Genetic and/or environmental-driven insulin hypersecretion as an early promoter of type 1 diabetes pathogenesis
The INS gene is the second most important genetic contributor to type 1 diabetes risk. Paradoxically, beta cells from people carrying INS risk alleles exhibited significantly higher levels of INS mRNA. Elevated insulin production can stress the endoplasmic reticulum leading to increased fragility and cell death, and also cause insulin production errors leading to neo-autoantigens. We are using mice prone to spontaneous type 1 diabetes development to study if genetically modifying beta cells to create an “insulin production limit” will alleviate endoplasmic reticulum stress and therefore delay or prevent onset of the disease. The overall goal of this project is to identify a method of type 1 diabetes prevention for high-risk individuals.
Targeting sodium channels and beta cell excitotoxity in type 1 diabetes
Our previous high-content screen identified the use-dependent sodium channel blocker carbamazepine as a powerful suppressor of apoptosis in mouse and human beta cells. An in vivo study then demonstrated that this approved drug can protect NOD mice from type 1 diabetes. We are now testing the hypothesis that this drug works primarily via the Scn9a sodium channel gene (Nav1.7) using genetically engineered NOD mice, further defining the molecular mechanisms, and working with drug companies to identify drugs with improved qualities ahead of a future clinical trial.
Understanding the work cycles of pancreatic beta cells from mice, humans, and stem cells.
We use live cell imaging to monitor and track dynamic insulin gene activity over time in genetically engineered mice and stem derived cells and utilize high throughput screens to identify key effectors of insulin gene activity and beta cell survival. The overall goal of our research is to better understand the dynamics and mechanisms that regulate insulin gene activity in insulin producing cells.
Understanding human variation in nutrient-stimulated insulin responses: Towards Personalized Nutrition
We are using human donor islets to better understand how insulin secretion in response to macronutrients is regulated. By comparing the functional responses to the unique genetic profile of the donor, we hope to better delineate the interactions between our genes and nutrient-stimulated insulin secretion. The overall goal of this project is to understand how personalized preventative and/or therapeutic intervention strategies can be implemented.
Sex differences in pancreatic beta cell resilience
In many age groups, both type 1 and type 2 diabetes are more common in men than women, and there are important biological differences in islet function between males and females. Yet, historically, females and women have been vastly understudied in diabetes research. In collaboration with the Rideout lab, we are systematically mining publicly available human islet datasets and conducting ex vivo experiments using isolated mouse islets to elucidate sex differences in islet function, with a particular focus on protein synthesis.
Lipidomics and lipid-induced insulin secretion in human beta cells and stem cell derived beta cells
One therapy for T1D includes the transplantation of stem cell derived (SC)- beta cells that secrete insulin. However, current SC-beta cells do not behave like a natural human beta cell, and it could be that underlying fat signaling networks are not forming properly. Together with Drs. Dan Luciani and Francis Lynn, we are investigating how fat signaling networks change over the course of SC-beta cell development and examining how these cells might differ in comparison to beta cells derived from human donors.
Understanding the role of hyperinsulinemia in sucrose-induced metabolic dysfunction across multiple insulin target tissues.
During the development of type 2 diabetes, the body often makes more of the blood sugar-lowering hormone insulin than normal. Recent research suggests excess insulin may cause weight gain and insensitivity to insulin. Too much sugar consumption also contributes to obesity and diabetes, but how this happens is still unclear. Therefore, we aim to find out whether reducing insulin can prevent the detrimental effects of high sucrose in mice and identify the underlying causes of obesity and diabetes. We are analyzing the liver, fat and muscle using powerful "omics" techniques that can profile thousands of genes, proteins and metabolites in these tissues. These analyses will reveal the detailed changes in the cells in response to sucrose and insulin, which will tell us how they cause obesity and diabetes and help us develop strategies for preventing diabetes.
How does exercise and exercise-cessation affect insulin secretion?
We are investigating how exercise and physical inactivity alter the risk of developing obesity and diabetes. Though the use of mouse models, we aim to understand the mechanisms by which beta-cell function and health are impacted by exercise and inactivity and whether excess insulin secretion when becoming physically inactive plays a role in the development of metabolic diseases.
Molecular mechanisms of corticosteroid-induced alterations in metabolism in male and female mice
We are investigating the short-term impact of a medium dose of dexamethasone on glucose and insulin tolerance, as well as the proteomic profiles of the liver, pancreas, and adipose fat in male and female C57BL/6J mice. Our research aims to shed light on the physiological responses to glucocorticoid exposure, providing valuable insights into metabolic regulation and sex differences.
Hyperinsulinemia as a driver of breast cancer initiation in the context of obesity
Our lab uses mouse models to study the causal role of elevated insulin levels, known as hyperinsulinemia, in the onset of breast cancer. This study aims to better understand how insulin can be used as a biological marker to identify individuals at risk. This approach will be most beneficial for the populations with obesity and/or type 2 diabetes, offering a preventative strategy against breast cancer.
Substrate Utilization in the Heart
Heart disease is a leading cause of death globally, characterized by altered metabolism. Since the heart has a high energy demand, it utilizes a variety of nutrient sources, chief of which are glucose and fats. Glucose and fats utilization in the heart is regulated reciprocally akin to the control of conflicting directions of traffic at an intersection by traffic lights. In hearts, when this regulation is altered, accidents occur leading to heart disease. Pyruvate dehydrogenase kinase 1 (PDK1) is one of the ‘traffic lights’ that controls the intersection of glucose and fats utilization in the heart. However, its precise role in this regulation is unknown. Further, its contribution to heart function is also a mystery. Our work seeks to thoroughly characterize PDK1 function in heart metabolism and function using system biology approaches.
How does diabetes affect donated blood?
With the recent expansion in Canadian Blood Services donor eligibility criteria to include most individuals with diabetes, we are investigating how the characteristics of their donated blood may differ from the rest of the donor population. The first part of this project involves an HbA1c screen of current donors with diabetes to gauge how well-controlled diabetes is in the donor population. We are then following this with a deeper characterization of blood products - platelets, plasma, and red blood cells - from donors with type 1 or type 2 diabetes and donors without diabetes. If there are marked differences in products from donors with diabetes, identifying and understanding them could lead to fine-tuning their applications in hospitals to improve transfusion recipient outcomes. If there are not clinically significant differences, that is valuable information for other blood services worldwide.
