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 and Shumiatcher R and Yeung A and Shih AZ and Dolinsky VW and Doucette CA and 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 and Hoeppli RE and Huang Q and Gillies J and Luciani DS and Orban PC and Broady R and Levings MK
DOI: 10.1172/JCI82771
PubMed: 26999600
04/2016

Myt3 Mediates Laminin-V/Integrin-ß1-Induced Islet-Cell Migration via Tgfbi.
Tennant BR and Chen J and Shih AZ and Luciani DS and 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 and Ou D and Luciani DS and 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 and Neal AS and Lisowski M and Rizzo N and Radtke J and White S and Luciani DS and Kim F and Hampe CS and 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 and Mosekilde E and Polonsky KS and 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 and Wambolt R and Luciani DS and Kulpa JE and Rodrigues B and Brownsey RW and Allard MF and 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 and White SA and Widenmaier SB and Saran VV and Taghizadeh F and Hu X and Allard MF and 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 and Bround MJ and White SA and 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 and Park D and Luciani DS and Kida K and Palmieri F and Blacque OE and Johnson JD and Riddle DL
DOI: 10.1371/journal.pone.0017827
PubMed: 21448454
2011

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

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

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

AMP-activated protein kinase confers protection against TNF-{alpha}-induced cardiac cell death.
Kewalramani G and Puthanveetil P and Wang F and Kim MS and Deppe S and Abrahani A and Luciani DS and Johnson JD and 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 and Luciani DS and Piret JM and 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 and Gwiazda KS and Yang TL and Kalynyak TB and Bychkivska Y and Frey MH and Jeffrey KD and Sampaio AV and Underhill TM and 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 and Huang BP and Luciani DS and Wang X and Johnson JD and 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 and Alejandro EU and Luciani DS and Kalynyak TB and Hu X and Li H and Lin Y and Townsend RR and Polonsky KS and 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 and Kalynyak TB and Bychkivska Y and Frey MH and Tee M and Jeffrey KD and Nguyen V and Luciani DS and 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 and Ao P and Hu X and Warnock GL and 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 and Satin LS and Pedersen MG and Luciani DS and Sherman A
DOI: 10.1529/biophysj.106.097154
PubMed: 17172305
03/2007

A simplified model for mitochondrial ATP production.
Bertram R and Gram Pedersen M and Luciani DS and 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 and Ford EL and Bernal-Mizrachi E and Kusser KL and Luciani DS and Han Z and Tran H and Randall TD and Lund FE and 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 and Misler S and 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 and 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 and Cras-Méneur C and Zhou Y and Bernal-Mizrachi E and Johnson JD and Luciani DS and Polonsky KS and Permutt MA
DOI: 10.1074/jbc.M411727200
PubMed: 15546857
02/2005

Increased islet apoptosis in Pdx1+/- mice.
Johnson JD and Ahmed NT and Luciani DS and Han Z and Tran H and Fujita J and Misler S and Edlund H and 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

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