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Elevated fasting glucagon concentrations and/or attenuated postprandial glucagon suppression are characteristics of type 2 diabetes (T2D) and contribute to hyperglycaemia. This study shows that hyperglucagonaemia is more prominent in males than females after a nutrient load in T2D, adding insights into sex differences in relation to the pathophysiology of T2D., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims/hypothesis: Metformin lowers postprandial glycaemic excursions in individuals with type 2 diabetes by modulating gastrointestinal function, including the stimulation of glucagon-like peptide-1 (GLP-1). The impact of varying the timing of metformin administration on postprandial glucose metabolism is poorly defined. We evaluated the effects of metformin, administered at different intervals before an intraduodenal glucose infusion, on the subsequent glycaemic, insulinaemic and GLP-1 responses in metformin-treated type 2 diabetes., Methods: Sixteen participants with type 2 diabetes that was relatively well-controlled by metformin monotherapy were studied on four separate days in a crossover design. On each day, participants were randomised to receive a bolus infusion of metformin (1000 mg in 50 ml 0.9% saline) via a nasoduodenal catheter at t = -60, -30 or 0 min (and saline at the other timepoints) or saline at all timepoints (control), followed by an intraduodenal glucose infusion of 12.56 kJ/min (3 kcal/min) at t = 0-60 min. The treatments were blinded to both participants and investigators involved in the study procedures. Plasma glucose, insulin and total GLP-1 levels were measured every 30 min between t = -60 min and t = 120 min., Results: There was a treatment-by-time interaction for metformin in reducing plasma glucose levels and increasing plasma GLP-1 and insulin levels (p<0.05 for each). The reduction in plasma glucose levels was greater when metformin was administered at t = -60 or -30 min vs t = 0 min (p<0.05 for each), and the increases in plasma GLP-1 levels were evident only when metformin was administered at t = -60 or -30 min (p<0.05 for each). Although metformin did not influence insulin sensitivity, it enhanced glucose-induced insulin secretion (p<0.05), and the increases in plasma insulin levels were comparable on the 3 days when metformin was given., Conclusions/interpretation: In well-controlled metformin-treated type 2 diabetes, glucose-lowering by metformin is greater when it is given before, rather than with, enteral glucose, and this is associated with a greater GLP-1 response. These observations suggest that administration of metformin before meals may optimise its effect in improving postprandial glycaemic control., Trial Registration: www.anzctr.org.au ACTRN12621000878875 FUNDING: The study was not funded by a specific research grant., (© 2024. The Author(s).)

Background: Gastric emptying (GE), with wide inter-individual but lesser intra-individual variations, is a major determinant of postprandial glycaemia in health and type 2 diabetes (T2D). However, it is uncertain whether GE of a carbohydrate-containing liquid meal is predictive of the glycaemic response to physiological meals, and whether antecedent hyperglycaemia influences GE in T2D. We evaluated the relationships of (i) the glycaemic response to both a glucose drink and mixed meals with GE of a 75 g glucose drink, and (ii) GE of a glucose drink with antecedent glycaemic control, in T2D., Methods: Fifty-five treatment-naive Chinese adults with newly diagnosed T2D consumed standardised meals at breakfast, lunch and dinner with continuous interstitial glucose monitoring. On the subsequent day, a 75 g glucose drink containing 150 mg 13 C-acetate was ingested to assess GE (breath test) and plasma glucose response. Serum fructosamine and HbA1c were also measured., Results: Plasma glucose incremental area under the curve (iAUC) within 2 hours after oral glucose was related inversely to the gastric half-emptying time (T50) (r = -0.34, P = 0.012). The iAUCs for interstitial glucose within 2 hours after breakfast (r = -0.34, P = 0.012) and dinner (r = -0.28, P = 0.040) were also related inversely to the T50 of oral glucose. The latter, however, was unrelated to antecedent fasting plasma glucose, 24-hour mean interstitial glucose, serum fructosamine, or HbA1c., Conclusions: In newly diagnosed, treatment-naive, Chinese with T2D, GE of a 75 g glucose drink predicts the glycaemic response to both a glucose drink and mixed meals, but is not influenced by spontaneous short-, medium- or longer-term elevation in glycaemia., (© 2024. The Author(s).)

Background: The pattern of the plasma glucose response curve during an oral glucose tolerance test (OGTT) is of prognostic significance with "biphasic" when compared with "monophasic" patterns being associated with greater insulin sensitivity/secretion and a reduced risk of progression to diabetes. The relationships of the glucose response curves with gastric emptying and incretin hormone secretion are not known., Methods: Thirty-six adults (age > 65 years) without known diabetes consumed a 300 mL drink containing 75 g glucose and 150 mg C 13 -acetate at baseline and follow-up after 5.8 ± 0.1 years. Plasma glucose, glucagon-like peptide-1 (GLP-1), glucose independent insulinotropic polypeptide (GIP) and insulin were measured, and participants classified according to the pattern of their glucose response. Gastric emptying was measured on breath samples (stable isotope breath test)., Results: At baseline, 22 participants had a "monophasic" and 14 a "biphasic" glucose response. The 1 h plasma glucose response curve was greater and the GLP-1 AUC 0-120 min and insulin secretion lower in the monophasic group. There were no differences in gastric emptying, GIP or insulin sensitivity. At the follow-up, the 1 h glucose response curve was greater again, while GLP-1 AUC 0-120 min was lower in the monophasic group., Conclusions: A biphasic curve is associated with a higher 60 min glucose response curve and increases in GLP-1, but no difference in either GIP or gastric emptying.

Aim: To evaluate the effect of gastric distension, induced using a gastric 'barostat', on the secretion of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in the presence and absence of small intestinal nutrients in healthy individuals., Materials and Methods: Eight healthy participants (two females, six males, mean age 69.3 ± 1.2 years, body mass index 23.5 ± 0.8 kg/m 2 ) were each studied on four occasions when they received an intraduodenal infusion of either (i) 0.9% saline or (ii) glucose delivered at a rate of 3 kcal/min both with, and without, an intragastric balloon with the pressure set to 8 mmHg above the intragastric minimum distending pressure., Results: Following intraduodenal saline or glucose infusion, there was no difference in plasma GLP-1 with or without gastric distension (P = 1.00 for both saline and glucose infusions). There was also no difference in plasma GIP with or without gastric distension (P = 1.00 for saline infusion and P = .99 for glucose infusion)., Conclusions: Gastric distension, either alone or during small intestinal glucose exposure, does not stimulate incretin hormone secretion significantly in healthy humans., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Caloric supplements are increasingly used by older people, aiming to increase their daily protein intake. These high caloric drinks, rich in glucose and whey-protein in particular, may result in potential harmful decreases in blood pressure (BP). The effect of ingesting whey-protein with glucose and fat on BP is unknown. It has also been assumed that the maximum fall in systolic blood pressure occurs within 2 h of a meal., Methods: This study aimed to determine in older men, the effects of whey-protein, alone and mixed with other macronutrients, on systolic (SBP) and diastolic (DBP) blood pressure and heart rate (HR) in older men for 3 h. Thirteen older men (age 75 ± 2yrs; body mass index (BMI) 25.6 ± 0.6 kg/m 2 ) ingested a drink on separate study days: (i) 70 g whey-protein (P 280 ) ; (ii) 14 g whey-protein, 28 g carbohydrate, 12.4 g fat (M 280 ); (iii) 70 g whey-protein, 28 g carbohydrate, 12.4 g fat (M 504 ); or (iv) a non-caloric control drink (C)., Results: SBP decreased after all three nutrient drinks compared to the C, with the greatest reduction after the M 504 drink (P = 0.008). Maximal decreases in SBP (C: -14 ± 2 mmHg, P 280 : -22 ± 2 mmHg, M 280 : -22 ± 4 mmHg, M 504 : -24 ± 3 mmHg) occurred about 2 h after drink ingestion and this fall was sustained thereafter (120-180 min: P 280 and M 504 vs. C P < 0.05). Maximum DBP decreases and HR increases occurred after M 504 , with no differences between the effects of the P 280 and M 280 drinks., Conclusions: The effects of whey-protein containing drinks to lower BP and increase HR appear to be primarily dependent on their energy content rather than macronutrient composition and may persist for at least 3 h after ingestion,. Pure whey-protein drinks may represent the best approach to maximize protein intake without increasing the potential for deleterious BP falls in older people., Trial Registration: ACTRN12614000846628 , 14/03/2019., (© 2022. The Author(s).)

The glucose portal sensor informs the brain of changes in glucose inflow through vagal afferents that require an activated glucagon-like peptide 1 receptor (GLP-1r). The GLP-1 system is known to be impaired in insulin-resistant conditions, and we sought to understand the consequences of GLP-1 resistance on glucose portal signaling. GLP-1-dependent portal glucose signaling was identified, in vivo, using a novel 68 Ga-labeled GLP-1r positron-emitting probe that supplied a quantitative in situ tridimensional representation of the portal sensor with specific reference to the receptor density expressed in binding potential units. It also served as a map for single-neuron electrophysiology driven by an image-based abdominal navigation. We determined that in insulin-resistant animals, portal vagal afferents failed to inhibit their spiking activity during glucose infusion, a GLP-1r-dependent function. This reflected a reduction in portal GLP-1r binding potential, particularly between the splenic vein and the entrance of the liver. We propose that insulin resistance, through a reduction in GLP-1r density, leads to functional portal desensitization with a consequent suppression of vagal sensitivity to portal glucose., (© 2020 by the American Diabetes Association.)

Intestinal glucose absorption is integral to postprandial glucose homeostasis. Glucose absorption is dependent on a number of factors, including the exposure of carbohydrate to the mucosa of the upper gastrointestinal tract (determined particularly by the rates of gastric emptying and small intestinal transit), the digestion of complex carbohydrate into monosaccharides, and glucose sensing and transport by the intestinal mucosa. The absorption of glucose in the small intestine is not only a determinant of the appearance of exogenous glucose in the peripheral circulation, but is also coupled to the release of gastrointestinal hormones that in turn influence postprandial glucose metabolism through modulating gastrointestinal motor function, insulin and glucagon secretion, and subsequent energy intake. This review describes the physiology and pathophysiology of intestinal glucose absorption in health and type 2 diabetes, including its relevance to glucose tolerance and the management of postprandial hyperglycaemia., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Context: Exposure of the small intestine to nutrients frequently leads to marked reductions in blood pressure (BP) in type 2 diabetes (T2DM). It remains unclear whether the region of the gut exposed to nutrients influences postprandial cardiovascular responses., Objective: To evaluate the cardiovascular responses to proximal and distal small intestinal glucose infusion in health and T2DM., Design: Double-blind, randomized, crossover design., Setting: Single center in Australia., Patients: 10 healthy subjects and 10 T2DM patients., Interventions: Volunteers were studied on 2 occasions, when a transnasal catheter was positioned with infusion ports opening 13 cm and 190 cm beyond the pylorus. A 30-g bolus of glucose was infused into either site and 0.9% saline into the alternate site over 60 minutes., Main Outcome Measures: BP, heart rate (HR), and superior mesenteric artery (SMA) blood flow were measured over 180 minutes., Results: Systolic BP was unchanged in response to both infusions in health, but decreased in T2DM, with a greater reduction after proximal versus distal infusion (all P ≤ .01). The increment in HR did not differ between treatments in health, but was greater after distal versus proximal infusion in T2DM (P = .02). The increases in SMA blood flow were initially greater, but less sustained, with proximal versus distal infusion in health (P < .001), a pattern less evident in T2DM., Conclusions: In T2DM, postprandial hypotension may be mitigated by diversion of nutrients from the proximal to the distal small intestine., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The rate of gastric emptying is a major determinant of the hypotensive response to a meal. Cross-sectional studies suggest that healthy aging is associated with a modest slowing of gastric emptying. We aimed to determine longitudinal changes in the blood pressure (BP) response to, and gastric emptying of, glucose in healthy older people. Thirty-three participants (77.0 ± 0.7 years) had baseline and follow-up measurements after 5.8 ± 0.1 years. Participants consumed a 300-mL drink containing 75 g glucose and 150 mg C13-acetate. BP and heart rate (HR) were measured at 5-minute intervals for 120 minutes after the drink. Exhaled breath was collected to calculate the gastric 50% emptying time. The prevalence of postprandial hypotension (PPH) doubled from 9.1% to 18.2%. Gastric emptying was slower at follow-up (p = .04). The fall in systolic BP (SBP) was related directly to the rate of gastric emptying at both the initial study (r = .54, p = .005) and at follow-up (r = .41, p = .04). The change in the maximum fall in SBP was related to the increase in baseline SBP (r = -.63, p < .001). In conclusion, in healthy older people over a period of ~5.8 years, there was an increased prevalence of PPH and a modest slowing of gastric emptying. The latter was related directly to a greater hypotensive response., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Cells releasing glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are distributed predominately in the proximal and distal gut, respectively. Hence, the region of gut exposed to nutrients may influence GIP and GLP-1 secretion and impact on the incretin effect and gastrointestinal-mediated glucose disposal (GIGD). We evaluated glycemic and incretin responses to glucose administered into the proximal or distal small intestine and quantified the corresponding incretin effect and GIGD in health and type 2 diabetes mellitus (T2DM)., Research Design and Methods: Ten healthy subjects and 10 patients with T2DM were each studied on four occasions. On two days, a transnasal catheter was positioned with infusion ports opening 13 cm and 190 cm beyond the pylorus, and 30 g glucose with 3 g 3- O -methylglucose (a marker of glucose absorption) was infused into either site and 0.9% saline into the alternate site over 60 min. Matching intravenous isoglycemic clamp studies were performed on the other two days. Blood glucose, serum 3- O -methylglucose, and plasma hormones were evaluated over 180 min., Results: In both groups, blood glucose and serum 3- O -methylglucose concentrations were higher after proximal than distal glucose infusion (all P < 0.001). Plasma GLP-1 increased minimally after proximal, but substantially after distal, glucose infusion, whereas GIP increased promptly after both infusions, with concentrations initially greater, but less sustained, with proximal versus distal infusion (all P < 0.001). Both the incretin effect and GIGD were less with proximal than distal glucose infusion (both P ≤ 0.009)., Conclusions: The distal, as opposed to proximal, small intestine is superior in modulating postprandial glucose metabolism in both health and T2DM., (© 2019 by the American Diabetes Association.)

Aims: The gastrointestinal tract, particularly the lower gut, may be key to the anti-diabetic action of metformin. We evaluated whether administration of metformin into the distal, vs the proximal, small intestine would be more effective in lowering plasma glucose by stimulating glucagon-like pepetide-1 (GLP-1) and/or slowing gastric emptying (GE) in type 2 diabetes (T2DM)., Materials and Methods: Ten diet-controlled T2DM patients were studied on three occasions. A transnasal catheter was positioned with proximal and distal infusion ports located 13 and 190 cm beyond the pylorus, respectively. Participants received infusions of (a) proximal + distal saline (control), (b) proximal metformin (1000 mg) + distal saline or (c) proximal saline + distal metformin (1000 mg) over 5 minutes, followed 60 minutes later by a glucose drink containing 50 g glucose and 150 mg 13 C-acetate. "Arterialized" venous blood and breath samples were collected over 3 hours for measurements of plasma glucose, GLP-1, insulin and glucagon, and GE, respectively., Results: Compared with control, both proximal and distal metformin reduced plasma glucose and augmented GLP-1 responses to oral glucose comparably (P < 0.05 each), without affecting plasma insulin or glucagon. GE was slower after proximal metformin than after control (P < 0.05) and tended to be slower after distal metformin, without any difference between proximal and distal metformin., Conclusions: In diet-controlled T2DM patients, glucose-lowering via a single dose of metformin administered to the upper and lower gut was comparable and was associated with stimulation of GLP-1 and slowing of GE. These observations suggest that the site of gastrointestinal administration is not critical to the glucose-lowering capacity of metformin., (© 2018 John Wiley & Sons Ltd.)

Meal consumption leads to an increase in sympathetic output to compensate for hemodynamic changes and maintain blood pressure (BP). Obesity is associated with a blunting of the sympathetic response to meal ingestion, but interpretation of studies investigating these responses is compromised by their failure to account for the rate of gastric emptying, which is an important determinant of postprandial cardiovascular and sympathetic responses and, in both health and obesity, exhibits a wide interindividual variation. We sought to determine the effects of intraduodenal glucose infusion, bypassing gastric emptying, on BP, heart rate (HR), and noradrenaline responses in obese and healthy control subjects. 12 obese subjects (age 36.6 ± 3.9 years, body mass index (BMI) 36.1 ± 1.3 kg/m 2 ) and 23 controls (age 27.8 ± 2.4 years, BMI 22.4 ± 0.5 kg/m 2 ) received intraduodenal infusions of glucose at 1 or 3 kcal/min, or saline, for 60 min (t = 0-60 min), followed by intraduodenal saline (t = 60-120 min). BP and HR were measured with an automatic cuff, and blood samples collected for measurement of plasma noradrenaline. Intraduodenal glucose at 1 kcal/min was associated with a fall in diastolic BP in the control subjects only (P < 0.01), with no change in systolic BP, HR or noradrenaline in either group. In both groups, intraduodenal glucose at 3 kcal/min was associated with a fall in diastolic (P < 0.01), but not systolic, BP, and rises in HR (P < 0.001) and plasma noradrenaline (P < 0.01), with no difference in responses between the groups. We conclude that cardiovascular and sympathetic responses to intraduodenal glucose infusion are comparable between obese and control subjects, and dependent on the rate of glucose delivery., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Postprandial hypotension (PPH) occurs frequently and is thought to reflect an inadequate increase in cardiac output to compensate for the rise in splanchnic blood flow after a meal. Gastric distension by water attenuates the postprandial fall in blood pressure (BP). Cardiac hemodynamics (stroke volume (SV), cardiac output (CO), and global longitudinal strain (GLS)) have hitherto not been measured in PPH We sought to determine the comparative effects of water and glucose drinks on cardiac hemodynamics in healthy older subjects and individuals with PPH Eight healthy older subjects (age 71.0 ± 1.7 years) and eight subjects with PPH (age 75.5 ± 1.0 years) consumed a 300 mL drink of either water or 75 g glucose (including 150 mg 13 C-acetate) in randomized order. BP and heart rate (HR) were measured using an automatic device, SV, CO, and GLS by transthoracic echocardiography and gastric emptying by measurement of 13 CO 2 In both groups, glucose decreased systolic BP ( P  < 0.001) and increased HR, SV, and CO ( P  < 0.05 for all). The fall in systolic BP was greater ( P  < 0.05), and increase in HR less ( P  < 0.05), in the PPH group, with no difference in SV or CO Water increased systolic BP ( P  < 0.05) in subjects with PPH and, in both groups, decreased HR ( P  < 0.05) without affecting SV, CO, or GLS In subjects with PPH, the hypotensive response to glucose and the pressor response to water were related ( R  = -0.75, P  < 0.05). These observations indicate that, in PPH, the hypotensive response to oral glucose is associated with inadequate compensatory increases in CO and HR, whereas the pressor response to water ingestion is maintained and, possibly, exaggerated., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

In rodents, metformin slows intestinal glucose absorption, potentially increasing exposure of the distal gut to glucose to enhance postprandial glucagon-like peptide-1 (GLP-1) secretion. We evaluated the effects of metformin on serum 3-O-methylglucose (3-OMG; a marker of glucose absorption) and plasma total GLP-1 concentrations during a standardized intraduodenal infusion of glucose and 3-OMG in patients with type 2 diabetes. A total of 12 patients, treated with metformin 850 mg twice daily or placebo for 7 days each in a double-blind, randomized, crossover design (14 days' washout between treatments), were evaluated on days 5 or 8 of each treatment (6 subjects each). On each study day, 30 minutes after ingesting 850 mg metformin or placebo, patients received an infusion of glucose (60 g + 5 g 3-OMG, dissolved in water to 240 mL) via an intraduodenal catheter over the course of 120 minutes. Compared with placebo, metformin was associated with lower serum 3-OMG ( P < .001) and higher plasma total GLP-1 ( P = .003) concentrations. The increment in plasma GLP-1 after metformin vs placebo was related to the reduction in serum 3-OMG concentrations ( P = .019). Accordingly, metformin inhibits small intestinal glucose absorption, which may contribute to augmented GLP-1 secretion in type 2 diabetes., (© 2016 John Wiley & Sons Ltd.)

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., (© The Author(s) 2016.)

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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Obesity and type 2 diabetes mellitus are risk factors for developing Alzheimer disease. Overlapping patterns of metabolic dysfunction may be common molecular links between these complex diseases. Amyloid-β (Aβ) precursor protein and associated β- and γ-secretases are expressed in adipose tissue. Aβ precursor protein is up-regulated with obesity and correlated to insulin resistance. Aβ may be secreted by adipose tissue, its production may be regulated through metabolic pathways, and Aβ may exert effects on adipose tissue insulin receptor signaling., Methods: Human stromal-vascular cells and differentiated adipocytes were cultured with different combinations of glucose and insulin and then assayed for Aβ in conditioned media. Aβ was measured in vivo using adipose tissue microdialysis., Results: Aβ secretion was increased by glucose and insulin in vitro. Adipose tissue microdialysates contained Aβ. Adipocytes treated with Aβ had decreased expression of insulin receptor substrate-2 and reduced Akt-1 phosphorylation., Conclusions: Aβ was made by adipose tissue cells in vitro at concentrations similar to in vivo measurements. Regulation of Aβ production by glucose and insulin and effects of Aβ on the insulin receptor pathway suggest similar cellular mechanisms may exist between neuronal dysfunction in Alzheimer disease and adipose dysfunction in type 2 diabetes., (© 2016 The Authors Obesity published by Wiley Periodicals, Inc. on behalf of The Obesity Society (TOS).)

Objective: Hydroxycitric acid (HCA), derived from the fruit Garcinia cambogia, reduces the rate of glucose absorption and lowers postprandial glycemia in rodents, but its effect in humans is unknown. The aim of this study was to investigate the effects of small intestinal perfusion with HCA on glucose absorption, as well as the incretin and glycemic responses to a subsequent intraduodenal glucose infusion, in both healthy individuals and patients with type 2 diabetes., Methods: Twelve healthy participants and 8 patients with type 2 diabetes received an intraduodenal infusion of HCA (2800 mg in water) or control (water) over 60 min, followed by an intraduodenal infusion of 60 g glucose over 120 min, in a double-blind, randomized crossover design. In healthy individuals, 5 g 3-O-methylglucose (3-OMG) was co-infused with glucose as a marker of glucose absorption. Blood was sampled frequently., Results: In healthy individuals, blood glucose was lower with HCA than control, both before and during the intraduodenal glucose infusion (P < 0.05 for each). Plasma glucose-dependent insulinotropic polypeptide (GIP; P = 0.01) and glucagon (P = 0.06) were higher with HCA, but there were no differences in plasma glucagon-like peptide (GLP)-1, insulin, or serum 3-OMG concentrations. In patients with type 2 diabetes, blood glucose, and plasma GIP, GLP-1, and insulin did not differ between HCA and control either before or after intraduodenal glucose, but during glucose infusion, plasma glucagon was higher with HCA (P = 0.04)., Conclusion: In healthy individuals, small intestinal exposure to HCA resulted in a modest reduction in glycemia and stimulation of plasma GIP and glucagon, but no effect on plasma GLP-1 or insulin, or on glucose absorption. HCA had no effect on glycemia in patients with type 2 diabetes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Postprandial hypotension occurs frequently in diabetes. We show in 9 type 2 patients, that the fall in systolic blood pressure is greater in response to intraduodenal glucose infused at 4 kcal/min than 2 kcal/min, implying that strategies to slow gastric emptying may be effective in the management of postprandial hypotension., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

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., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Aims/hypothesis: A postprandial fall in BP occurs frequently in older individuals and in patients with type 2 diabetes. The magnitude of this decrease in BP is related to the rate of gastric emptying (GE). Intravenous administration of glucagon-like peptide-1 (GLP-1) attenuates the hypotensive response to intraduodenal glucose in healthy older individuals. We sought to determine the effects of exogenous GLP-1 on BP, GE, superior mesenteric artery (SMA) flow and glycaemic response to oral ingestion of glucose in healthy older individuals and patients with type 2 diabetes., Methods: Fourteen older volunteers (six men, eight women; age 72.1 ± 1.1 years) and ten patients with type 2 diabetes (six men, four women; age 68.7 ± 3.4 years; HbA1c 6.6 ± 0.2% [48.5 ± 2.0 mmol/mol]; nine with blood glucose managed with metformin, two with a sulfonylurea and one with a dipeptidyl-peptidase 4 inhibitor) received an i.v. infusion of GLP-1 (0.9 pmol kg(-1) min(-1)) or saline (154 mmol/l NaCl) for 150 min (t = -30 min to t = 120 min) in randomised order. At t = 0 min, volunteers consumed a radiolabelled 75 g glucose drink. BP was assessed with an automated device, GE by scintigraphy and SMA flow by ultrasonography. Blood glucose and serum insulin were measured., Results: GLP-1 attenuated the fall in diastolic BP after the glucose drink in older individuals (p < 0.05) and attenuated the fall in systolic and diastolic BP in patients with type 2 diabetes (p < 0.05). GE was faster in patients with type 2 diabetes than in healthy individuals (p < 0.05). In both groups, individuals had slower GE (p < 0.001), decreased SMA flow (p < 0.05) and a lower degree of glycaemia (p < 0.001) when receiving GLP-1., Conclusions/interpretation: Intravenous GLP-1 attenuates the hypotensive response to orally administered glucose and decreases SMA flow, probably by slowing GE. GLP-1 and 'short-acting' GLP-1 agonists may be useful in the management of postprandial hypotension.

Context: Studies relating to the cardiovascular effects of glucagon-like peptide-1 (GLP-1) and its agonists, which slow gastric emptying, have not discriminated between fasting and postprandial, blood pressure (BP) and heart rate (HR)., Objective: To determine whether exogenous GLP-1 modulates the effects of an intraduodenal (ID) glucose infusion on BP, HR, and splanchnic blood flow in healthy older subjects., Design: A double-blind randomized trial was conducted., Setting: Community-dwelling residents attended a clinical research laboratory., Patients: Ten healthy "older" subjects (9 male, 1 female; age 73.2 ± 1.5 y) were studied., Interventions: Intravenous infusion of GLP-1 (0.9 pmol/kg/min), or saline (0.9%) for 90 min (t = -30-60 min). Between t = 0-60 min, ID glucose was infused at 3 kcal/min., Main Outcome Measures: BP, HR, superior mesenteric artery (SMA) flow, blood glucose, and serum insulin were measured., Results: During the fasting period (t = -30-0 min), GLP-1 had no effect on BP or HR. In response to ID glucose (t = 0-60 min), systolic BP decreased (P < .001), and both HR (P < .001) and SMA flow (P < .05) increased, on both days. GLP-1 attenuated the maximum decrease in systolic BP (P < .05), tended to increase HR (P = .09), and increased SMA flow (P < .01). GLP-1 diminished the glycemic response (P < .05)., Conclusions: In healthy older subjects, acute administration of GLP-1 attenuates the hypotensive response to ID glucose, and potentiates the increase in SMA flow.

The potential influence of gastric emptying on the "incretin effect," mediated by glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), is unknown. The objectives of this study were to determine the effects of intraduodenal (ID) glucose infusions at 2 (ID2) and 4 (ID4) kcal/min (equating to two rates of gastric emptying within the physiological range) on the size of the incretin effect, gastrointestinal glucose disposal (GIGD), plasma GIP, GLP-1, and glucagon secretion in health and type 2 diabetes. We studied 10 male BMI-matched controls and 11 male type 2 patients managed by diet or metformin only. In both groups, GIP, GLP-1, and the magnitude of incretin effect were greater with ID4 than ID2, as was GIGD; plasma glucagon was suppressed by ID2, but not ID4. There was no difference in the incretin effect between the two groups. Based on these data, we conclude that the rate of small intestinal glucose exposure (i.e., glucose load) is a major determinant of the comparative secretion of GIP and GLP-1, as well as the magnitude of the incretin effect and GIGD in health and type 2 diabetes., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Context: In vitro and animal studies suggest that bile acids have the capacity to reduce blood glucose by stimulating glucagon-like peptide-1 (GLP-1) and, thereby, insulin., Objective: This study evaluated the effects of intrajejunal taurocholic acid (TCA) on blood glucose, GLP-1, and insulin responses to jejunal glucose infusion in healthy men., Participants and Design: Ten healthy men were each studied on 2 days in a double-blind, randomized order. After the subjects fasted overnight, a jejunal catheter was positioned and a balloon inflated 30 cm beyond the pylorus with aspiration of endogenous bile. Two grams TCA in saline, or saline control, was infused beyond the balloon over 30 minutes, followed by 2 g TCA or control, together with 60 g glucose, over the next 120 minutes. Blood was sampled frequently for the measurements of blood glucose, total GLP-1, insulin, C-peptide, and glucagon., Results: Intrajejunal infusion of TCA alone (t = -30 to 0 minutes) had no effect on blood glucose, GLP-1, insulin, C-peptide, or glucagon concentrations. During intrajejunal glucose infusion (t = 0 to 120 minutes), blood glucose concentrations were lower (P < .001), and plasma GLP-1 (P < .001) and the C-peptide/glucose ratio (P = .008) were both greater, whereas plasma insulin, C-peptide, and glucagon levels were not significantly different after TCA than after control., Conclusions: In healthy humans, small intestinal infusion of TCA potently reduces the glycemic response to small intestinal glucose, associated with an increase in GLP-1 and C-peptide/glucose ratio. These observations indicate the potential for bile acid-based therapy in type 2 diabetes.

Introduction: Studies in the critically ill that evaluate intragastric and post-pyloric delivery of nutrient have yielded conflicting data. A limitation of these studies is that the influence in the route of feeding on glucose absorption and glycaemia has not been determined., Methods: In 68 mechanically ventilated critically ill patients, liquid nutrient (100 ml; 1 kcal/ml containing 3 g of 3-O-Methyl-D-glucopyranose (3-OMG), as a marker of glucose absorption), was infused into either the stomach (n = 24) or small intestine (n = 44) over six minutes. Blood glucose and serum 3-OMG concentrations were measured at regular intervals for 240 minutes and the area under the curves (AUCs) calculated for 'early' (AUC60) and 'overall' (AUC240) time periods. Data are presented as mean (95% confidence intervals)., Results: Glucose absorption was initially more rapid following post-pyloric, when compared with intragastric, feeding (3-OMG AUC60: intragastric 7.3 (4.3, 10.2) vs. post-pyloric 12.5 (10.1, 14.8) mmol/l.min; P = 0.008); however, 'overall' glucose absorption was similar (AUC240: 49.1 (34.8, 63.5) vs. 56.6 (48.9, 64.3) mmol/l.min; P = 0.31). Post-pyloric administration of nutrients was also associated with greater increases in blood glucose concentrations in the 'early' period (AUC60: 472 (425, 519) vs. 534 (501, 569) mmol/l.min; P = 0.03), but 'overall' glycaemia was also similar (AUC240: 1,875 (1,674, 2,075) vs. 1,898 (1,755, 2,041) mmol/l.min; P = 0.85)., Conclusions: In the critically ill, glucose absorption was similar whether nutrient was administered via a gastric or post-pyloric catheter. These data may have implications for the perceived benefit of post-pyloric feeding on nutritional outcomes and warrant further investigation.

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.

PPH (postprandial hypotension), leading to increased morbidity and mortality, is an important clinical problem, particularly in the elderly and individuals with autonomic dysfunction. The magnitude of the postprandial fall in BP (blood pressure) appears to be dependent on the rate of nutrient entry into the small intestine and may be related to changes in splanchnic blood flow and sympathetic nerve activity. We aimed at determining the comparative effects of different ID (intraduodenal) glucose loads on BP, HR (heart rate), SMA (superior mesenteric artery) flow and vascular conductance and plasma NA (noradrenaline) in 'young' and 'older' subjects. A total of 12 'young' (six male and six female; age, 22.2±2.3 years) and 12 'older' (six male and six female; age, 68.7±1.0 years) subjects, the latter who have been studied previously [Vanis, Gentilcore, Rayner, Wishart, Horowitz, Feinle-Bisset and Jones (2011) Am. J. Physiol. Regul. Integr. Comp. Physiol., 300, R1524-R1531], had measurements of BP, HR, SMA flow and plasma NA before, and during, ID infusions of glucose at 1, 2 or 3 kcal/min ('G1', 'G2' and 'G3') (where 1 kcal≈4.184 J), or 'S' (saline) for 60 min. In 'young' subjects, there was no change in BP during any of the four infusions. In contrast, in 'older' subjects, SBP (systolic BP) fell during 'G2', and 'G3' (P<0.005 for both), but not during 'S' or 'G1'. In 'young' and 'older' subjects HR increased during 'G2' (P<0.05) and 'G3' (P<0.001), a response that was greater (P<0.05) in the young, but not during 'S' or 'G1'. The rise in SMA flow and vascular conductance in response to ID glucose were load-dependent in both 'young' and 'older' subjects (P<0.001 for all), with no difference between them. Plasma NA rose in response to 'G2' and 'G3' (P<0.05) in the young, but in 'G3' (P<0.05) only in the 'older' subjects, with no difference between them. Hence, in response to small intestinal glucose infusions at 1, 2 and 3 kcal/min, 'older', but not 'young', subjects exhibit a comparable fall in BP in response to the two higher glucose loads, which may reflect an inadequate, compensatory, rise in HR, in the 'older' subjects, but not a greater increase in SMA conductance.

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.

Postprandial hypotension is an important problem, particularly in the elderly. The fall in blood pressure is dependent on small intestinal glucose delivery and, possibly, changes in splanchnic blood flow, the release of glucagon-like peptide-1 (GLP-1), and sympathetic nerve activity. We aimed to determine in healthy older subjects, the effects of variations in small intestinal glucose load on blood pressure, superior mesenteric artery flow, GLP-1, and noradrenaline. Twelve subjects (6 male, 6 female; ages 65-76 yr) were studied on four separate occasions, in double-blind, randomized order. On each day, subjects were intubated via an anesthetized nostril, with a nasoduodenal catheter, and received an intraduodenal infusion of either saline (0.9%) or glucose at a rate of 1, 2, or 3 kcal/min (G1, G2, G3, respectively), for 60 min (t = 0-60 min). Between t = 0 and 60 min, there were falls in systolic and diastolic blood pressure following G2 and G3 (P = 0.003 and P < 0.001, respectively), but no change during saline or G1. Superior mesenteric artery flow increased slightly during G1 (P = 0.01) and substantially during G2 (P < 0.001) and G3 (P < 0.001), but not during saline. The GLP-1 response to G3 was much greater (P < 0.001) than to G2 and G1. Noradrenaline increased (P < 0.05) only during G3. In conclusion, in healthy older subjects the duodenal glucose load needs to be > 1 kcal/min to elicit a significant fall in blood pressure, while the response may be maximal when the rate is 2 kcal/min. These observations have implications for the therapeutic strategies to manage postprandial hypotension by modulating gastric emptying.

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.

The contribution of small intestinal motor activity to nutrient absorption is poorly defined. A reduction in duodenal flow events after hyoscine butylbromide, despite no change in pressure waves, was associated with reduced secretion of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and a delay in glucose absorption. The aim of this study was to investigate the effect of metoclopramide on duodenal motility and flow events, incretin hormone secretion, and glucose absorption. Eight healthy volunteers (7 males and 1 female; age 29.8 ± 4.6 yr; body mass index 24.5 ± 0.9 kg/m²) were studied two times in randomized order. A combined manometry and impedance catheter was used to measure pressure waves and flow events in the same region of the duodenum simultaneously. Metoclopramide (10 mg) or control was administered intravenously as a bolus, followed by an intraduodenal glucose infusion for 60 min (3 kcal/min) incorporating the ¹⁴C-labeled glucose analog 3-O-methylglucose (3-OMG). We found that metoclopramide was associated with more duodenal pressure waves and propagated pressure sequences than control (P < 0.05 for both) during intraduodenal glucose infusion. However, the number of duodenal flow events, blood glucose concentration, and plasma 3-[¹⁴C]OMG activity did not differ between the two study days. Metoclopramide was associated with increased plasma concentrations of GLP-1 (P < 0.05) and GIP (P = 0.07) but lower plasma insulin concentrations (P < 0.05). We concluded that metoclopramide was associated with increased frequency of duodenal pressure waves but no change in duodenal flow events and glucose absorption. Furthermore, GLP-1 and GIP release increased with metoclopramide, but insulin release paradoxically decreased.

Postprandial hypotension occurs frequently and is associated with increased morbidity. Gastric distension may attenuate the postprandial fall in blood pressure (BP). Using a barostat, we sought to determine the effects of gastric distension on BP, heart rate (HR), and superior mesenteric artery (SMA) blood flow responses to intraduodenal glucose in eight (6 men, 2 women) healthy older (65-75 yr old) subjects. BP and HR were measured using an automated device and SMA blood flow was measured using Doppler ultrasound on 4 days in random order. SMA blood flow was calculated using the radius of the SMA and time-averaged mean velocity. Subjects were intubated with a nasoduodenal catheter incorporating a duodenal infusion port. On 2 of the 4 days, they were intubated orally with a second catheter, incorporating a barostat bag, positioned in the fundus and set at 8 mmHg above minimal distending pressure. Each subject received a 60-min (0-60 min) intraduodenal infusion of glucose (3 kcal/min) or saline (0.9%); therefore, the four study conditions were as follows: intraduodenal glucose + barostat (glucose + distension), intraduodenal saline + barostat (saline + distension), intraduodenal glucose (glucose), and intraduodenal saline (saline). Systolic and diastolic BP fell during glucose compared with saline (P = 0.05 and P = 0.003, respectively) and glucose + distension (P = 0.01 and P = 0.05, respectively) and increased during saline + distension compared with saline (P = 0.04 and P = 0.006, respectively). The maximum changes in systolic BP were -14 +/- 5, +11 +/- 2, -3 +/- 4, and +15 +/- 3 mmHg for glucose, saline, glucose + distension, and saline + distension, respectively. There was an increase in HR during glucose and glucose + distension (maximum rise = 14 +/- 2 and 14 +/- 3 beats/min, respectively), but not during saline or saline + distension. SMA blood flow increased during glucose and glucose + distension (2,388 +/- 365 and 1,673 +/- 187 ml/min, respectively), but not during saline, and tended to decrease during saline + distension (821 +/- 115 and 864 +/- 116 ml/min, respectively). In conclusion, gastric distension has the capacity to abolish the fall in BP and attenuate the rise in SMA blood flow induced by intraduodenal glucose in healthy older subjects.

It has been reported that the artificial sweetener, sucralose, stimulates glucose absorption in rodents by enhancing apical availability of the transporter GLUT2. We evaluated whether exposure of the proximal small intestine to sucralose affects glucose absorption and/or the glycaemic response to an intraduodenal (ID) glucose infusion in healthy human subjects. Ten healthy subjects were studied on two separate occasions in a single-blind, randomised order. Each subject received an ID infusion of sucralose (4 mM in 0.9% saline) or control (0.9% saline) at 4 ml/min for 150 min (T = - 30 to 120 min). After 30 min (T = 0), glucose (25 %) and its non-metabolised analogue, 3-O-methylglucose (3-OMG; 2.5 %), were co-infused intraduodenally (T = 0-120 min; 4.2 kJ/min (1 kcal/min)). Blood was sampled at frequent intervals. Blood glucose, plasma glucagon-like peptide-1 (GLP-1) and serum 3-OMG concentrations increased during ID glucose/3-OMG infusion (P < 0.005 for each). However, there were no differences in blood glucose, plasma GLP-1 or serum 3-OMG concentrations between sucralose and control infusions. In conclusion, sucralose does not appear to modify the rate of glucose absorption or the glycaemic or incretin response to ID glucose infusion when given acutely in healthy human subjects.

Context: Acute hyperglycemia slows gastric emptying, but its effects on small intestinal motor activity and glucose absorption are unknown. In type 2 diabetes, the postprandial secretion of glucose-dependent insulinotropic polypeptide (GIP) is preserved, but that of glucagon-like peptide-1 (GLP-1) is possibly reduced; whether the latter is secondary to hyperglycemia or diabetes per se is unknown., Aim: The aim was to investigate the effects of acute hyperglycemia on duodenal motility and flow events, glucose absorption, and incretin hormone secretion., Methods: Nine healthy volunteers were studied on two occasions. A combined manometry/impedance catheter was positioned in the duodenum. Blood glucose was clamped at either 9 mmol/liter (hyperglycemia) or 5 mmol/liter (euglycemia) throughout the study. Manometry and impedance recordings continued between T=-10 min and T=180 min. Between T=0 and 60 min, an intraduodenal glucose infusion was given (approximately 3 kcal/min), together with 14C-labeled 3-O-methylglucose (3-OMG) to evaluate glucose absorption., Results: Hyperglycemia had no effect on duodenal pressure waves or flow events during the 60 min of intraduodenal glucose infusion, when compared to euglycemia. During hyperglycemia, there was an increase in plasma GIP (P<0.05) and 14C-3-OMG (P<0.05) but no effect on GLP-1 concentrations in response to the intraduodenal infusion, compared to euglycemia., Conclusion: Acute hyperglycemia in the physiological range has no effect on duodenal pressure waves and flow events but is associated with increased GIP secretion and rate of glucose absorption in response to intraduodenal glucose.

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 microg 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 curve(0-330), 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 curve(0-330), 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 (GE) of glucose is regulated closely, not only as a result of inhibitory feedback arising from the small intestine, but also because of the resulting hyperglycemia. Fructose is used widely in the diabetic diet and is known to empty from the stomach slightly faster than glucose but substantially slower than water. The aims of this study were to determine whether intravenous (iv) fructose affects GE and antropyloroduodenal motility and how any effects compare to those induced by iv glucose. Six healthy males (age: 26.7 +/- 3.8 yr) underwent concurrent measurements of GE of a solid meal (100 g ground beef labeled with 20 MBq (99m)Tc-sulfur colloid) and antropyloroduodenal motility on three separate days in randomized order during iv infusion of either fructose (0.5 g/kg), glucose (0.5 g/kg), or isotonic saline for 20 min. GE (scintigraphy), antropyloroduodenal motility (manometry), and blood glucose (glucometer) were measured for 120 min. There was a rise in blood glucose (P < 0.001) after iv glucose (peak 16.4 +/- 0.6 mmol/l) but not after fructose or saline. Intravenous glucose and fructose both slowed GE substantially (P < 0.005 for both), without any significant difference between them. Between t = 0 and 30 min, the number of antral pressure waves was less after both glucose and fructose (P < 0.002 for both) than saline, and there were more isolated pyloric pressure waves during iv glucose (P = 0.003) compared with fructose and saline (P = NS for both) infusions. In conclusion, iv fructose slows GE and modulates gastric motility in healthy subjects, and the magnitude of slowing of GE is comparable to that induced by iv glucose.

Postprandial hypotension occurs frequently, particularly in the elderly. The magnitude of the fall in blood pressure (BP) and rise in heart rate (HR) in response to enteral glucose are greater when gastric emptying (GE) or small intestinal infusion are more rapid. Meal ingestion is associated with an increase in splanchnic blood flow. In contrast, gastric distension may attenuate the postprandial fall in BP. The aims of this study were to evaluate, in older subjects, the comparative effects of intraduodenal glucose infusion, at a rate similar to GE of oral glucose, on BP, HR, superior mesenteric artery (SMA) flow, and blood glucose. Eight healthy subjects (5 men, 3 women, age 66-75 yr) were studied on two occasions. On day 1, each subject ingested 300 ml of water containing 75 g glucose. GE was quantified by three-dimensional ultrasonography between time t = 0-120 min, and the rate of emptying (kcal/min) was calculated. On day 2, glucose was infused intraduodenally at the same rate as that on day 1. On both days, BP, HR, SMA flow, and blood glucose were measured. The mean GE of oral glucose was 1.3 +/- 0.1 kcal/min. Systolic BP (P < 0.01), SMA flow (P < 0.05), and blood glucose (P < 0.01) were greater and HR less (P < 0.01) after oral, compared with intraduodenal, glucose. There were comparable falls in diastolic BP during the study days (P < 0.01 for both). We conclude that the magnitude of the fall in systolic BP and rise in HR are less after oral, compared with intraduodenal, glucose, presumably reflecting the "protective" effect of gastric distension.

Objective: Enterally administered glucose modifies gut sensation, diminishes hunger, and slows gastric emptying by suppressing antral motility and stimulating pyloric pressures. We aimed to clarify the mechanism of small intestinal glucose sensing., Methods: We studied eight healthy males twice, in random order. An antroduodenal manometry catheter was positioned with a sleeve sensor across the pylorus. Benzocaine, or vehicle alone, was given into the proximal duodenum as a bolus, followed by continuous infusion for 105 min (T=-15 to 90 min). Glucose was also infused into the proximal duodenum at 3 kcal/min for 90 min (T=0-90 min). Sensations of hunger, bloating, and nausea were assessed with visual analog questionnaires, blood was sampled at intervals, and energy intake at a buffet meal (T=90-120 min) was measured., Results: Perceptions of bloating and nausea were markedly less with benzocaine when compared with vehicle (P<0.05 for each), with no difference in hunger, or energy intake. In contrast, the suppression of antral waves and stimulation of phasic and tonic pyloric pressures, duodenal waves, and propagated duodenal wave sequences by intraduodenal glucose infusion did not differ between the 2 days. No difference in blood glucose, plasma insulin, or plasma glucagon-like peptide 1 between benzocaine and control was observed, whereas glucose-dependent insulinotropic polypeptide and cholecystokinin concentrations were slightly higher with benzocaine (P<0.05 for both)., Conclusion: Mucosal anesthesia ameliorates unpleasant sensations induced by enteral glucose, but does not inhibit the release of gut peptides that feed back on appetite and gastroduodenal motility.

Introduction: Cells containing GIP and CCK predominate in the upper small intestine, while those containing GLP-1 are located more distally. Our aim was to compare the hormonal, glycemic and appetite responses to different sites of glucose delivery., Methods: Ten healthy males were each studied twice, in randomized order. A catheter was positioned with openings 15 cm beyond the pylorus ("duodenal"), and 100 cm beyond ("mid-jejunal"). On one day, glucose was infused into the duodenum (1 kcal/min) and saline into the mid-jejunum, for 90 min. On the other day, the infusion sites were reversed. Blood was sampled frequently, and hunger was scored by questionnaires. The tube was removed and energy intake measured from a buffet meal., Results: Stimulation of CCK and suppression of hunger were greater (each P<0.05), and energy intake less (P=0.05), with duodenal compared to mid-jejunal glucose infusion. Blood glucose, GIP, and insulin did not differ, and there was minimal GLP-1 increment on either day., Conclusions: There is regional variation in CCK, but not incretin hormone release, in the upper small intestine, and modest differences in the site of glucose exposure affect appetite and energy intake.

Postprandial hypotension occurs frequently, and current management is suboptimal. Recent studies suggest that the magnitude of the fall in postprandial blood pressure (BP) may be attenuated by gastric distension. The aim of this study was to determine the effect of gastric distension on the hypotensive response to intraduodenal (ID) glucose. Eight healthy subjects (5 males, 3 females, aged 65-76 years) received an ID infusion of either 1) 50 g glucose in 300 ml saline (ID glucose) over 60 min (t=0-60 min), 2) 50 g glucose in 300 ml saline over 60 min and intragastric (4) infusion of 500 ml water between t=7-10 min (IG water and ID glucose), or 3) ID saline (0.9%) infusion over 60 min and IG infusion of 500 ml water (IG water and ID saline) all followed by ID saline infusion for another 60 min (t=60-120 min) on three separate days. BP and heart rate (HR) were measured. Gastric emptying (GE) of the IG water was quantified by two-dimensional ultrasonography. Between t=0-60 min, systolic and diastolic BP was greater (P<0.05 for both) with IG water and ID saline compared with IG water and ID glucose, and less (P<0.05 for both) with ID glucose compared with IG water and ID glucose. These effects were evident at relatively low IG volumes (approximately 300 ml). GE was faster with IG water and ID saline when compared with IG water and ID glucose. We conclude that, in healthy older subjects, IG administration of water markedly attenuates the hypotensive response to ID glucose, presumably as a result of gastric distension.

Context: The "incretin" hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), account for some 60% of the stimulation of insulin by oral glucose, but the determinants of their secretion from the small intestine are poorly understood. Cells which release GIP (K cells) are localized to the proximal small intestine, while GLP-1 releasing cells (L cells) predominate in the distal gut. It has been suggested that a threshold rate of duodenal glucose delivery (approximately 1.8 kcal/min) needs to be exceeded for stimulation of GLP-1., Objective: To determine whether a low intraduodenal glucose load (1 kcal/min) has the capacity to stimulate GLP-1, and if so, the characteristics of the response., Design: Retrospective analysis of all studies in our laboratory involving healthy humans administered intraduodenal glucose at 1 kcal/min for 120 min., Setting: Clinical research laboratory., Participants: 27 healthy subjects (24 male; age 36+/-3 years; BMI 25.2+/-0.7 kg/m(2))., Main Outcome Measures: Plasma GLP-1, GIP, insulin, and blood glucose concentrations, reported as mean+/-SEM., Results: During intraduodenal glucose, plasma GLP-1 increased at 15 and 30 min (P<0.001 for both) and returned to baseline thereafter. In contrast, there were sustained increases in plasma GIP (P<0.001), insulin (P<0.001), and blood glucose (P<0.001)., Conclusion: In healthy subjects, there is early, transient stimulation of GLP-1 by glucose loads hitherto believed to be "sub-threshold". The mechanisms underlying this effect, which could be attributed to initially rapid transit to jejunal L cells, or a duodeno-jejunoileal neural or hormonal loop, remain to be determined.

Background: Postprandial hypotension frequently occurs in the elderly. The hypotensive response to a meal is triggered by the interaction of nutrients with the small intestine; information relating to the effects of different macronutrients on blood pressure (BP) is limited and inconsistent., Objective: The objective of the study was to determine the effects of intraduodenal glucose, fat, and protein on BP, heart rate (HR), and superior mesenteric artery (SMA) blood flow in healthy older subjects., Design: Eight subjects received intraduodenal glucose (64 g), fat (10% oil emulsion), protein (72 g whey), or saline (0.9%) at a rate of 2.7 mL/min for 90 min, followed by intraduodenal saline for 30 min. BP, HR, and SMA blood flow were measured., Results: The falls in systolic BP during infusions of glucose, fat, and protein did not differ significantly (P=0.97); however, the fall occurred significantly earlier during the glucose infusion; (18+/-3.0 min) than during the fat (46+/-11.0 min; P=0.02) and protein 33+/-7 min; P=0.04) infusions. The increases in HR during glucose, fat, and protein infusions (P<0.0001 for all) did not differ significantly. SMA blood flow increased significantly after all infusions (P<0.001 for all), but the increase was significantly (P<0.05) lower after protein than after the other infusions., Conclusions: Intraduodenal glucose, fat, and protein decrease systolic BP in healthy older subjects, but the onset of the hypotensive response is earlier after glucose, and the effect of protein on SMA blood flow is less than that of the other nutrients.

Background: Dietary interventions represent a promising therapeutic strategy to optimize postprandial glycemia. The addition of protein to oral glucose has been reported to improve the glycemic profile., Objective: The aim of the current study was to evaluate the mechanisms by which protein supplementation lowers the blood glucose response to oral glucose., Design: Nine healthy men were studied on 3 d each in a random order. Subjects consumed 300-mL drinks containing either 50 g glucose (Glucose), 30 g gelatin (Protein), or 50 g glucose with 30 g gelatin (Glucose + Protein) in water labeled with 150 mg [(13)C]acetate. Blood and breath samples were subsequently collected for 3 h to measure blood glucose and plasma insulin, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) concentrations and gastric half-emptying time, which was calculated from (13)CO(2) excretion., Results: The blood glucose response was less after Glucose + Protein than after Glucose (P < 0.005); GIP was lower (P < 0.005), and there were no significant differences in plasma insulin or GLP-1. Protein alone stimulated insulin, GLP-1, and GIP (P < 0.05 for each) without elevating blood glucose. The gastric half-emptying time was greater after Glucose + Protein than after Glucose (P < 0.05) and tended to be greater for Glucose than for Protein (P = 0.06)., Conclusions: In healthy humans, the addition of protein to oral glucose lowers postprandial blood glucose concentrations acutely, predominantly by slowing gastric emptying, although protein also stimulates incretin hormones and non-glucose-dependent insulin release.

Postprandial hypotension is an important clinical problem, particularly in the elderly. 5-Hydroxytryptamine3 (5-HT3) mechanisms may be important in the regulation of splanchnic blood flow and blood pressure (BP), and in mediating the effects of small intestinal nutrients on gastrointestinal motility. The aims of this study were to evaluate the effects of the 5-HT3 antagonist granisetron on the BP, heart rate (HR), and antropyloroduodenal (APD) motility responses to intraduodenal glucose in healthy older subjects. Ten subjects (5 male, 5 female, aged 65-76 yr) received an intraduodenal glucose infusion (3 kcal/min) for 60 min (t = 0-60 min), followed by intraduodenal saline for a further 60 min (t = 60-120 min) on 2 days. Granisetron (10 microg/kg) or control (saline) was given intravenously at t = -25 min. BP (systolic and diastolic), HR, and APD pressures were measured. Pressure waves in the duodenal channel closest ("local") to the infusion site were quantified separately. During intraduodenal glucose, there were falls in systolic and diastolic BP and a rise in HR (P < 0.0001 for all); granisetron had no effect on these responses. Granisetron suppressed the number and amplitude (P < 0.05 for both) of local duodenal pressures during intraduodenal glucose. Otherwise, the effects of intraduodenal glucose on APD motility did not differ between study days. We conclude that in healthy older subjects, 5-HT3 mechanisms modulate the local duodenal motor effects of, but not the cardiovascular responses to, small intestinal glucose.

Gastric emptying is a major determinant of glycemia, gastrointestinal hormone release, and appetite. We determined the effects of different intraduodenal glucose loads on glycemia, insulinemia, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and cholecystokinin (CCK), antropyloroduodenal motility, and energy intake in healthy subjects. Blood glucose, plasma hormone, and antropyloroduodenal motor responses to 120-min intraduodenal infusions of glucose at 1) 1 ("G1"), 2) 2 ("G2"), and 3) 4 ("G4") kcal/min or of 4) saline ("control") were measured in 10 healthy males in double-blind, randomized fashion. Immediately after each infusion, energy intake at a buffet meal was quantified. Blood glucose rose in response to all glucose infusions (P < 0.05 vs. control), with the effect of G4 and G2 being greater than that of G1 (P < 0.05) but with no difference between G2 and G4. The rises in insulin, GLP-1, GIP, and CCK were related to the glucose load (r > 0.82, P < 0.05). All glucose infusions suppressed antral (P < 0.05), but only G4 decreased duodenal, pressure waves (P < 0.01), resulted in a sustained stimulation of basal pyloric pressure (P < 0.01), and decreased energy intake (P < 0.05). In conclusion, variations in duodenal glucose loads have differential effects on blood glucose, plasma insulin, GLP-1, GIP and CCK, antropyloroduodenal motility, and energy intake in healthy subjects. These observations have implications for strategies to minimize postprandial glycemic excursions in type 2 diabetes.

Upper gastrointestinal motor function and incretin hormone secretion are major determinants of postprandial glycemia and insulinemia. However, the impact of small intestinal flow events on glucose absorption and incretin release is poorly defined. Intraluminal impedance monitoring is a novel technique that allows flow events to be quantified. Eight healthy volunteers were studied twice, in random order. A catheter incorporating six pairs of electrodes at 3-cm intervals, and six corresponding manometry sideholes, was positioned in the duodenum. Hyoscine butylbromide (20 mg) or saline was given as an intravenous bolus, followed by a continuous intravenous infusion of either hyoscine (20 mg/h) or saline over 60 min. Concurrently, glucose and 3-O-methylglucose (3-OMG) were infused into the proximal duodenum (3 kcal/min), with frequent blood sampling to measure glucose, 3-OMG, insulin, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The frequency of duodenal pressure waves and propagated pressure wave sequences was reduced by hyoscine in the first 10 min (P<0.01 for both), but not after that time. In contrast, there were markedly fewer duodenal flow events throughout 60 min with hyoscine (P<0.005). Overall, blood glucose (P<0.01) and plasma 3-OMG concentrations (P<0.05) were lower during hyoscine than saline, whereas plasma insulin, GLP-1, and GIP concentrations were initially (t=20 min) lower during hyoscine (P<0.05). In conclusion, intraluminal impedance measurement may be more sensitive than manometry in demonstrating alterations in duodenal motor function. A reduction in the frequency of duodenal flow events is associated with a decreased rate of glucose absorption and incretin release in healthy subjects.

Previous observations suggest that glucagon-like peptide-1 (GLP-1) is released into the bloodstream only when dietary carbohydrate enters the duodenum at rates that exceed the absorptive capacity of the proximal small intestine to contact GLP-1 bearing mucosa in more distal bowel. The aims of this study were to determine the effects of modifying the length of small intestine exposed to glucose on plasma concentrations of GLP-1 and also glucose-dependent insulinotropic peptide (GIP), insulin, cholecystokinin (CCK) and ghrelin, and antropyloric pressures. Glucose was infused at 3.5 kcal/min into the duodenum of eight healthy males (age 18-59 yr) over 60 min on the first day into an isolated 60-cm segment of the proximal small intestine ("short-segment infusion"); on the second day, the same amount of glucose was infused with access to the entire small intestine ("long-segment infusion"). Plasma GLP-1 increased and ghrelin decreased (P < 0.05 for both) during the long-, but not the short-, segment infusion. By contrast, increases in plasma CCK and GIP did not differ between days. The rises in blood glucose and plasma insulin were greater during the long- than during the short-segment infusion (P < 0.05). During the long- but not the short-segment infusion, antral pressure waves (PWs) were suppressed (P < 0.05). Isolated pyloric PWs and basal pyloric pressure were stimulated on both days. In conclusion, the release of GLP-1 and ghrelin, but not CCK and GIP, is dependent upon >60 cm of the intestine being exposed to glucose.