Suspecting that paracrine inhibition might influence neuronal regulation of the endocrine L cells, we studied the role of somatostatin (SS) in the regulation of the secretion of the proglucagon-derived hormones glucagon-like peptide-1 and -2 (GLP-1 and GLP-2). This was examined using the isolated perfused porcine ileum stimulated with acetylcholine (ACh, 10(-6) M), neuromedin C (NC, 10(-8) M), and electrical nerve stimulation (NS) with or without alpha-adrenergic blockade (phentolamine 10(-5) M), and perfusion with a high-affinity monoclonal antibody against SS. ACh and NC significantly increased GLP secretion, whereas NS had little effect. SS immunoneutralization increased GLP secretion eight- to ninefold but had little influence on the GLP responses to ACh, NC, and NS. Basal SS secretion (mainly SS28) was unaffected by NS alone. Phentolamine + NS and NC abstract strongly stimulated release mainly of SS14, whereas ACh had little effect. Infused intravascularly, SS14 weakly and SS28 strongly inhibited GLP secretion. We conclude that GLP secretion is tonically inhibited by a local release of SS28 from epithelial paracrine cells, whereas SS14, supposedly derived from enteric neurons, only weakly influences GLP secretion.

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...

An Ussing chamber technique was used to determine the effects of three indigestible disaccharides on net Ca transport from the luminal side to the basolateral side of isolated preparations of jejunal, ileal, cecal and colonic epithelium in rats. Permeability of Lucifer Yellow (LY) and transepithelial electrical resistance (TEER), which are indicators of intercellular passage of the intestinal mucosa, were also determined. The concentrations of Ca in the serosal and mucosal media were 1.25 mmol/L and 10 mmol/L, respectively. After a 30-min incubation, the net Ca transport, LY passage and TEER were determined. In the control experiment, LY permeability was lowest, and TEER value was highest in the colon. The addition of 1-100 mmol/L melibiose, difructose anhydride (DFA)III, or DFAIV to the mucosal medium increased the net Ca absorption and LY permeability dose-dependently in the jejunum, ileum, cecum and colon preparations. Melibiose decreased TEER dose-dependently in the jejunum and cecum, but not in the ileum and colon. DFAIII decreased TEER dose-dependently in the jejunum, cecum and colon, but not in the ileum. DFAIV decreased TEER dose-dependently in all four intestinal portions. Positive linear relationships were found between net Ca transport and LY passage in all portions of the intestine, whereas negative linear relationships were found between net Ca absorption and TEER. We concluded that the three indigestible saccharides directly affect the epithelial tissue and activate the passage of tight junctions, thereby promoting Ca absorption in the small and large intestine in vitro.

An Ussing chamber technique was used to determine the effects of six indigestible saccharides on net Ca absorption from the luminal side to the basolateral side of isolated preparations of rat jejunal, ileal, cecal and colonic epithelium in vitro. The concentrations of Ca in the Tris buffer solution on the serosal side and on the mucosal side were 1.25 and 10 mmol/L, respectively. After a 30-min incubation, the Ca concentration in the serosal medium was determined and the net transepithelial Ca transport was calculated. The addition of 0.1-200 mmol/L maltitol, difructose anhydride (DFA)III, DFAIV, raffinose, fructooligosaccharide (FOS) or polydextrose (PD) to the mucosal medium increased the net Ca absorption dose-dependently in the jejunum, ileum, cecum and colon preparations. The threshold concentration required to enhance Ca transport and the extent of enhancement of Ca transport differed among the saccharides tested and among the portions of the intestine examined. Among the saccharides tested, DFA IV had the strongest effect on Ca absorption in the jejunum and cecum. We conclude that indigestible carbohydrates directly affect the epithelial tissue and promote Ca absorption in both the small and large intestine in vitro.

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