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Targeting GLP-1 receptor trafficking to improve agonist efficacy.

ABSTRACT: Glucagon-like peptide-1 receptor (GLP-1R) activation promotes insulin secretion from pancreatic beta cells, causes weight loss, and is an important pharmacological target in type 2 diabetes (T2D). Like other G protein-coupled receptors, the GLP-1R undergoes agonist-mediated endocytosis, but the functional and therapeutic consequences of modulating GLP-1R endocytic trafficking have not been clearly defined. Here, we investigate a series of biased GLP-1R agonists with variable propensities for GLP-1R internalization and recycling. Compared to a panel of FDA-approved GLP-1 mimetics, compounds that retain GLP-1R at the plasma membrane produce greater long-term insulin release, which is dependent on a reduction in ?-arrestin recruitment and faster agonist dissociation rates. Such molecules elicit glycemic benefits in mice without concomitant increases in signs of nausea, a common side effect of GLP-1 therapies. Our study identifies a set of agents with specific GLP-1R trafficking profiles and the potential for greater efficacy and tolerability as T2D treatments.

SUBMITTER: Jones B

PROVIDER: S-EPMC5913239 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Targeting GLP-1 receptor trafficking to improve agonist efficacy.

Jones Ben B Buenaventura Teresa T Kanda Nisha N Chabosseau Pauline P Owen Bryn M BM Scott Rebecca R Goldin Robert R Angkathunyakul Napat N Corrêa Ivan R IR Bosco Domenico D Johnson Paul R PR Piemonti Lorenzo L Marchetti Piero P Shapiro A M James AMJ Cochran Blake J BJ Hanyaloglu Aylin C AC Inoue Asuka A Tan Tricia T Rutter Guy A GA Tomas Alejandra A Bloom Stephen R SR

Nature communications 20180423 1

Glucagon-like peptide-1 receptor (GLP-1R) activation promotes insulin secretion from pancreatic beta cells, causes weight loss, and is an important pharmacological target in type 2 diabetes (T2D). Like other G protein-coupled receptors, the GLP-1R undergoes agonist-mediated endocytosis, but the functional and therapeutic consequences of modulating GLP-1R endocytic trafficking have not been clearly defined. Here, we investigate a series of biased GLP-1R agonists with variable propensities for GLP ...[more]

PMID: 29686402

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Project description:B6.Cg-Lep ob/ob mice females were surgically implanted in an age of 10-12 weeks with Alzet osmotic mini pumps (model 1002, 0,25l/h, Cupertino, CA, USA) in two groups of ten mice each to perform continuous subcutaneous infusions of Dulbecco's phosphate buffered saline (vehicle; n = 8) or GLP-1 (GLP-1; n = 9) agonist Liraglutide (Victoza, batch# CS6C214, Novo Nordisk A/S, Bagsvaerd, Denmark) to investigate the effects of the respective treatment on peri-gonadal epididymal white adipose tissue gene expression. Vehicle or Liraglutide at a dose of 600 g/kg/d were continuously infused (at a dose of 600 g/kg/d) over a 14 days period. On the morning after the osmotic mini pump reservoirs liquid content should have been consumed mice were dissected to remove the peri-gonadal epididymal fat pad for white adipose tissue gene expression analysis. At least 220 mg of white adipose tissue was quickly removed, shock-frozen in liquid nitrogen and thereafter stored at -80C for mRNA extraction. To perform RNA-Seq analysis, samples were single-end sequenced at a depth of 75 80M reads per sample with a read-length of 51 bp using an Illumina Hiseq2500. Raw sequencing files were quality controlled with FastQC. Alignment and trimming of reads was performed using the OSA algorithm against the mouse reference genome b38.1 with RefSeq as the gene model as implemented in OmicSoft ArraySuite software, version 8. RNA transcripts were quantified using RSEM methods as implemented in Arraystudio counting count the read fragments mapping to each individual gene and quantify expression by the corresponding FPKM. In summary, expression was measured as FPKM for 25,054 unique genes. Principal component analysis was then performed to check for possible batch effects and outliers complemented by calculating the RNA-Seq 5'->3' trend for each sample. One sample for the vehicle control as well as for the Liraglutide group were identified as outliers and removed from subsequent analysis, resulting in 7 and 8 samples remaining for each group respectively. Abundance values (counts) were normalized and compared between liraglutide treated mice versus baseline controls using DESeq2. All P-values were adjusted for multiple testing by the Benjamini-Hochberg method.

Dataset Information

Targeting GLP-1 receptor trafficking to improve agonist efficacy.

Publications

Targeting GLP-1 receptor trafficking to improve agonist efficacy.

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