Presence Of Glucagon-like Peptide-1 Receptor Research Articles

Glucagon-like peptide-1 receptor mediates the improvement in glycolipid metabolism disorder via AKT and AMPK signalling pathways in L02 cells with insulin resistance

Glucagon-like peptide 1 (GLP-1) has previously been found to regulate glycolipid metabolism in the liver by promoting insulin secretion. However, the presence of GLP-1 receptors (GLP-1R) in the human liver has not been determined. In this research, GLP-1R was found to be expressed in L02 cells and decreased in insulin resistant (IR) cells. Compared with LG treatment group, GLP-1R knockdown significantly decreased glucose utilization (from 143.13% to 118.41%.) and intracellular glycogen content (from 122.77% to 105.72%). Furthermore, the transcription levels of PEPCK and G6Pase increased, and the phosphorylation levels of AKT, FOXO1 and GSK3β decreased in siGLP-1R group. Similarly, the contents of triglyceride and total cholesterol in siGLP-1R group increased by 43.23% and 24.19%, respectively. PCR and WB results showed that knockdown of GLP-1R increased the levels of ACC, FAS, and SREBP-1c, and decreased the levels of CPT-1 via AMPK pathway. GLP-1R knockdown changed the LG-induced promotion of glucose utilization and inhibition of lipid synthesis. These findings demonstrated that GLP-1R is the molecular basis for GLP-1 to improve glycolipid metabolism in L02 cells.

Liraglutide Inhibits the Apoptosis of MC3T3-E1 Cells Induced by Serum Deprivation through cAMP/PKA/β-Catenin and PI3K/AKT/GSK3β Signaling Pathways.

In recent years, the interest towards the relationship between incretins and bone has been increasing. Previous studies have suggested that glucagon-like peptide-1 (GLP-1) and its receptor agonists exert beneficial anabolic influence on skeletal metabolism, such as promoting proliferation and differentiation of osteoblasts via entero-osseous-axis. However, little is known regarding the effects of GLP-1 on osteoblast apoptosis and the underlying mechanisms involved. Thus, in the present study, we investigated the effects of liraglutide, a glucagon-like peptide-1 receptor agonist, on apoptosis of murine MC3T3-E1 osteoblastic cells. We confirmed the presence of GLP-1 receptor (GLP-1R) in MC3T3-E1 cells. Our data demonstrated that liraglutide inhibited the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation, as detected by Annexin V/PI and Hoechst 33258 staining and ELISA assays. Moreover, liraglutide upregulated Bcl-2 expression and downregulated Bax expression and caspase-3 activity at intermediate concentration (100 nM) for maximum effect. Further study suggested that liraglutide stimulated the phosphorylation of AKT and enhanced cAMP level, along with decreased phosphorylation of GSK3β, increased β-catenin phosphorylation at Ser675 site and upregulated nuclear β-catenin content and transcriptional activity. Pretreatment of cells with the PI3K inhibitor LY294002, PKA inhibitor H89, and siRNAs GLP-1R, β-catenin abrogated the liraglutide-induced activation of cAMP, AKT, β-catenin, respectively. In conclusion, these findings illustrate that activation of GLP-1 receptor by liraglutide inhibits the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation through cAMP/PKA/β-catenin and PI3K/Akt/GSK3β signaling pathways.

Short communication: Expression of peptide YY, proglucagon, neuropeptide Y receptor Y2, and glucagon-like peptide-1 receptor in bovine peripheral tissues

The role of distal gut signals in control of feed intake and metabolism in cattle has received scant attention. Peptide YY (PYY) and glucagon-like peptide-1, which are secreted from enteroendocrine cells of the distal gut in monogastrics have several functions, including regulation of energy balance. However, little is known of the tissue expression of these peptides and their receptors in cattle. The aim of the current study was to characterize the tissue distribution of PYY, neuropeptide Y receptor Y2 (Y2), proglucagon (GCG), and glucagon-like peptide-1 receptor (GLP1R) in various peripheral tissues of cattle. Four male 7-wk-old dairy calves were euthanized and 16 peripheral tissues were collected. Conventional PCR and quantitative real-time PCR were performed to confirm tissue expression and quantify the transcript abundance in various tissues. The results of conventional PCR revealed that mRNA for both PYY and Y2 was detectable in the rumen, abomasum, duodenum, jejunum, ileum, and colon but not in other tissues. Quantitative real-time PCR data demonstrated that PYY mRNA was 2- to 3-fold greater in the pancreas, kidney, and heart relative to the liver. By conventional PCR, GCG mRNA was detected in the abomasum, duodenum, jejunum, ileum, and colon and GLP1R mRNA was expressed in all gut segments, pancreas, spleen, and kidney. Quantitative real-time PCR data demonstrated that, relative to transcript abundance in the liver, GCG mRNA was 4- to 40-fold higher from abomasum to colon, and GLP1R mRNA was 50- to 300-fold higher from the rumen to colon, 14-fold greater in the pancreas, 18-fold higher in the spleen, and 166-fold greater in the kidney. The tissue distribution of PYY, GCG, and their receptors observed in the current study is, in general, consistent with expression patterns in monogastrics. The predominant expression of PYY, Y2, and GCG in the gut, and the presence of GLP1R in multiple peripheral tissues suggest a role for PYY in controlling gut functions and for GLP-1 in regulating multiple physiological functions in cattle.

Inhibition of the Expression of TGF-β1 and CTGF in Human Mesangial Cells byExendin-4, a Glucagon-like Peptide-1Receptor Agonist

Background: Despite the presence of glucagon-like peptide-1 receptor (GLP-1R) in kidney tissues, its direct effect on diabetic nephropathy remains unclear. The transforming growth factor-β₁(TGF-β₁) and the connective tissue growth factor (CTGF) both induce extracellular matrix accumulation and persistent fibrosis in the glomerular mesangium of patients with diabetic nephropathy. Objective: Herein, we demonstrate that a GLP-1R agonist, exendin-4, exerts renoprotective effects through its influence on TGF-β₁and CTGF in human mesangial cells (HMCs), cultured in a high glucose medium. Method: HMCs, cultured in a high glucose medium, were used for the current study. The direct effect of exendin-4 on TGF-β₁and CTGF expression was confirmed in HMCs. MDL-12330A (a specific adenylate cyclase inhibitor) and PKI14-22 (a protein kinase A inhibitor) were used to examine the role of the cAMP signaling pathway in exendin’s anti-fibrosis action. Results: The findings showed that exendin-4 inhibited the proliferation of HMCs, and upregulated the expression of TGF-β₁and CTGF, induced by high glucose. The effect of exendin-4 is largely dependent on the activation of adenylate cyclase. Conclusion: This study provides new evidence that GLP-1 acts as an antifibrotic agent in HMCs.

The GLP-1 Concept in the Treatment of Type 2 Diabetes—Still Standing at the Gate of Dawn?

The pandemic explosion of type 2 diabetes incidence is well established, due to dramatic global changes in lifestyle over the past few decades and in the foreseeable future. To alter the course of this trend may take, at best, up to half a century. Until then, we need, in addition to lifestyle guidance, pharmacological solutions to reduce the markedly increasing incidence of macrovascular complications that, in its wake, confer a huge burden on patients and their families as well as an enormous economic burden to society. In the United States, for example, diabetes afflicts more than 21 million people, with an estimated cost of around $130 billion annually (http://diabetes.niddk.nih.gov/ dm/pubs/statistics/index.htm#7). The Steno 2 study has clearly demonstrated the efficacy of aggressive intervention against dyslipidemia, hypertension, and elevated glycemia brought on by diabetes (1). In daily life, however, it is also clear that less than half of the type 2 diabetic patients reach the recommended glycemic level employing so-called standard therapy, i.e. sulfonylureas, metformin, thiazolidinediones, and insulin. Hence, all new efficient blood glucose-lowering compounds without serious side effects are greeted with open arms. The glucagon like peptide-1 (GLP-1) concept holds promise. GLP-1 is mainly secreted by the intestinal L cells, although neural signals probably also contribute. The active peptides [GLP-1(7-37) and GLP-1(7-36) amide] increase insulin secretion in a glucose-dependent manner, i.e. lowering risk of hypoglycemia, decreasing basal as well as postprandial glucagon secretion, delaying gastric emptying, and increasing satiety by actions in the hypothalamus. Animal and in vitro models have shown that GLP-1 also increases -cell proliferation and neogenesis and decreases apoptosis (2). In these models, GLP-1 has other extrapancreatic effects beyond those described above, but whether these effects are also reflected in humans remains to be seen. In the circulation, GLP-1 undergoes enzymatic deactivation to GLP-1(9-37) and GLP-1(9-36) amide within minutes, primarily by dipeptidyl peptidase-4 (DPP-4), an enzyme present on the surface of lymphocytes, macrophages, and endothelial cells, and in tissues, such as the pancreas, liver, intestine, kidneys, and lungs. Localization of DDP-4 in endothelial cells indicates that degradation already takes place upon GLP-1 entry into the capillaries; endothelial DPP-4 in the liver degrades 50% of the protein. From this it can be deduced that only approximately 15% of the secreted GLP-1 reaches the pancreas in its intact form (3). DPP-4 also metabolizes other biologically active peptides of relevance in the regulation of carbohydrate metabolism such as glucose-dependent insulinotropic polypeptide, vasoactive intestinal polypeptide, and gastrin-releasing polypeptide. Active GLP-1 operates through the GLP-1 receptor (GLP-1R) belonging to the class B family of seven-transmembrane-spanning, heterotrimeric G protein-coupled receptors. Apart from the cells of the islet of Langerhans, several tissues express GLP-1R, including the heart, central nervous system, kidneys, lungs, stomach, intestine, and pituitary gland, as well as the nodose ganglion of abdominal vagal afferent nerve fibers, the central branches of which terminate in the brain stem. The presence of GLP-1Rs in skeletal muscle, liver, and adipose tissue is debatable. Due to the short half-life of native GLP-1, it is not feasible for long-term use, but its parenteral use may be of interest during acute medical and/or surgical conditions (4). For long-term therapy, two classes of pharmaceutical agents are involved and are still in development: 1) long-acting analogs, or so-called GLP-1 mimetics; and 2) DPP-4 inhibitors, or so-called incretin enhancers.

The role of glucagon-like peptide 1 in the regulation of glucose homeostasis and satiety.

Glucagon-like peptide 1 (GLP-1) is an insulinotropic peptide secreted by intestinal L-cells (mucosal cells belonging to the APUD (amine precursor uptake and decarboxylation) system in response to oral food intake. GLP-1 is co-encoded in the proglucagon gene and while post-translational processing of proglucagon in the pancreas gives rise to glucagon, GLP-1 (7‐36 amide) is produced in the intestine and to a lesser extent in the hypothalamus. The postprandial secretion of an intestinal factor that lowers plasma glucose levels (incretin) had already been hypothesized a century ago. However, only 10 years ago, when GLP-1 was discovered as a second incretin besides gastric inhibitory peptide (GIP), this concept of an entero‐insular axis became established. Since then the implication of GLP-1 in glucose metabolism and the potential use of this incretin in diabetes have been studied in different models including clinical studies. Recently, GLP-1 has been reported to act centrally as a satiety factor in rodents and this hormone is now also thought of as a ‘gut‐brain peptide’. Finally, a GLP-1 receptor knock-out mouse could be created, confirming the importance of GLP-1 in glucose homeostasis, but casting doubts on its role in appetite regulation. These recent findings help to clarify the physiological importance of GLP-1 and are discussed in the present highlight. GLP-1 concentrations in the picomolar range induce insulin secretion from pancreatic b-cells in vitro and in vivo when elevated glucose concentrations (> 5 mmol/l) are present. In patients with non-insulin-dependent diabetes mellitus (NIDDM) parenteral (i.v. and s.c.) administration of GLP-1 led to reconstitution of the early phase insulin secretion and reduction of postprandial glucose excursions. Even in insulin-deficient type-1 diabetic patients GLP-1 reduced the insulin requirements, suggesting additional peripheral activities (1, 2). In contrast to sulfonylurea drugs, GLP-1 not only stimulates insulin secretion, but also proinsulin gene transcription via activation of the transcription factor CREB (cyclic AMP-responsive element binding protein), potentially counteracting the problem of insulin depletion of the b-cell (1). In patients with NIDDM, overnight infusion of GLP-1 improved basal and stimulated b-cell function to the level of non-diabetic controls (3). GLP-1 plasma levels are elevated in patients with NIDDM and even pharmacological doses of GLP-1 have attenuated glucose-lowering effects compared with healthy subjects. This partial resistance to GLP-1 in NIDDM is not due to a receptor defect (4) but is speculated to be caused by GLP-1 induced desensitization of pancreatic GLP-1 receptors. The GLP-1 receptor, a 63 kDa protein belonging to the group of trimeric G-protein linked receptors signaling via cyclic AMP, is found on pancreatic islets (b and d cells), adipose tissue, skeletal muscle, liver, intestine, stomach, lung and brain (hypothalamus) (1). The presence of GLP-1 receptors in hypothalamic nuclei implicated in appetite regulation raised the question whether GLP-1 might be involved in feeding behavior (5). In addition, intestinal GLP-1 secretion seems to be attenuated in obese subjects (6).