Chronic, but not acute, treatment with GLP-2 and GIP in combination increases glucose absorption in the isolated vascularly perfused rat intestine.

The gut hormones, glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP), may be important regulators of intestinal nutrient absorption. Using the isolated vascularly perfused rat intestine of male rats, we investigated the chronic and subacute (injections 6 days and 2 h, respectively, prior to perfusion) effects of a long-acting GLP-2-receptor (GLP-2R) agonist, a long-acting GIP-receptor (GIPR) agonist, and their combination on nutrient absorption. Potential acute effects were studied by administering native GLP-2, GIP, and GLP-2 + GIP intravascularly during the perfusion. During the perfusions investigating the effects of GLP-2, GIP, and the long-acting receptor agonists, the arterial perfusion flow was kept constant. In separate experiments, the dependency of superior mesenteric artery flow on nutrient absorption was studied by changing the arterial perfusion flow. The effects of the long-acting receptor agonists on superior mesenteric blood flow were additionally assessed in vivo using a transit time flow probe. Chronic GLP-2R agonist treatment alone increased intestinal size and glucose absorption, and combination with GIPR agonist treatment did not further increase intestinal size and glucose absorption. None of the treatments affected the absorption of short- and medium-chain fatty acids or amino acids. Nutrient absorption increased with the vascular perfusion flow rate. The GIPR agonist increased superior mesenteric artery blood flow alone and when combined with the GLP-2R agonist, whereas the GLP-2R agonist had no significant effect. Our results suggest that chronic GLP-2R agonism may increase glucose absorption by increasing intestinal size, and that increasing intestinal blood flow may increase nutrient absorption.