Overview

In diabetes mellitus the pancreas' insulin-producing beta cells have impaired function or are destroyed, resulting in deficient insulin secretion. This leads to high blood glucose levels and later complications, including kidney disease and blindness. In type 1 (juvenile onset) diabetes the patient's own immune system kills the beta cells. In type 2 (adult onset) diabetes, the body is less sensitive to insulin produced, and the beta cells cannot secrete enough insulin to compensate. Over time, insulin secretion declines, probably due to a progressive loss of beta cells from the toxic effects of elevated blood glucose as well as the accumulation of protein-containing deposits called islet amyloid. We are trying to understand how beta cells normally function and why they are dysfunctional and/or are destroyed in both types of diabetes. We hope to devise new ways to protect beta cells, thereby slowing or preventing disease onset, and to enhance beta cell survival following transplantation of pancreatic islets into diabetic patients.

Publications

Glucagon-Like Peptide-1 Receptor Agonists: Beta-Cell Protection or Exhaustion?
Trends in Endocrinology & Metabolism
Daniël H van Raalte and C. Bruce Verchere
DOI: 10.1016/j.tem.2016.04.009
05/2016

Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics
eLife
Andisheh Abedini and Annette Plesner and Ping Cao and Zachary Ridgway and Jinghua Zhang and Ling-Hsien Tu and Chris T Middleton and Brian Chao and Daniel J Sartori and Fanling Meng and Hui Wang and Amy G Wong and Martin T Zanni and C Bruce Verchere and Daniel P Raleigh and Ann Marie Schmidt
DOI: 10.7554/elife.12977
05/2016

Myt3 suppression sensitizes islet cells to high glucose-induced cell death via Bim induction
Cell Death Dis
B R Tennant and B Vanderkruk and J Dhillon and D Dai and C B Verchere and B G Hoffman
DOI: 10.1038/cddis.2016.141
05/2016

ABCA1 deficiency and cellular cholesterol accumulation increases islet amyloidogenesis in mice
Diabetologia
Nadeeja Wijesekara and Achint Kaur and Clara Westwell-Roper and Dominika Nackiewicz and Galina Soukhatcheva and Michael R. Hayden and C. Bruce Verchere
DOI: 10.1007/s00125-016-3907-6
03/2016

T regulatory cell chemokine production mediates pathogenic T cell attraction and suppression
Journal of Clinical Investigation
Scott J. Patterson and Anne M. Pesenacker and Adele Y. Wang and Jana Gillies and Majid Mojibian and Kim Morishita and Rusung Tan and Timothy J. Kieffer and C. Bruce Verchere and Constadina Panagiotopoulos and Megan K. Levings
DOI: 10.1172/jci83987
02/2016

Reawakening the Duct Cell Progenitor?
Endocrinology
C. Bruce Verchere and Francis C. Lynn
DOI: 10.1210/en.2015-2008
01/2016

Differential Activation of Innate Immune Pathways by Distinct Islet Amyloid Polypeptide (IAPP) Aggregates
J. Biol. Chem.
Clara Westwell-Roper and Heather C. Denroche and Jan A. Ehses and C. Bruce Verchere
DOI: 10.1074/jbc.m115.712455
01/2016

CCL22 Prevents Rejection of Mouse Islet Allografts and Induces Donor-Specific Tolerance
cell transplant
Joel Montane and Merce Obach and Sigrid Alvarez and Loraine Bischoff and Derek L. Dai and Galina Soukhatcheva and John J. Priatel and Gijs Hardenberg and Megan K. Levings and Rusung Tan and Paul C. Orban and C. Bruce Verchere
DOI: 10.3727/096368914x685249
10/2015

IL-33 Reverses an Obesity-Induced Deficit in Visceral Adipose Tissue ST2+ T Regulatory Cells and Ameliorates Adipose Tissue Inflammation and Insulin Resistance
The Journal of Immunology
J. M. Han and D. Wu and H. C. Denroche and Y. Yao and C. B. Verchere and M. K. Levings
DOI: 10.4049/jimmunol.1500020
04/2015

Amyloid Formation in Human Islets Is Enhanced by Heparin and Inhibited by Heparinase
American Journal of Transplantation
K. J. Potter and I. Werner and H. C. Denroche and J. Montane and A. Plesner and Y. Chen and D. Lei and G. Soukhatcheva and G. L. Warnock and J. Oberholzer and P. E. Fraser and C. B. Verchere
DOI: 10.1111/ajt.13134
04/2015

Cellular Mechanisms of CCL22-Mediated Attenuation of Autoimmune Diabetes
The Journal of Immunology
L. Bischoff and S. Alvarez and D. L. Dai and G. Soukhatcheva and P. C. Orban and C. B. Verchere
DOI: 10.4049/jimmunol.1400567
03/2015

Loss of Cyp8b1 Improves Glucose Homeostasis by Increasing GLP-1
Diabetes
Achint Kaur and Jay V. Patankar and Willeke de Haan and Piers Ruddle and Nadeeja Wijesekara and Albert K. Groen and C. Bruce Verchere and Roshni R. Singaraja and Michael R. Hayden
DOI: 10.2337/db14-0716
10/2014

Islet Remodeling in Female Mice with Spontaneous Autoimmune and Streptozotocin-Induced Diabetes
PLoS ONE
Annette Plesner and Joris T. ten Holder and C. Bruce Verchere
DOI: 10.1371/journal.pone.0102843
08/2014

Thioredoxin-interacting Protein Promotes Islet Amyloid Polypeptide Expression through miR-124a and FoxA2
Journal of Biological Chemistry
G. Jing and C. Westwell-Roper and J. Chen and G. Xu and C. B. Verchere and A. Shalev
DOI: 10.1074/jbc.m113.525022
03/2014

IL-1 mediates amyloid-associated islet dysfunction and inflammation in human islet amyloid polypeptide transgenic mice
Diabetologia
Clara Y. Westwell-Roper and Cyrus A. Chehroudi and Heather C. Denroche and Jaques A. Courtade and Jan A. Ehses and C. Bruce Verchere
DOI: 10.1007/s00125-014-3447-x
2014

Resident Macrophages Mediate Islet Amyloid Polypeptide–Induced Islet IL-1ß Production and ß-Cell Dysfunction
Diabetes
Clara Y. Westwell-Roper and Jan A. Ehses and C. Bruce Verchere
DOI: 10.2337/db13-0863
11/2013

Endogenous Expression of B7-H4 Improves Long-term Murine Islet Allograft Survival
Transplantation Journal
Xiaojie Wang and Jianqiang Hao and Daniel L. Metzger and Alice Mui and I-Fang Lee and Noushin Akhoundsadegh and Ziliang Ao and Lieping Chen and Dawei Ou and C. Bruce Verchere and Garth L. Warnock
DOI: 10.1097/tp.0b013e318277229d
01/2013

Activating the NLRP3 Inflammasome Using the Amyloidogenic Peptide IAPP
The Inflammasome
Clara Westwell-Roper and Aisling Dunne and Man Lyang Kim and C. Bruce Verchere and Seth L. Masters
DOI: 10.1007/978-1-62703-523-1_2
2013

Death and Dysfunction of Transplanted  -Cells: Lessons Learned From Type 2 Diabetes?
Diabetes
K. J. Potter and C. Y. Westwell-Roper and A. M. Klimek-Abercrombie and G. L. Warnock and C. B. Verchere
DOI: 10.2337/db12-0364
2013

Endogenous Expression of B7-H4 Improves Long Term Murine Islet Allograft Survival
Transplantation Journal
X. Wang and J. Hao and D. Metzger and I.-F. Lee and A. Mui and Z. Ao and L. Chen and D. Ou and B. Verchere and G. Warnock
DOI: 10.1097/00007890-201211271-00647
11/2012

Metabolic stress, IAPP and islet amyloid
Diabetes Obes Metab
J. Montane and A. Klimek-Abercrombie and K. J. Potter and C. Westwell-Roper and C. Bruce Verchere
DOI: 10.1111/j.1463-1326.2012.01657.x
08/2012

Blockade of both B7-H4 and CTLA-4 co-signaling pathways enhances mouse islet allograft survival
Islets
Xiaojie Wang and Jianqiang Hao and Daniel L. Metzger and Alice Mui and I-Fang Lee and Noushin Akhoundsadegh and C. Lieping Chen and Dawei Ou and Ziliang Ao and C. Bruce Verchere and Garth L. Warnock
DOI: 10.4161/isl.21239
07/2012

TRAIL-engineered pancreas-derived mesenchymal stem cells: characterization and cytotoxic effects on pancreatic cancer cells
Cancer Gene Ther
M R Moniri and X-Y Sun and J Rayat and D Dai and Z Ao and Z He and C B Verchere and L-J Dai and G L Warnock
DOI: 10.1038/cgt.2012.46
07/2012

Translational Control of Glucose-Induced Islet Amyloid Polypeptide Production in Pancreatic Islets
Endocrinology
Cristina Alarcon and C. Bruce Verchere and Christopher J. Rhodes
DOI: 10.1210/en.2011-2019
05/2012

miR-33a Modulates ABCA1 Expression, Cholesterol Accumulation, and Insulin Secretion in Pancreatic Islets
Diabetes
N. Wijesekara and L.-h. Zhang and M. H. Kang and T. Abraham and A. Bhattacharjee and G. L. Warnock and C. B. Verchere and M. R. Hayden
DOI: 10.2337/db11-0944
02/2012

Loss of Both ABCA1 and ABCG1 Results in Increased Disturbances in Islet Sterol Homeostasis, Inflammation, and Impaired  -Cell Function
Diabetes
J. K. Kruit and N. Wijesekara and C. Westwell-Roper and T. Vanmierlo and W. de Haan and A. Bhattacharjee and R. Tang and C. L. Wellington and D. LutJohann and J. D. Johnson and L. R. Brunham and C. B. Verchere and M. R. Hayden
DOI: 10.2337/db11-1341
02/2012

B7-H4 Induces Donor-Specific Tolerance in Mouse Islet Allografts
cell transplant
Xiaojie Wang and Jianqiang Hao and Daniel L. Metzger and Alice Mui and Ziliang Ao and C. Bruce Verchere and Lieping Chen and Dawei Ou and Garth L. Warnock
DOI: 10.3727/096368911x582750
01/2012

B7-H4 Treatment of T Cells Inhibits ERK, JNK, p38, and AKT Activation
PLoS ONE
Xiaojie Wang and Jianqiang Hao and Daniel L. Metzger and Ziliang Ao and Lieping Chen and Dawei Ou and C. Bruce Verchere and Alice Mui and Garth L. Warnock
DOI: 10.1371/journal.pone.0028232
01/2012

Reverse engineering an amyloid aggregation pathway with dimensional analysis and scaling
Phys. Biol.
J Bailey and K J Potter and C B Verchere and L Edelstein-Keshet and D Coombs
DOI: 10.1088/1478-3975/8/6/066009
11/2011

Altered Glutathione Homeostasis in Heart Augments Cardiac Lipotoxicity Associated with Diet-induced Obesity in Mice
Journal of Biological Chemistry
S. Ghosh and D. C. Sulistyoningrum and M. B. Glier and C. B. Verchere and A. M. Devlin
DOI: 10.1074/jbc.m111.304592
10/2011

Islet Cholesterol Accumulation Due to Loss of ABCA1 Leads to Impaired Exocytosis of Insulin Granules
Diabetes
J. K. Kruit and N. Wijesekara and J. E. M. Fox and X.-Q. Dai and L. R. Brunham and G. J. Searle and G. P. Morgan and A. J. Costin and R. Tang and A. Bhattacharjee and J. D. Johnson and P. E. Light and B. J. Marsh and P. E. MacDonald and C. B. Verchere and M. R. Hayden
DOI: 10.2337/db11-0081
10/2011

Early Treatment of NOD Mice With B7-H4 Reduces the Incidence of Autoimmune Diabetes
Diabetes
X. Wang and J. Hao and D. L. Metzger and A. Mui and Z. Ao and N. Akhoundsadegh and S. Langermann and L. Liu and L. Chen and D. Ou and C. B. Verchere and G. L. Warnock
DOI: 10.2337/db11-0375
10/2011

Prevention of murine autoimmune diabetes by CCL22-mediated Treg recruitment to the pancreatic islets
J. Clin. Invest.
Joel Montane and Loraine Bischoff and Galina Soukhatcheva and Derek L. Dai and Gijs Hardenberg and Megan K. Levings and Paul C. Orban and Timothy J. Kieffer and Rusung Tan and C. Bruce Verchere
DOI: 10.1172/jci43048
08/2011

IL-1 Blockade Attenuates Islet Amyloid Polypeptide-Induced Proinflammatory Cytokine Release and Pancreatic Islet Graft Dysfunction
The Journal of Immunology
C. Westwell-Roper and D. L. Dai and G. Soukhatcheva and K. J. Potter and N. van Rooijen and J. A. Ehses and C. B. Verchere
DOI: 10.4049/jimmunol.1002854
08/2011

Kinetics and genomic profiling of adult human and mouse ß-cell maturation
Islets
Marta Szabat and Poya Pourghaderi and Galina Soukhatcheva and C. Bruce Verchere and Garth L. Warnock and James M. Piret and James D Johnson
DOI: 10.4161/isl.3.4.15881
07/2011

Advances and Challenges in Islet Transplantation: Islet Procurement Rates and Lessons Learned from Suboptimal Islet Transplantation
Journal of Transplantation
Annette Plesner and C. Bruce Verchere
DOI: 10.1155/2011/979527
2011

Improving Islet Engraftment by Gene Therapy
Journal of Transplantation
Xiaojie Wang and Mark Meloche and C. Bruce Verchere and Dawei Ou and Alice Mui and Garth L. Warnock
DOI: 10.1155/2011/594851
2011

B7-H4 Pathway in Islet Transplantation andß-Cell Replacement Therapies
Journal of Transplantation
Xiaojie Wang and Jianqiang Hao and Daniel L. Metzger and Ziliang Ao and Mark Meloche and C. Bruce Verchere and Lieping Chen and Dawei Ou and Alice Mui and Garth L. Warnock
DOI: 10.1155/2011/418902
2011

The Flavanol (-)-Epigallocatechin 3-Gallate Inhibits Amyloid Formation by Islet Amyloid Polypeptide, Disaggregates Amyloid Fibrils, and Protects Cultured Cells against IAPP-Induced Toxicity
Biochemistry
Fanling Meng and Andisheh Abedini and Annette Plesner and C. Bruce Verchere and Daniel P. Raleigh
DOI: 10.1021/bi100939a
09/2010

Cholesterol toxicity in pancreatic islets from LDL receptor-deficient mice. Reply to: de Souza JC, de Oliveira CAM, Carneiro EM et al. [letter]
Diabetologia
J. K. Kruit and L. R. Brunham and C. B. Verchere and M. R. Hayden
DOI: 10.1007/s00125-010-1877-7
08/2010

Selecting exercise regimens and strains to modify obesity and diabetes in rodents: an overview
Clin. Sci.
Sanjoy Ghosh and Saeid Golbidi and Isa Werner and Bruce C. Verchere and Ismail Laher
DOI: 10.1042/cs20090389
07/2010

The Sulfated Triphenyl Methane Derivative Acid Fuchsin Is a Potent Inhibitor of Amyloid Formation by Human Islet Amyloid Polypeptide and Protects against the Toxic Effects of Amyloid Formation
Journal of Molecular Biology
Fanling Meng and Andisheh Abedini and Annette Plesner and Chris T. Middleton and Kathryn J. Potter and Martin T. Zanni and C. Bruce Verchere and Daniel P. Raleigh
DOI: 10.1016/j.jmb.2010.05.001
07/2010

T REGULATORY CELL MEDIATED PROTECTION OF ALLOGRAFT IN TYPE 1 DIABETES
Transplantation Journal
J. Montane and L. Bischoff and G. Soukhatcheva and G. Hardenberg and M. K. Levings and R. Tan and C. B. Verchere
DOI: 10.1097/00007890-201007272-00686
07/2010

HDL and LDL cholesterol significantly influence ß-cell function in type 2 diabetes mellitus
Current Opinion in Lipidology
Janine K Kruit and Liam R Brunham and C Bruce Verchere and Michael R Hayden
DOI: 10.1097/mol.0b013e328339387b
06/2010

Role of the TLR signaling molecule TRIF in ß-cell function and glucose homeostasis
Islets
Meredith J. H. Hutton and Galina Soukhatcheva and James D. Johnson and C. Bruce Verchere
DOI: 10.4161/isl.2.2.11209
03/2010

Cholesterol efflux via ATP-binding cassette transporter A1 (ABCA1) and cholesterol uptake via the LDL receptor influences cholesterol-induced impairment of beta cell function in mice
Diabetologia
J. K. Kruit and P. H. C. Kremer and L. Dai and R. Tang and P. Ruddle and W. de Haan and L. R. Brunham and C. B. Verchere and M. R. Hayden
DOI: 10.1007/s00125-010-1691-2
03/2010

Toxic oligomers and islet beta cell death: guilty by association or convicted by circumstantial evidence?
Diabetologia
S. Zraika and R. L. Hull and C. B. Verchere and A. Clark and K. J. Potter and P. E. Fraser and D. P. Raleigh and S. E. Kahn
DOI: 10.1007/s00125-010-1671-6
02/2010

Cholesterol in ß-cell Dysfunction: The Emerging Connection Between HDL Cholesterol and Type 2 Diabetes
Curr Diab Rep
Liam R. Brunham and Janine K. Kruit and Michael R. Hayden and C. Bruce Verchere
DOI: 10.1007/s11892-009-0090-x
01/2010

XIAP inhibition of ß-cell apoptosis reduces the number of islets required to restore euglycemia in a syngeneic islet transplantation model
Islets
Annette Plesner and Galina Soukhatcheva and Robert G. Korneluk and C. Bruce Verchere
DOI: 10.4161/isl.2.1.9997
01/2010

Research

Pancreatic islet transplantation
Transplantation of pancreatic islets as a means of beta cell replacement in patients with type 1 diabetes has shown tremendous promise, but is still limited by uncertainty regarding the long-term survival of transplanted beta cells and the need for lifelong immunosuppression. Apoptotic death of beta cells occurs during islet isolation, culture, and transplantation, as well as during the immune attack on transplanted islet cells. We are trying to devise novel ways to protect transplanted beta cells in order to enhance the long-term success of islet transplants. For example, we have used viral vectors to transfer genes that inhibit apoptotic cell death and found that it protects transplanted islets from allograft rejection. We are also testing whether inhibition of islet amyloid formation enhances survival of transplanted islets. This research is funded by the Juvenile Diabetes Research Foundation, BC's Children's Hospital Foundation, and Neurochem Inc.

Immune-mediated beta cell death in type 1 diabetes
In type 1 diabetes, beta cell death is caused by the action of pro-inflammatory cytokines as well as autoreactive T lymphocytes that specifically target beta cells for destruction. In collaboration with Dr. Rusung Tan and others, we are trying to elucidate the mechanisms by which cytokines and T cells, in particular CD8+ cytotoxic T lymphocytes (CTL), kill beta cells with a long-term aim of blocking these processes as a way of preventing disease. As one approach we are actively trying to identify novel beta cell proteins (epitopes) that CTL recognize on the surface of beta cells, in both new-onset diabetic children and in the non-obese diabetic (NOD) mouse model of type 1 diabetes. Identification of the beta cell autoepitopes targeted by CTL in type 1 diabetes may lead to new tools for disease prediction and prevention. Funding for this research is from CIHR and the Juvenile Diabetes Research Foundation.

Islet amyloid and type 2 diabetes
Islet amyloid is composed primarily of a beta cell peptide named islet amyloid polypeptide (IAPP or amylin), which accumulates in the pancreatic islets of persons with type 2 diabetes and kills the insulin-producing beta cells. My laboratory is trying to understand why IAPP aggregates to form these toxic deposits and how these deposits kill beta cells, in the hope that we may be able to find ways to inhibit these processes. We have elucidated the pathway by which the IAPP precursor peptide (proIAPP) is likely processed to produce mature IAPP in beta cells, and have proposed a mechanism by which defective processing of proIAPP may lead to islet amyloid formation. We have also begun to dissect the molecular pathway by which amyloid induces beta cell apoptosis. Funding for this research is from CIHR and the Canadian Diabetes Association.

Grants

CIHR Operating Grant - Project: "Amyloid-induced islet inflammation and beta cell dysfunction"

Honours & Awards

CIHR Institute of Nutrition, Metabolism and Diabetes New Institute Advisory Member

Best overall abstract, World Artificial-Organ, Implants and Transplantation Society (WAITS) Symposium, Ottawa - 2001

Research Group Members

Sigrid Alvarez, Graduate Student
Yi-Chun Chen
Derek Dai, Research Assistant / Research Technician
Meixia Dan, Research technician, Research technician
Heather Denroche
Aleisha Durmaz
Kavi Grewal, Undergraduate student
Alex Hsu, Research Assistant
Meg Hughes, Administrator
Nahae Kim
Mitsu Komba, Lab Tech
Dominika Nackiewicz, PhD Trainee
Paul Orban, Research Associate I (Postdoctoral Fellows submit
Brian Park, Research Assistant
Galina Soukhatcheva
Austin Taylor, Trainee
Breanna Watson, Research Projects Coordinator
Kai Zhu