A Biphasic Glucose Response during an Oral Glucose Tolerance Test Is Associated with Greater Plasma Insulin and GLP-1 Responses and a Reduction in 1-Hour Glucose but Does Not Relate to the Rate of Gastric Emptying in Healthy, Older Adults

Published: 6 September 2023Background: 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 C¹³-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 AUC₀_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 AUC₀_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.Ryan J. Jalleh, Chinmay S. Marathe, Laurence G. Trahair, Karen L Jones, and Michael Horowit

Effect of gastric distension with concurrent small intestinal saline or glucose infusion on incretin hormone secretion in healthy individuals - a randomised, controlled, cross-over study.

Aims There is increasing interest in the use of intragastric balloons as a weight loss procedure, however, the underlying mechanism(s) remain unclear. In rodents, gastric distension has recently been shown to stimulate the secretion of the incretin hormone glucagon-like peptide-1 (GLP-1) substantially, but the effect of gastric distension on GLP-1 and the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), in humans is not known. We conducted a randomized, controlled, crossover study to evaluate the effect of gastric distension, induced using a gastric 'barostat' on incretin hormones in healthy individuals Materials and methods Eight healthy participants (2 female, 6 male, mean age 69.3±1.2 years, and body mass index 23.5±0.8 kg/m²) 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=0.99 for glucose infusion). Conclusion We conclude that gastric distension, either alone or during small intestinal glucose exposure, does not stimulate incretin hormone secretion significantly in healthy humans. This article is protected by copyright. All rights reserved.Ryan J. Jalleh, Laurence G. Trahair, Tongzhi Wu, Scott Standfield, Christine Feinle-Bisset, Christopher K. Rayner, Michael Horowitz, Karen L. Jone

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

Published online 22 April 2022Introduction: 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 lg 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 lg 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.Chinmay S. Marathe . Hung Pham . Tongzhi Wu . Laurence G. Trahair . Rachael S. Rigda . Madeline D. M. Buttfield . Seva Hatzinikolas . Kylie Lange . Christopher K. Rayner . Andrea Mari . Michael Horowitz . Karen L. Jone

Comparative effects of low-carbohydrate, full-strength and low-alcohol beer on gastric emptying, alcohol absorption, glycemia and insulinemia in health

First published: 05 March 2022Aims: The aim of this study was to evaluate the comparative effects of low-carbohy-drate (LC), full-strength (FS), and low-alcohol (LA) beer on gastric emptying (GE), eth-anol absorption, glycaemia and insulinaemia in health. Methods: Eight subjects (four male, four female; age: 20.4 ± 0.4 years; BMI 22.7± 0.4 kg/m2) had concurrent measurements of GE, plasma ethanol, blood glucose and plasma insulin for 180 min on three separate occasions after ingesting 600 mL of(i) FS beer (5.0% w/v, 246 kcal, 19.2 g carbohydrate), (ii) LC beer (4.6% w/v, 180 kcal,5.4 g carbohydrate) and (iii) LA beer (2.6% w/v, 162 kcal, 17.4 g carbohydrate)labelled with 20 MBq 99mTc-calcium phytate, in random order.Results:There was no difference in the gastric 50% emptying time (T50) (FS: 89.0± 13.5 minvs LC: 79.5 ± 12.9 minvs LA: 74.6 ± 12.4 min;P=.39). Plasma ethanol was less after LA than LC (P< .001) and FS (P< .001), with no difference between LC and FS (P=1.0). There was an inverse relationship between plasma ethanol at15 min and GE after LA (r= 0.87,P< .01) and a trend for inverse relationships after LC (r= 0.67,P=.07) and FS (r=0.69,P=.06). The AUC 0–180 min for blood glucose was greater for LA than LC (P< .001), with no difference between LA and FS (P=.40) or LC and FS (P=1.0). Conclusion: In healthy young subjects, GE of FS, LC and LA beer is comparable and adeterminant of the plasma ethanol response.Julie E. Stevens, Ryan J. Jalleh, Laurence G. Trahair, Chinmay S. Marathe, Michael Horowitz, Karen L. Jone

Effects of small intestinal glucose on glycaemia, insulinaemia and incretin hormone release are load-dependent in obese subjects

BACKGROUND/OBJECTIVES: Studies concerning the glycaemic response to oral glucose, or meals in obesity have usually failed to account for gastric emptying. It has been suggested that the incretin effect may be diminished in obesity as a result of a reduction in glucagon-like peptide-1 (GLP-1) secretion. We sought to determine the effect of two different rates of intraduodenal glucose infusions on glycaemic, insulinaemic and incretin hormone responses in lean and obese subjects and compare the effects of oral and intraduodenal glucose in obese subjects. SUBJECTS/METHODS: Eleven obese subjects (age 37.5±4.1 years, body mass index (BMI) 35.7±1.4 kg m(-)(2)) and 12 controls (age 34.7±4.0 years, BMI 23.9±0.7 kg m(-)(2)) received intraduodenal infusions of glucose at 1 or 3 kcal min(-1), or saline for 60 min (t=0-60 min), followed by intraduodenal saline (t=60-120 min). In obese subjects, an oral glucose tolerance test was performed. Blood glucose, serum insulin, plasma total GLP-1 and total gastric inhibitory polypeptide (GIP) were measured. RESULTS: In both the groups (P<0.001), the incremental areas under the curve (iAUC)0-60 min for glucose was greater with the 3 kcal min(-1) than the 1 kcal min(-1) infusion; the iAUC0-120 min for glucose during 3 kcal min(-1) was greater (P<0.05), in the obese. Insulin responses to 1 kcal min(-1) and, particularly, 3 kcal min(-1) were greater (P<0.001) in the obese. Stimulation of GLP-1 and GIP were greater (P<0.001) in response to 3 kcal min(-1), compared with 1 kcal min(-1) and saline, without any difference between the groups. In the obese, glycaemic, insulinaemic and GIP, but not GLP-1, responses to oral and intraduodenal glucose were related (P<0.05). CONCLUSIONS: The rate of duodenal glucose delivery is a major determinant of glycaemia, insulinaemia and incretin hormone release in obese subjects. Obesity is not apparently associated with impaired GLP-1 secretion.International Journal of Obesity advance online publication, 6 December 2016; doi:10.1038/ijo.2016.202.L.G. Trahair, C.S. Marathe, S Standfield, C.K. Rayner, C. Feinle-Bisset, M. Horowitz and K.L. Jone

Gastric emptying in health and type 2 diabetes: an evaluation using a 75g oral glucose drink

Aim: Gastric emptying is a major determinant of the glycaemic response to carbohydrate and is frequently abnormal in type 2 diabetes (T2DM). There is little information about how chronic glycaemic control affects gastric emptying in T2DM. We evaluated gastric emptying of a 75 g glucose drink in community-based patients with T2DM of short duration with good or poor glycaemic control, and compared this to young and older controls. Methods: T2DM patients managed by diet and/or metformin, either well-controlled or poorly-controlled, together with young and age-matched older controls without diabetes, consumed a 75 g oral glucose drink containing 150 mg 13C-acetate for evaluation of gastric emptying (breath test) and blood glucose over 180 min. Results: The gastric half-emptying time (T50) was longer in the older than the young non-diabetic subjects (P = 0.041), but shorter in well-controlled T2DM patients than age-matched older controls (P = 0.043). The T50 in poorly-controlled T2DM patients was shorter than in older controls (P = 0.006), but similar to young non-diabetic subjects. Conclusions: Gastric emptying of a glucose drink is delayed with ageing, but more rapid in patients with T2DM of relatively short duration, regardless of their glycaemic status. These observations support interventions that slow gastric emptying to improve postprandial glycaemia in these patients with T2DM.Cong Xie, Weikun Huang, Xuyi Wang, Laurence G.Trahair, Hung T.Pham, Chinmay S.Marathe ... et al

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.Karen L. Jones, Rachael S. Rigda, Madeline D.M. Buttfield, Seva Hatzinikolas, Hung T. Pham, Chinmay S. Marathe, Tongzhi Wu, Kylie Lange, Laurence G. Trahair, Christopher K. Rayner, Michael Horowit

Acute effects of lixisenatide on intragastric meal distribution: impact on energy intake

International audienceBackground and aims: Glucagon-like peptide-1 agonists (GLP-1RAs) induce weight loss in obese patients and, particularly with ‘short-acting’ GLP-1RAs, slow gastric emptying (GE). In healthy subjects, energy intake after a nutrient ‘preload’ is more strongly related to the content of the distal, than the total, stomach. The effect of GLP-1RAs on intragastric meal distribution has not been reported.We evaluated the acute effects of lixisenatide (LIXI) on intragastric distribution of a glucose drink and subsequent energy intake in health and type 2 diabetes (T2DM). Materials and methods: 15 healthy subjects (9M, 6F; age: 67.2 ± 2.3 yr; BMI: 25.4 ± 0.8 kg/m2) and 15 T2DMpatients managed by diet ormetformin (9M, 6F; age: 61.9 ± 2.3 yr; BMI: 30.3 ± 0.7 kg/m2; duration of known diabetes: 5.3 ± 1.2 yr; HbA1c: 6.9 ± 0.2%were studied. All subjects received LIXI (10mcg sc) or placebo (PLAC) on 2 separate days in a randomised, double-blind, crossover fashion 30 min before a 75g glucose drink labelled with 20MBq 99mTc-Calcium Phytate. A lower than usual dose of LIXI was used to maximise tolerability. GE was measured by scintigraphy for 180 min. A region-of-interest was drawn around the total stomach, which was divided into proximal and distal stomach regions. At 180 min each participant was offered a buffet meal and allowed to eat for 30 min to assess subsequent energy intake. Nausea was measured, using a visual analogue questionnaire, prior to receiving study drug, before the drink and at regular intervals during the study. Data are mean ± SEM and PResults: The studies were well tolerated; scores for nausea were uniformly lowwith no difference between PLAC and LIXI in either group. LIXI slowed GE (% total stomach retention at 180 min - health: PLAC 16.0 ± 11.1 vs LIXI 59.5 ± 24.6 ; T2DM: PLAC 14.5 ± 7.5 vs LIXI 54.4 ± 27.5) and increased retention in both the proximal stomach (health: PLAC 6.6 ± 3.5 vs LIXI 40.9 ± 24.6 ; T2DM: PLAC 6.3 ± 4.1 vs LIXI 34.8 ± 24.5) and distal stomach (health: PLAC 9.4 ± 9.1 vs LIXI 18.6 ± 11.1 ; T2DM: PLAC 8.2 ± 4.2 vs LIXI 19.6 ± 10.4); P<0.001 for PLAC vs LIXI in all groups. LIXI decreased energy intake (P<0.001) in both health and T2DM (Figure). Energy intake was inversely related to the distal stomach content at 180 min in health on PLAC (r=-0.58, P=0.03), but not in T2DM (r=-0.31, P=0.27), nor after LIXI (health: r=-0.16, P=0.58 vs T2DM: r=-0.004, P=0.99). Conclusion: In healthy subjects and T2DM patients, LIXI (10mcg) decreases energy intake in the absence of nausea, slows GE and increases retention in the distal and proximal stomach. The acute reduction in energy intake by LIXI is unrelated to changes in GE/intragastric distribution, consistent with a centrally-mediated effect