Determining the role of pancreatic parasympathetic innervation in Type 1 Diabetes

Type 1 Diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing beta cells leading to hyperglycemia. In parallel, dysfunctional glucagon-producing alpha cells do not respond adequately to low glucose resulting in frequent episodes of hypoglycemia in T1D. Glucose regulation by the endocrine pancreas is highly regulated by the autonomic nervous system. Specifically, sympathetic nervous system activity inhibits insulin secretion and activates glucagon secretion, and leads to intra-islet vasoconstriction that together increase blood glucose. Importantly, sympathetic activity has been reported to exacerbate the early inflammatory process of several autoimmune diseases such as rheumatoid arthritis. However, the contributions of sympathetic innervation to metabolic and autoimmune pathology in T1D is largely unexplored. Existing structural and functional studies of sympathetic innervation in T1D are conflicting, in part because many of these studies used techniques that are not pancreas-specific. Importantly, there are no detailed longitudinal studies of the structure or function of pancreatic sympathetic innervation during both development of T1D and at later stages of the disease. Our previous studies and preliminary results strongly indicate increased islet sympathetic innervation occurs in early T1D, potentially contributing to accelerated immune activity, beta cell loss, hyperglycemia and hyperglucagonemia. Additionally, our data suggest that systemic and pancreas-specific sympathetic inactivation delays the onset of hyperglycemia in a mouse model of T1D. These data strongly support the hypothesis that increased sympathetic innervation accelerates immune destruction and hyperglycemia in T1D. We will test this hypothesis in two Specific Aims: 1) To determine the extent, changes and time-course of pancreatic islet sympathetic innervation in the NOD mouse model of T1D using unbiased 3D imaging; and, 2) Determining the effects of highly targeted ablation and activation of pancreatic sympathetic innervation in vivo on immune islet infiltration and metabolic function.