title: Molecular mechanisms redirecting the GLP-1 receptor signalling profile in pancreatic β-cells during type 2 diabetes.
abstract: Treatments with β-cell preserving properties are essential for the management of type 2 diabetes (T2D), and the new therapeutic avenues, developed over the last years, rely on the physiological role of glucagon-like peptide-1 (GLP-1). Sustained pharmacological levels of GLP-1 are achieved by subcutaneous administration of GLP-1 analogues, while transient and lower physiological levels of GLP-1 are attained following treatment with inhibitors of dipeptidylpeptidase 4 (DPP4), an endoprotease which degrades the peptide. Both therapeutic classes display a sustained and durable hypoglycaemic action in patients with T2D. However, the GLP-1 incretin effect is known to be reduced in patients with T2D, and GLP-1 analogues and DPP4 inhibitors were shown to lose their effectiveness over time in some patients. The pathological mechanisms behind these observations can be either a decrease in GLP-1 secretion from intestinal L-cells and, as a consequence, a reduction in GLP-1 plasma concentrations, combined or not with a reduced action of GLP-1 in the β-cell, the so-called GLP-1 resistance. Much evidence for a GLP-1 resistance of the β-cell in subjects with T2D have emerged. Here, we review the potential roles of the genetic background, the hyperglycaemia, the hyperlipidaemia, the prostaglandin E receptor 3, the nuclear glucocorticoid receptor, the GLP-1R desensitization and internalisation processes, and the β-arrestin-1 expression levels on GLP-1 resistance in β-cells during T2D.
authors.forename: Morgane
authors.initials: M
authors.lastname: Roussel
authors.forename: Julia
authors.initials: J
authors.lastname: Mathieu
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dalle
mesh_terms: D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism; D006949:Hyperlipidemias / Q000150:complications / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin