Laurence G. Trahair

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.

Comparative effects of variations in duodenal glucose load on glycemic, insulinemic, and incretin responses in healthy young and older subjects

CONTEXT Aging is associated with deteriorating glucose tolerance. Studies assessing glucose tolerance and subsequent insulin and incretin hormone release often fail to take into account the rate of gastric emptying when evaluating these responses. OBJECTIVE Our objective was to determine the comparative effects of variations in the small intestinal glucose load on the glycemic, insulinemic, and incretin responses in healthy young and older subjects. MATERIALS AND METHODS Twelve healthy young (six males, six females; age 22.2±2.3 yr) and 12 older (six males, six females; age 68.7±1.0 yr) subjects had measurements of blood glucose, serum insulin and plasma incretin hormones [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] and calculations of insulin resistance (homeostatic model assessment) and β-cell function corrected for insulin sensitivity, before and during intraduodenal infusions of glucose at 1, 2, or 3 kcal/min or saline for 60 minutes. The study was double-blinded and randomized, and performed in the Discipline of Medicine at the Royal Adelaide Hospital. RESULTS At baseline, blood glucose and serum insulin were slightly higher in the older subjects (P<0.001), whereas GLP-1 and GIP were comparable between groups. In both groups, the glycemic, insulinemic, and GLP-1 responses were dependent on the duodenal glucose load in a nonlinear fashion (P<0.001). The glycemic response was greater (P<0.001) in the older subjects, whereas GLP-1 and GIP responses were comparable between groups. The older subjects were more insulin resistant (P<0.001) and had impaired β-cell function, particularly at higher glucose loads (P<0.05). CONCLUSION When glucose is infused into the small intestine at equal rates in healthy young and older subjects, GLP-1 and GIP responses are comparable, indicating that impaired incretin secretion does not account for age-related glucose intolerance.

Postprandial Hypotension: A Systematic Review

BACKGROUND Postprandial hypotension (PPH) is an important clinical problem, which has received inappropriately little attention. METHODS A systematic search of the databases PubMed, Embase, Cochrane Library, and Web of Knowledge, from their inception to the present time, was conducted to identify studies relevant to the epidemiology, pathophysiology, and/or management of PPH. RESULTS A total of 417 full-text papers were retrieved from database searching and, following screening, 248 were retained. Of these, 167 papers were considered eligible for inclusion. CONCLUSIONS PPH occurs commonly in older people and represents a major cause of morbidity. Although the pathophysiology of PPH remains poorly defined, diverse factors, including impairments in sympathetic and baroreflex function, release of vasodilatory peptides, the rate of small intestinal nutrient delivery, gastric distension, and splanchnic blood pooling, appear important. Current pharmacologic and nonpharmacologic management is suboptimal. Research into the pathophysiology of PPH represents a priority so that management can be targeted more effectively.

Relationships of Early And Late Glycemic Responses With Gastric Emptying During An Oral Glucose Tolerance Test

CONTEXT The early glycemic response during a 75-g oral glucose tolerance test (OGTT) is directly related to the rate of gastric emptying (GE). There is little information about the effect of GE on the blood glucose at either 60 min (a predictor of diabetes) or 120 min (used diagnostically). OBJECTIVE This study aimed to evaluate the relationships between glycemic responses at 30, 60, and 120 min and GE following a 75-g OGTT in subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (T2D). DESIGN, SETTING, AND SUBJECTS Eighty-two subjects in the general community without diabetes (57 NGT, 25 IGT) and 16 with T2D consumed a 75-g glucose drink labeled with (99m)Tc-sulfur colloid. GE (by scintigraphy) and glycemia were measured from t = 0-120 min and relationships between blood glucose (absolute, change from baseline, and area under the curve) and GE at 30, 60, and 120 min determined. RESULTS There were no differences in GE. There were relationships between the blood glucose at 30 min and GE (NGT: r = 0.40; P < .01; IGT: r = 0.49; P = .02; T2D: r = 0.62; P = .01). There was also a relationship between the blood glucose at 60 min and GE in IGT (r = 0.52; P = .02) and T2D (r = 0.77; P < .01), but not NGT (r = 0.16; P = .24). In NGT, there was an inverse relationship between blood glucose at 120 min and GE (r = -0.30; P = .02), but not in IGT (r = 0.05; P = .82) or T2D (r = 0.37; P = .16). CONCLUSIONS GE is a determinant of the glycemic response to an OGTT in NGT, IGT, and T2D but these relationships differ and are time dependent.

Lesser suppression of energy intake by orally ingested whey protein in healthy older men compared with young controls

Protein-rich supplements are used widely for the management of malnutrition in young and older people. Protein is the most satiating of the macronutrients in young. It is not known how the effects of oral protein ingestion on energy intake, appetite, and gastric emptying are modified by age. The aim of the study was to determine the suppression of energy intake by protein compared with control and underlying gastric-emptying and appetite responses of oral whey protein drinks in eight healthy older men (69-80 yr) compared with eight young male controls (18-34 yr). Subjects were studied on three occasions to determine the effects of protein loads of 30 g/120 kcal and 70 g/280 kcal compared with a flavored water control-drink (0 g whey protein) on energy intake (ad libitum buffet-style meal), and gastric emptying (three-dimensional-ultrasonography) and appetite (0-180 min) in a randomized, double-blind, cross-over design. Energy intake was suppressed by the protein compared with control (P = 0.034). Suppression of energy intake by protein was less in older men (1 ± 5%) than in young controls (15 ± 2%; P = 0.008). Cumulative energy intake (meal+drink) on the protein drink days compared with the control day increased more in older (18 ± 6%) men than young (1 ± 3%) controls (P = 0.008). Gastric emptying of all three drinks was slower in older men (50% gastric-emptying time: 68 ± 5 min) than young controls (36 ± 5 min; P = 0.007). Appetite decreased in young, while it increased in older (P < 0.05). In summary, despite having slower gastric emptying, elderly men exhibited blunted protein-induced suppression of energy intake by whey protein compared with young controls, so that in the elderly men, protein ingestion increased overall energy intake more than in the young men.

Effects of variations in intragastric volume on blood pressure and splanchnic blood flow during intraduodenal glucose infusion in healthy older subjects

The postprandial reduction in blood pressure (BP) is triggered by the interaction of nutrients with the small intestine and associated with an increase in splanchnic blood flow. Gastric distension may attenuate the postprandial fall in BP. The aim of this study was to determine the effects of differences in intragastric volume, including distension at a low (100 ml) volume, on BP and superior mesenteric artery (SMA) blood flow responses to intraduodenal glucose in healthy older subjects. BP and heart rate (HR; automated device), SMA blood flow (Doppler ultrasound), mesenteric vascular resistance (MVR), and plasma norepinephrine of nine male subjects (65-75 yr old) were measured after an overnight fast on 4 separate days in random order. On each day, subjects were intubated with a nasoduodenal catheter, incorporating a duodenal infusion port, and orally with a second catheter, incorporating a barostat bag, positioned in the fundus. Each subject received a 60-min (t = 0-60 min) intraduodenal glucose infusion (3 kcal/min) and gastric distension at a volume of 1) 0 ml (V0), 2) 100 ml (V100), 3) 300 ml (V300), or 4) 500 ml (V500). Systolic BP fell (P < 0.05) during V0, but not during V100, V300, or V500. In contrast, HR (P < 0.01) and SMA blood flow (P < 0.001) increased and MVR decreased (P < 0.05) comparably on all 4 days. Plasma norepinephrine rose (P < 0.01) in response to intraduodenal glucose, with no difference between the four treatments. There was a relationship between the areas under the curve for the change in systolic BP from baseline with intragastric volume (r = 0.60, P < 0.001). In conclusion, low-volume (≤100 ml) gastric distension has the capacity to abolish the fall in BP induced by intraduodenal glucose in healthy older subjects without affecting SMA blood flow or MVR. These observations support the concept that nonnutrient gastric distension prior to a meal has potential therapeutic applications in the management of postprandial hypotension.

Effects of randomized whey-protein loads on energy intake, appetite, gastric emptying, and plasma gut-hormone concentrations in older men and women

Background: Protein- and energy-rich supplements are used widely for the management of malnutrition in the elderly. Information about the effects of protein on energy intake and related gastrointestinal mechanisms and whether these differ between men and women is limited.Objective: We determined the effects of whey protein on energy intake, appetite, gastric emptying, and gut hormones in healthy older men and women.Design: Eight older women and 8 older men [mean ± SEM age: 72 ± 1 y; body mass index (in kg/m2): 25 ± 1] were studied on 3 occasions in which they received protein loads of 30 g (120 kcal) or 70 g (280 kcal) or a flavored water control drink (0 kcal). At regular intervals over 180 min, appetite (visual analog scales), gastric emptying (3-dimensional ultrasonography), and blood glucose and plasma gut-hormone concentrations [insulin, glucagon, ghrelin, cholecystokinin, gastric inhibitory polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and peptide tyrosine tyrosine (PYY)] were measured, and ad libitum energy intake was quantified from a buffet meal (180-210 min; energy intake, appetite, and gastric emptying in the men have been published previously).Results: Energy intake at the buffet meal was ∼80% higher in older men than in older women (P < 0.001). Energy intake was not suppressed by protein compared with the control in men or women (P > 0.05). There was no effect of sex on gastric emptying, appetite, gastrointestinal symptoms, glucose, or gut hormones (P > 0.05). There was a protein load-dependent slowing of gastric emptying, an increase in concentrations of insulin, glucagon, cholecystokinin, GIP, GLP-1, and PYY, and an increase in total energy intake (drink plus meal: 12% increase with 30 g and 32% increase with 70 g; P < 0.001). Energy intake at the buffet meal was inversely related to the stomach volume and area under the curve of hormone concentrations (P < 0.05).Conclusion: In older men and women, whey-protein drinks load-dependently slow gastric emptying and alter gut hormone secretion compared with a control but have no suppressive effect on subsequent ad libitum energy intake. This trial was registered at www.anzctr.org.au as ACTRN12612000941864.

Impact of gastric emptying to the glycemic and insulinemic responses to a 75‐g oral glucose load in older subjects with normal and impaired glucose tolerance

The majority of studies relating to the oral glucose tolerance test (OGTT) have not taken gastric emptying (GE), which exhibits a substantial inter‐individual variation, into account. We sought to evaluate the impact of GE, on the glycemic and insulinemic responses to a 75‐g oral glucose load in older subjects with normal and impaired glucose tolerance. Eighty‐seven healthy ‘older’ subjects (47F, 40M; age 71.0 ± 0.5 year) were given a drink comprising of 75‐g glucose and 150 mg C13‐acetate made up to 300 mL with water on a single occasion. Exhaled breath was obtained for analysis of 13CO2 and calculation of the 50% GE time (T50). Blood glucose, serum insulin and plasma glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic peptide (GIP) were measured, and the insulin sensitivity index (ISI), and the disposition index (DI), were calculated. Thirty‐one subjects had normal glucose tolerance (NGT) and 46 had impaired glucose tolerance (IGT). Blood glucose at t = 60 min and t = 120 min were related inversely to ISI (P < 0.001) and DI P < 0.001). The rise in blood glucose at t = 60 min was related inversely to the T50 in all subjects (P < 0.01), and those with IGT (P < 0.001), but not NGT. There were no significant relationships between the blood glucose at t = 120 min with the T50, but in both groups the change in blood glucose from baseline at t = 180 min was related (NGT: P < 0.001; IGT: P < 0.001) to the T50. We conclude that in NGT and IGT, the effect of GE on both the ‘early’ and ‘late’ glycemic responses to a 75‐g oral glucose load is complementary to that of insulin sensitivity.

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.

Gastric emptying, postprandial blood pressure, glycaemia and splanchnic flow in Parkinson’s disease

AIM To determine gastric emptying, blood pressure, mesenteric artery blood flow, and blood glucose responses to oral glucose in Parkinsons disease. METHODS Twenty-one subjects (13 M, 8 F; age 64.2 ± 1.6 years) with mild to moderate Parkinsons disease (Hoehn and Yahr score 1.4 ± 0.1, duration of known disease 6.3 ± 0.9 years) consumed a 75 g glucose drink, labelled with 20 MBq (99m)Tc-calcium phytate. Gastric emptying was quantified with scintigraphy, blood pressure and heart rate with an automated device, superior mesenteric artery blood flow by Doppler ultrasonography and blood glucose by glucometer for 180 min. Autonomic nerve function was evaluated with cardiovascular reflex tests and upper gastrointestinal symptoms by questionnaire. RESULTS The mean gastric half-emptying time was 106 ± 9.1 min, gastric emptying was abnormally delayed in 3 subjects (14%). Systolic and diastolic blood pressure fell (P < 0.001) and mesenteric blood flow and blood glucose (P < 0.001 for both) increased, following the drink. Three subjects (14%) had definite autonomic neuropathy and 8 (38%) had postprandial hypotension. There were no significant relationships between changes in blood pressure, heart rate or mesenteric artery blood flow with gastric emptying. Gastric emptying was related to the score for autonomic nerve function (R = 0.55, P < 0.01). There was an inverse relationship between the blood glucose at t = 30 min (R = -0.52, P < 0.05), while the blood glucose at t = 180 min was related directly (R = 0.49, P < 0.05), with gastric emptying. CONCLUSION In mild to moderate Parkinsons disease, gastric emptying is related to autonomic dysfunction and a determinant of the glycaemic response to oral glucose.