Regional specificity of the gut-incretin response to small intestinal glucose infusion in healthy older subjects

•Exposure of the distal small intestine to glucose promotes GLP-1 release.•Exposure of proximal and distal small intestine promotes GIP, with less GLP-1, release.•Bypassing the proximal small intestine potentiates the GLP-1 response.•These findings indicate the regional specificity of the gut-incretin axis.

The importance of the region, as opposed to the length, of small intestine exposed to glucose in determining the secretion of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) remains unclear. We sought to compare the glycemic, insulinemic and incretin responses to glucose administered to the proximal (12-60 cm beyond the pylorus), or more distal ( > 70 cm beyond the pylorus) small intestine, or both. 10 healthy subjects (9M,1F; aged 70.3 ± 1.4 years) underwent infusion of glucose via a catheter into the proximal (glucose proximally; GP), or distal (glucose distally; GD) small intestine, or both (GPD), on three separate days in a randomised fashion. Blood glucose, serum insulin and plasma GLP-1, GIP and CCK responses were assessed. The iAUC for blood glucose was greater in response to GPD than GP (P < 0.05), with no difference between GD and GP. GP was associated with minimal GLP-1 response (P = 0.05), but substantial increases in GIP, CCK and insulin (P < 0.001 for all). GPD and GD both stimulated GLP-1, GIP, CCK and insulin (P < 0.001 for all). Compared to GP, GPD induced greater GLP-1, GIP and CCK responses (P < 0.05 for all). Compared with GPD, GD was associated with greater GLP-1 (P < 0.05), but reduced GIP and CCK (P < 0.05 for both), responses. We conclude that exposure of glucose to the distal small intestine appears necessary for substantial GLP-1 secretion, while exposure of both the proximal and distal small intestine result in substantial secretion of GIP.