Distinct Identity of GLP-1R, GLP-2R, and GIPR Expressing Cells and Signaling Circuits Within the Gastrointestinal Tract

Abstract

Enteroendocrine cells directly integrate signals of nutrient content within the gut lumen with distant hormonal responses and nutrient disposal via the production and secretion of peptides, including glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2). Given their direct and indirect control of post-prandial nutrient uptake and demonstrated translational relevance for the treatment of type 2 diabetes, malabsorption and cardiometabolic disease, there is significant interest in the locally engaged circuits mediating these metabolic effects. Although several specific populations of cells in the intestine have been identified to express endocrine receptors, including intraepithelial lymphocytes (IELs) and αβ and γδ T-cells (Glp1r+) and smooth muscle cells (Glp2r+), the definitive cellular localization and co-expression, particularly in regards to the Gipr remain elusive. Here we review the current state of the literature and evaluate the identity of Glp1r, Glp2r, and Gipr expressing cells within preclinical and clinical models. Further elaboration of our understanding of the initiating G-protein coupled receptor (GPCR) circuits engaged locally within the intestine and how they become altered with high-fat diet feeding can offer insight into the dysregulation observed in obesity and diabetes.

The Interaction of Food Allergy and Diabetes: Food Allergy Effects on Diabetic Mice by Intestinal Barrier Destruction and Glucagon-like Peptide 1 Reduction in Jejunum

“…GLP-1 binds to the GLP-1R, a G-protein–coupled receptor widely expressed in the pancreas, gastrointestinal tracts, kidneys, lungs, and hearts [ 79 ]. Glp-1R mRNA expression is the highest in the epithelial fraction of the jejunum, followed by the ileum and colon [ 80 ]. Recently, He and collaborators reported that gut intraepithelial T cells regulate GLP-1 bioavailability by capturing GLP-1 on GLP-1Rs and impacting L cell numbers [ 81 ].…”

Sodium-glucose co-transporter 1 (SGLT1) differentially regulates gluconeogenesis and GLP-1 receptor (GLP-1R) expression in different diabetic rats: a preliminary validation of the hypothesis of “SGLT1 bridge” as an indication for “surgical diabetes”

“…Further, in GLP-1R knockout mice, RYGB still exhibited improved glucose homeostasis (9,14), and a GLP-1R antagonist did not deteriorate glucose homeostasis in patients who achieved diabetes remission following RYGB (5). Our previous study (15) involving ileal transposition performed on Goto-Kakizaki (GK) rats showed rapid improvement of glucose tolerance and a delayed improvement of insulin resistance, accompanied with a decreased insulin level instead of the increased insulin secretion subsequently induced by increased GLP-1 expression (16,17), suggesting that it might have been glucose tolerance improvement rather than increased GLP-1 expression that led to the improvement of insulin resistance. Taken together, the EIA hypothesis cannot fully explain diabetic improvement in MBS, and further studies are required to define the role of GLP-1 in glucose metabolism (18).…”

Glucagon-like Peptide-2 Depresses Ileal Contractility in Preparations from Mice through Opposite Modulatory Effects on Nitrergic and Cholinergic Neurotransmission

“…GLP-2 effects are mediated by its interaction with a specific receptor (GLP-2R), a G protein-coupled receptor expressed in both humans and animals at either the central or the peripheral level [1,6,7], including the gastrointestinal tract [8][9][10]. In the latter, GLP-2R expression occurs in enteroendocrine and subepithelial cells, myofibroblasts and in myenteric neurons [11].…”