Welcome to the Kahn Laboratory

Our research involves both basic and clinical investigation and is focused on furthering our understanding of the pathophysiology, prevention and treatment of type 2 diabetes and related disorders.

Research:
Our basic science studies focus on the role of islet amyloid in the β-cell loss observed in type 2 diabetes and islet transplantation. These amyloid deposits contain as their unique peptide component islet amyloid polypeptide (IAPP), which misfolds to form amyloid fibrils and induces β-cell death. For this work we perform in vivo and in vitro studies using transgenic mouse models, islet and cell cultures aimed at understanding the cellular mechanisms by which amyloid results in β-cell apoptosis and impaired β-cell function. The ultimate goal is to identify novel approaches to reduce islet amyloidogenesis and its downstream adverse effects.

Our current work is focused on the following:
1.      The innate immune system is intimately involved in amyloid-induced β-cell loss, with macrophages playing a critical role. We have been examining the role of cytokines, including IL-1β and TNF-α, in this process. While large doses of IL-1β clearly induce cell death, we are interested in the effects of more physiological concentrations of the cytokine and the process by which it induces amyloid formation and β-cell loss. We are also studying necroptosis, a novel TNF-α dependent mechanism of cell death, that we have identified to occur with amyloid-induced production of TNF-α. Our goal is to fully delineate how these two cytokines result in cell loss with the ultimate goal to identify approaches to interrupt their action and thereby maintain β-cell number.
2.      Steroidogenic Acute Regulatory Protein (StAR) normally transports cholesterol across the mitochondria for subsequent metabolism to corticosteroids, sex steroids, neurosteroids, oxysterols and bile acids. We have found that StAR expression in β-cell mitochondria is selectively upregulated by amyloid resulting in abnormal mitochondrial function and apoptosis. We are pursuing studies to further understand the physiological role of StAR in the β-cell and to limit its deleterious effects when amyloid is present.
3.      Expression of tissue plasminogen activator (tPA) is also selectively increased by islet amyloid formation. We have found that tPA, which plays an important role in the plasmin system that is responsible for blood clot dissolution, is expressed in macrophages and limits amyloid fibril formation by IAPP by cleaving the peptide to render it non-amyloidogenic. Current work is aimed at developing approaches to increase its activity in order to reduce amyloid formation.
4.      Our efforts to limit islet amyloid formation are using a number of other approaches, many being done in collaboration with scientists at the University of Washington and outside of Seattle. One example is based on the concept that the α-sheet secondary structure of IAPP plays a critical role in both the aggregation and toxicity of soluble oligomers of this fibrillogenic peptide. Using specifically designed peptides with an α-sheet structure, we are studying in vitro and in vivo whether these peptides can preferentially interact with toxic intermediates of IAPP and thereby inhibit aggregation and prevent cell death.

Our clinical research work focuses primarily on the islet β-cell’s role in the development of the dysglycemia that characterizes prediabetes and type 2 diabetes. We have highlighted the importance of considering the magnitude of the insulin response relative to prevailing insulin sensitivity when assessing the adequacy of the β-cell’s response to secretory demand. This approach continues to be used by in our work and has been adopted by many others.

In line with this interest we are collaborating with colleagues interested in the pathophysiology of type 2 diabetes in adults and youth to further our understanding of the development of prediabetes and type 2 diabetes. Interestingly, this work suggests that the pathogenesis of the disease differs in younger and older individuals and that this may be why the progression of dysglycemia and loss of β-cell function is more rapid in youth, resulting in a poorer response to therapies commonly used in adults. Current work focuses on mechanisms that may underlie these differences with the long term goal being to identify approaches that can reduce disease progression in both age groups.

Our basic science studies using animal models of islet amyloid formation have allowed us to develop a PET-based imaging approach that provides a good quantitative measure of amyloid deposition determined by histology. We are now undertaking studies to determine whether this same PET approach using a tracer specific for amyloid in humans can provide insight into the degree of islet damage in humans.

Aside from these studies, we are also participating in a number of multicenter clinical trials the goals of which are to enhance our understanding of the best approaches to intervene in adults to prevent and treat type 2 diabetes. Our expertise in β-cell function is an important component being employed in the design and analyses of these studies.

Contact Us

VA Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA 98108

206-277-5515

Members of the Laboratory

Steven E. Kahn, MB, ChB

Professor of Medicine, Division of Metabolism, Endocrinology and Nutrition, UW and VA Puget Sound Health Care System
Director, UW Diabetes Research Center
Director, Diabetes, Obesity and Metabolism Training Program
Director, Diabetes Research Group, VA Puget Sound Health Care System

Meghan Hogan, PhD

Research Fellow/Acting Instructor
Dr. Hogan received her Bachelor of Arts from Wellesley College followed by her Ph.D. in 2013 from the UCSD and the Salk Institute under the mentorship of Dr. Marc Montminy. She joined Dr. Kahn’s laboratory in 2014 and in 2016 was awarded the Division of Metabolism, Endocrinology and Nutrition’s Trainee of the Year Award. She is currently funded by a prestigious Postdoctoral Fellowship Award from the American Diabetes Association. Dr. Hogan’s research focuses on the role of Steroidogenic Acute Regulatory Protein (StAR) in the development of islet amyloid-induced mitochondrial dysfunction and -cell loss.

Andrew Templin, PhD

Research Fellow/Acting Instructor
Dr. Templin received his Bachelor of Science from Indiana University in Bloomington, IN. Subsequently he obtained his Ph.D. from Indiana University where he studied with Dr. Raghu Mirmira. He joined the Kahn Laboratory in 2014 and successfully competed for a Ruth L. Kirschstein National Research Service Award from NIDDK. He was awarded the University of Washington’s Brunzell Fellow Award in 2016. He is funded by a Career Development Award from the Department of Veterans Affairs and is pursuing studies of RIPK3-mediated β-cell necroptosis and its effects on β-cell death.

Nathalie Esser, MD, PhD

Research Fellow
Dr. Esser received her M.D. and Ph.D. degrees from the University of Liege in Belgium 2010, after which she undertook her postgraduate clinical training that included clinical research. During her training she received awards from the Endocrine Society in the United States, French Society of Diabetes and Belgian Association of Diabetes. She joined Dr. Kahn and his group in 2017 and has mastered basic laboratory skills while studying islet biology interrogating the role of the tissue plasminogen activator/plasmin system in islet amyloidosis and β-cell survival. Recently the University of Washington awarded her the Dick and Julia McAbee Fellowship in Diabetes to support her research.

Steve Mongovin

Research Technician

Christine Weber-Schmidt

Research Technician


Clinical Research Group

Edward J. Boyko, MD, MPH

Co-investigator

Lorena Wright, MD

Co-investigator

Elaine Tsai, MD

Co-investigator

Karen Atkinson

Program Manager

Basma Fattaleh

Study Coordinator

Alexandra Kozedub

Nurse Practitioner

Jola Socha

Research Assistant

Ivy Morgan-Taggart

Administrator

Nina Prikhodko

Research Assistant

Heidi Urquart

Research Nurse


Laboratory Alumni

Sofianos Andrikopoulos, PhD

Dr. Andrikopoulos is an Associate Professor in the Department of Medicine at the University of Melbourne at Austin Health in Australia. He is Head of Islet Biology and the Metabolism Research Group that is studying the genetic susceptibility of islet dysfunction using animal models of diabetes and the role of glucose and lipids in the development of β-cell dysfunction.

Miriam Cnop, MD, PhD

Dr. Cnop is a Professor of Medicine at Université Libre de Bruxelles and Clinical Director of Erasmus Hospital’s Endocrinology Department, all in Brussels, Belgium. Her research work is focused on monogenic forms of diabetes involving genes with a role in endoplasmic reticulum stress, mitochondrial function and tRNA biology. She is also studying the relationship between Friedreich’s ataxia and diabetes.

Rebecca L. Hull, PhD

Dr. Hull is a Research Associate Professor of Medicine at the University of Washington. Her research is focused on the role of the islet endothelial cell and islet extracellular matrix in determining β-cell function and survival in normal physiology and their role in the development of type 2 diabetes. She is also studying the pathology of the islet in cystic fibrosis-related diabetes.

Jenny Tong, MD, MPH

Dr. Tong is an Associate Professor of Medicine at Duke University where she provides patient care and undertakes research. Her research interests are focused on the role of the orexigenic gut hormone ghrelin. Her studies in humans and rodents are examining its role in regulating glucose and energy homeostasis through effects on islet cell function and energy intake.

Kristina M. Utzschneider, MD

Dr. Utzschneider is an Associate Professor of Medicine at the University of Washington. Aside from her leadership role in delivering diabetes care to patients at VA Puget Sound Health Care System, she is doing research focused on the pathogenesis of fatty liver and the use of mathematical modeling of glucose metabolism.

C. Bruce Verchere, PhD

Dr. Verchere is a Professor in the Department of Surgery and Department of Pathology and Laboratory Medicine, and heads the Diabetes Research Program at the Child and Family Research Institute, all at the University of British Columbia. His research focuses on normal β-cell function and why these cells are dysfunctional and die in type 1 diabetes, type 2 diabetes and following islet transplantation.

Josep Vidal, MD, PhD

Dr. Vidal is the Head of the Department of Endocrinology and Nutrition, Hospital Clinic, at the University of Barcelona, Spain. Aside from his clinical duties, he has an active clinical research program studying the mechanisms by which metabolic and bariatric surgery impact glucose control and body weight. He is also interested in the role of GLP-1 receptor agonists on body weight regulation.

Sakeneh Zraika, PhD

Dr. Zraika is currently a Research Associate Professor of Medicine at the University of Washington. She is undertaking studies examining the effects of the protease neprilysin in regulating glucose metabolism in the liver and islet as well as the role of the renin-angiotensin system in the control of β-cell function.