Table 1.

Open questions in the field of pancreatic innervation.

Innervation Branch	Open questions in the field
Intrinsic pancreatic innervation	Differences in postganglionic cholinergic innervation of rodent and human endocrine pancreas raise many questions about postsynaptic targets, molecular mechanisms, and the physiological role of this innervation branch in different species. The role of neuroinsular complexes and how they differ from other intrinsic ganglia that are not directly associated with endocrine islets remains unknown. The anti-inflammatory effect of cholinergic innervation on resident macrophages has been proposed, but not confirmed.
Parasympathetic	Although the vago-vagal reflex has been proposed to be involved in the regulation of glucose metabolism, the parts of the circuit have not been linked together. It has not been determined if the parasympathetic efferent output depends on vagal sensory input from the pancreas. Hypothalamic and higher brain centers control of parasympathetic innervation in glucose metabolism is not fully understood. The anti-inflammatory properties of parasympathetic innervation have been described systemically as well as in many visceral systems, but has been barely studied in the pancreas.
Sympathetic	Adrenergic neurons innervate pancreatic islets and draining lymph nodes and are suspected to be important players in the pathogenesis of autoimmune diabetes. The anatomical, physiological, and molecular properties of the interactions between sympathetic neurons and the local components of the immune system requires further research.
Enteric	Extensive tracing studies suggest that the enteric nervous system extends projections into the pancreas. The physiological significance of the entero-pancreatic network, however, is poorly understood.
Sensory	Sensory transduction mechanisms and sensory modalities transmitted via spinal and vagal afferents are not well understood. Although systemic manipulation of sensory innervation affects glucose metabolism, it is still not clear if and how pancreas-specific sensory pathways affect glucose metabolism and exocrine secretion, and whether the vagal sensory component is involved in the mediation of the vago-vagal reflex. The etiology and pathogenesis of chronic pain in pancreatitis and pancreatic cancer is widely studied, but still not fully understood. Sensory innervation is proposed to be an important mediator in pathogenesis of pancreatic cancers.