The Molecular Determinants of Glucagon-like Peptide Secretion by the Intestinal L cell

Abstract

The intestinal L-cell secretes a diversity of biologically-active hormones, most notably the glucagon-like peptides, GLP-1 and GLP-2. The highly-successful introduction of GLP-1-based drugs into the clinic for the treatment of patients with type 2 diabetes and obesity, and of a GLP-2 analog for patients with short bowel syndrome, has led to the suggestion that stimulation of the endogenous secretion of these peptides may serve as a novel therapeutic approach in these conditions. Situated in the intestinal epithelium, the L-cell demonstrates complex relationships with not only circulating, paracrine and neural regulators, but also ingested nutrients and other factors in the lumen, most notably the microbiota. The integrated input from these numerous secretagogues results in a variety of temporal patterns in L-cell secretion, ranging from minutes to 24-hours. This review combines the findings of traditional, physiological studies with those using newer molecular approaches to describe what is known and what remains to be elucidated after 5 decades of research on the intestinal L-cell and its secreted peptides, GLP-1 and GLP-2.

Activation of TLRs Triggers GLP-1 Secretion in Mice

“…Moreover, it is well established (and observed in the present study) that pro-inflammatory cytokines are secreted upon activation of TLRs. Since it has been demonstrated that IL6 and TNFA induce the secretion of GLP-1 [ 15 ], we can assume that the observed TLR-induced GLP-1 secretion could be indirectly mediated through cytokine expression. In this study, both the CLP model and the injection of TLR agonists induced cytokine release.…”

“…Moreover, it was suggested to have a protective role in gut permeability [ 14 ]. GLP-1 secretion mechanisms have been extensively described [ 15 ], and gut microbiota is involved in these secretory pathways through different mechanisms. Short-chain fatty acids produced by gut bacteria increase GLP-1 secretion through G-protein-coupled receptors GPR41/GPR43 [ 16 ].…”

“…In different studies aiming to mimic sepsis using the cecal ligation puncture (CLP), which is one of the most frequently used models, TLR expression was modulated in the lungs, liver, kidneys and intestines [ 24 , 25 , 26 ]. EECs express multiple TLRs [ 27 ] and are targets of pro-inflammatory cytokines such as interleukin-6 (IL6) and tumor necrosis factor alpha (TNFA), which are known to stimulate GLP-1 secretion [ 15 ]. The aim of this study was therefore to investigate whether, besides TLR4, the only TLR involved to date in GLP-1 secretion, other TLRs could also be implicated in the control of GLP-1 secretion.…”

Progress in the contrary effects of glucagon-like peptide-1 and chemerin on obesity development

“…DOI: 10.1177/15353702231214270 homeostasis. 2 In addition, exogenous infusion of GLP-1 has been shown to lower glucagon secretion, inhibit hepatic glucose production, delay gastric emptying, and induce satiety, which collectively leads to improved glycemia and enhanced insulin sensitivity. The insulinotropic and anorexigenic actions of GLP-1 make it an appealing candidate for the treatment of obesity.…”

“…The most well-known action of GLP-1 is to potentiate postprandial insulin release in a glucose-dependent manner through directly acting on pancreatic β-cells, which is essential for glucose homeostasis. 2 In addition, exogenous infusion of GLP-1 has been shown to lower glucagon secretion, inhibit hepatic glucose production, delay gastric emptying, and induce satiety, which collectively leads to improved glycemia and enhanced insulin sensitivity. The insulinotropic and anorexigenic actions of GLP-1 make it an appealing candidate for the treatment of obesity.…”