Chronic liraglutide therapy induces an enhanced endogenous glucagon‐like peptide‐1 secretory response in early type 2 diabetes

Sustained exogenous stimulation of a hormone‐specific receptor can affect endogenous hormonal regulation. In this context, little is known about the impact of chronic treatment with glucagon‐like peptide‐1 ( GLP ‐1) agonists on the endogenous GLP ‐1 response. We therefore evaluated the impact of chronic liraglutide therapy on endogenous GLP ‐1 and glucose‐dependent insulinotropic polypeptide ( GIP ) response to an oral glucose challenge. A total of 51 people with type 2 diabetes of 2.6 ± 1.9 years’ duration were randomized to daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with an oral glucose tolerance test ( OGTT ) every 12 weeks. GLP ‐1 and GIP responses were assessed according to their respective area under the curve ( AUC ) from measurements taken at 0, 30, 60, 90 and 120 minutes during each OGTT . There were no differences in AUC GIP between the groups. By contrast, although fasting GLP ‐1 was unaffected, the liraglutide arm had ~2‐fold higher AUC GLP ‐1 at 12 weeks ( P  < .001), 24 weeks ( P  < .001), 36 weeks ( P  = .03) and 48 weeks ( P  = .03), as compared with placebo. Thus, chronic liraglutide therapy induces a previously unrecognized, robust and durable enhancement of the endogenous GLP ‐1 response, highlighting the need for further study of the long‐term effects of incretin mimetics on L ‐cell physiology.