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

Abstract

OBJECTIVEAcute hyperglycemia markedly slows gastric emptying. Exogenous GLP-1 also slows gastric emptying, leading to diminished glycemic excursions. The primary objective was to determine whether hyperglycemia potentiates the slowing of gastric emptying induced by GLP-1 administration. RESEARCH DESIGN AND METHODSTen healthy participants were studied on 4 separate days. Blood glucose was clamped at hyperglycemia using an intravenous infusion of 25% dextrose (∼12 mmol/L; hyper) on 2 days, or maintained at euglycemia (∼6 mmol/L; eu) on 2 days, between t = 215 and 240 min. During hyperglycemic and euglycemic days, participants received intravenous GLP-1 (1.2 pmol/kg/min) and placebo in a randomized double-blind fashion. At t = 0 min, subjects ingested 100 g beef mince labeled with 20 MBq technetium-99m-sulfur colloid and 3 g 3-O-methyl-glucose (3-OMG), a marker of glucose absorption. Gastric emptying was measured scintigraphically from t = 0 to 240 min and serum 3-OMG taken at regular intervals from t = 15 to 240 min. The areas under the curve for gastric emptying and 3-OMG were analyzed using one-way repeated-measures ANOVA with Bonferroni-Holm adjusted post hoc tests. RESULTSHyperglycemia slowed gastric emptying (eu/placebo vs. hyper/placebo; P < 0.001) as did GLP-1 (eu/placebo vs. eu/GLP-1; P < 0.001). There was an additive effect of GLP-1 and hyperglycemia, such that gastric emptying was markedly slower compared with GLP-1 administration during euglycemia (eu/GLP-1 vs. hyper/GLP-1; P < 0.01). CONCLUSIONSAcute administration of exogenous GLP-1 profoundly slows gastric emptying during hyperglycemia in excess of the slowing induced by GLP-1 during euglycemia. Studies are required to determine the effects of hyperglycemia on gastric emptying with the subcutaneously administered commercially available GLP-1 agonists in patients with type 2 diabetes.Gastric emptying is a major determinant of postprandial glycemia in health, as well as in type 1 and type 2 diabetes (1,2), and accounts for ;35% of the variance in the initial glycemic response to oral carbohydrate (1). Accordingly, dietary and pharmacological strategies that slow gastric emptying, including short-acting GLP-1 agonists, are useful interventions to attenuate postprandial glycemic excursions and overall glycemia in type 2 diabetes (3).

Esophageal and Gastric Dysmotilities are Associated with Altered Glucose Homeostasis and Plasma Levels of Incretins and Leptin

“…Such a compensatory downregulating mechanism has previously been described for oxytocin, as oxytocin attenuated gastric emptying in patients with gastroparesis [22,30]. GLP-1 administration during hyperglycemia has a markedly greater impact on the gastric emptying rate compared with GLP-1 administration during euglycemia [31]. When the hormone levels are analyzed on a single occasion in patients already suffering from gastrointestinal dysmotility, it is difficult to determine these mechanisms, but a compensatory mechanism seems most plausible as baseline levels of GLP-1 were already lowered.…”

Pathophysiology and Treatment of Gastrointestinal Motility Disorders in the Acutely Ill

“…On the available evidence, there is currently no second‐line drug that can be recommended for patients who remain enteral feed–intolerant on dual‐drug therapy, and we favor alternative approaches to gastric feeding, ie, small intestinal feeding or parenteral nutrition as determined by availability at individual institutions . The effect of drugs on gastrointestinal motility is substantially modified by glycemia such that promotility drugs are less effective at higher blood glucose concentrations . Accordingly, minimizing other systemic factors that contribute to gastrointestinal dysmotility, such as excessive exogenous opiates and hyperglycaemia, may improve response to drugs.…”

GLP-1 based therapies: clinical implications for gastroenterologists

“…Higher glucose levels delay, whereas lower levels stimulate gastric emptying 52–54. As a result, the inhibitory effect of GLP-1 on gastric emptying is more pronounced during hyperglycaemia and reduced during hypoglycaemia 52 53. Conversely, gastric emptying rate is accountable for approximately 35% of the postprandial glucose excursions 55 56.…”