Grant: Project Grant

Diabetes affects nearly 3 million Canadians, and is associated with significant healthcare costs and a reduced quality of life. Impaired insulin secretion by the pancreas is a critical determinant of all forms of diabetes, including type 2 diabetes (T2D) which accounts for ~80% of cases. T2D results from an inability of insulin secretion by the pancreatic islets of Langerhans to compensate appropriately for insulin resistance, often associated with obesity. We will study the cellular mechanisms within islets that determine the amount of insulin secreted when blood sugar increases, and how this process fails in T2D. This follows on our recent discovery of a cellular pathway within islets that acts as an amplifier, or 'dimmer switch' for insulin secretion through a signalling process called SUMOylation. We showed that this is impaired in islets from organ donors with T2D. Restoration of this pathway in T2D islets rescued their insulin secretory function. We now propose to determine exactly how this process works, what its role is in T2D, and how we can use it to rescue impaired insulin secretion. Our group has unique access to human tissue that is clinically relevant to diabetes, since we isolate islets from non-diabetic and T2D organ donors through our in-house biobanking program. This allows us to perform human-relevant experiments using cutting-edge cell biology approaches to study cell function visually (microscopic imaging), electrically (islet cells, like brain neurons, are electrically active), and biochemically. This will be combined with the use of model systems that include cultured cell lines, rodent islet cells, and novel genetic mouse models that will allow us to determine the impact of the pathway we are studying on whole-body glucose control. Understanding the cellular mechanisms that control insulin secretion in health and T2D is critical to gain further insight into causes, treatments, and prevention strategies for human diabetes.