Effects of co-ingesting glucose and whey protein on blood glucose, plasma insulin and glucagon concentrations, and gastric emptying, in older men with and without type 2 diabetes.

AIM: To investigate whether co-ingestion of dietary protein with, or before, carbohydrate may be a useful strategy to reduce postprandial hyperglycaemia in older men with type 2 diabetes (T2D). MATERIALS AND METHODS: Blood glucose, plasma insulin and glucagon concentrations were measured for 180 minutes following ingestion of a drink containing 30 g of glucose (G; 120 kcal), 30 g of whey protein (120 kcal), 30 g of glucose plus 30 g of whey protein (GP; 240 kcal), or control (~2 kcal) in older men with T2D (n = 10, 77 ± 1 years; 31 ± 1.7 kg/m2 ) and without T2D (n = 10, 78 ± 2 years; 27 ± 1.4 kg/m2 ). Mixed model analysis was used. RESULTS: GP versus G markedly reduced the increase in blood glucose concentrations (P < .001) and had a synergistic effect on the increase in insulin concentrations (P < .001), in men both with and without T2D. Glucose concentrations were higher in men with T2D compared with those without T2D, whereas insulin and glucagon concentrations were largely unaffected by the presence of T2D. Gastric emptying was faster in men with T2D than in those without T2D. CONCLUSIONS: The ability of whey protein to reduce carbohydrate-induced, postprandial hyperglycaemia is retained in older men with T2D compared with those without T2D, and whey protein supplementation may be a useful strategy in the prevention and management of T2D in older people.

Comparative Effects of Co-Ingesting Whey Protein and Glucose Alone and Combined on Blood Glucose, Plasma Insulin and Glucagon Concentrations in Younger and Older Men.

The ingestion of dietary protein with, or before, carbohydrate may be a useful strategy to reduce postprandial hyperglycemia, but its effect in older people, who have an increased predisposition for type 2 diabetes, has not been clarified. Blood glucose, plasma insulin and glucagon concentrations were measured for 180 min following a drink containing either glucose (120 kcal), whey-protein (120 kcal), whey-protein plus glucose (240 kcal) or control (~2 kcal) in healthy younger (n = 10, 29 ± 2 years; 26.1 ± 0.4 kg/m2) and older men (n = 10, 78 ± 2 years; 27.3 ± 1.4 kg/m2). Mixed model analysis was used. In both age groups the co-ingestion of protein with glucose (i) markedly reduced the increase in blood glucose concentrations following glucose ingestion alone (p < 0.001) and (ii) had a synergistic effect on the increase in insulin concentrations (p = 0.002). Peak insulin concentrations after protein were unaffected by ageing, whereas insulin levels after glucose were lower in older than younger men (p < 0.05) and peak insulin concentrations were higher after glucose than protein in younger (p < 0.001) but not older men. Glucagon concentrations were unaffected by age. We conclude that the ability of whey-protein to reduce carbohydrate-induced postprandial hyperglycemia is retained in older men and that protein supplementation may be a useful strategy in the prevention and management of type 2 diabetes in older people.

Acute Administration of the GLP-1 Receptor Agonist Lixisenatide Diminishes Postprandial Insulin Secretion in Healthy Subjects But Not in Type 2 Diabetes, Associated with Slowing of Gastric Emptying.

INTRODUCTION: It is uncertain whether lixisenatide has postprandial insulinotropic effects when its effect on slowing gastric emptying is considered, in healthy subjects and type 2 diabetes mellitus (T2DM). We evaluated the effects of single administration of 10 µg sc lixisenatide on glycaemia, insulin secretion and gastric emptying (GE), measured using the 'gold standard' technique of scintigraphy following an oral glucose load (75 g glucose). METHODS: Fifteen healthy subjects (nine men, six women; age 67.2 ± 2.3 years) and 15 patients with T2DM (nine men, six women; age 61.9 ± 2.3 years) had measurements of GE, plasma glucose, insulin and C-peptide for 180 min after a radiolabeled 75 g glucose drink on two separate days. All subjects received lixisenatide (10 µg sc) or placebo in a randomised, double-blind, crossover fashion 30 min before the drink. Insulin secretory response (ISR) was determined using the C-peptide deconvolution method. RESULTS: GE was markedly slowed by lixisenatide compared with placebo in both healthy subjects (1.45 ± 0.10 kcal/min for placebo vs. 0.60 ± 0.14 kcal/min for lixisenatide) and diabetes (1.57 ± 0.06 kcal/min for placebo vs. 0.75 ± 0.13 kcal/min for lixisenatide) (both P < 0.001) with no difference between the two groups (P = 0.42). There was a moderate to strong inverse correlation between the early insulin secretory response calculated at 60 min and gastric retention at 60 min with lixisenatide treatment in healthy subjects (r = - 0.8, P = 0.0003) and a trend in type 2 diabetes (r = - 0.4, P = NS), compared with no relationships in the placebo arms (r = - 0.02, P = NS, healthy subjects) and (r = - 0.16, P = NS, type 2 diabetes). CONCLUSION: The marked slowing of GE of glucose induced by lixisenatide is associated with attenuation in the rise of postprandial glucose in both healthy subjects and diabetes and early insulin secretory response in healthy subjects. CLINICAL TRIALS REGISTRATION NUMBER: NCT02308254.

Acute Effects of Lixisenatide on Energy Intake in Healthy Subjects and Patients with Type 2 Diabetes: Relationship to Gastric Emptying and Intragastric Distribution.

Glucagon-like peptide-1 receptor agonists induce weight loss, which has been suggested to relate to the slowing of gastric emptying (GE). In health, energy intake (EI) is more strongly related to the content of the distal, than the total, stomach. We evaluated the effects of lixisenatide on GE, intragastric distribution, and subsequent EI in 15 healthy participants and 15 patients with type 2 diabetes (T2D). Participants ingested a 75-g glucose drink on two separate occasions, 30 min after lixisenatide (10 mcg) or placebo subcutaneously, in a randomised, double-blind, crossover design. GE and intragastric distribution were measured for 180 min followed by a buffet-style meal, where EI was quantified. Relationships of EI with total, proximal, and distal stomach content were assessed. In both groups, lixisenatide slowed GE markedly, with increased retention in both the proximal (p < 0.001) and distal (p < 0.001) stomach and decreased EI (p < 0.001). EI was not related to the content of the total or proximal stomach but inversely related to the distal stomach at 180 min in health on placebo (r = -0.58, p = 0.03) but not in T2D nor after lixisenatide in either group. In healthy and T2D participants, the reduction in EI by lixisenatide is unrelated to changes in GE/intragastric distribution, consistent with a centrally mediated effect.

Exenatide once weekly slows gastric emptying of solids and liquids in healthy, overweight people at steady-state concentrations.

AIMS: To evaluate the effects of 8 weeks' administration of exenatide (EXE) once weekly on gastric emptying of solids and liquids (using the "gold standard" technique, scintigraphy), glucose absorption and postprandial glycaemia in healthy people. MATERIAL AND METHODS: A total of 32 healthy participants were randomized to receive either EXE once weekly (2 mg/wk subcutaneously; six men, 10 women, mean age 59.9 ± 0.9 years, mean body mass index [BMI] 29.6 ± 0.6 kg/m2 ) or matching placebo (PBO; six men, 10 women, mean age 60.6 ± 1.2 years, mean BMI 29.5 ± 1.0 kg/m2 ) for 8 weeks. Gastric emptying, nausea (visual analogue scale), and plasma glucose, insulin, C-peptide and glucagon were measured for 120 min after a solid/liquid meal, comprising 100 g ground beef (radiolabelled with 20 MBq 99m Tc-sulphur colloid) and 150 mL 10% glucose (radiolabelled with 7 MBq 67 Ga-EDTA), and containing 5 g 3-O-methyl-glucose (3-OMG) as a marker of glucose absorption, at baseline and after 8 weeks' treatment. RESULTS: The study treatments were well tolerated. Scores for nausea were consistently low, with no difference between the EXE once weekly and PBO groups. EXE once weekly slowed gastric emptying of solids (area under the curve [AUC]0-120min : P < 0.05) and liquids (AUC0-120min : P = 0.01) substantially, and attenuated glucose absorption (3-OMG incremental AUC [iAUC]0-30min : P = 0.001) and the postprandial rise in plasma glucose (iAUC0-30min : P = 0.008). Plasma glucagon at 2 h was reduced by EXE once weekly (P = 0.001). The magnitude of the reduction in plasma glucose at t = 30 min from baseline to 8 weeks with EXE once weekly was related inversely to the 50% emptying time of the glucose drink (r = -0.55, P = 0.03). CONCLUSIONS: In healthy participants, 8 weeks' administration of the "long-acting" glucagon-like peptide-1 receptor agonist EXE, slowed gastric emptying of solids and liquids substantially, with consequent reductions in glucose absorption and postprandial glycaemia.

Effects of lixisenatide on postprandial blood pressure, gastric emptying and glycaemia in healthy people and people with type 2 diabetes.

AIM: To evaluate the effects of the prandial glucagon-like peptide-1 receptor agonist lixisenatide on gastric emptying and blood pressure (BP) and superior mesenteric artery (SMA) blood flow, and the glycaemic responses to a 75-g oral glucose load in healthy people and those with type 2 diabetes (T2DM). MATERIALS AND METHODS: Fifteen healthy participants (nine men, six women; mean ± SEM age 67.2 ± 2.3 years) and 15 participants with T2DM (nine men, six women; mean ± SEM age 61.9 ± 2.3 years) underwent measurement of gastric emptying, BP, SMA flow and plasma glucose 180 minutes after a radiolabelled 75-g glucose drink on two separate days. All participants received lixisenatide (10 µg subcutaneously) or placebo in a randomized, double-blind, crossover fashion 30 minutes before the glucose drink. RESULTS: Lixisenatide slowed gastric emptying (retention at 120 minutes, P < 0.01), attenuated the rise in SMA flow (P < 0.01) and markedly attenuated the decrease in systolic BP (area under the curve [AUC] 0-120 minutes, P < 0.001) compared to placebo in healthy participants and those with T2DM. Plasma glucose (incremental AUC 0-120 minutes) was greater in participants with T2DM (P < 0.005) than in healthy participants, and lower after lixisenatide in both groups (P < 0.001). CONCLUSIONS: In healthy participants and those with T2DM, the marked slowing of gastric emptying of glucose induced by lixisenatide was associated with attenuation of the increments in glycaemia and SMA flow and decrease in systolic BP. Accordingly, lixisenatide may be useful in the management of postprandial hypotension.

Effects of intraduodenal administration of the artificial sweetener sucralose on blood pressure and superior mesenteric artery blood flow in healthy older subjects.

Background: Postprandial hypotension (PPH) occurs frequently, particularly in older people and those with type 2 diabetes, and is associated with increased morbidity and mortality. The magnitude of the decrease in blood pressure (BP) induced by carbohydrate, fat, and protein appears to be comparable and results from the interaction of macronutrients with the small intestine, including an observed stimulation of mesenteric blood flow. It is not known whether artificial sweeteners, such as sucralose, which are widely used, affect BP. Objective: The aim of this study was to evaluate the effects of intraduodenal sucralose on BP and superior mesenteric artery (SMA) blood flow, compared with intraduodenal glucose and saline (control), in healthy older subjects. Design: Twelve healthy subjects (6 men, 6 women; aged 66-79 y) were studied on 3 separate occasions in a randomized, double-blind, crossover design. After an overnight fast, subjects had concurrent measurements of BP and heart rate (HR; automated device), SMA blood flow (Doppler ultrasound), and blood glucose (glucometer) during intraduodenal infusion of 1) glucose (25% wt:vol, ∼1400 mOsmol/L), 2) sucralose (4 mmol/L, ∼300 mOsmol/L), or 3) saline (0.9% wt:vol, ∼300 mOsmol/L) at a rate of 3 mL/min for 60 min followed by intraduodenal saline for a further 60 min. Results: There was a decrease in mean arterial BP (P < 0.001) during intraduodenal glucose [baseline (mean ± SEM): 91.7 ± 2.6 mm Hg compared with t = 60 min: 85.9 ± 2.8 mm Hg] but not during intraduodenal saline or intraduodenal sucralose. The HR (P < 0.0001) and SMA blood flow (P < 0.0001) also increased during intraduodenal glucose but not during intraduodenal saline or intraduodenal sucralose. As expected, blood glucose concentrations increased in response to glucose (P < 0.0001) but not saline or sucralose. Conclusions: In healthy older subjects, intraduodenal administration of the artificial sweetener sucralose was not associated with changes in BP or SMA blood flow. Further studies are therefore warranted to determine the potential role for artificial sweeteners as a therapy for PPH. This trial was registered at http://www.ANZCTR.org.au as ACTRN12617001249347.

Acute effects of the glucagon-like peptide-1 receptor agonist, exenatide, on blood pressure and heart rate responses to intraduodenal glucose infusion in type 2 diabetes.

AIM: To evaluate the effects of the glucagon-like peptide-1 receptor agonist, exenatide, on blood pressure and heart rate during an intraduodenal glucose infusion in type 2 diabetes. METHODS: Nine subjects with type 2 diabetes were randomised to receive intravenous exenatide or saline control in a crossover design. Glucose (3 kcal min-1) was infused via an intraduodenal manometry catheter for 60 min. Blood pressure, heart rate, and the frequency and amplitude of duodenal pressure waves were measured at regular intervals. Gastrointestinal symptoms were monitored using 100 mm visual analogue scales. RESULTS: During intraduodenal glucose infusion (0-60 min), diastolic (p(0-60) = 0.03) and mean arterial (p(0-60) = 0.03) blood pressures and heart rate (p(0-60) = 0.06; p(0-120) = 0.03)) were higher with exenatide compared to placebo. The increase in the area under the curve for diastolic blood pressure and mean arterial blood pressure was related directly to the suppression of the duodenal motility index with exenatide compared to control (p = 0.007 and 0.04, respectively). CONCLUSION: In type 2 diabetes, intravenous exenatide increases mean arterial blood pressure and heart rate during an intraduodenal glucose infusion, supporting the need for further research with exenatide for its potential use in postprandial hypotension.

Regional specificity of the gut-incretin response to small intestinal glucose infusion in healthy older subjects.

The importance of the region, as opposed to the length, of small intestine exposed to glucose in determining the secretion of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) remains unclear. We sought to compare the glycemic, insulinemic and incretin responses to glucose administered to the proximal (12-60cm beyond the pylorus), or more distal (>70cm beyond the pylorus) small intestine, or both. 10 healthy subjects (9M,1F; aged 70.3±1.4years) underwent infusion of glucose via a catheter into the proximal (glucose proximally; GP), or distal (glucose distally; GD) small intestine, or both (GPD), on three separate days in a randomised fashion. Blood glucose, serum insulin and plasma GLP-1, GIP and CCK responses were assessed. The iAUC for blood glucose was greater in response to GPD than GP (P<0.05), with no difference between GD and GP. GP was associated with minimal GLP-1 response (P=0.05), but substantial increases in GIP, CCK and insulin (P<0.001 for all). GPD and GD both stimulated GLP-1, GIP, CCK and insulin (P<0.001 for all). Compared to GP, GPD induced greater GLP-1, GIP and CCK responses (P<0.05 for all). Compared with GPD, GD was associated with greater GLP-1 (P<0.05), but reduced GIP and CCK (P<0.05 for both), responses. We conclude that exposure of glucose to the distal small intestine appears necessary for substantial GLP-1 secretion, while exposure of both the proximal and distal small intestine result in substantial secretion of GIP.

The Glucagon-Like Peptide 1 Receptor Agonist Exenatide Inhibits Small Intestinal Motility, Flow, Transit, and Absorption of Glucose in Healthy Subjects and Patients With Type 2 Diabetes: A Randomized Controlled Trial.

The short-acting glucagon-like peptide 1 receptor agonist exenatide reduces postprandial glycemia, partly by slowing gastric emptying, although its impact on small intestinal function is unknown. In this study, 10 healthy subjects and 10 patients with type 2 diabetes received intravenous exenatide (7.5 µg) or saline (-30 to 240 min) in a double-blind randomized crossover design. Glucose (45 g), together with 5 g 3-O-methylglucose (3-OMG) and 20 MBq (99m)Tc-sulfur colloid (total volume 200 mL), was given intraduodenally (t = 0-60 min; 3 kcal/min). Duodenal motility and flow were measured using a combined manometry-impedance catheter and small intestinal transit using scintigraphy. In both groups, duodenal pressure waves and antegrade flow events were fewer, and transit was slower with exenatide, as were the areas under the curves for serum 3-OMG and blood glucose concentrations. Insulin concentrations were initially lower with exenatide than with saline and subsequently higher. Nausea was greater in both groups with exenatide, but suppression of small intestinal motility and flow was observed even in subjects with little or no nausea. The inhibition of small intestinal motor function represents a novel mechanism by which exenatide can attenuate postprandial glycemia.

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.

Comparative effects of glucose and xylose on blood pressure, gastric emptying and incretin hormones in healthy older subjects.

Postprandial hypotension is an important disorder for which current management is suboptimal. In healthy older subjects, oral and small-intestinal glucose administration decreases blood pressure (BP), and the magnitude of the reduction is dependent on the rate of glucose entry into the small intestine and, possibly, the release of glucagon-like peptide-1 (GLP-1). There is little information about the effects of other carbohydrates, particularly those poorly absorbed, on BP. The aim of the present study was to compare the effects of drinks containing xylose, glucose or water alone on BP, gastric emptying (GE), incretin hormone secretion, glycaemia and insulinaemia in healthy older subjects. A total of eight healthy older subjects (aged 65-75 years) had simultaneous measurements of BP (DINAMAP), GE (three-dimensional ultrasound), blood glucose, serum insulin, GLP-1 and glucose-dependent insulinotropic peptide (GIP), on three separate occasions, in a double-blind, randomised order. On each day, subjects consumed a 300 ml drink of water, glucose (50 g) or d-xylose (50 g). Glucose (P = 0·02), but not xylose (P = 0·63), was associated with a fall in BP. There was no difference in the GE of glucose and xylose (P = 0·47); both emptied slower than water (P < 0·001). Xylose had minimal effects on blood glucose, serum insulin or serum GIP, but was more potent than glucose in stimulating GLP-1 (P = 0·002). In conclusion, in healthy older subjects, xylose empties from the stomach at the same rate as glucose, but has no effect on BP, possibly because it is a potent stimulus for GLP-1 release. Xylose may be considered as an alternative sweetener to glucose in the management of postprandial hypotension.

Interaction between bed sharing and other sleep environments during the first six months of life.

This investigation was carried out to determine the relationship between bed sharing and other places of infant sleep in the first six months of life, and to identify patterns of change in the place of infant sleep for infants who do and do not routinely bed share in the first six months of life. The sleep--wake behaviour and place of infant sleep were recorded, at weekly intervals, for bed sharing (n=25) and non-bed sharing (n=68) infants between 2 and 24 weeks after birth. Bed sharing infants spent a significantly increased proportion of their total sleep time per 24 h in other sleep environments which favoured close parental proximity and significantly less time in solitary sleep. Non-bed sharing infants spent a substantial proportion of their time sleeping alone from 2 weeks of age whereas the transition to sleeping alone occurred after 16 weeks for bed sharing infants. We have found that bed sharing acts as a proxy for increased close parental proximity during the first six months of life. This may be of significance in studies which examine the relationship between bed sharing and sudden infant death syndrome.