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, C. Bruce Verchere
DOI: 10.1016/j.tem.2016.04.009
05/2016

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

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

ABCA1 deficiency and cellular cholesterol accumulation increases islet amyloidogenesis in mice
Diabetologia
Nadeeja Wijesekara, Achint Kaur, Clara Westwell-Roper, Dominika Nackiewicz, Galina Soukhatcheva, Michael R. Hayden, 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, Anne M. Pesenacker, Adele Y. Wang, Jana Gillies, Majid Mojibian, Kim Morishita, Rusung Tan, Timothy J. Kieffer, C. Bruce Verchere, Constadina Panagiotopoulos, Megan K. Levings
DOI: 10.1172/jci83987
02/2016

Reawakening the Duct Cell Progenitor?
Endocrinology
C. Bruce Verchere, 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, Heather C. Denroche, Jan A. Ehses, 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, Merce Obach, Sigrid Alvarez, Loraine Bischoff, Derek L. Dai, Galina Soukhatcheva, John J. Priatel, Gijs Hardenberg, Megan K. Levings, Rusung Tan, Paul C. Orban, 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, D. Wu, H. C. Denroche, Y. Yao, C. B. Verchere, M. K. Levings
DOI: 10.4049/jimmunol.1500020
04/2015

Amyloid Formation in Human Islets Is Enhanced by Heparin and Inhibited by HeparinaseHeparin Stimulates Islet Amyloid Formation
American Journal of Transplantation
K. J. Potter, I. Werner, H. C. Denroche, J. Montane, A. Plesner, Y. Chen, D. Lei, G. Soukhatcheva, G. L. Warnock, J. Oberholzer, P. E. Fraser, 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, S. Alvarez, D. L. Dai, G. Soukhatcheva, P. C. Orban, C. B. Verchere
DOI: 10.4049/jimmunol.1400567
03/2015

Loss of Cyp8b1 Improves Glucose Homeostasis by Increasing GLP-1
Diabetes
Achint Kaur, Jay V. Patankar, Willeke de Haan, Piers Ruddle, Nadeeja Wijesekara, Albert K. Groen, C. Bruce Verchere, Roshni R. Singaraja, 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, Joris T. ten Holder, 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, C. Westwell-Roper, J. Chen, G. Xu, C. B. Verchere, 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, Cyrus A. Chehroudi, Heather C. Denroche, Jaques A. Courtade, Jan A. Ehses, 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, Jan A. Ehses, 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, Jianqiang Hao, Daniel L. Metzger, Alice Mui, I-Fang Lee, Noushin Akhoundsadegh, Ziliang Ao, Lieping Chen, Dawei Ou, C. Bruce Verchere, Garth L. Warnock
DOI: 10.1097/tp.0b013e318277229d
01/2013

Activating the NLRP3 Inflammasome Using the Amyloidogenic Peptide IAPP
The Inflammasome
Clara Westwell-Roper, Aisling Dunne, Man Lyang Kim, C. Bruce Verchere, 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, C. Y. Westwell-Roper, A. M. Klimek-Abercrombie, G. L. Warnock, C. B. Verchere
DOI: 10.2337/db12-0364
2013

Endogenous Expression of B7-H4 Improves Long Term Murine Islet Allograft Survival852
Transplantation Journal
X. Wang, J. Hao, D. Metzger, I.-F. Lee, A. Mui, Z. Ao, L. Chen, D. Ou, B. Verchere, G. Warnock
DOI: 10.1097/00007890-201211271-00647
11/2012

Metabolic stress, IAPP and islet amyloid
Diabetes Obes Metab
J. Montane, A. Klimek-Abercrombie, K. J. Potter, C. Westwell-Roper, 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, Jianqiang Hao, Daniel L. Metzger, Alice Mui, I-Fang Lee, Noushin Akhoundsadegh, C. Lieping Chen, Dawei Ou, Ziliang Ao, C. Bruce Verchere, 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, X-Y Sun, J Rayat, D Dai, Z Ao, Z He, C B Verchere, L-J Dai, 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, C. Bruce Verchere, 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, L.-h. Zhang, M. H. Kang, T. Abraham, A. Bhattacharjee, G. L. Warnock, C. B. Verchere, 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, N. Wijesekara, C. Westwell-Roper, T. Vanmierlo, W. de Haan, A. Bhattacharjee, R. Tang, C. L. Wellington, D. LutJohann, J. D. Johnson, L. R. Brunham, C. B. Verchere, M. R. Hayden
DOI: 10.2337/db11-1341
02/2012

B7-H4 Induces Donor-Specific Tolerance in Mouse Islet Allografts
cell transplant
Xiaojie Wang, Jianqiang Hao, Daniel L. Metzger, Alice Mui, Ziliang Ao, C. Bruce Verchere, Lieping Chen, Dawei Ou, 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, Jianqiang Hao, Daniel L. Metzger, Ziliang Ao, Lieping Chen, Dawei Ou, C. Bruce Verchere, Alice Mui, 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, K J Potter, C B Verchere, L Edelstein-Keshet, D Coombs
DOI: 10.1088/1478-3975/8/6/066009
11/2011

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

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

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

Prevention of murine autoimmune diabetes by CCL22-mediated Treg recruitment to the pancreatic islets
J. Clin. Invest.
Joel Montane, Loraine Bischoff, Galina Soukhatcheva, Derek L. Dai, Gijs Hardenberg, Megan K. Levings, Paul C. Orban, Timothy J. Kieffer, Rusung Tan, 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, D. L. Dai, G. Soukhatcheva, K. J. Potter, N. van Rooijen, J. A. Ehses, 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, Poya Pourghaderi, Galina Soukhatcheva, C. Bruce Verchere, Garth L. Warnock, James M. Piret, 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, C. Bruce Verchere
DOI: 10.1155/2011/979527
2011

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

B7-H4 Pathway in Islet Transplantation andß-Cell Replacement Therapies
Journal of Transplantation
Xiaojie Wang, Jianqiang Hao, Daniel L. Metzger, Ziliang Ao, Mark Meloche, C. Bruce Verchere, Lieping Chen, Dawei Ou, Alice Mui, 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, Andisheh Abedini, Annette Plesner, C. Bruce Verchere, 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, L. R. Brunham, C. B. Verchere, M. R. Hayden
DOI: 10.1007/s00125-010-1877-7
08/2010

T REGULATORY CELL MEDIATED PROTECTION OF ALLOGRAFT IN TYPE 1 DIABETES2628
Transplantation Journal
J. Montane, L. Bischoff, G. Soukhatcheva, G. Hardenberg, M. K. Levings, R. Tan, C. B. Verchere
DOI: 10.1097/00007890-201007272-00686
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, Andisheh Abedini, Annette Plesner, Chris T. Middleton, Kathryn J. Potter, Martin T. Zanni, C. Bruce Verchere, Daniel P. Raleigh
DOI: 10.1016/j.jmb.2010.05.001
07/2010

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

HDL and LDL cholesterol significantly influence ß-cell function in type 2 diabetes mellitus
Current Opinion in Lipidology
Janine K Kruit, Liam R Brunham, C Bruce Verchere, 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, Galina Soukhatcheva, James D. Johnson, 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, P. H. C. Kremer, L. Dai, R. Tang, P. Ruddle, W. de Haan, L. R. Brunham, C. B. Verchere, 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, R. L. Hull, C. B. Verchere, A. Clark, K. J. Potter, P. E. Fraser, D. P. Raleigh, 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, Janine K. Kruit, Michael R. Hayden, 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, Galina Soukhatcheva, Robert G. Korneluk, 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

Paul Orban, Research Associate I (Postdoctoral Fellows submit
Galina Soukhatcheva
Yi-Chun Chen
Derek Dai, Research Assistant / Research Technician
Heather Denroche
Austin Taylor
Mitsu Komba, Lab Tech
Sigrid Alvarez, Graduate Student
Aleisha Durmaz
Alex Hsu
Meixia Dan, Research technician
Dominika Nackiewicz
Kai Zhu
Kenny Fok, Undergraduate Student
Nahae Kim