lactisole and 3-deoxyglucosone

Sweet taste receptors (STRs) expressed on β‑cells stimulate insulin secretion in response to an increase in the circulating level of glucose, maintaining glucose homeostasis. 3‑Deoxyglucosone (3DG), a highly reactive α‑dicarbonyl compound, has been previously described as an independent factor associate with the development of prediabetes. In our previous study, pathological plasma levels of 3DG were induced in normal rats with a single intravenous injection of 50 mg/kg 3DG, and an acute rise in circulating 3DG induced glucose intolerance by impairing the function of pancreatic β‑cells. The present study aimed to investigate whether the deleterious effects of pathological plasma levels of 3DG on β‑cell function and insulin secretion were associated with STRs. INS‑1 cells, an in vitro model to study rat β‑cells, were treated with various concentrations of 3DG (1.85, 30.84 and 61.68 mM) or lactisole (5 mM). Pancreatic islets were collected from rats 2 h after a single intravenous injection of 50 mg/kg 3DG + 0.5 g/kg glucose. The insulin concentration was measured by ELISA. The protein expression levels of components of the STR signaling pathways were determined by western blot analysis. Treatment with 3DG and 25.5 mM glucose for 1 h significantly reduced insulin secretion by INS‑1 cells, which was consistent with the phenotype observed in INS‑1 cells treated with the STR inhibitor lactisole. Accordingly, islets isolated from rats treated with 3DG exhibited a significant reduction in insulin secretion following treatment with 25.5 mM glucose. Furthermore, acute exposure of INS‑1 cells to 3DG following treatment with 25.5 mM glucose for 1 h significantly reduced the protein expression level of the STR subunit taste 1 receptor member 3 and its downstream factors, transient receptor potential cation channel subfamily M member 5 and glucose transporter 2. Notably, islet tissues collected from rats treated with 3DG exhibited a similar downregulation of these factors. The present results suggested that acute exposure to pathologically relevant levels of 3DG in presence of high physiological levels of glucose decreased insulin secretion from β‑cells by, at least in part, downregulating the STR signaling pathway.

Topics: Animals; Benzene Derivatives; Cells, Cultured; Deoxyglucose; Down-Regulation; Glucose; Glucose Transporter Type 2; Insulin Secretion; Insulin-Secreting Cells; Male; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Signal Transduction; TRPM Cation Channels

Sweet taste receptors (STRs) involve in regulating the release of glucose-stimulated glucagon-like peptide-1 (GLP-1). Our in vivo and in vitro studies found that 3-deoxyglucosone (3DG) inhibited glucose-stimulated GLP-1 secretion.. This study investigated the role of STRs in 3DG-induced inhibition of high glucose-stimulated GLP-1 secretion.. STC-1 cells were incubated with lactisole or 3DG for 1 h under 25 mM glucose conditions. Western blotting was used to study the expression of STRs signaling molecules and ELISA was used to analyse GLP-1 and cyclic adenosine monophosphate (cAMP) levels.. Lactisole inhibited GLP-1 secretion. Exposure to 25 mM glucose increased the expressions of STRs subunits when compared with 5.6 mM glucose. 3DG decreased GLP-1 secretion and STRs subunits expressions, with affecting other components of STRs pathway, including the downregulation of transient receptor potential cation channel subfamily M member 5 (TRPM5) expression and the reduction of intracellular cAMP levels.. 3DG attenuates high glucose-stimulated GLP-1 secretion by reducing STR subunit expression and downstream signaling components.

Topics: Animals; Benzene Derivatives; Blotting, Western; Cell Line; Cyclic AMP; Deoxyglucose; Dietary Sugars; Down-Regulation; Enteroendocrine Cells; Enzyme-Linked Immunosorbent Assay; Glucagon-Like Peptide 1; Glucose; Intestinal Secretions; Mice; Osmolar Concentration; Protein Subunits; Receptors, G-Protein-Coupled; Second Messenger Systems; TRPM Cation Channels