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-week 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 < .05). On the 8-week OGTT, baseline-adjusted GLP-1 was the highest in Glar/Exe at each of 30 minutes (P = .037), 60 minutes (P = .007), and 90 minutes (P = .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 the highest in Glar/Exe (P = .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.