The nitric oxide synthase inhibitor, N^g‐nitro‐l‐arginine‐methyl‐ester, attenuates the delay in gastric emptying induced by hyperglycaemia in healthy humans

Abstract

The aim of this study was to determine whether the nitric oxide (NO) synthase inhibitor, N(g)-nitro-L-arginine-methyl-ester (L-NAME), reverses the effects of acute hyperglycaemia on gastric emptying and antropyloroduodenal (APD) motility. The study had a four-way randomized crossover (hyperglycaemia vs euglycaemia; L-NAME vs placebo) design in a clinical laboratory setting. Seven healthy volunteers [four males; age 30.3 +/- 3.8 years; body mass index (BMI) 23.6 +/- 1.2 kg m(-2)] were the study subjects. After positioning a transnasal manometry catheter across the pylorus, the blood glucose concentration was maintained at either 15 or 5 mmol L(-1) using a glucose/insulin clamp. An intravenous infusion of L-NAME (180 microg kg(-1 )h(-1)) or placebo (0.9% saline) was commenced (T = -30 min) and continued for 150 min. At T = -2 min, subjects ingested a drink containing 50 g of glucose made up to 300 mL with water. Gastric emptying was measured using 3D ultrasound, and APD motility using manometry. Hyperglycaemia slowed gastric emptying (P < 0.05), and this effect was abolished by L-NAME. L-NAME had no effect on gastric emptying during euglycaemia. Hyperglycaemia suppressed fasting antral motility [motility index: 3.9 +/- 0.8 (hyperglycaemia) vs 6.5 +/- 0.6 (euglycaemia); P < 0.01]; l-NAME suppressed postprandial antral motility [motility index: 3.6 +/- 0.2 (L-NAME) vs 5.1 +/- 0.2 (placebo); P < 0.001]. Postprandial basal pyloric pressure was higher during hyperglycaemia (P < 0.001), and lower after administration of L-NAME (P < 0.001). Slowing of gastric emptying induced by hyperglycaemia is mediated by NO, and may involve the modulation of tonic pyloric activity.

Hyperglycemia Potentiates the Slowing of Gastric Emptying Induced by Exogenous GLP-1

“…The magnitude of deceleration of emptying, the prolongation of the lag phase, and the slowing of the postlag emptying rate that we observed during hyperglycemia are consistent with these previous studies (20,22,23). Purported mechanisms governing this response include nitrergic pathways (24), direct stimulation of glucose-dependent neurons within the myenteric plexus (25), and suppression of vagal cholinergic activity, which has been demonstrated via reduced pancreatic polypeptide levels during hyperglycemia (26). Gastric emptying is the major ratelimiting step for glucose absorption from the gastrointestinal tract and therefore the primary determinant of postprandial glucose excursions (2,27).…”

“…1). GLP-1 markedly increased the intravenous glucose required to maintain hyperglycemia (hyper/GLP-1 vs. hyper/placebo; Δ91 [24] g; P , 0.001) (Fig. 2).…”

Effects of intravenous fructose on gastric emptying and antropyloroduodenal motility in healthy subjects

“…This appears, however, unlikely given that acute hyperglycemia has been shown to stimulate pyloric (13) and suppress antral (19) motility in the fasted state and that differences in distal stomach content were modest. The mechanism(s) mediating the effects of hyperglycemia on gastric motility are poorly defined but appear to involve nitric oxide pathways (34). Glucose-dependent neurons are also known to be present in the myenteric plexus (39) and central nervous system (44).…”

Gastric emptying and glycaemia in health and diabetes mellitus

“…77 Other putative mediators of the effects of glycaemia on gastric emptying include ghrelin and nitric oxide. 78,79 Acute glycaemia-induced changes in gastric emptying have clear implications in the setting of the diagnosis of gastro paresis, and the effects of glycaemia need to be acknowledged. Unequivocal evidence has demonstrated that improved glycaemic control reduces microvascular, and probably macrovascular, complications of diabetes mellitus; 25,80 emerging evidence supports a similar improvement in gastric emptying and gastrointestinal symptoms following a major improvement in glycaemic control.…”