Noninvasive in vivo model demonstrating the effects of autonomic innervation on pancreatic islet function

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-12, Vol.109 (52), p.21456-21461
• Main Authors: Rodriguez-Diaz, Rayner, Speier, Stephan, Molano, Ruth Damaris, Formoso, Alexander, Gans, Itai, Abdulreda, Midhat H., Cabrera, Over, Molina, Judith, Fachado, Alberto, Ricordi, Camillo, Leibiger, Ingo, Pileggi, Antonello, Berggren, Per-Olof, Caicedo, Alejandro
• Format: Article
• Language: English
• Subjects: Animals; antagonists; Anterior chamber; atropine; autonomic nervous system; Autonomic Nervous System - physiology; Axons; Biological Sciences; Blood glucose; cell physiology; Cholinergics; Diabetes; Eye - innervation; eyes; fasting; Glucose; glucose tolerance; Green Fluorescent Proteins - metabolism; Homeostasis; Innervation; Insulin; Iris - innervation; Iris - physiology; Islets of Langerhans; Islets of Langerhans - physiology; Islets of Langerhans Transplantation; lighting; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; Nerve Fibers; Nervous system; Physiology; Rodents; strain differences; Tissue grafting; topical application; Transgenic animals; Transplantation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1211659110

The autonomic nervous system is thought to modulate blood glucose homeostasis by regulating endocrine cell activity in the pancreatic islets of Langerhans. The role of islet innervation, however, has remained elusive because the direct effects of autonomic nervous input on islet cell physiology cannot be studied in the pancreas. Here, we used an in vivo model to study the role of islet nervous input in glucose homeostasis. We transplanted islets into the anterior chamber of the eye and found that islet grafts became densely innervated by the rich parasympathetic and sympathetic nervous supply of the iris. Parasympathetic innervation was imaged intravitally by using transgenic mice expressing GFP in cholinergic axons. To manipulate selectively the islet nervous input, we increased the ambient illumination to increase the parasympathetic input to the islet grafts via the pupillary light reflex. This reduced fasting glycemia and improved glucose tolerance. These effects could be blocked by topical application of the muscarinic antagonist atropine to the eye, indicating that local cholinergic innervation had a direct effect on islet function in vivo. By using this approach, we found that parasympathetic innervation influences islet function in C57BL/6 mice but not in 129X1 mice, which reflected differences in innervation densities and may explain major strain differences in glucose homeostasis. This study directly demonstrates that autonomic axons innervating the islet modulate glucose homeostasis.