Recent advances in understanding GLP-1R (glucagon-like peptide-1 receptor) function

Koole, Cassandra; Pabreja, Kavita; Savage, Emilia Elizabeth; Wootten, Denise; Furness, Sebastian G.B.; Miller, Laurence J.; Christopoulos, Arthur; Sexton, Patrick M.

doi:10.1042/bst20120236

Cited by 61 publications

(52 citation statements)

References 51 publications

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“…FASN is the key enzyme in the de novo lipogenesis, whereas ATGL is an important enzyme for lipolysis. In consistency with previous studies [11,41,52,53], we found that LG treatment significantly reduced FASN expression in both protein and mRNA levels, but had on obvious effect on ATGL expression. Additional experiments showed that LG-induced down-regulation of FASN was accompanied with increased phosphorylation of pCREB and ERK, and specific inhibitors for PKA and ERK partially prevented LG induced FASN down-regulation.…”

Section: Discussionsupporting

confidence: 81%

GLP-1/GLP-1R Signaling in Regulation of Adipocyte Differentiation and Lipogenesis

Chen

Zhao

et al. 2017

Cell Physiol Biochem

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Key Words Liraglutide • 3T3-L1 preadipocytes • Adipogenesis • FASN AbstractBackground/Aims: The aim of this study was to determine the direct role of liraglutide (LG) in adipogenesis and lipid metabolism. Methods: Lipid accumulation was evaluated by oil red O staining, quantitative real-time PCR (qPCR) was performed to determine glucagon-like peptide 1 receptor (GLP-1R), fatty acid synthase (FASN) and adipose triglyceride lipase (ATGL) expression in 3T3-L1 preadipocytes, differentiated adipocytes and in adipose tissues from mice. The effects of LG on 3T3-L1 adipogenesis and lipid metabolism were analyzed with qPCR, Western Blotting, oil red O staining, immunohistochemistry (IHC) and immunofluorescence (IF). All measurements were performed at least three times. Results: LG increased the expression of differentiation marker genes and lipid accumulation during preadipocyte differentiation. In differentiated adipocytes, LG decreased FASN expression, and simultaneously led to CREB phosphorylation and ERK1/2 activation which were abolished by a GLP-1R antagonist, exendin (9-39).LG induced-FASN down-regulation was partially reversed by PKA and ERK1/2 inhibitors. Consistent with above in vitro findings, LG treatment significantly reduced FASN expression in visceral adipose tissues of ob/ob mice, and reduced body weight gain. Conclusion: LG promotes preadipocytes differentiation, and inhibits FASN expression in adipocytes.LG induced down-regulation of FASN is at least partially mediated by PKA and MAPK signaling pathways.

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Section: Discussionsupporting

confidence: 81%

GLP-1/GLP-1R Signaling in Regulation of Adipocyte Differentiation and Lipogenesis

Chen

Zhao

et al. 2017

Cell Physiol Biochem

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“…The reason for the apparent failure to find such a mimetic agonist for the PTHR1 remains unresolved, but the problem can be seen as a common thread within the family B peptide hormone GPCRs, which, as a class, have yielded only very few small molecule agonist ligands and likely relates to their basic molecular modes of action (Hoare, 2007;Koole et al, 2013). Defining these modes of action could thus provide insights not only into the basic mechanism by which these receptors function but also into how they might be better targeted for the development of more effective therapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCIII. The Parathyroid Hormone Receptors—Family B G Protein–Coupled Receptors

Gardella

Vilardaga

2015

Pharmacol Rev

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“…Moreover, this hormone stimulates the transcription of insulin and Interestingly, the positive effect of GLP-1 seems not to be limited to glycemic control, 5 in fact it delays gastric emptying, inducing satiety with a consequent reduction in food intake and it seems to have a cardio-, vaso-and nephroprotective effect. [7][8][9][10] Due to various favorable cardiometabolic and insulinotropic effects, GLP-1 is a very attractive candidate in the management of T2DM. Exogenous administration of GLP-1 analogues (exenatide, liraglutide) and the abatement of degradation by DPP-4 inhibitors (saxagliptin, sitagliptin, vildagliptin) are the two approaches used to obtain or maintain high levels of GLP-1.…”

Section: Introductionmentioning

confidence: 99%

Sitagliptin versus saxagliptin in decompensated type 2 diabetes mellitus patients

et al. 2016

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Type 2 diabetes mellitus (T2DM) is a chronic and progressive disease, characterized by persistent hyperglycemia, due to both a decline of b-pancreatic insulin production and an increased peripheral insulin resistance. The incidence of this pathology is increasing rapidly, indeed, it was estimated that the number of diabetics will arise from 371 million (2012) to 552 million (2030), representing one of the major challenge to health care worldwide. 1Traditional therapies can be still considered suboptimal, since there are no treatments able to guarantee a perfect glycemic control and a stable prevention of diabetic complications, without the risk of hypoglycemia.2 For these reasons, the finding that particular hormones, called glucon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, are able to induce a greater secretion of insulin only in the presence of high level of glucose, has quickly attracted the attention of scientists. 3,4 GLP-1 is a polypeptide, secreted by endocrine cells of small intestine during the digestive phase; the glucose in the intestinal lumen acts as a trigger and induces the release of this hormone. Through the circulation, GLP-1 reaches its receptor on bpancreatic cells, stimulating the secretion of insulin in relation to the amount of glucose concentration. Physiologically, the half-life of endogenous GLP-1 is around 2 min; this hormone, indeed, is quickly degraded by a specific peptidase, the dipeptdylpeptidase 4 (DPP-4). 5In addition to the stimulus of insulin secretion, the hypoglycemic effect of this substance is enhanced by the inhibition of glucagon release. Moreover, this hormone stimulates the transcription of insulin and ABSTRACTSitagliptin and saxagliptin are oral hypoglycemic agents inhibitors of DPP-4, indicated in the treatment of type 2 diabetes mellitus in combination with metformin, in patients who have not achieved adequate glycemic control. In our study we enrolled 128 decompensated type 2 diabetes patients while on metformin maximum dosage. At time 0' we have detected, body mass index (BMI), total cholesterol, high-and low-density lipoproteins (HDL and LDL), triglycerides, transaminases and pancreatic amylase; patients were randomized to receive sitagliptin or saxagliptin; follow-up was performed after 4 months with the revaluation of the same variables and adverse events. In both sitagliptin and saxagliptin groups we observed a significant reduction in fasting glucose, glycated hemoglobin, weighing, BMI, triglycerides, while the reduction in total cholesterol, LDL cholesterol did not reach statistical significance. There was no suspension of therapy, adverse events appeared minor and temporary. In conclusion, our observations highlight the almost identical efficacy of sitagliptin and saxagliptin. These data reinforce even more the idea that we should think about this class of drugs as the next step in patients failing therapy with metformin.

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Recent advances in understanding GLP-1R (glucagon-like peptide-1 receptor) function

Cited by 61 publications

References 51 publications

GLP-1/GLP-1R Signaling in Regulation of Adipocyte Differentiation and Lipogenesis

GLP-1/GLP-1R Signaling in Regulation of Adipocyte Differentiation and Lipogenesis

International Union of Basic and Clinical Pharmacology. XCIII. The Parathyroid Hormone Receptors—Family B G Protein–Coupled Receptors

Sitagliptin versus saxagliptin in decompensated type 2 diabetes mellitus patients

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