Adam M. Deane

Endogenous Glucagon-Like Peptide-1 Slows Gastric Emptying in Healthy Subjects, Attenuating Postprandial Glycemia

INTRODUCTION The role of glucagon-like peptide-1 (GLP-1) in the regulation of gastric emptying is uncertain. The aim of this study was to determine the effects of endogenous GLP-1 on gastric emptying, glucose absorption, and glycemia in health. METHODS Ten healthy fasted subjects (eight males, two females; 48 +/- 7 yr) received the specific GLP-1 antagonist, exendin(9-39) amide [ex(9-39)NH(2)] (300 pmol/kg x min iv), or placebo, between -30 and 180 min in a randomized, double-blind, crossover fashion. At 0 min, a mashed potato meal ( approximately 2600 kJ) containing 3 g 3-ortho-methyl-D-glucose (3-OMG) and labeled with 20 MBq (99m)Technetium-sulphur colloid was eaten. Gastric emptying, including the time taken for 50% of the meal to empty from the stomach (T50), blood glucose, plasma 3-OMG, and plasma insulin were measured. RESULTS Ex(9-39)NH(2) accelerated gastric emptying [T50 ex(9-39)NH(2), 68 +/- 8 min, vs. placebo, 83 +/- 7 min; P < 0.001] and increased the overall glycemic response to the meal [area under the curve (0-180 min) ex(9-39)NH(2), 1540 +/- 106 mmol/liter x min, vs. placebo, 1388 +/- 90 mmol/liter x min; P < 0.02]. At 60 min, ex(9-39)NH(2) increased the rise in glycemia [ex(9-39)NH(2), 9.9 +/- 0.5 mmol/liter, vs. placebo, 8.4 +/- 0.5 mmol/liter; P < 0.01], plasma 3-OMG [ex(9-39)NH(2), 0.25 +/- 0.01 mmol/liter, vs. placebo, 0.21 +/- 0.01 mmol/liter; P < 0.05], and plasma insulin [ex(9-39)NH(2), 82 +/- 13 mU/liter, vs. placebo, 59 +/- 9 mU/liter; P < 0.05] concentrations. There was a close within-subject correlation between glycemia and gastric emptying [e.g. at 60 min, the increment in blood glucose and gastric emptying (T50); r = -0.89; P < 0.001]. CONCLUSION GLP-1 plays a physiological role to slow gastric emptying in health, which impacts on glucose absorption and, hence, postprandial glycemia.

The effect of exogenous glucagon-like peptide-1 on the glycaemic response to small intestinal nutrient in the critically ill: a randomised double-blind placebo-controlled cross over study.

IntroductionHyperglycaemia occurs frequently in the critically ill, affects outcome adversely, and is exacerbated by enteral feeding. Furthermore, treatment with insulin in this group is frequently complicated by hypoglycaemia. In healthy patients and those with type 2 diabetes, exogenous glucagon-like peptide-1 (GLP-1) decreases blood glucose by suppressing glucagon, stimulating insulin and slowing gastric emptying. Because the former effects are glucose-dependent, the use of GLP-1 is not associated with hypoglycaemia. The objective of this study was to establish if exogenous GLP-1 attenuates the glycaemic response to enteral nutrition in patients with critical illness induced hyperglycaemia.MethodsSeven mechanically ventilated critically ill patients, not previously known to have diabetes, received two intravenous infusions of GLP-1 (1.2 pmol/kg/min) and placebo (4% albumin) over 270 minutes. Infusions were administered on consecutive days in a randomised, double-blind fashion. On both days a mixed nutrient liquid was infused, via a post-pyloric feeding catheter, at a rate of 1.5 kcal/min between 30 and 270 minutes. Blood glucose and plasma GLP-1, insulin and glucagon concentrations were measured.ResultsIn all patients, exogenous GLP-1 infusion reduced the overall glycaemic response during enteral nutrient stimulation (AUC30–270 min GLP-1 (2077 ± 144 mmol/l min) vs placebo (2568 ± 208 mmol/l min); P = 0.02) and the peak blood glucose (GLP-1 (10.1 ± 0.7 mmol/l) vs placebo (12.7 ± 1.0 mmol/l); P < 0.01). The insulin/glucose ratio at 270 minutes was increased with GLP-1 infusion (GLP-1 (9.1 ± 2.7) vs. placebo (5.8 ± 1.8); P = 0.02) but there was no difference in absolute insulin concentrations. There was a transient, non-sustained, reduction in plasma glucagon concentrations during GLP-1 infusion (t = 30 minutes GLP-1 (90 ± 12 pmol/ml) vs. placebo (104 ± 10 pmol/ml); P < 0.01).ConclusionsAcute, exogenous GLP-1 infusion markedly attenuates the glycaemic response to enteral nutrition in the critically ill. These observations suggest that GLP-1 and/or its analogues have the potential to manage hyperglycaemia in the critically ill.Trial RegistrationAustralian New Zealand Clinical Trials Registry number: ACTRN12609000093280.

Effects of exogenous glucagon-like peptide-1 on gastric emptying and glucose absorption in the critically ill: Relationship to glycemia

Objective:To determine the acute effects of exogenous glucagon-like peptide-1 on gastric emptying, glucose absorption, glycemia, plasma insulin, and glucagon in critically ill patients. Design:Randomized, double-blind, crossover study. Setting:Intensive care unit. Subjects:Twenty-five mechanically ventilated patients, without known diabetes, studied on consecutive days. Interventions:Intravenous glucagon-like peptide-1 (1.2 pmol/kg/min) or placebo was infused between −30 and 330 mins. At 0 min, 100 mL liquid nutrient (1 kcal/mL) including 100 &mgr;g of 13C-octanoic acid and 3 grams of 3-O-methyl-glucose was administered. Measurements and Main Results:Blood glucose, serum 3-O-methyl-glucose (as an index of glucose absorption), insulin and glucagon concentrations, as well as exhaled 13CO2 were measured. The gastric emptying coefficient was calculated to quantify gastric emptying. Data are presented as mean (sd). There was a nonsignificant trend for glucagon-like peptide-1 to slow gastric emptying (gastric emptying coefficient) (glucagon-like peptide-1, 2.45 [0.93] vs. placebo, 2.75 [0.83]; p = .09). In 11 of the 25 patients, gastric emptying was delayed during placebo infusion and glucagon-like peptide-1 had no detectable effect on gastric emptying in this group (1.92 [0.82] vs. 1.90 [0.68]; p = .96). In contrast, in patients who had normal gastric emptying during placebo, glucagon-like peptide-1 slowed gastric emptying substantially (2.86 [0.58] vs. 3.41 [0.37]; p = .006). Glucagon-like peptide-1 markedly reduced the rate of glucose absorption (3-O-methyl-glucose area under the curve0–330, 37 [35] vs. 76 [51] mmol/L/min; p < .001), decreased preprandial glucagon (at 0 min change in glucagon, −15 [15] vs. −3 [14] pmol/L; p < .001), increased the insulin/glucose ratio throughout the infusion (area under the curve−30–330, 1374 [814] vs. 1172 [649] mU/mmol/min; p = .041), and attenuated the glycemic response to the meal (glucose area under the curve0–330, 2071 [353] vs. 2419 [594] mmol/L/min; p = .001). Conclusions:Exogenous glucagon-like peptide-1 lowers postprandial glycemia in the critically ill. This may occur, at least in part, by slowing gastric emptying when the latter is normal but not when it is delayed.

Gastric emptying and glycaemia in health and diabetes mellitus

The rate of gastric emptying is a critical determinant of postprandial glycaemia and, accordingly, is fundamental to maintaining blood glucose homeostasis. Disordered gastric emptying occurs frequently in patients with longstanding type 1 diabetes mellitus and type 2 diabetes mellitus (T2DM). A complex bidirectional relationship exists between gastric emptying and glycaemia—gastric emptying accounts for ∼35% of the variance in peak postprandial blood glucose concentrations in healthy individuals and in patients with diabetes mellitus, and the rate of emptying is itself modulated by acute changes in glycaemia. Clinical implementation of incretin-based therapies for the management of T2DM, which diminish postprandial glycaemia, in part by slowing gastric emptying, is widespread. Other therapies for patients with T2DM, which specifically target gastric emptying include pramlintide and dietary-based treatment approaches. A weak association exists between upper gastrointestinal symptoms and the rate of gastric emptying. In patients with severe diabetic gastroparesis, pathological changes are highly variable and are characterized by loss of interstitial cells of Cajal and an immune infiltrate. Management options for patients with symptomatic gastroparesis remain limited in their efficacy, which probably reflects the heterogeneous nature of the underlying pathophysiology.

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.

Prevalence, Risk Factors, Clinical Consequences, and Treatment of Enteral Feed Intolerance During Critical Illness

BACKGROUND We aimed to determine the incidence of enteral feed intolerance and factors associated with intolerance and to assess the influence of intolerance on nutrition and clinical outcomes. METHODS We conducted a retrospective analysis of data from an international observational cohort study of nutrition practices among 167 intensive care units (ICUs). Data were collected on nutrition adequacy, ventilator-free days (VFDs), ICU stay, and 60-day mortality. Intolerance was defined as interruption of enteral nutrition (EN) due to gastrointestinal (GI) reasons (large gastric residuals, abdominal distension, emesis, diarrhea, or subjective discomfort). Logistic regression was used to determine risk factors for intolerance and their clinical significance. A sensitivity analysis restricted to sites specifying a gastric residual volume ≥200 mL to identify intolerance was also conducted. RESULTS Data from 1,888 ICU patients were included. The incidence of intolerance was 30.5% and occurred after a median 3 days from EN initiation. Patients remained intolerant for a mean (±SD) duration of 1.9 ± 1.3 days . Intolerance was associated with worse nutrition adequacy vs the tolerant (56% vs 64%, P < .0001), fewer VFDs (2.5 vs 11.2, P < .0001), increased ICU stay (14.4 vs 11.3 days, P < .0001), and increased mortality (30.8% vs 26.2, P = .04). The sensitivity analysis demonstrated that intolerance remained associated with negative outcomes. Although mortality was greater among the intolerant patients, this was not statistically significant. CONCLUSIONS Intolerance occurs frequently during EN in critically ill patients and is associated with poorer nutrition and clinical outcomes.

The effects of critical illness on intestinal glucose sensing, transporters, and absorption.

Objectives:Providing effective enteral nutrition is important during critical illness. In health, glucose is absorbed from the small intestine via sodium-dependent glucose transporter-1 and glucose transporter-2, which may both be regulated by intestinal sweet taste receptors. We evaluated the effect of critical illness on glucose absorption and expression of intestinal sodium-dependent glucose transporter-1, glucose transporter-2, and sweet taste receptors in humans and mice. Design:Prospective observational study in humans and mice. Setting:ICU and university-affiliated research laboratory. Subjects:Human subjects were 12 critically ill patients and 12 healthy controls. In the laboratory 16-week-old mice were studied. Interventions:Human subjects underwent endoscopy. Glucose (30 g) and 3-O-methylglucose (3 g), used to estimate glucose absorption, were infused intraduodenally over 30 minutes. Duodenal mucosa was biopsied before and after infusion. Mice were randomized to cecal ligation and puncture to model critical illness (n = 16) or sham laparotomy (control) (n = 8). At day 5, mice received glucose (100 mg) and 3-O-methylglucose (10 mg) infused intraduodenally prior to mucosal tissue collection. Measurements and Main Results:Quantitative polymerase chain reaction was performed to measure absolute (human) and relative levels of sodium-dependent glucose transporter-1, glucose transporter-2, and taste receptor type 1 member 2 (T1R2) transcripts. Blood samples were assayed for 3-O-methylglucose to estimate glucose absorption. Glucose absorption was three-fold lower in critically ill humans than in controls (p = 0.002) and reduced by a similar proportion in cecal ligation and puncture mice (p = 0.004). In critically ill patients, duodenal levels of sodium-dependent glucose transporter-1, glucose transporter-2, and T1R2 transcript were reduced 49% (p < 0.001), 50% (p = 0.009), and 85% (p = 0.007), whereas in the jejunum of cecal ligation and puncture mice sodium-dependent glucose transporter-1, glucose transporter-2, and T1R2 transcripts were reduced by 55% (p < 0.001), 50% (p = 0.002), and 69% (p = 0.004). Conclusions:Critical illness is characterized by markedly diminished glucose absorption, associated with reduced intestinal expression of glucose transporters (sodium-dependent glucose transporter-1 and glucose transporter-2) and sweet taste receptor transcripts. These changes are paralleled in cecal ligation and puncture mice.

Glucose absorption and small intestinal transit in critical illness

Objectives: Although enteral nutrition is standard care for critically ill patients, nutrient absorption has not been quantified in this group and may be impaired due to intestinal dysmotility. The objectives of this study were to measure small intestinal glucose absorption and duodenocecal transit and determine their relationship with glycemia in the critically ill. Design: Prospective observational study of healthy and critically ill subjects. Setting: Tertiary mixed medical-surgical adult intensive care unit. Subjects: Twenty-eight critically ill patients and 16 healthy subjects were studied. Materials and Main Results: Liquid feed (100 kcal/100 mL), labeled with Tc-sulfur colloid and including 3 g of 3-O-methylglucose, was infused into the duodenum. Glucose absorption and duodenocecal transit were measured using the area under the 3-O-methylglucose concentration curve and scintigraphy, respectively. Data are median (range). Results and Discussion: Glucose absorption was reduced in critical illness when compared to health (area under the concentration curve: 16 [1–32] vs. 20 [14–34] mmol/L·min; p = .03). Small intestinal transit times were comparable in patients and healthy subjects (192 [9–240] vs. 168 [6–240] min; p = .99) and were not related to glucose absorption. Despite higher fasting blood glucose concentrations (6.3 [5.1–9.3] vs. 5.7 [4.6–7.6] mmol/L; p < .05), the increment in blood glucose was sustained for longer in the critically ill (&Dgr; glucose at t = 60; 1.9 [−2.1–5.0] mmol/L vs. −0.2 [−1.3–2.3] mmol/L; p < .01). Conclusions: Critical illness is associated with reduced small intestinal glucose absorption, but despite this, the glycemic response to enteral nutrient is sustained for longer. (Crit Care Med 2011; 39:1282–1288)

Definition, prevalence, and outcome of feeding intolerance in intensive care: a systematic review and meta‐analysis

Clinicians and researchers frequently use the phrase ‘feeding intolerance’ (FI) as a descriptive term in enterally fed critically ill patients. We aimed to: (1) determine what is the most accepted definition of FI; (2) estimate the prevalence of FI; and (3) evaluate whether FI is associated with important outcomes. Systematic searches of peer‐reviewed publications using PubMed, MEDLINE, and Web of Science were performed with studies reporting FI extracted. We identified 72 studies defining FI. In 33 studies, the definition was based on large gastric residual volumes (GRVs) together with other gastrointestinal symptoms, while 30 studies relied solely on large GRVs, six studies used inadequate delivery of enteral nutrition (EN) as a threshold, and three studies gastrointestinal symptoms without reference to GRV. The median volume used to define a ‘large’ GRV was 250 ml (ranges from 75 to 500 ml). The pooled proportion (n = 31 studies) of FI was 38.3% (95% CI 30.7–46.2). Five studies reported outcomes, all of them observed adverse outcome in FI patients. In three studies, respectively, FI was associated with increased mortality and ICU length‐of‐stay. In summary, FI is inconsistently defined but appears to occur frequently. There are preliminary data indicating that FI is associated with adverse outcomes. A standard definition of FI is required to determine the accuracy of these preliminary data.

Comparisons between intragastric and small intestinal delivery of enteral nutrition in the critically ill: a systematic review and meta-analysis.

INTRODUCTION The largest cohort of critically ill patients evaluating intragastric and small intestinal delivery of nutrients was recently reported. This systematic review included recent data to compare the effects of small bowel and intragastric delivery of enteral nutrients in adult critically ill patients. METHODS This is a systematic review of all randomised controlled studies published between 1990 and March 2013 that reported the effects of the route of enteral feeding in the critically ill on clinically important outcomes. RESULTS Data from 15 level-2 studies were included. Small bowel feeding was associated with a reduced risk of pneumonia (Relative Risk, RR, small intestinal vs. intragastric: 0.75 (95% confidence interval 0.60 to 0.93); P=0.01; I2=11%). The point estimate was similar when only studies using microbiological data were included. Duration of ventilation (weighted mean difference: -0.36 days (-2.02 to 1.30); P=0.65; I2=42%), length of ICU stay (WMD: 0.49 days, (-1.36 to 2.33); P=0.60; I2=81%) and mortality (RR 1.01 (0.83 to 1.24); P=0.92; I2=0%) were unaffected by the route of feeding. While data were limited, and there was substantial statistical heterogeneity, there was significantly improved nutrient intake via the small intestinal route (% goal rate received: 11% (5 to 16%); P=0.0004; I2=88%). CONCLUSIONS Use of small intestinal feeding may improve nutritional intake and reduce the incidence of ICU-acquired pneumonia. In unselected critically ill patients other clinically important outcomes were unaffected by the site of the feeding tube.