Exenatide induces an Enhanced Endogenous Glucagon-like Peptide-1 Secretory Response in Patients receiving Basal Insulin

Context Prolonged exposure to hormonal therapy can affect endogenous hormone secretion. In type 2 diabetes (T2DM), glucagon-like peptide-1 (GLP-1) receptor agonists are increasingly being administered in combination with therapies targeting additional hormones (including glucose-dependent insulinotropic polypeptide (GIP), glucagon, and insulin). However, little is known on how they affect endogenous GLP-1 secretion. Objective We sought to evaluate the effect of exenatide b.i.d on endogenous secretion of GLP-1, GIP and glucagon in patients treated concurrently with basal insulin. Design/Setting/Patients In this trial, adults with T2DM were randomized to 8-weeks treatment with basal insulin glargine (Glar;n=30), glargine plus thrice-daily lispro (Glar/Lispro;n=32), or glargine plus twice-daily exenatide (Glar/Exe;n=31). Outcome Endogenous secretion of glucagon, GIP and GLP-1 was assessed on 2-hour oral glucose tolerance test (OGTT) at baseline and after stopping therapy at 8-weeks, during which their circulating concentrations were measured every 30-minutes. Results There were no differences between groups in response profiles of glucagon and GIP. While there were no differences in fasting GLP-1, Glar/Exe induced higher GLP-1 concentrations than the other treatments at 30- and 60-minutes post-challenge at 8-weeks (both p<0.05). On the 8-week OGTT, baseline-adjusted GLP-1 was highest in Glar/Exe at each of 30-minutes (p=0.037), 60-minutes (p=0.007) and 90-minutes (p=0.039). Unlike the respective between-group comparisons of baseline-adjusted area-under-the-curve (AUC) for glucagon and GIP (both p=NS), baseline-adjusted AUCGLP-1 at 8-weeks was highest in Glar/Exe (p=0.037). Conclusion When combined with basal insulin therapy, exenatide induces an enhanced post-challenge endogenous GLP-1 secretory response following its cessation, with no differential effect on glucagon and GIP secretion.