1546-P: Autonomic Intrapancreatic Neurons Alterations in Type 1 Diabetes

Introduction: Little is known about parasympathetic intrapancreatic neurons despite their important role in regulation of endocrine and exocrine functions. 3D imaging studies show innervation of these ganglia and islets in organ donors with type 1 diabetes (T1D). This study analyzed intrapancreatic ganglia from organ donors without and with T1D.

Methods: Paraffin sections from donors with no diabetes (ND, n=15) or T1D (n=9) were obtained from nPOD. Multiplex immunofluorescence was performed using antibodies to HuC/D, synapsin (SYN), and allograft inhibitory factor 1 (IBA1) to define neurons, synapses, and macrophages, respectively. Confocal images from 83 ganglia were analyzed using QuPATH software to quantify each ganglia area and immunopositive areas within ganglia. Ganglion sizes were binned into four groups. Neuron analyses included area (size) and numbers/ganglion (density). Statistical comparisons were made using non-parametric t-tests.

Results: A significant reduction in HuC/D+ area/ganglia was observed in T1D donors compared to ND (p < 0.01). Neuron sizes were smallest in T1D donors in the smallest ganglia (<3000 µm2). Comparisons of all neuron sizes, regardless of ganglia size, showed trends for smaller neurons and lower neuron density in T1D donors. No significant differences were found in synaptic or macrophage areas between groups.

Conclusions: Our results represent the first study analyzing human intrapancreatic ganglia for neurons, synapses, and macrophages. Our analysis indicates a significant reduction in neuronal HuC/D expression and trends for smaller and fewer neurons in T1D donor intrapancreatic ganglia. However, synapse loss or increased macrophage-mediated inflammation were not observed. Future studies will examine whether these findings are observed in at-risk autoantibody-positive donors. Understanding which neuron subtypes are affected by T1D is important for understanding altered islet compositions and dysregulated hormone secretion in the natural history of T1D.