The underlying hypothesis of this proposal is that pancreatic beta cell mass can be estimated noninvasively by positron emission tomography (PET) using the radiopharmaceutical 18F-fluorobenzyltrozamicol (FBT). This tracer is a cholinergic neuroreceptor ligand that binds to the presynaptic vesicular acetylcholine transporter (VAChT). The pancreas is heavily innervated by parasympathetic cholinergic neurons that stimulate beta cell production of insulin, an effect further potentiated by increased serum glucose. With FBTPET, we have produced striking images of the pancreas in rodents, nonhuman primates, and humans. A number of pancreatic cell types are innervated by cholinergic nerves. However, the beta cells receive 10-fold more cholinergic input that the remainder of the pancreas. For this reason, we believe that cholinergic imaging may be a valid surrogate of beta cell mass and/or function. The goal of this proposal is to validate FBT-PET as a noninvasive imaging method for quantifying beta cell mass and function in specific murine model of diabetes. This project includes three specific aims:
Specific Aim 1 : To determine FBT-PET activity in normal control mice and in two commonly utilized murine models of type-1 diabetes. These include a model of quick, streptozocin-induced diabetes mellitus and a model of progressive autoimmune beta cell destruction similar to type 1 diabetes mellitus.
Specific Aim 2 : To determine whether FBT-PET activity in the pancreas is a valid surrogate of beta cell mass and function as determined by gold standard methods of quantifying beta cell mass as function.
Specific Aim 3 : To determine whether FBT-PET activity in the pancreas is specific and proportionate to the density and activity of cholinergic ganglia as determined by in vitro measurements. This neurofunctional approach to pancreatic beta cell imaging is innovative. No similar research has been performed. The success of this research is of great potential significance. It may provide a noninvasive method to monitor beta cell mass and function that is applicable to both humans and to animal models of diabetes. The translational application of this technology to the clinic would be expected to be rapid. This could facilitate earlier detection of diabetes, before the onset of hyperglycemia, to allow prophylactic intervention. This imaging tool could provide a noninvasive approach to monitoring the efficacy of immunosuppressive and gene therapies that focus on halting or reversing the progression of diabetes. The method could also be useful in evaluating the function of pancreatic transplants and successful engraftment of transplanted progenitor or beta cells.
|Clark, Paige B; Kavanagh, Kylie; Gage, H Donald et al. (2009) Enhanced cholinergic response in pancreata of nonhuman primates with impaired glucose tolerance shown on [18F]fluorobenzyltrozamicol positron emission tomography. Diabetes Technol Ther 11:451-5|
|Clark, Paige B; Plaza, Michael J; Kraas, Jonathan et al. (2009) Dual radiotracer analysis of cholinergic neuronal changes in prediabetic mouse pancreas. Diabetes Technol Ther 11:107-11|