Clinical and Patient Research Studies
The iCARE (improving renal complications in adolescents with type 2 diabetes through research) study was designed to address the extremely high rates of early kidney damage in youth with type 2 diabetes. This study has recently expanded to include national cohorts, and the revised objects are; 1) Characterize the primary bio-psycho-social (BPS) risk factors associated with prevalent and progressive albuminuria, 2) Determine individual, family and community level factors that influence biological and psychological risk factors and behaviours (adherence) that could be modified to protect against prevalent and progressive albuminuria, 3) Determine if systemic renal inflammation is the common pathway through which BPS risk factors lead to albuminuria in youth with type 2 diabetes.
(Aboriginal Youth Mentorship Program)
AYMP was developed as a school-based program designed to reduce the risk of type 2 diabetes in Indigenous youth. The program is designed to create mentorship relationships between elementary and high school students by using the principles of the Circle of Courage to share knowledge of healthy food and activities. This program relies on high school students as mentors to run all of the activities, with the supervision of and adult mentor. The youth mentors meet before the program in order to plan activities, and on the program day mentors prepare the snack, set up the gym for the activities, run the program, and do all of the clean-up. AYMP started as a one site study but has evolved into a program that can be found in 5 locations within Manitoba, and more recently has been approved to expand nationally to 7 more sites.
Non-alcoholic fatty liver disease (NAFLD) affects 30% of overweight adolescents and increases the risk of type 2 diabetes. The current project is designed as a 30-day pilot trial to demonstrate proof of principle of resveratrol in the population to determine the effect size of the intervention on hepatic steatosis and whole body insulin sesnsitivity, and to determine the effectiveness, safety, tolerability and feasability for a larger trial. The primary objective is to evaluate a twice daily supplementation of resveratrol for safety and tolerability in an overwight and obese adolescent population with NAFLD. Secondary objectives are to evaluate efficacy of resveratrol for reduction of fatty liver and cardiac triglyceride content, as well as whole body insulin resistance and lipid metabolism in overweight and obese adolescents with NAFLD. We also want to evaluate the effects of resveratrol on cardiac function and morphology, serum markers of inflammation, and anthropometirc measures in this population.
The Next Generation cohort is a unique prospective birth cohort designed to examine metabolic and anthropometric outcomes of offspring born to mothers or fathers diagnosed in childhood with type 2 diabetes. The aims of this include; 1) Determining how diabetes during pregnancy affects DNA methylation of genetic loci associated wtih obesity and obesity-related complications in children, 2) Determine tissue-level mechanisms that explain programming of metabolic disease, 3) Develop novel early-life interventions that prevent obesity and obesity-related diseases in children. Testing of these interventions will be done to see whether interventions delivered in early life (i.e. maternal exercise, breastfeeding etc.) modify epigenetic biomarkers and reduce the risk of pediatric obesity and its complications due to the early life environmental exposure to maternal diabetes during pregnancy.
This research is being conducted to study a new, non-invasive test to examine nerve damage in people with diabetes. The results from this study may help to understand how nerve damage develops, to detect very early nerve damage and how we might be able to repair this nerve damage. This technique has been used previously in adults with diabetes, but has not yet been used in youth with type 2 diabetes. The objectives of this study are; 1) Determine the performance of corneal confocal microscopy and its individual parameters to identify the prescence or absence of diabetic neuropathy in adolescents with type 2 diabetes, 2) explore the relationship between corneal nerve fibre branch density and fibre length and known risk factors for diabetic neuropathy, 3) Examine the relationship between corneal nerve fibre density, branch density and fibre length and complications and co-morbidities of type 2 diabetes.
Basic Science Research Programs
Epigenetic and transcriptional regulation of mitochondrial function in beta cells and peripheral tissues
(Environments, Genes and Chronic Disease)
We hypothesize that environmental exposure to maternal diabetes during gestation alters DNA methylation, contributing to the development of obesity and obesity-related complications in the offspring. We plan to analyze biological samples from two populations of children at high-risk for chronic metabolic diseases (iCARE/NextGen) to discover epigenetic signatures associated with childhood obesity. These findings will be replicated in two large population based cohorts of pregnant women and their children (CHILD/Gen3G). Upon discovery of the epigenetic signature of diabetes during pregnancy, we will mechanistically validate this using rodent models under controlled conditions to see how gestational diabetes influences gene expression in metabolic tissues that cannot be routinely sampled in pediatric populations (e.g. liver, pancreatic islets, heart, skeletal muscle).
Research in the Doucette Lab is focused on defining the molecular and metabolic factors that regulate pancreatic insulin secretion and importantly, learning how these factors are disrupted in the development of youth-onset type 2 diabetes. Being a pre-clinical laboratory, we use rodent and cell models to “reverse engineer” diabetes in our lab so that we can explore the pathological mechanisms that contribute to diabetes onset and progression. Specific projects currently include investigating the role of the circadian clock not only in the regulation of every day cycles of insulin secretion but also in contributing to metabolic dysfunction, impaired insulin secretion and diabetes development. Additionally, we have a project that aims to investigate the role of a gene variant called HNF-1aG319S. This gene variant strongly associates with youth living with type 2 diabetes in Manitoba; however, it’s mechanistic contribution to insulin secretion failure is not yet understood. We are using state-of-the-art gene editing technologies to develop rodent and cell models of this gene variant and exploring how it impacts metabolic health. Importantly, we hope that the discoveries from our research will yield much needed insights into how and why the pancreas fails during youth-onset type 2 diabetes so that we can develop improved treatment and prevention approaches for Manitoban children and children worldwide.
Dr. Davie has over thirty years of experience in the field of epigenetics, which is the study of heritable changes in gene function that do not involve changes in the DNA sequence. His ongoing research studies will provide information about alterations in the epigenome that are related to type 2 diabetes. His research team studies nuclear and mitochondrial DNA methylation (a well known epigenetic mark that influences gene expression) in peripheral blood monocytes (circulating white blood cells) from individuals with and without type 2 diabetes. His research team uses model systems (e.g. mouse models and mouse pancreatic cell line) to understand the cause and consequence of alterations in epigenetic processes in obesity and type 2 diabetes.
Dr. Gordon’s research focuses on the regulation of mitochondrial function during cardiac and skeletal muscle differentiation and remodeling, including diabetic cardiomyopathy, insulin resistance, and hypoxia/ischemia. Dr. Gordon’s laboratory utilizes cell and molecular approaches to understand mitochondrial function, dynamics, and turn-over including the regulation of mitophagy and mitochondrial permeability transition. Specifically, Dr. Gordon’s laboratory studies the transcriptional regulation and post-translational modification of Bcl-2 family members utilizing both primary and immortalized cells, differentiated human induced pluripotent stem cells, and conditional knockout mice.
Dr. Grant Hatch studies a fat in the body called cardiolipin. Cardiolipin is needed by the body to make and burn energy. Cardiolipin is like ice cream…it comes in many flavors. When the flavor of cardiolipin is changed the ability of the body to burn energy is changed. This can cause fat accumulation and lead to diabetes. In diabetes we know the flavor of cardiolipin is changed. Dr. Hatch is using animal models of obesity and diabetes to try to understand how cardiolipin is changed and if prevention of these changes in cardiolipin in these animal models can prevent obesity and diabetes.