TY - JOUR
T1 - Metabolic responses to xenin-25 are altered in humans with Roux-en-Y gastric bypass surgery
AU - Sterl, Karin
AU - Wang, Songyan
AU - Oestricker, Lauren
AU - Wallendorf, Michael J.
AU - Patterson, Bruce W.
AU - Reeds, Dominic N.
AU - Wice, Burton M.
N1 - Funding Information:
Portions of this research were supported by funds from the American Diabetes Association (Grant #1-10-CT-58 ); the Blum Kovler Foundation; NIH (Grant numbers 5RC1DK086163 and 1R01DK088126 ); the Washington University Diabetes Research Center Immunoassay Core ( P60 DK020579 ); the Washington University Nutrition Obesity Research Center Grant ( P30DK056341 ) from the National Institute of Diabetes and Digestive and Kidney Diseases ; the Washington University Digestive Disease Research Core Center ( P30 DK52574-16 ); the Washington University Clinical and Translational Science Award ( UL1 TR000448 ) from the National Center for Advancing Translational Sciences (NCATS ); the Biologic Therapy Core Facility of the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, Mo . (NCI Cancer Center Support Grant P30 CA91842 ); the NIH National Center for Research Resources ( P41 RR00954 and UL1 RR024992 ). The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH.
Publisher Copyright:
© 2016 Elsevier Inc. All rights reserved.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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 12 pmol 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.
AB - 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 12 pmol 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.
KW - GIP
KW - GLP-1
KW - Gastric bypass
KW - Insulin secretion
KW - Xenin
UR - http://www.scopus.com/inward/record.url?scp=84975292846&partnerID=8YFLogxK
U2 - 10.1016/j.peptides.2016.06.001
DO - 10.1016/j.peptides.2016.06.001
M3 - Article
C2 - 27288245
AN - SCOPUS:84975292846
VL - 82
SP - 76
EP - 84
JO - Peptides
JF - Peptides
SN - 0196-9781
ER -