Peptide Tyrosine-Tyrosine Triggers GLP-2-Mediated Intestinal Hypertrophy After Roux-en-Y Gastric Bypass

Abstract

Purpose Intestinal remodeling and adaptation of the alimentary limb after Roux-en-Y gastric bypass (RYGB) play an important role in the pathophysiological events that lead to type 2 diabetes mellitus (T2DM) improvement. Intestinal absorptive loop hypertrophy and growth following surgery have been related to GLP-2 secretion by ileal L-cells. The secretion of peptide tyrosine-tyrosine (PYY) enterohormone after a meal has been proposed as a trigger for ileal secretion of GLP-1. Our aim is to determine the role of PYY as a GLP-2 secretion modulator as an adaptation result in the alimentary limb after RYGB. Method We used a non-obese euglycemic rodent model. Circulating glucose, insulin, PYY, and GLP-2 were measured in the experimental and control groups. We used four groups: fasting control, Sham-operated, RYGB-operated (RYGB), and RYGB-operated and treated with BIIE0246 (RYGB + BII). BIIE0246 is a NPY2 receptor antagonist in L-cells. Intestinal glucose transporters and GLP-1 and PYY gut expression and hypertrophy were analyzed after 12 weeks of surgery. Results RYGB increased PYY3-36 plasma levels in rats with or without BII treatment. A high-insulin response was observed in the RYGB group but not in the control or RYGB + BII groups. BIIE0246 treatment limited plasma GLP-2 levels. In the alimentary intestinal limb, hypertrophy and SGLT1 and GLUT1 expression appeared to be reduced after RYGB compared to controls. Conclusion The postprandial ileal PYY secretion is enhanced after RYGB. This increase mediates GLP-2 release through its binding to the Y2 receptor on L-cells. This mechanism plays a role in alimentary limb hypertrophy after surgery. Graphical abstract

RYGB surgery has modest effects on intestinal morphology and gut hormone populations in the bypassed biliopancreatic limb but causes reciprocal changes in GLP-2 and PYY in the alimentary limb

“…This may indicate villi hypertrophy, a hallmark of mucosal adaptation, in response to increased nutrient stimulation [ 13 ]. Thus, our observations are consistent with intestinal hyperplasia in the alimentary limb of these rats, which has been described before [ 13 , 18 ]. However, in ND-RYGB rats, AL villi width was decreased, suggesting previous nutrient composition, rather than levels of intestinal cell stimulation per se , play a key role in these changes of intestinal morphology.…”

“…This may indicate villi hypertrophy, a hallmark of mucosal adaptation, in response to increased nutrient stimulation [13]. Thus, our observations are consistent with intestinal hyperplasia in the alimentary limb of these rats, which has been described before [13,18]. However, in ND-RYGB rats, AL villi width…”

The role of glucagon after bariatric/metabolic surgery: much more than an “anti-insulin” hormone

“…Within the glucagon family of molecules, GLP-2 also appears to be increased after RYGB ( 53 ), which is consistent with high postprandial glucagon levels given the glucagonotropic effect of GLP-2. This relationship suggests a dual role for GLP-2 in maintaining glucose homeostasis indirectly by stimulating glucagon secretion and facilitating the growth and adaptive response of the intestinal absorptive loop ( 54 ).…”