Obesity-linked type 2 diabetes is a major health problem of worldwide epidemic proportions. The onset of the disease is marked by failure of the functional pancreatic islet -cell mass to meet metabolic demand, and is thus an insulin insufficient state. It follows that a means to protect and preserve adequate functional -cell mass has therapeutic potential for type 2 diabetes. Much is known about nutrient and hormonal regulation of -cell function. However, despite it being known for more than 160 years that the central nervous system (CNS) has a significant degree of control over pancreatic islet functions, mechanisms of CNS control over pancreatic -cells remain vague. Indeed, the precise regions of the CNS that link to pancreatic islets are unknown. In this proposal it is intended to utilize a novel class of pseudorabies viral vectors (PRV) as retrograde transynaptic neuronal tracers to accurately track the neuronal link between pancreatic islets and specific regions of the CNS in vivo. This will be complemented by several in vivo anterograde-tracing techniques to refine the PRV retrograde tracing.
Aim -1 will use both retrograde and anterograde neuronal tracking approaches to reveal a CNS `brain-to-islet topographical map' in mice, at a 5m-resolution and in 3D. This map will be characterized in detail, particularly to unveil what kind of neuronal cells are within it and to utilize novel anterograde-tracking techniques to identify specific neuronal circuitries that can be activated within this map.
In Aim -2 glucose-sensing neurons within the `brain-to-islet map' will be manipulated, using accurate stereotaxic delivery of adenoviral vectors that alter glucokinase activity in specific sub-regions of the hypothalamus. Likewise, in Aim-3, a similar stereotaxic approach will be taken, but aimed at specifically targeting particular hypothalamic insulin-signaling neurons, where insulin receptor and IRS-2 gene function will be manipulated. Then, it will be assessed whether alteration of glucose-sensing and/or insulin-signaling in regions of the CNS which link to pancreatic islets will affect islet cell function in ivo, particularly in regard to control of -cell mass, insulin and glucagon secretion. This will be measured relative to metabolic homeostasis and insulin sensitivity, so as to distinguish between direct acute effects of the CNS on islet cell function rather than peripheral metabolic effects to which islet cells act secondarily. Thus, the newly revealed `brain-to-islet map' will be validated as a functional guide, and novel mechanistic insight into CNS neuronal control of pancreatic islet cell functions gained. It is anticipated that this research will eventually translate into noel therapeutic approaches for the treatment of diabetes/obesity.
Obesity-linked type-2 diabetes is caused by insufficient functional pancreatic -cell mass that is no longer able to compensate for the peripheral insulin resistance. It has been known for more than 160 years that the brain has influence over pancreatic islet cell function, but the mechanism is poorly understood. The overall goal of this application is to generate a high-resolution brain-to-pancreatic islet functional map that will be landmark in the diabetes/obesity research field which will then likely lead to novel therapeutic approaches which alleviate symptoms and delay, perhaps indefinitely, the onset of type 2 diabetes.
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