Variation in responses to incretin therapy: Modifiable and non-modifiable factors

Frontiers in Molecular Biosciences, Journal Year: 2023, Volume and Issue: 10

Published: April 7, 2023

Type 2 diabetes (T2D) and obesity have reached epidemic proportions. Incretin therapy is the second line of treatment for T2D, improving both blood glucose regulation weight loss. Glucagon-like peptide-1 (GLP-1) glucose-stimulated insulinotropic polypeptide (GIP) are incretin hormones that provide foundations these drugs. While therapies been highly effective some, results variable. target class B G protein-coupled receptors GLP-1R GIPR, expressed mainly in pancreas hypothalamus, while some therapeutical approaches include additional targeting related glucagon receptor (GCGR) liver. The proper functioning crucial success here we review several mechanisms at cellular molecular level influence an individual’s response to therapy.

Language: Английский

---

NanoSIMS Imaging Reveals the Impact of Ligand-ASO Conjugate Stability on ASO Subcellular Distribution

Pharmaceutics, Journal Year: 2022, Volume and Issue: 14(2), P. 463 - 463

Published: Feb. 21, 2022

The delivery of antisense oligonucleotides (ASOs) to specific cell types via targeted endocytosis is challenging due the low surface expression target receptors and inefficient escape ASOs from endosomal pathway. Conjugating glucagon-like peptide 1 (GLP1) leads efficient knockdown, specifically in pancreatic β-cells. It presumed that dissociate GLP1 intracellularly enable an ASO interaction with its RNA. unknown where or when this happens following GLP1-ASO binding GLP1R endocytosis. Here, we use correlative nanoscale secondary ion mass spectroscopy (NanoSIMS) transmission electron microscopy explore subcellular trafficking overexpressing HEK293 cells. We isotopically label both eGLP1 ASO, which do not affect eGLP1-ASO conjugate function. found are detected at same level endosomes, within 30 min GLP1R-HEK293 exposure eGLP1-ASO. When utilized different linker chemistry stabilize conjugate, observed more located compared incubation less stable conjugate. Overall, our work suggests separates relatively early endocytic pathway, might impact

Language: Английский

---

Peptide-Coated Polycaprolactone-Benzalkonium Chloride Nanocapsules for Targeted Drug Delivery to the Pancreatic β-Cell

ACS Applied Bio Materials, Journal Year: 2024, Volume and Issue: 7(10), P. 6451 - 6466

Published: Sept. 24, 2024

Targeting current therapies to treat or prevent the loss of pancreatic islet β-cells in Type 1 Diabetes (T1D) may provide improved efficacy and reduce off-target effects. Current efforts target β-cell are limited by a lack β-cell-specific targets inability test multiple targeting moieties with same delivery vehicle. Here, we fabricate tailorable polycaprolactone nanocapsule (NC) which different peptides can be interchangeably attached for delivery. Incorporation cationic surfactant NC shell allows attachment Exendin-4 an antibody ectonucleoside triphosphate diphosphohydrolase 3 (ENTPD3) targeting. The average size ranges from 250 300 nm polydispersity index under 0.2. NCs nontoxic, stable media culture, lyophilized reconstituted. coated peptide were taken up human cadaveric stem cell-derived β-like cells (sBC) vitro high level specificity. Furthermore, successfully delivered both hydrophobic hydrophilic cargo β-cells. Additionally, Exendin-4-coated targeted mouse vivo. Overall, our have potential improve cell-targeted drug utilized as screening platform cell-targeting peptides.

Language: Английский

---

Evaluation of efficacy- versus affinity-driven agonism with biased GLP-1R ligands P5 and exendin-F1

Biochemical Pharmacology, Journal Year: 2021, Volume and Issue: 190, P. 114656 - 114656

Published: June 12, 2021

The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of glucose homeostasis and has been successfully targeted for the treatment type 2 diabetes. Recently described biased GLP-1R agonists with selective reductions in β-arrestin versus G protein coupling show improved metabolic actions vivo. However, two prototypical protein-favouring agonists, P5 exendin-F1, are reported to divergent effects on insulin secretion. In this study we aimed resolve discrepancy by performing a side-by-side characterisation these ligands across variety vitro vivo assays. Exendin-F1 showed reduced acute efficacy several readouts, including recruitment mini-G proteins, protein-coupled kinases (GRKs) β-arrestin-2. Maximal responses were also lower both internalisation presence active GLP-1R-mini-G

Language: Английский

---

In vivo and in vitro characterization of GL0034, a novel long‐acting glucagon‐like peptide‐1 receptor agonist

Diabetes Obesity and Metabolism, Journal Year: 2022, Volume and Issue: 24(11), P. 2090 - 2101

Published: June 9, 2022

Abstract Aims To describe the in vitro characteristics and antidiabetic vivo efficacy of novel glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) GL0034. Materials Methods Glucagon‐like (GLP‐1R) kinetic binding parameters, cyclic adenosine monophosphate (cAMP) signalling, endocytosis recycling were measured using HEK293 INS‐1832/3 cells expressing human GLP‐1R. Insulin secretion was cells, mouse islets islets. Chronic administration studies to evaluate weight loss glycaemic effects performed db/db diet‐induced obese mice. Results Compared leading GLP‐1RA semaglutide, GL0034 showed increased affinity potency‐driven bias favour cAMP over GLP‐1R β‐arrestin‐2 recruitment. secretory responses similar for both ligands. (6 nmol/kg) led at least as much lowering blood glucose did semaglutide a higher dose (14 nmol/kg). Conclusions is G protein‐biased that shows powerful mice, may serve promising new patients with type 2 diabetes.

Language: Английский

---