Metabolic responses to xenin-25 are altered in humans with Roux-en-Y gastric bypass surgery

Abstract

Xenin-25 (Xen) is a neurotensin-related peptide secreted by a subset of enteroendocrine cells located in the proximal small intestine. Many effects of Xen are mediated by neurotensin receptor-1 on neurons. In healthy humans with normal glucose tolerance (NGT), Xen administration causes diarrhea and inhibits postprandial glucagon-like peptide-1 (GLP-1) release but not insulin secretion. This study determines (i) if Xen has similar effects in humans with Roux-en-Y gastric bypass (RYGB) and (ii) whether neural pathways potentially mediate effects of Xen on glucose homeostasis. Eight females with RYGB and no history of type 2 diabetes received infusions with 0, 4 or 12pmol Xen/kg/min with liquid meals on separate occasions. Plasma glucose and gastrointestinal hormone levels were measured and insulin secretion rates calculated. Pancreatic polypeptide and neuropeptide Y levels were surrogate markers for parasympathetic input to islets and sympathetic tone, respectively. Responses were compared to those in well-matched non-surgical participants with NGT from our earlier study. Xen similarly increased pancreatic polypeptide and neuropeptide Y responses in patients with and without RYGB. In contrast, the ability of Xen to inhibit GLP-1 release and cause diarrhea was severely blunted in patients with RYGB. With RYGB, Xen had no statistically significant effect on glucose, insulin secretory, GLP-1, glucose-dependent insulinotropic peptide, and glucagon responses. However, insulin and glucose-dependent insulinotropic peptide secretion preceded GLP-1 release suggesting circulating GLP-1 does not mediate exaggerated insulin release after RYGB. Thus, Xen has unmasked neural circuits to the distal gut that inhibit GLP-1 secretion, cause diarrhea, and are altered by RYGB.

Keywords: GIP; GLP-1; Gastric bypass; Insulin secretion; Xenin.

Copyright © 2016 Elsevier Inc. All rights reserved.

Figures

Figure 1. Postprandial plasma glucose and hormone profiles are different in subjects with and without RYGB

Panels A–E: Outcomes were determined at the indicated times in patients with and without RYGB. Panels F–J: iAUCs were calculated for the 0 to 300 minute time window. All subjects received the Alb infusion until 300-min and were included in the analysis. P values for iAUCs were determined by Student's t-test. Patients with and without RYGB ingested the meal from 0-3 and 0–30 minutes, respectively.

Figure 2. Xen-induced diarrhea is greatly reduced after RYGB

Panel A: Xen was measured in plasma samples collected at the 300-minute time point. The 75-minute time point was used for the RYGB subject with the aborted Lo-Xen and Hi-Xen infusions. Note that Xen levels are similarly increased in a dose-dependent fashion in subjects with and without RYGB. Panel B: The number of subjects with and without prior RYGB experiencing diarrhea during or after infusion of Xen at the indicated dose is shown. The non-surgical group includes all subjects from our earlier study (36 subjects with NGT, impaired glucose tolerance, and T2DM). * and ** represent p values of 0.0018 and 0.038, respectively.

Figure 3. Xen has no significant effect on glucose homeostasis after RYGB

On 3 separate occasions, fasted patients with RYGB received an infusion with Alb alone or Xen at a rate of 4 or 12 pmol/kg/min (Lo-Xen and Hi-Xen, respectively) beginning at minus 15 minutes. The meal (Boost Plus) was ingested from 0 to 30 minutes. Values for glucose, insulin, C-peptide, ISR, GLP-1, and GIP (Panels A–F, respectively) are shown for the indicated times. P values for time-Xen interactions are shown and were determined by repeated measures two-way ANOVA. Data for all subjects were incorporated in plots because outcomes had returned to near baseline levels by this time point but data for one subject were not included in the analysis that extended to 300 minutes.

Figure 4. Secretion of GIP and insulin precedes GLP-1 release after RYBG

Selected data from Figure 3 were re-plotted to allow comparison of ISR, GIP, and GLP-1 during infusion with Alb (Panel A), Lo-Xen (Panel B) and Hi-Xen (Panel C). Symbols were omitted for clarity. Numerical p values are for interactions between time and all outcomes (for each infusate) and a, b, c, and d represent p≤ 0.05, 0.01, 0.001, and 0.0001, respectively. Yellow and red letters represent p values for GLP-1 versus ISR and GIP versus ISR, respectively for individual time points. GIP was not measured in the samples collected at 15 minutes and this time point was not included in the statistical analysis. Data for all subjects were included because all studies went to 75-minutes, the endpoint of this analysis.

Figure 5. Xen increases PP and NPY responses in humans with and without RYGB

Plasma levels of PP for the indicated times after starting meal ingestion are shown for subjects with (Panel A) and without (Panel B) RYGB. PP AUCs (Panels C,E) and iAUCs (Panels D,F) from 0 to 300 minutes are shown for subjects with (Panels C,D) and without (Panels E,F) RYGB. Plasma levels of NPY for the indicated times after starting meal ingestion are shown for subjects with (Panel G) and without (Panel H) RYGB. NPY AUCs (Panels I,K) and iAUCs (Panels J,L) from 0 to 300 minutes are shown for subjects with (Panels I,J) and without (Panels K,L) RYGB. All values represent group means ± SEM. The effects of Xen on PP iAUCs (p=0.46), PP AUCs (p=0.58), NPY iAUCs (p=0.16), and NPY AUCs (p=0.34) were not different in groups with and without RYGB. Thus, differences in AUCs and iAUCs for Lo-Xen versus Alb and Hi-Xen versus Alb were analyzed collectively for both groups and were highly significant (p values ranged from 0.0079 to <0.0001). Data for one subject with RYGB were not included because Xen infusions were terminated at 75-minutes.