GLP1R

AIMS/HYPOTHESIS: Diabetes mellitus is associated with impaired insulin secretion, often aggravated by oversecretion of glucagon. Therapeutic interventions should ideally correct both defects. Glucagon-like peptide 1 (GLP-1) has this capability but exactly how it exerts its glucagonostatic effect remains obscure. Following its release GLP-1 is rapidly degraded from GLP-1(7-36) to GLP-1(9-36). We hypothesised that the metabolite GLP-1(9-36) (previously believed to be biologically inactive) exerts a direct inhibitory effect on glucagon secretion and that this mechanism becomes impaired in diabetes...

The neurobiology of eating disorders [EDs; anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED)] remains poorly understood. Here, I describe how neuroimaging, accompanied by peripheral endocrine measures, can provide insights into the neurobiological drivers of eating disorders. Orexins/hypocretins, glucagon-like peptide-1 receptor (GLP1R) agonists, and psilocybin are highlighted as avenues for investigation.

The Cre-loxP strategy for tissue-specific gene inactivation has become a widely employed tool in several research studies. Conversely, inadequate breeding and genotyping without considering the potential for non-specific Cre-recombinase expression may lead to misinterpretations of results. Nestin-Cre transgenic mice, widely used for the selective deletion of genes in neurons, have been observed to have an incidence of Cre-line germline recombination. In this study, we attempted to generate neuron-specific Glucagon-like peptide 1 receptor (Glp1r) knock-out mice by crossing mice harboring the Nestin-Cre transgene with mice harboring the Glp1r gene modified with loxP insertion, in order to elucidate the role of Glp1r signaling in the nervous system...

The melanocortin-3 receptor (MC3R) acts presynaptically to regulate GABA release from agouti-related protein (AgRP) nerve terminals and thus may be a negative regulator of multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of MC3R in regulating the response to various anorexigenic agents. Our findings reveal that genetic deletion or pharmacological inhibition of MC3R improves the dose responsiveness to Glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss...

The metabolic benefits of GLP-1 receptor (GLP-1R) agonists on glycemic and weight control are well established as therapy for type 2 diabetes and obesity. Glucagon's ability to increase energy expenditure is well described, and the combination of these mechanisms-of-actions has the potential to further lower hepatic steatosis in metabolic disorders and could therefore be attractive for the treatment for non-alcoholic steatohepatitis (NASH). Here, we have investigated the effects of a dual GLP-1/glucagon receptor agonist NN1177 on hepatic steatosis, fibrosis, and inflammation in a preclinical mouse model of NASH...

Food-derived biological signals are transmitted to the brain via peripheral nerves through the paracrine activity of gastrointestinal (GI) hormones. The signal transduction circuit of the brain-gut axis has been analyzed in animals; however, species-related differences and animal welfare concerns necessitate investigation using in vitro human experimental models. Here, we focused on the receptors of five GI hormones (CCK, GLP1, GLP2, PYY, and serotonin (5-HT)), and established human induced pluripotent stem cell (iPSC) lines that functionally expressed each receptor...

BACKGROUND: Both genetic and epigenetic variations of GLP1R influence the development and progression of obesity. However, the underlying mechanism remains elusive. This study aims to explore the mediation roles of obesity-related methylation sites in GLP1R gene variants-obesity association. METHODS: A total of 300 Chinese adult participants were included in this study and classified into two groups: 180 metabolically healthy obesity (MHO) cases and 120 metabolically healthy normal-weight (MHNW) controls...

Conjugates of therapeutic oligonucleotides (ONs) including peptide conjugates, provide a potential solution to the major challenge of specific tissue delivery faced by this class of drugs. Conjugations are often positioned terminal at the ONs, although internal placement of other chemical modifications are known to be of critical importance. The introduction of internal conjugation handles in chemically modified ONs require highly specialized and expensive nucleoside phosphoramidites. Here, we present a method for synthesizing a library of peptide-siRNA conjugates by conjugation at internal phosphorous positions via sulfonylphosphoramidate modifications incorporated into the sense strand...

Glucose is essential to the physiological processes of vertebrates. Mammalian physiological stability requires a relatively stable blood glucose level (~5 mmol/L), whereas other vertebrates have greater flexibility in regulating blood glucose (0.5-25 mmol/L). GCGR family receptors play an important role in vertebrate glucose regulation. Here, we examine the evolution of the GCGR family ligand‒receptor systems in different species. Comparatively, we discover that the conserved sequences among GCG family ligands lead to the non-specific activation of ligands across species...

Liraglutide and other agonists of the glucagon-like peptide 1 receptor (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. GLP-1RAs inhibit hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc) but only indirectly, implicating synaptic afferents to AgRP neurons. To investigate, we developed a method combining rabies-based connectomics with single-nuclei transcriptomics. Applying this method to AgRP neurons in mice predicts 21 afferent subtypes in the mediobasal and paraventricular hypothalamus...

Dipeptidyl-peptidase IV (DPP4) inhibitors are an important class of anti-diabetic drugs recognised for their systemic biological actions. Polyherbal preparations like Ayurveda formulations are considered to be ideal sources for discovering novel DPP4 inhibitors owing to their rich phytochemical composition. The current study reports the DPP4 inhibitory potential of a clinically established Ayurvedic anti-diabetic formulation Nisakathakadi Kashaya (NK) using in vitro assay and substantiates it by identifying potential bioactives responsible for DPP4 inhibition using computational biology tools...

Partial leptin reduction can induce significant weight loss, while weight loss contributes to partial leptin reduction. The cause-and-effect relationship between leptin reduction and weight loss remains to be further elucidated. Here, we show that FGF21 and the GLP1R agonist liraglutide rapidly induce a reduction in leptin. This leptin reduction contributes to the beneficial effects of GLP1R agonism in metabolic health, as transgenically maintaining leptin levels during treatment partially curtails the beneficial effects seen with these agonists...

The canonical target of the glucagon-like peptide-1 receptor (GLP-1R), Protein Kinase A (PKA), has been shown to stimulate mechanistic Target of Rapamycin Complex 1 (mTORC1) by phosphorylating the mTOR-regulating protein Raptor at Ser791 following β-adrenergic stimulation. The objective of these studies is to test whether GLP-1R agonists similarly stimulate mTORC1 via PKA phosphorylation of Raptor at Ser791 and whether this contributes to the weight loss effect of the therapeutic GLP-1R agonist liraglutide...

The objective is to review the newer pharmacological interventions for obesity, specifically single, dual, and triple incretin receptor agonists that are either available or in the pipeline for treatment of obesity. The three incretin receptor targets are glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon. There are several approved single or dual incretin agonists which are administered subcutaneously daily (e.g., liraglutide) or weekly (e.g., semaglutide, dulaglutide, and exenatide QW), and experimental dual or triple incretin agonists...

The increase in the prevalence of overweight, obesity and associated diseases is a serious problem. The aim of the study was to identify rare variants in obesity-associated genes in young adults with abdominal obesity in our population and to analyze information about these variants in other populations. Targeted high-throughput sequencing of obesity-associated genes was performed (203 young adults with an abdominal obesity phenotype). In our study, all of the 203 young adults with abdominal obesity had some rare variant in the genes associated with obesity...

The pancreatic β cell synthesizes, packages, and secretes insulin in response to glucose-stimulation to maintain blood glucose homeostasis. Under diabetic conditions, a subset of β cells fail and lose expression of key transcription factors (TFs) required for insulin secretion. Among these TFs is Pancreatic and duodenal homeobox 1 (PDX1), which recruits a unique subset of transcriptional coregulators to modulate its activity. Here we describe a novel interacting partner of PDX1, the Staphylococcal Nuclease and Tudor domain-containing protein (SND1), which has been shown to facilitate protein-protein interactions and transcriptional control through diverse mechanisms in a variety of tissues...

AIM: Earlier studies have shown that peptide glucagon-like peptide-1 receptor (GLP-1R) agonists with reduced β-arrestin recruitment show enhanced anti-hyperglycaemic efficacy through avoidance of GLP-1R desensitization. However, the ligand modifications needed to decrease β-arrestin recruitment usually also reduces GLP-1R affinity, therefore higher doses are needed. Here we aimed to develop new, long-acting, G protein-biased GLP-1R agonists with acute signalling potency comparable with semaglutide, to provide insights into specific experimental and therapeutic scenarios...

BACKGROUNDProglucagon can be processed to glucagon-like peptide1 (GLP-1) within the islet, but its contribution to islet function in humans remains unknown. We sought to understand whether pancreatic GLP-1 alters islet function in humans and whether this is affected by type 2 diabetes.METHODSWe therefore studied individuals with and without type 2 diabetes on two occasions in random order. On one occasion, exendin 9-39, a competitive antagonist of the GLP-1 Receptor (GLP1R), was infused, while on the other, saline was infused...

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The glucagon-like peptide 1 receptor (GLP1R) is a major drug target with several agonists being prescribed in individuals with type 2 diabetes and obesity1,2 . The impact of genetic variability of GLP1R on receptor function and its association with metabolic traits are unclear with conflicting reports. Here, we show an unexpected diversity of phenotypes ranging from defective cell surface expression to complete or pathway-specific gain of function (GoF) and loss of function (LoF), after performing a functional profiling of 60 GLP1R variants across four signalling pathways...