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

Abstract

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.diabetes | beta cell | alpha cell | insulin | glucagon

Young capillary vessels rejuvenate aged pancreatic islets

“…Islet isolation, transplantation into the anterior chamber of the mouse eye, and in vivo islet imaging were performed as previously described (17,31). Blood vessels were labeled by tail vein injection of 150,000 Da Dextran-FITC.…”

“…strategy in which islets are transplanted into the anterior chamber of the mouse eye. Transplanted islets have been shown to engraft on the iris, reverse diabetes, and regulate glucose homeostasis in the recipient mice (17,30,31). We transplanted 200 islets from young (2 mo) and aged (18 mo) mice into the eye of young mice with diabetes (2 mo; Fig.…”

“…Islet function was monitored by measuring glycemia and plasma insulin under fed conditions, as well as during glucose and insulin tolerance tests (17). 2+ ] I were performed as previously described (49).…”

“…Our strategy to discern age-related intrinsic changes in islet function was to study islets from young mature (2 mo) and aged (18 mo) mice and to follow these same groups of islets in three different environments: in vivo in the body of young and aged mice, in vitro after isolation, and again in vivo after transplantation into the anterior chamber of the eye in young mice (17). We also examined a large number of human islets from young mature and old pancreatic donors (17-65 y of age).…”

Multifunctional in vivo imaging of pancreatic islets during diabetes development

“…The transplanted islets in the eye (intraocular islets) have been used as optically accessible reporters of the endogenous islets, because they have similar structural and functional features as those in the native pancreas (Ilegems et al, 2013;Rodriguez-Diaz et al, 2012;Speier et al, 2008a). Despite several of its excellent utilities, the most essential application -the ability to repeatedly measure an islet's response to glucose stimulation in real time -has yet to be established.…”