Caroline E. Cousins

Comparative Effects of Prolonged and Intermittent Stimulation of the Glucagon-Like Peptide 1 Receptor on Gastric Emptying and Glycemia

Acute administration of glucagon-like peptide 1 (GLP-1) and its agonists slows gastric emptying, which represents the major mechanism underlying their attenuation of postprandial glycemic excursions. However, this effect may diminish during prolonged use. We compared the effects of prolonged and intermittent stimulation of the GLP-1 receptor on gastric emptying and glycemia. Ten healthy men received intravenous saline (placebo) or GLP-1 (0.8 pmol/kg ⋅ min), as a continuous 24-h infusion (“prolonged”), two 4.5-h infusions separated by 20 h (“intermittent”), and a 4.5-h infusion (“acute”) in a randomized, double-blind, crossover fashion. Gastric emptying of a radiolabeled mashed potato meal was measured using scintigraphy. Acute GLP-1 markedly slowed gastric emptying. The magnitude of the slowing was attenuated with prolonged but maintained with intermittent infusions. GLP-1 potently diminished postprandial glycemia during acute and intermittent regimens. These observations suggest that short-acting GLP-1 agonists may be superior to long-acting agonists when aiming specifically to reduce postprandial glycemic excursions in the treatment of type 2 diabetes.

Glucagon-Like Peptide 1 Attenuates the Acceleration of Gastric Emptying Induced by Hypoglycemia in Healthy Subjects

OBJECTIVE Exogenous GLP-1 slows gastric emptying in health and diabetes leading to diminished glycemic excursions. Gastric emptying is markedly accelerated by hypoglycemia. The primary objective was to determine whether GLP-1 attenuates the acceleration of gastric emptying induced by hypoglycemia. RESEARCH DESIGN AND METHODS Ten healthy volunteers were studied on four separate days in a randomized double-blind fashion. Blood glucose was stabilized using a glucose/insulin clamp at hypoglycemia (2.6 mmol/L on two occasions [hypo]) or euglycemia (6.0 mmol/L on two occasions [eu]) between T = −15 and 45 min before clamping at 6.0 mmol/L until 180 min. During hypoglycemia and euglycemia, subjects received intravenous GLP-1 (1.2 pmol/kg/min) or placebo. At T = 0 min, subjects ingested 100 g beef mince labeled with 20 MBq 99mTc-sulfur-colloid and 3 g of 3-O-methyl-glucose (3-OMG), a marker of glucose absorption. Gastric emptying was measured scintigraphically from T = 0 to 180 min and serum 3-OMG taken at 15-min intervals. The areas under the curve for gastric emptying and 3-OMG concentration were analyzed using one-way repeated-measures ANOVA with Bonferroni-Holm adjusted post hoc tests. RESULTS Gastric emptying was accelerated during hypoglycemia (hypo/placebo vs. eu/placebo; P < 0.001), as was glucose absorption (P < 0.03). GLP-1 slowed emptying during euglycemia (eu/placebo vs. eu/GLP-1; P < 0.001). However, hypoglycemia-induced acceleration of gastric emptying on placebo was markedly diminished by GLP-1 (hypo/placebo vs. hypo/GLP-1; P < 0.008), as was glucose absorption (P < 0.01). CONCLUSIONS Acute administration of exogenous GLP-1 attenuates, but does not abolish, the acceleration of gastric emptying by insulin-induced hypoglycemia in healthy subjects.

Effect of Critical Illness on Triglyceride Absorption

BACKGROUND Adequate nutrition support for critically ill patients optimizes outcome, and enteral feeding is the preferred route of nutrition. Small intestinal glucose absorption is frequently impaired in critical illness. Despite lipid being a major constituent of liquid nutrient administered, there is little information about lipid absorption during critical illness. OBJECTIVES To determine small intestinal lipid, as well as glucose, absorption in critical illness compared with health. MATERIALS AND METHODS Twenty-nine mechanically ventilated critically ill patients and 16 healthy volunteers were studied. Liquid nutrient (60 mL, 1 kcal/mL), containing 200 µL (13)C-triolein and 3 g 3-O-methyl-glucose (3-OMG), was infused directly into the duodenum at a rate of 2 kcal/min. Exhaled (13)CO2 and serum 3-OMG concentrations were measured at timed intervals over 360 minutes. Lipid absorption was measured as the cumulative percentage dose (cPDR) of (13)CO2 recovered at 360 minutes. Glucose absorption was measured as the area under the 3-OMG concentration curve. Data are median (range) and analyzed using the Mann-Whitney U and Pearson correlation tests. RESULTS Lipid absorption was markedly less in the critically ill (cPDR(13)CO2: patients, 22.6% [0%-100%] vs healthy participants, 40.7% [5.3%-84.7%]; P = .018). While glucose absorption was less at 60 minutes in the critically ill (3-OMG60: 13.2 [3.5-29.5] vs 21.1 [9.3-31.9] mmol/L·min; P = .003), this was not apparent at 360 minutes (3-OMG360: 92.7 [54.5-147.9] vs 107.9 [64.0-168.7] mmol/L·min; P = .126). There was no relationship between lipid and glucose absorption. CONCLUSION Small intestinal absorption of lipid is diminished during critical illness.

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

OBJECTIVE Acute 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 METHODS Ten 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 = −15 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. RESULTS Hyperglycemia 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). CONCLUSIONS Acute 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.

Critical Illness Is Associated With Impaired Gallbladder Emptying as Assessed by 3d Ultrasound

Objective: To quantify gallbladder dysfunction during critical illness. Design: Prospective observational comparison study of nutrient-stimulated gallbladder emptying in health and critical illness. Setting: Single-centre mixed medical/surgical ICU. Patients: Twenty-four mechanically ventilated critically ill patients suitable to receive enteral nutrition were compared with 12 healthy subjects. Interventions: Participants were studied after an 8-hour fast. Between 0 and 120 minutes, high-fat nutrient (20% intralipid) was infused via a postpyloric catheter into the duodenum at 2 kcal/min. Measurements and Main Results: Three-dimensional images of the gallbladder were acquired at 30-minute intervals from –30 to 180 minutes. Ejection fraction (%) was calculated as changes between 0 and 120 minutes. Blood samples were obtained at 30-minute intervals for plasma cholecystokinin. Data are mean (SD) or median [interquartile range]. In the critically ill, fasting gallbladder volumes (critically ill, 61 mL [36–100 mL] vs healthy, 22 mL [15–25] mL; p < 0.001] and wall thickness (0.45 mm [0.15 mm] vs 0.26 mm [0.08 mm]; p < 0.001] were substantially greater, and sludge was evident in the majority of patients (71% vs 0%). Nutrient-stimulated emptying was incomplete in the critically ill after 120 minutes but was essentially complete in the healthy individuals (22 mL [9–66 mL] vs 4 mL [3–5 mL]; p < 0.01]. In five critically ill patients (21%), there was no change in gallbladder volume in response to nutrient, and overall ejection fraction was reduced in the critically ill (50% [8–83%] vs 77 [72–84%]; p = 0.01]. There were no differences in fasting or incremental cholecystokinin concentrations. Conclusions: Fasted critically ill patients have larger, thicker-walled gallbladders than healthy subjects and nutrient-stimulated gallbladder emptying is impaired with “gallbladder paresis” occurring in approximately 20%.

Nutrient-stimulated gallbladder emptying is incomplete during critical illness as assessed by 3D ultrasound

Gallbladder dysmotility has been implicated as a putative mechanism underlying acute acalculous cholecystitis and lipid malabsorption in the critically ill, despite nutrient-stimulated gallbladder emptying never having been quantified in this population. In health, endogenous cholecystokinin (CCK) stimulates gallbladder emptying.