...the consequences of long-term stimulation of healthy β cells with incretin mimetics have, until now, been uncertain

Credit: Jennie Vallis/NPG

Incretin mimetics (analogues of glucagon-like peptide 1 (GLP-1)) improve glycaemic control in patients with type 2 diabetes mellitus (T2DM) by stimulating pancreatic β cells to produce insulin. However, although clinical evidence supports short-term benefits of these agents, the consequences of long-term stimulation of healthy β cells with incretin mimetics have, until now, been uncertain.

In a new study published in Cell Metabolism, daily treatment of humanized mice with the incretin mimetic liraglutide for >200 days is shown to impair insulin secretion and islet function. These findings raise concern about the long-term use of GLP-1 analogues in patients with T2DM.

The investigators transplanted human pancreatic islets into the anterior chamber of the eye in nude mice treated with streptozotocin to induce diabetes mellitus. Mice were then injected subcutaneously with either liraglutide (300 μg/kg) or saline daily for up to 250 days. Initially, liraglutide-treated mice exhibited superior islet function compared with saline-treated controls, consistent with the short-term benefits observed in human patients. However, glycaemic control progressively deteriorated in mice treated with liraglutide for ≥200 days, both under basal conditions and high-glucose challenge. Consistent with this observation, analysis of plasma levels of insulin indicated that the hormone was released more slowly from islets of liraglutide-treated mice than from those of saline-treated controls during high-glucose challenge, which is indicative of compromised insulin secretion.

In their report, the authors state that their findings are “consistent with the notion that 'excessive' activation of an already overworked β cell under diabetic conditions during long-term treatment with incretin mimetics may lead to metabolic exhaustion of the β cell ... and, ultimately, compromised glucose homeostasis.” According to Per-Olof Berggren, one of the leaders of the study, the next step is to use more relevant diabetic models, such as humanized mice engrafted with β cells from patients with T2DM, to investigate the effects of incretin mimetics alone and in combination with other drugs.