Glucagon-like peptide-1 excites pancreas-projecting preganglionic vagal motoneurons

Abstract

Glucagon-like peptide-1 (GLP-1) increases pancreatic insulin secretion via a direct action on pancreatic beta-cells. A high density of GLP-1-containing neurons and receptors is also present in brain stem vagal circuits; therefore, the aims of the present study were to investigate 1) whether identified pancreas-projecting neurons of the dorsal motor nucleus of the vagus (DMV) respond to exogenously applied GLP-1, 2) the mechanism(s) of action of GLP-1, and 3) whether the GLP-1-responsive neurons (putative modulators of endocrine secretion) could be distinguished from DMV neurons responsive to peptides that modulate pancreatic exocrine secretion, specifically pancreatic polypeptide (PP). Whole cell recordings were made from identified pancreas-projecting DMV neurons. Perfusion with GLP-1 induced a concentration-dependent depolarization in approximately 50% of pancreas-projecting DMV neurons. The GLP-1 effects were mimicked by exendin-4 and antagonized by exendin-(9-39). In approximately 60% of the responsive neurons, the GLP-1-induced depolarization was reduced by tetrodotoxin (1 microM), suggesting both pre- and postsynaptic sites of action. Indeed, the GLP-1 effects were mediated by actions on potassium currents, GABA-induced currents, or both. Importantly, neurons excited by GLP-1 were unresponsive to PP and vice versa. These data indicate that 1) GLP-1 may act on DMV neurons to control pancreatic endocrine secretion, 2) the effects of GLP-1 on pancreas-projecting DMV neurons are mediated both via a direct excitation of their membrane as well as via an effect on local circuits, and 3) the GLP-1-responsive neurons (i.e., putative endocrine secretion-controlling neurons) could be distinguished from neurons responsive to PP (i.e., putative exocrine secretion-controlling neurons).

PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation

“…This mirrors functional studies from rat, which demonstrated that about 50% of pancreas-projecting dorsal vagal neurons respond electrically to GLP-1 in vitro (101) and that Ex4 injection into the dorsal vagal complex reduces gut motility in vivo (38). Thus, PPG axons innervating dorsal vagal neurons would be in a prime position to affect both gut function and, thus, potentially indirectly appetite, and pancreatic endocrine secretions and, thereby, blood glucose homeostasis.…”

Presynaptic Melanocortin-4 Receptors on Vagal Afferent Fibers Modulate the Excitability of Rat Nucleus Tractus Solitarius Neurons

“…At the conclusion of electrophysiological recording, the position of the neuron was noted before Neurobiotin was injected by passing positive current pulses into the NTS neuron (1 s duration, 0.5 Hz for 20 min); the brainstem slice was then fixed overnight at 4°C in Zamboni's solution [1.6% (w/v) para-formaldehyde, 19 mM KH 2 PO 4 , and 100 mM Na 2 HPO 4 in 240 ml of saturated picric acid-1600 ml of H 2 O; adjusted to pH 7.4 with HCl]. The fixative was cleared from the slice with multiple washes of PBS (in mM: 115 NaCl, 75 Na 2 HPO 4 ⅐7H 2 O, 7.5 KH 2 PO 4 , 0.15% Triton X-100, and 0.1% bovine serum albumin), and the injected neurobiotin was visualized using a cobalt-nickel enhancement of the Avidin D-horseradish peroxidase (0.05% diaminobenzidine in PBS containing 0.5% gelatin supplemented with 0.025% CoCl 2 and 0.02% NiNH 4 SO 4 ) technique as described previously (Browning et al, 1999(Browning et al, , 2005Martinez-Pena y Valenzuela et al, 2004;Baptista et al, 2005b;Wan et al, 2007).…”

“…Data analysis was performed as described previously (Browning et al, 1999(Browning et al, , 2005Martinez-Pena y Valenzuela et al, 2004;Baptista et al, 2005b;Wan et al, 2007). Micrograph of representative neurons were taken using a Spot Insight camera and software (Diagnostic Instruments, Sterling Heights, MI) connected to a Nikon (Tokyo, Japan) E400 microscope; the contrast and brightness of the micrographs were digitally enhanced with Adobe software (Adobe Systems).…”

Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas

“…One recent study on exendin-4 and GLP-1 suggested that these products stimulate exocrine and endocrine pancreatic secretion through local and central neurons of the vagus, offering a broad spectrum of effects on the pancreas [15]. It has also been reported that the biological product (exenatide purified from Heloderma suspectum venom) caused pancreatitis in humans [5], although the level of purification of that product was not available.…”