The functional impact of pancreatic islet innervation

The three components of the peripheral autonomic nervous system, the parasympathetic, sympathetic and
sensory nerves, work together to prevent life-threatening fluctuations in glucose homeostasis. They do so in
part by regulating hormone secretion from the pancreatic islet. Stimulating autonomic nerves with electrodes
has recently been recognized as a potential way to treat diseases (neuromodulation). Given its central role in
glucose metabolism and diabetes, the pancreatic islet is considered a primary target for neuromodulation. To
propose electrical stimulation of nerves to treat diabetes, however, it is essential to understand how islet
nerves impact insulin secretion from the beta cell. The objective of this application is to determine the
mechanisms nerves use to control hormone secretion from the pancreas. Recent anatomical studies show in
detail how autonomic nerves innervate the islet, but how exactly autonomic nerves impact hormone secretion
from the islet is not known. We hypothesize that parasympathetic, enteric, and sensory neural pathways act
through intrapancreatic ganglia to modulate local cholinergic control of islet cell function. The rationale for the
proposed research is that there is a need to understand the local mechanisms of autonomic nerve control of
hormone secretion from the islet, which is relevant to the mission of the NIH. Guided by preliminary data, our
hypothesis will be tested by pursuing two specific aims: (1) the role of pancreas sensory innervation in
regulating islet function, and (2) the role of the intrapancreatic ganglion as a signaling hub controlling islet
function. Under the first aim, we will test that the vagal sensory innervation of the islet participates in a
vagovagal neuronal circuit regulating islet hormone secretion. We will selectively stimulate islet cells with a
chemogenetic approach and gain genetic access to activated neurons with the Targeted Recombination in
Active Populations (TRAP) system. We will combine TRAP with tools for labeling, tracing, recording, and
manipulating neurons in the brainstem activated by islet cell stimulation. Under the second aim, we will test
that intrapancreatic ganglia integrate signals from parasympathetic efferent nerves, enteric neurons, and
sensory axons to compute an executive summary of gut and brain inputs to adjust the local cholinergic control
they exert on islet cells. We will stimulate parasympathetic, enteric and sensory innervation of the ganglion ex
vivo and in vivo with chemogenetic and optogenetic tools and measure the effects in intrapancreatic neurons.
We will further study how manipulating intrapancreatic neuronal activity affects islet function and glucose
metabolism (insulin plasma levels and glycemia). We expect that applying our novel approaches to measure
and manipulate pancreas nerve activity will yield important information about how nerves affect islet biology.
This contribution is significant because it will provide fundamental knowledge that will complete and revise
models about the influence of autonomic nerves on endocrine pancreas function. Once a functional map of
islet innervation is available, we will be able to propose neuromodulation to improve islet function in diabetes.

Grant Number: 5R01DK130328-04
NIH Institute/Center: NIH
Principal Investigator: Alejandro Caicedo