The regulation of function, growth and survival of GLP-1-producing L-cells

Abstract

Glucagon-like peptide-1 (GLP-1) is a peptide hormone, released from intestinal L-cells in response to hormonal, neural and nutrient stimuli. In addition to potentiation of meal-stimulated insulin secretion, GLP-1 signalling exerts numerous pleiotropic effects on various tissues, regulating energy absorption and disposal, as well as cell proliferation and survival. In Type 2 Diabetes (T2D) reduced plasma levels of GLP-1 have been observed, and plasma levels of GLP-1, as well as reduced numbers of GLP-1 producing cells, have been correlated to obesity and insulin resistance. Increasing endogenous secretion of GLP-1 by selective targeting of the molecular mechanisms regulating secretion from the L-cell has been the focus of much recent research. An additional and promising strategy for enhancing endogenous secretion may be to increase the L-cell mass in the intestinal epithelium, but the mechanisms that regulate the growth, survival and function of these cells are largely unknown. We recently showed that prolonged exposure to high concentrations of the fatty acid palmitate induced lipotoxic effects, similar to those operative in insulin-producing cells, in an in vitro model of GLP-1-producing cells. The mechanisms inducing this lipototoxicity involved increased production of reactive oxygen species (ROS). In this review, regulation of GLP-1-secreting cells is discussed, with a focus on the mechanisms underlying GLP-1 secretion, long-term regulation of growth, differentiation and survival under normal as well as diabetic conditions of hypernutrition.

Vertical sleeve gastrectomy activates GPBAR‐1/TGR5 to sustain weight loss, improve fatty liver, and remit insulin resistance in mice

“…GLP‐1 is a powerful hormone whose ability to stimulate insulin secretion and normalize glucose levels has been widely documented, and GLP‐1 levels increase after bariatric surgery . Surprisingly, it has been reported that the GLP‐1 receptor is not required for the therapeutic effects of bariatric surgeries .…”

“…Furthermore, the activation of TGR5 by the selective agonist INT‐777 triggers an increase in glucagon‐like peptide‐1 (GLP‐1) secretion in enteroendocrine L cells of the intestinal epithelium . This incretin gut hormone modulates insulin secretion and sensitivity, glucagon secretion, and β cell mass, thus improving glucose homeostasis . In light of these findings, we hypothesized that the activation of BA signaling, through its receptor TGR5, contributes to the insulin‐sensitizing effects of VSG surgery.…”

On the relationship between glucose absorption and glucose‐stimulated secretion of GLP ‐1, neurotensin, and PYY from different intestinal segments in the rat

“…; Gribble and Reimann ; Kuhre et al. ). For instance, the high concentration of these peptides in the colon raises the question whether a similarly large secretion can be elicited from this part of the gut.…”

Investigation of triamterene as an inhibitor of the TGR5 receptor: identification in cells and animals

“…GLP-1 plays an important role in the regulation of glucose homeostasis via actions including increasing glucose-dependent insulin secretion, proinsulin gene expression, and β-cell proliferation and anti-apoptotic signaling 31. Therefore, we investigated the in vivo effects of triamterene on STZ-induced diabetic rats.…”