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 99mTc-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.

Therapies specifically targeting postprandial glycemia are important in the management of type 2 diabetes, especially in patients with relatively good overall glycemic control (HbA1c ≤7.5%; 58 mmol/mol) (1). The rate of gastric emptying is an established determinant of postprandial blood glucose (2), a principle illustrated by “short-acting” glucagon-like peptide 1 (GLP-1) receptor agonists, such as exenatide, where the capacity to slow gastric emptying predominates over the insulinotropic effect in the postprandial setting (3).

Small intestinal glucose absorption, predominantly via sodium–glucose cotransporter 1 and GLUT2 transporters, is limited to ∼0.5 g/min per 30 cm (2). Interventions that increase the exposure of luminal glucose to the mucosal surface can therefore augment glucose absorption. We previously reported that the anticholinergic agent hyoscine delays the absorption of intraduodenally infused glucose in humans by decreasing small intestinal flow (4), indicating that modulation of small intestinal motor function can impact substantially on postprandial glycemia. Exogenous GLP-1 has been reported to inhibit both fasting and postprandial duodenal motility in humans (5,6), but its impact on the flow of chyme and on small intestinal transit and glucose absorption have not previously been explored. We therefore examined the effects of the short-acting form of exenatide on small intestinal motor function and glucose absorption in response to an intraduodenal glucose infusion in both healthy subjects and patients with type 2 diabetes.

Subjects

We studied 10 healthy subjects and 10 patients with type 2 diabetes managed by diet alone, after obtaining written informed consent (Table 1). None had any significant medical comorbidity or used medications known to affect gastrointestinal motility. The protocol was approved by the Human Research Ethics Committee of the Royal Adelaide Hospital and was conducted in accordance with the principles of the Declaration of Helsinki as revised in 2000.

Table 1

Demographics of the study subjects, number of duodenal pressure waves, mean duodenal pressure wave amplitude, MI, and number of anterior flow events in the duodenum during fasting (−30 to 0 min) and in response to intraduodenal glucose infusion (3 kcal/min; 0–240 min) with intravenous exenatide or saline control in healthy subjects (n = 10) and in patients with type 2 diabetes (n = 10)

Healthy
Type 2 diabetes
ExenatideControlPExenatideControlP
Age (years) 36.8 ± 4.5  60.5 ± 2.3 – 
Sex (male:female) 8:2  7:3 – 
BMI (kg ⋅ m−227.4 ± 1.7  29.1 ± 1.5 – 
Duration of diabetes (months) –  60.5 ± 2.3 – 
HbA1c, % (mmol ⋅ mol−1–  6.1 ± 0.2 (43.4 ± 2.6) – 
Number of duodenal pressure waves (−30 to 0 min) 267 ± 67 365 ± 90 0.426 299 ± 58 233 ± 57 0.262 
Number of duodenal pressure waves (0–240 min) 577 ± 98 2,088 ± 282 <0.001 781 ± 149 1,976 ± 446 0.016 
MI (mmHg) (−30 to 0 min) 6.7 ± 0.6 8.0 ± 0.3 0.094 7.2 ± 0.8 7.6 ± 0.4 0.350 
MI (mmHg) (0–240 min) 4.8 ± 0.4 7.5 ± 0.3 0.001 4.5 ± 0.7 7.3 ± 0.3 0.001 
Number of antegrade flow events (−30 to 0 min) 10 ± 2 24 ± 4 <0.001 8 ± 2 22 ± 4 0.015 
Number of antegrade flow events (0–240 min) 55 ± 12 114 ± 15 <0.05 36 ± 8 105 ± 10 <0.001 
Healthy
Type 2 diabetes
ExenatideControlPExenatideControlP
Age (years) 36.8 ± 4.5  60.5 ± 2.3 – 
Sex (male:female) 8:2  7:3 – 
BMI (kg ⋅ m−227.4 ± 1.7  29.1 ± 1.5 – 
Duration of diabetes (months) –  60.5 ± 2.3 – 
HbA1c, % (mmol ⋅ mol−1–  6.1 ± 0.2 (43.4 ± 2.6) – 
Number of duodenal pressure waves (−30 to 0 min) 267 ± 67 365 ± 90 0.426 299 ± 58 233 ± 57 0.262 
Number of duodenal pressure waves (0–240 min) 577 ± 98 2,088 ± 282 <0.001 781 ± 149 1,976 ± 446 0.016 
MI (mmHg) (−30 to 0 min) 6.7 ± 0.6 8.0 ± 0.3 0.094 7.2 ± 0.8 7.6 ± 0.4 0.350 
MI (mmHg) (0–240 min) 4.8 ± 0.4 7.5 ± 0.3 0.001 4.5 ± 0.7 7.3 ± 0.3 0.001 
Number of antegrade flow events (−30 to 0 min) 10 ± 2 24 ± 4 <0.001 8 ± 2 22 ± 4 0.015 
Number of antegrade flow events (0–240 min) 55 ± 12 114 ± 15 <0.05 36 ± 8 105 ± 10 <0.001 

Data are mean ± SEM.

Protocol

Each subject underwent two study visits separated by at least 5 days in double-blind, randomized fashion. Computerized randomization was undertaken by the Royal Adelaide Hospital Pharmacy, which supplied a 50-mL solution in a masked bag containing either exenatide (40 μL Byetta solution [AstraZeneca, North Ryde, Australia], 0.5 mL 20% albumin, and 49.5 mL 0.9% saline, to a final concentration of 10 μg/50 mL) or 0.9% saline alone (control).

Each subject attended the Department of Nuclear Medicine at 8:30 a.m. after an overnight fast. A multilumen silicone catheter (Dentsleeve, Mississauga, Canada) bound to an impedance catheter (Sandhill Scientific, Highlands Ranch, CO) was introduced through an anesthetized nostril and allowed to pass into the duodenum by peristalsis, with continuous monitoring of its position by measurement of antroduodenal transmucosal potential difference via saline-perfused side-holes (4). The assembly was positioned with six water-perfused manometry side-holes at 3-cm intervals, seven impedance electrode pairs (2 cm between each electrode), and an infusion port in the duodenum.

Subjects remained supine under a gamma camera (7,8). At −30 min, an intravenous infusion of exenatide or control was commenced and continued for 270 min (50 ng/min exenatide for the first 30 min and then 25 ng/min). Between 0 and 60 min, an intraduodenal glucose infusion (45 g glucose, mixed with 5 g 3-O-methylglucose [3-OMG] and 20 MBq 99mTc-sulfur colloid in water to a total volume of 200 mL) was administered at a rate of 3.3 mL/min (3 kcal/min). 3-OMG is absorbed by the same mechanisms as glucose but is not metabolized; serum concentrations therefore represent an index of glucose absorption (9). A cobalt marker was placed over the right superior iliac spine as a reference (10). Anterior scintigraphic images were acquired every 3 min from 0 to 240 min. Venous blood was sampled frequently for blood glucose, serum 3-OMG and insulin, and plasma C-peptide concentrations, and gastrointestinal sensations were assessed using 100-mm visual analog questionnaires (11).

Measurements

Both the manometric and impedance data were recorded digitally (InSIGHT stationary system; Sandhill Scientific). The number and amplitude of duodenal waves over successive 15-min periods were analyzed with custom-designed software (Andre J. Smout, Academic Medical Center, Amsterdam, the Netherlands). Flow events were defined as a transient reduction in impedance of ≥12% from baseline in three or more sequential electrode pairs (4). Small intestinal transit time was determined from the scintigraphic data (IDL v6.2 software; RSI, Boulder, CO). A region of interest was drawn around the colon using a composite image and used to identify the cecal arrival time (10). Blood glucose concentrations were measured by the glucose oxidase method (MediSense Optium, Bedford, MA), serum 3-OMG by liquid chromatography and mass spectrometry (10), and serum insulin and plasma C-peptide by ELISA immunoassays (Mercodia, Uppsala, Sweden).

Statistical Analysis

On the basis of our previous study (4), we determined that 10 subjects would provide 80% power to detect a 50% reduction in duodenal pressure waves and 90% power to detect a 50% reduction in flow events, with exenatide compared with control (α = 0.05). The area under the curves (AUCs) for different parameters were calculated using the trapezoidal rule. Paired Student t test and two-factor repeated-measures ANOVA, with treatment and time as factors (adjusted by Bonferroni correction), were used to compare variables within each group. Motility indices (MIs) were calculated as ln[(sum of amplitudes × number of duodenal waves) + 1] (12). Wilcoxon signed rank test was used for intragroup comparisons of nausea scores. Within-subject correlations using univariate analysis, with subject number as a fixed factor, were used to assess relationships between variables. This method allows assessment of “weighted correlations” between variables in the total data pool, with P values adjusted for the total number of subjects (13). All analyses were performed using SPSS 21 (IBM, Armonk, NY). Results are expressed as mean ± SEM; P < 0.05 was considered statistically significant.

Duodenal Motility and Flow

During and after intraduodenal glucose infusion (0–240 min), there were marked reductions in the frequency and MI of duodenal pressure waves with exenatide compared with control, in both healthy subjects and subjects with type 2 diabetes (all P < 0.05). Duodenal flow events were mainly (>95%) antegrade and were substantially fewer with exenatide compared with control, in both groups (all P < 0.05) (Fig. 1 and Table 1).

Figure 1

Effects of intravenous exenatide compared with saline control, in healthy subjects (n = 10) and in subjects with type 2 diabetes (n = 10), on duodenal pressure wave frequency (A and B), MIs (C and D), and duodenal antegrade flow events (E and F) during fasting and in response to intraduodenal (ID) glucose infusion. Two-factor repeated-measures ANOVA, with treatment and time as factors, adjusted by Bonferroni correction, was used to compare these variables. Ex, exenatide.

Figure 1

Effects of intravenous exenatide compared with saline control, in healthy subjects (n = 10) and in subjects with type 2 diabetes (n = 10), on duodenal pressure wave frequency (A and B), MIs (C and D), and duodenal antegrade flow events (E and F) during fasting and in response to intraduodenal (ID) glucose infusion. Two-factor repeated-measures ANOVA, with treatment and time as factors, adjusted by Bonferroni correction, was used to compare these variables. Ex, exenatide.

Small Intestinal Transit

With saline control, the mean small intestinal transit time was 121 min (95% CI 98–144) in healthy subjects and 120 min (95% CI 85–155) in patients with type 2 diabetes (n = 9), without a difference between the groups. The remaining patient with type 2 diabetes had a transit time >240 min. With exenatide, there was a marked slowing of transit, such that the radiolabel did not reach the cecum within 240 min in any healthy subject or subject with type 2 diabetes.

Blood Glucose, Serum Insulin, Plasma C-Peptide, and Serum 3-OMG

From −30 to 0 min, blood glucose decreased slightly on both days in healthy volunteers (P ≤ 0.05), but only with exenatide (P < 0.001) in subjects with type 2 diabetes. During this period, insulin and C-peptide increased only with exenatide in each group (all P < 0.05) (Fig. 2 and Table 2).

Figure 2

Effects of intravenous exenatide compared with saline control, in healthy subjects (n = 10) and subjects with type 2 diabetes (n = 10), on blood glucose (A and B), serum insulin (C and D), plasma C-peptide (E and F), and serum 3-OMG concentrations (G and H) during fasting and in response to intraduodenal (ID) glucose infusion. Two-factor repeated-measures ANOVA, with treatment and time as factors, adjusted by Bonferroni correction, was used to compare these variables. *P < 0.05 for post hoc comparison of specified time points. Ex, exenatide.

Figure 2

Effects of intravenous exenatide compared with saline control, in healthy subjects (n = 10) and subjects with type 2 diabetes (n = 10), on blood glucose (A and B), serum insulin (C and D), plasma C-peptide (E and F), and serum 3-OMG concentrations (G and H) during fasting and in response to intraduodenal (ID) glucose infusion. Two-factor repeated-measures ANOVA, with treatment and time as factors, adjusted by Bonferroni correction, was used to compare these variables. *P < 0.05 for post hoc comparison of specified time points. Ex, exenatide.

Table 2

Basal values, fasting values after intravenous exenatide or saline control (−30 to 0 min), and AUCs in response to intraduodenal glucose infusion (3 kcal/min) with intravenous exenatide or saline control (0–240 min), for blood glucose, serum insulin and plasma C-peptide, and serum 3-OMG concentrations in healthy subjects (n = 10) and patients with type 2 diabetes (n = 10)

Healthy
Type 2 diabetes
ExenatideControlPExenatideControlP
Basal glucose (mmol ⋅ L−15.5 ± 0.2† 5.4 ± 0.2* 0.196 7.3 ± 0.4‡ 6.6 ± 0.4 0.003 
Glucose at 0 min (mmol ⋅ L−14.9 ± 0.2† 5.2 ± 0.2* 0.057 6.6 ± 0.3‡ 6.4 ± 0.4 0.345 
Peak glucose (mmol ⋅ L−1 ⋅ min) 7.9 ± 0.4 10.7 ± 0.5 <0.001 11.5 ± 0.7 13.4 ± 0.7 0.023 
Glucose AUC (0–240 min) (mmol ⋅ L−1 ⋅ min) 1,272 ± 65 1,548 ± 75 <0.001 1,754 ± 81 2,229 ± 128 <0.001 
Peak 3-OMG (mmol ⋅ L−10.5 ± 0.0 0.8 ± 0.1 0.001 0.6 ± 0.1 0.9 ± 0.1 0.005 
3-OMG AUC (0–240 min) (mmol ⋅ L−1 ⋅ min) 68.3 ± 3.4 101.5 ± 6.7 0.001 81.0 ± 6.1 128.7 ± 10.3 <0.001 
Basal insulin (mU ⋅ L−14.7 ± 1.4# 5.5 ± 1.9 0.235 7.8 ± 1.5 6.7 ± 1.2 0.100 
Insulin at 0 min (mU ⋅ L−113.1 ± 4.6# 4.8 ± 1.6 0.019 24.9 ± 6.6 6.3 ± 0.9 0.011 
Peak insulin (mU ⋅ L−1140.5 ± 29.0 86.8 ± 18.9 0.060 155.4 ± 35.3 77.8 ± 22.7 0.013 
Insulin AUC (0–240 min) (mU ⋅ L−1 ⋅ min) 9,300 ± 2,444 6,227 ± 1,260 0.078 15,787 ± 4,312 7,803 ± 1,850 0.013 
Basal C-peptide (pmol ⋅ L−1374 ± 64.0^ 410 ± 80§ 0.132 703 ± 87$ 662 ± 80 0.279 
C-peptide at 0 min (pmol ⋅ L−1675 ± 112^ 369 ± 77§ 0.001 1,212 ± 174$ 638 ± 71 0.002 
Peak C-peptide (pmol ⋅ L−13,137 ± 362 2,500 ± 295 0.105 3,661 ± 448 2,490 ± 437 0.007 
C-peptide AUC (0–240 min) (pmol ⋅ L−1 ⋅ min) 295,234 ± 40,832 278,725 ± 28,433 0.536 517,356 ± 77,199 404,219 ± 64,075 0.023 
Healthy
Type 2 diabetes
ExenatideControlPExenatideControlP
Basal glucose (mmol ⋅ L−15.5 ± 0.2† 5.4 ± 0.2* 0.196 7.3 ± 0.4‡ 6.6 ± 0.4 0.003 
Glucose at 0 min (mmol ⋅ L−14.9 ± 0.2† 5.2 ± 0.2* 0.057 6.6 ± 0.3‡ 6.4 ± 0.4 0.345 
Peak glucose (mmol ⋅ L−1 ⋅ min) 7.9 ± 0.4 10.7 ± 0.5 <0.001 11.5 ± 0.7 13.4 ± 0.7 0.023 
Glucose AUC (0–240 min) (mmol ⋅ L−1 ⋅ min) 1,272 ± 65 1,548 ± 75 <0.001 1,754 ± 81 2,229 ± 128 <0.001 
Peak 3-OMG (mmol ⋅ L−10.5 ± 0.0 0.8 ± 0.1 0.001 0.6 ± 0.1 0.9 ± 0.1 0.005 
3-OMG AUC (0–240 min) (mmol ⋅ L−1 ⋅ min) 68.3 ± 3.4 101.5 ± 6.7 0.001 81.0 ± 6.1 128.7 ± 10.3 <0.001 
Basal insulin (mU ⋅ L−14.7 ± 1.4# 5.5 ± 1.9 0.235 7.8 ± 1.5 6.7 ± 1.2 0.100 
Insulin at 0 min (mU ⋅ L−113.1 ± 4.6# 4.8 ± 1.6 0.019 24.9 ± 6.6 6.3 ± 0.9 0.011 
Peak insulin (mU ⋅ L−1140.5 ± 29.0 86.8 ± 18.9 0.060 155.4 ± 35.3 77.8 ± 22.7 0.013 
Insulin AUC (0–240 min) (mU ⋅ L−1 ⋅ min) 9,300 ± 2,444 6,227 ± 1,260 0.078 15,787 ± 4,312 7,803 ± 1,850 0.013 
Basal C-peptide (pmol ⋅ L−1374 ± 64.0^ 410 ± 80§ 0.132 703 ± 87$ 662 ± 80 0.279 
C-peptide at 0 min (pmol ⋅ L−1675 ± 112^ 369 ± 77§ 0.001 1,212 ± 174$ 638 ± 71 0.002 
Peak C-peptide (pmol ⋅ L−13,137 ± 362 2,500 ± 295 0.105 3,661 ± 448 2,490 ± 437 0.007 
C-peptide AUC (0–240 min) (pmol ⋅ L−1 ⋅ min) 295,234 ± 40,832 278,725 ± 28,433 0.536 517,356 ± 77,199 404,219 ± 64,075 0.023 

Data are mean ± SEM. †, *,‡,#,^,§,$P < 0.05 (t = −30 vs. 0 min) by paired Student t test.

During and after intraduodenal glucose infusion (0–240 min), blood glucose, insulin, and C-peptide concentrations increased to a peak before decreasing to near-baseline values. Both the peak and AUC for blood glucose were lower with exenatide than with control in both groups (P < 0.05), whereas the peak and AUC for insulin and C-peptide were higher with exenatide than with control in patients with type 2 diabetes (P < 0.05), but not in healthy subjects. With exenatide, blood glucose and insulin both decreased slightly during the initial 30 min of intraduodenal glucose infusion in both groups, in contrast to control. Peak and AUC for serum 3-OMG concentrations were markedly lower with exenatide than with control in both groups (all P < 0.005) (Fig. 2 and Table 2).

Nausea

During (but not before) intraduodenal glucose infusion (0–60 min), nausea increased in each group only with exenatide and returned to baseline after the end of the glucose infusion, such that the mean and peak nausea scores were higher with exenatide than with control (all P < 0.05) (Supplementary Fig. 1).

Even in subjects with a peak nausea score below the median of 27.5 mm (n = 10; four healthy subjects and six subjects with type 2 diabetes), the suppression of duodenal pressure waves (678 ± 137 vs. 1,963 ± 467; P < 0.01) and antegrade flow events (58 ± 9 vs. 106 ± 6; P < 0.001) with exenatide remained significantly different from control and was still associated with lower mean blood glucose and serum 3-OMG concentrations (P < 0.001 for each).

Relationships Between Variables

On pooling the data from both groups on both study days, the AUCs for serum 3-OMG and blood glucose concentrations were related directly to the frequency of duodenal pressure waves (r = 0.66, P = 0.001 and r = 0.58, P = 0.006, respectively), duodenal MI (r = 0.84, P < 0.001 and r = 0.67, P = 0.001, respectively), and antegrade flow events (r = 0.75, P < 0.001 and r = 0.59, P = 0.005, respectively) but were not related to small intestinal transit time on control days.

We observed that exenatide, when administered intravenously in both healthy subjects and patients with type 2 diabetes, 1) markedly suppressed duodenal motility and flow, 2) slowed small intestinal transit, 3) decreased 3-OMG absorption, and 4) delayed and suppressed glycemic increments in response to an intraduodenal glucose infusion. The dose of exenatide (7.5 μg) was within the usual clinical range and was infused in a regimen shown previously to achieve steady therapeutic plasma concentrations (14,15).

In addition to manometry, we evaluated small intestinal motor function using the impedance technique (16), which is more sensitive than manometry for assessing flow (17). We observed a direct relationship between absorption of the glucose analog, 3-OMG, and the frequency of both duodenal pressure waves and flow events; the latter is likely to be more important based on our previous study (4).

The inhibition of motility and flow that we observed with exenatide is likely to have reduced the length of small intestinal mucosa exposed to glucose (18), which is supported by our scintigraphic data, and to have diminished the thinning of the unstirred water layer, which occurs with flow of chyme (19); both phenomena would contribute to reduced absorption of glucose, indicated by lower 3-OMG concentrations, despite a possible increase in mesenteric blood flow that occurs with GLP-1 receptor stimulation (20). That GLP-1 receptor agonists are associated with diarrhea in some patients may seem at odds with our observations but could be due to acceleration of colonic transit, which was observed independently of any effect on small intestinal motility with the GLP-1 receptor agonist ROSE-010 (21).

During the intraduodenal glucose infusion (0–60 min), we noted a delay in the rise of blood glucose with exenatide compared with control, associated with initially lower insulin concentrations, suggesting that inhibition of gut motility at first outweighed the insulinotropic effects of exenatide in contributing to lowering of blood glucose. A similar phenomenon has been demonstrated previously in health, when gastric emptying was slowed by infusion of exogenous GLP-1 (22). After the intraduodenal glucose infusion was completed (60–240 min), the insulinotropic effect of exenatide became manifest, which undoubtedly contributed to the reduction in glycemia during this later phase of the study.

Nausea is an established adverse effect of exenatide and is thought to be less with intravenous than subcutaneous administration (23). In our study, nausea tended not to occur with intravenous exenatide until the stimulus of intraduodenal glucose was added, perhaps due to synergy between central and gastrointestinal stimuli. It is unlikely that nausea accounted for the suppression of small intestinal motor function by exenatide, since the latter was evident even in subjects with little or no nausea.

Limitations of this technically challenging, proof-of-concept study include the relatively small sample size and very good glycemic control of our patients with type 2 diabetes. Further studies would be required to evaluate the effects in less well-controlled patients and to determine whether there is tachyphylaxis for the suppression of small intestinal motor function with repeated dosing and whether the effects would be less pronounced if baseline motility were already impaired, as is the case with gastric emptying (24).

Nevertheless, our observations represent a hitherto unrecognized mechanism for lowering postprandial glycemia by GLP-1 receptor agonists in type 2 diabetes.

Clinical trial reg. no. ACTRN12608000428369, www.anzctr.org.au.

J.K. is currently affiliated with the Department of Endocrinology, Changi General Hospital, Singapore.

Acknowledgments. The authors thank Andre J. Smout (Academic Medical Center, Amsterdam, the Netherlands), who provided the software for duodenal motility analysis. The authors particularly wish to acknowledge the contribution of their late colleague Antonietta Russo (Discipline of Medicine, The University of Adelaide) to the acquisition and analysis of small intestinal transit data for this study.

Funding. This study was supported by funding from the National Health and Medical Research Council of Australia. S.S.T. and C.S.M. received scholarship funding from The University of Adelaide, and S.S.T. also received funding from the Rebecca L. Cooper Medical Research Foundation. T.W. has been supported by a Royal Adelaide Hospital Research Committee Early Career Fellowship.

Duality of Interest. This study was supported by funding from AstraZeneca Australia. K.L.J. has received research funding from Merck Sharp & Dohme and Sanofi. M.H. has participated on advisory boards and/or in symposia for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Merck Sharp & Dohme, Novartis, Novo Nordisk, and Sanofi and has received honoraria for this activity. C.K.R. has received funding from AstraZeneca, Merck Sharp & Dohme, and Novartis. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. S.S.T. and C.S.M. were involved in the subject recruitment, coordination, data collection and interpretation, statistical analysis, and drafting of the manuscript. T.W. was involved in the data collection, data interpretation, statistical analysis, and drafting of the manuscript. J.C. and J.K. were involved in the subject recruitment, coordination, and data collection. P.K. was involved in the conception and design of the study, subject recruitment, coordination, and data collection. H.L.C., M.J.B., and R.S.R. assisted in recruitment and data collection. B.C. was involved in the design of the study and in the development of the software for analysis of small bowel transit. K.L.J. was involved in the conception and design of the study and data analysis and interpretation. M.H. was involved in the conception and design of the study and data interpretation. C.K.R. was involved in the conception and design of the study and data analysis and interpretation. All authors critically reviewed the manuscript and have approved the final version. C.K.R. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

1.
Ceriello
A
.
Point: postprandial glucose levels are a clinically important treatment target
.
Diabetes Care
2010
;
33
:
1905
1907
[PubMed]
2.
Thazhath
SS
,
Wu
T
,
Young
RL
,
Horowitz
M
,
Rayner
CK
.
Glucose absorption in small intestinal diseases
.
Expert Rev Gastroenterol Hepatol
2014
;
8
:
301
312
[PubMed]
3.
Linnebjerg
H
,
Park
S
,
Kothare
PA
, et al
.
Effect of exenatide on gastric emptying and relationship to postprandial glycemia in type 2 diabetes
.
Regul Pept
2008
;
151
:
123
129
[PubMed]
4.
Chaikomin
R
,
Wu
KL
,
Doran
S
, et al
.
Concurrent duodenal manometric and impedance recording to evaluate the effects of hyoscine on motility and flow events, glucose absorption, and incretin release
.
Am J Physiol Gastrointest Liver Physiol
2007
;
292
:
G1099
G1104
[PubMed]
5.
Schirra
J
,
Kuwert
P
,
Wank
U
, et al
.
Differential effects of subcutaneous GLP-1 on gastric emptying, antroduodenal motility, and pancreatic function in men
.
Proc Assoc Am Physicians
1997
;
109
:
84
97
[PubMed]
6.
Hellström
PM
,
Näslund
E
,
Edholm
T
, et al
.
GLP-1 suppresses gastrointestinal motility and inhibits the migrating motor complex in healthy subjects and patients with irritable bowel syndrome
.
Neurogastroenterol Motil
2008
;
20
:
649
659
[PubMed]
7.
Bonapace
ES
,
Maurer
AH
,
Davidoff
S
,
Krevsky
B
,
Fisher
RS
,
Parkman
HP
.
Whole gut transit scintigraphy in the clinical evaluation of patients with upper and lower gastrointestinal symptoms
.
Am J Gastroenterol
2000
;
95
:
2838
2847
[PubMed]
8.
Grybäck
P
,
Jacobsson
H
,
Blomquist
L
,
Schnell
PO
,
Hellström
PM
.
Scintigraphy of the small intestine: a simplified standard for study of transit with reference to normal values
.
Eur J Nucl Med Mol Imaging
2002
;
29
:
39
45
[PubMed]
9.
Fordtran
JS
,
Clodi
PH
,
Soergel
KH
,
Ingelfinger
FJ
.
Sugar absorption tests, with special reference to 3-0-methyl-d-glucose and d-xylose
.
Ann Intern Med
1962
;
57
:
883
891
[PubMed]
10.
Deane
AM
,
Summers
MJ
,
Zaknic
AV
, et al
.
Glucose absorption and small intestinal transit in critical illness
.
Crit Care Med
2011
;
39
:
1282
1288
[PubMed]
11.
Parker
BA
,
Sturm
K
,
MacIntosh
CG
,
Feinle
C
,
Horowitz
M
,
Chapman
IM
.
Relation between food intake and visual analogue scale ratings of appetite and other sensations in healthy older and young subjects
.
Eur J Clin Nutr
2004
;
58
:
212
218
[PubMed]
12.
Camilleri
M
,
Malagelada
JR
.
Abnormal intestinal motility in diabetics with the gastroparesis syndrome
.
Eur J Clin Invest
1984
;
14
:
420
427
[PubMed]
13.
Bland
JM
,
Altman
DG
.
Calculating correlation coefficients with repeated observations: part 1--correlation within subjects
.
BMJ
1995
;
310
:
446
[PubMed]
14.
Fehse
F
,
Trautmann
M
,
Holst
JJ
, et al
.
Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes
.
J Clin Endocrinol Metab
2005
;
90
:
5991
5997
[PubMed]
15.
Kendall
DM
,
Riddle
MC
,
Rosenstock
J
, et al
.
Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea
.
Diabetes Care
2005
;
28
:
1083
1091
[PubMed]
16.
Nguyen
HN
,
Silny
J
,
Matern
S
.
Multiple intraluminal electrical impedancometry for recording of upper gastrointestinal motility: current results and further implications
.
Am J Gastroenterol
1999
;
94
:
306
317
[PubMed]
17.
Imam
H
,
Sanmiguel
C
,
Larive
B
,
Bhat
Y
,
Soffer
E
.
Study of intestinal flow by combined videofluoroscopy, manometry, and multiple intraluminal impedance
.
Am J Physiol Gastrointest Liver Physiol
2004
;
286
:
G263
G270
[PubMed]
18.
Little
TJ
,
Doran
S
,
Meyer
JH
, et al
.
The release of GLP-1 and ghrelin, but not GIP and CCK, by glucose is dependent upon the length of small intestine exposed
.
Am J Physiol Endocrinol Metab
2006
;
291
:
E647
E655
[PubMed]
19.
Lewis
LD
,
Fordtran
JS
.
Effect of perfusion rate on absorption, surface area, unstirred water layer thickness, permeability, and intraluminal pressure in the rat ileum in vivo
.
Gastroenterology
1975
;
68
:
1509
1516
[PubMed]
20.
Trahair
LG
,
Horowitz
M
,
Hausken
T
,
Feinle-Bisset
C
,
Rayner
CK
,
Jones
KL
.
Effects of exogenous glucagon-like peptide-1 on the blood pressure, heart rate, mesenteric blood flow, and glycemic responses to intraduodenal glucose in healthy older subjects
.
J Clin Endocrinol Metab
2014
;
99
:
E2628
E2634
[PubMed]
21.
Camilleri
M
,
Vazquez-Roque
M
,
Iturrino
J
, et al
.
Effect of a glucagon-like peptide 1 analog, ROSE-010, on GI motor functions in female patients with constipation-predominant irritable bowel syndrome
.
Am J Physiol Gastrointest Liver Physiol
2012
;
303
:
G120
G128
[PubMed]
22.
Nauck
MA
,
Niedereichholz
U
,
Ettler
R
, et al
.
Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans
.
Am J Physiol
1997
;
273
:
E981
E988
[PubMed]
23.
Nauck
MA
,
Baranov
O
,
Ritzel
RA
,
Meier
JJ
.
Do current incretin mimetics exploit the full therapeutic potential inherent in GLP-1 receptor stimulation?
Diabetologia
2013
;
56
:
1878
1883
[PubMed]
24.
Deane
AM
,
Chapman
MJ
,
Fraser
RJ
, et al
.
Effects of exogenous glucagon-like peptide-1 on gastric emptying and glucose absorption in the critically ill: relationship to glycemia
.
Crit Care Med
2010
;
38
:
1261
1269
[PubMed]

Supplementary data