Species-Dependent Mechanisms Regulating Glucose-Dependent GLP-1 Secretion?

Since the discovery of glucagon-like peptide 1^7–36NH2 (GLP-1) as an “incretin” hormone (1), numerous GLP-1 receptor agonists and incretin hormone degradation (dipeptidyl peptidase 4) inhibitors have been developed for the treatment of patients with type 2 diabetes (2). The success of these therapeutics in reducing HbA_1c levels, as well as decreasing body weight and exerting cardioprotective actions in the case of the agonists, has been well established, and incretin-based drugs are now recommended for dual-therapy management of type 2 diabetes (3). However, considerable interest has been engendered in a third possible approach to GLP-1–based therapy, that being enhancement of endogenous secretion, either alone or with a degradation inhibitor (4). GLP-1 is secreted by the endocrine L cell of the intestinal epithelium in rodents and humans (5). GLP-1 release is stimulated by ingested nutrients, including glucose, although neural and hormonal secretagogues have also been described (4). However, a thorough understanding of the molecular underpinnings of human L-cell secretory responses is critical if GLP-1 secretagogues are to be considered for therapeutic use.

L cells are diffusely scattered through the gut epithelium, providing a major challenge to their study (5). Furthermore, although the advent of techniques to fluorescently label murine L cells has enabled their isolation, purified L cells fail to survive in vitro (6). Consequently, the cellular mechanisms underlying GLP-1 secretion by the primary murine L cell are now commonly studied using heterogeneous cultures derived from isolated crypts (6,7). Such in vitro models have been generated from all regions …