Metabolic responses to xenin-25 are altered in humans with Roux-en-Y gastric bypass surgery.
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.
Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, Saint Louis, MO 63110.
Karin
K
Sterl
Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, Saint Louis, MO 63110.
Songyan
S
Wang
Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, Saint Louis, MO 63110.
Lauren
L
Oestricker
Department of Internal Medicine, Divsion of Biostatistics, Washington University School of Medicine, Saint Louis, MO 63110.
Michael J
MJ
Wallendorf
Department of Internal Medicine, Division of Nutritional Science, Washington University School of Medicine, Saint Louis, MO 63110.
Bruce W
BW
Patterson
Department of Internal Medicine, Division of Nutritional Science, Washington University School of Medicine, Saint Louis, MO 63110.
Dominic N
DN
Reeds
Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, Saint Louis, MO 63110.
Burton M
BM
Wice
D000293:Adolescent; D000328:Adult; D000368:Aged; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D015390:Gastric Bypass / Q000379:methods; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D009478:Neuropeptide Y / Q000378:metabolism; D009496:Neurotensin / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D010191:Pancreatic Polypeptide / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; D009478:Neuropeptide Y; C077659:xenin 25; D009496:Neurotensin; D005749:Gastric Inhibitory Polypeptide; D010191:Pancreatic Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005947:Glucose
GIP; GLP-1; Gastric bypass; Insulin secretion; Xenin