

Juvenile Diabetes Research Foundation (JDRF), Career Development Award, 2013-2018

Michael Smith Foundation for Health Research (MSFHR) Postdoctoral Fellowship, 2008-2009

Canadian Diabetes Association (CDA) Postdoctoral Fellowship, 2008-2009

Research Group Members

Yaathavan Suresh
Yuanjie Zou, Doctoral Student
Rocky Shi, Masters Student
Mitsu Komba, Lab Tech
Mei Tang, Research Technician
Jingfei Zhang, Student
Sajad Niyyati
Daniel Pasula, Graduate Student