Neural regulation of glucagon-like peptide-1 secretion in pigs

Abstract

like peptide (GLP)-1 is secreted rapidly from the intestine postprandially. We therefore investigated its possible neural regulation. With the use of isolated perfused porcine ileum, GLP-1 secretion was measured in response to electrical stimulation of the mixed, perivascular nerve supply and infusions of neuroactive agents alone and in combination with different blocking agents. Electrical nerve stimulation inhibited GLP-1 secretion, an effect abolished by phentolamine. Norepinephrine inhibited secretion, and phentolamine abolished this effect. GLP-1 secretion was stimulated by isoproterenol (abolished by propranolol). Acetylcholine stimulated GLP-1 secretion, and atropine blocked this effect. Dimethylphenylpiperazine stimulated GLP-1 secretion. In chloralose-anesthetized pigs, however, electrical stimulation of the vagal trunks at the level of the diaphragm had no effect on GLP-1 or GLP-2 and weak effects on glucose-dependent insulinotropic peptide and somatostatin secretion, although this elicited a marked atropine-resistant release of the neuropeptide vasoactive intestinal polypeptide to the portal circulation. Thus GLP-1 secretion is inhibited by the sympathetic nerves to the gut and may be stimulated by intrinsic cholinergic nerves, whereas the extrinsic vagal supply has no effect. somatostatin; nerve stimulation; enteric nervous system; vasoactive intestinal polypeptide; incretin hormones GLUCAGON-LIKE PEPTIDE (GLP)-1 is a peptide primarily produced in the lower part of the gut (reviewed in Ref. 22). It is known as an incretin hormone (stimulating insulin secretion) (27) and thought to be part of the "ileal brake" mechanism (inhibition of upper gut motility and secretion elicited by the presences of unabsorbed nutrients in the ileum) (28,32,44). Thus infusions of GLP-1 have been shown to reduce appetite and energy intake in humans (14). Relatively little is known about the mechanisms that regulate GLP-1 secretion in pigs and humans.The presence of unabsorbed nutrients in the lumen seems to be an important stimulus for GLP-1 secretion in rats (38), pigs (23), and humans (28). However, the response to a meal is usually rapid, with increases in the plasma concentration occurring within a few minutes after the start of meal ingestion (6,10,24,34,38), before the bulk of the meal is thought to have reached the lower gut. This suggests that a neural and/or an endocrine pathway from the upper part of the gastrointestinal tract to the lower gut may exist.In rats, glucose-dependent insulinotropic peptide (GIP) has been shown to stimulate GLP-1 secretion (9,20,35,38), although recent studies have indicated that a neural pathway involving the vagus nerve (2, 39) might predominate compared with a direct endocrine pathway. Infusions of muscarinic cholinergic agonists into isolated perfused rat ileum and colon resulted in stimulation of GLP-1 secretion (9,19,35), and studies in anesthetized rats and in fetal rat intestinal cells suggested that both M1 and M2 muscarinic receptors could be involved in control of GLP-1 rel...

Roles of the Gut in Glucose Homeostasis

“…In fact, in a recent study where glucose levels were clamped at a permissive level (6 mmol/L [108 mg/dL]), an insulin response could not be demonstrated, whereas the secretion of pancreatic polypeptide (known to strongly depend on vagal efferent activity [12]) was greatly increased (13). Similarly, demonstrating any clear cephalic phase for the secretion of gut hormones involved in the incretin effect has been difficult (13), and although it is easy to demonstrate experimentally an effect of the efferent vagus nerves on the secretion of gastric and pancreatic hormones (14) (but not gut hormones [15]), this mechanism is not clearly activated in the initial response to meals.…”

“…Of note, GPR40-dependent fatty acid detection by L cells also seems to depend on the rate of nutrient absorption, as intestinal perfusion experiments have indicated that the receptor is accessible from the basolateral rather than luminal direction (67). Although close apposition of enteroendocrine cells with the terminals of enteric neurons has been described, the physiological role of neuronal signals in regulating gut hormone secretion remains uncertain (15). Expression of sweet taste receptors on gut endocrine cells, in particular L cells, has been reported as well as activation of these associated with increased secretion (68).…”

GLUT2 and the incretin receptors are involved in glucose-induced incretin secretion

“…For both assays sensitivity was below 1 pmol/l, intrassay coefficient of variation below 6 % at 20 pmol/l, and recovery of standard, added to plasma before extraction, about 100 % when corrected for losses inherent in the plasma extraction procedure. Plasma GLP-1 and GIP concentrations were determined as previously described (Hansen et al, 2004). Intestinal content of incretins was determined by radioimmunoassay after extraction of intestinal biopsies (duodenum for GIP assay and ileon and colon for GLP-1 assay) by the method for small samples as described (Holst, Bersani, 1991).…”

“…This mechanism seems to be similar to the one described for the insulin secreting β-cell. Furthermore, an important regulator of both β-cells and L intestinal cells is the ANS (Hansen et al, 2004;Rocca, Brubaker, 1999). We have previously shown that the glucose transporter GLUT2 and the GLP-1 receptor are key mechanisms required for glucose-dependent insulin secretion (Guillam et al, 1997;Thorens and Waeber, 1993) and for function of the hepatoportal vein glucose sensor (Burcelin et al, 2000b).…”

Autonomic Diabetic Neuropathy Impairs Glucose and Dipeptidyl Peptidase 4 Inhibitor-Regulated Glucagon Concentration in Type 1 Diabetic Patients

“…The impaired GLP-1 response may contribute to the impaired regulation of glucagon secretion observed in patients with AN. Possibly an impaired function of the autonomic nervous system may result in impaired GLP-1 secretion, perhaps by influencing gastrointestinal motility [50][51][52]. However, our data show that the total GLP-1 concentration was not dramatically affected by the AN, most likely ruling out impaired neural regulation of GLP-1 secretion.…”