Dataset Information

Development of a novel peripherally acting alpha2A- adrenergic receptor antagonist for anti-diabetic

ABSTRACT: Studies have consistently highlighted the role of the alpha2A-adrenergic receptor (α2AAR) in the pathophysiology of type 2 diabetes (T2D), particularly its contribution to impaired insulin release and β-cell dysfunction. Yohimbine, a potent α2AAR antagonist, has shown therapeutic potential for T2D by improving insulin release, but its clinical application has been limited by central nervous system (CNS) side effects. In this study, we developed a novel, peripherally acting α2AAR antagonist (CDS479-2) using molecular docking analysis and a bioisosteric replacement strategy applied to yohimbine`s structure. cryo-EM structures of α2AAR bound to either yohimbine or CDS479-2 confirm the molecular basis of α2AAR antagonism, validate our docking models, and reveal key ligand-receptor interactions for future drug design. Importantly, animal studies demonstrated that acute administration of CDS479-2 effectively lowered blood glucose and improved glucose tolerance in diabetic mice, without central side effects such as anxiety or blood pressure elevation commonly associated with α2AAR antagonism. Remarkably, once-daily administration of CDS479-2 for 2 weeks resulted in sustained normoglycemia and increased pancreatic β-cell density in diet-induced obese (DIO) mice, with upregulation of key genes involved in β-cell maturation and proliferation. These findings suggest that CDS479-2 represents a promising new approach for the treatment of T2D. Furthermore, the strategy we employed here may serve as a model for optimization for other drugs that with both peripheral and central targets.

ORGANISM(S): Mus musculus

PROVIDER: GSE304258 | GEO | 2026/08/01

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Relative beta cell deficit and increased beta cell apoptosis are hallmarks of type 2 diabetes (T2D). The Insulin/Insulin Growth Factor (Igf) signaling pathway is an established regulator of beta cell survival and is found downregulated in human T2D islets. The Insulin Receptor Substrate 2 (Irs2) plays a central role in the coordination of this pathway in beta cells. Thus, Irs2 knockout mice (Irs2 -/-) exhibit increased beta cell apoptosis that leads to a progressive decline of beta cell mass and hyperglycaemia. In this study, we sought to determine whether the anti-diabetic compound sodium tungstate could prevent the onset of diabetes in Irs2 -/- mice. Oral administration of tungstate resulted in an overall improvement in whole-body glucose tolerance in Irs2 -/- mice which correlated with increased beta cell mass. Enhanced beta cell mass was due to a dramatic reduction of beta cell apoptosis without changes in proliferation. Whole genome gene profiling analysis of islets isolated from treated Irs2 -/- mice confirmed a broad impact of tungstate on cell death pathways. Mechanistically, tungstate induced Erk1/2 phosphorylation in islets in vitro and, in agreement, treated Irs2 -/- islets exhibited increased basal Erk1/2 phosphorylation. Tungstate also downregulated expression of apoptosis-related genes in Irs2-/- islets in vitro, uncovering a direct effect of this compound in islets. All together, our data demonstrate that tungstate can restore beta cell mass and glucose homeostasis in a context of deficient Insulin/Igf signaling. This study underscores the importance of developing strategies specifically designed to arrest beta cell apoptosis as a means to prevent progressive beta cell failure in diabetes. 10-week old WT and Irs2 -/- mice were randomly divided into two treatment group, in a total of 4 experimental groups. For 21 days one group received distilled water as drinking water (untreated group) whilst the other received ad libitum a solution of 2mg/ml of sodium tungstate in distilled water (treated group). For each experimental group 2 independent samples were analysed, in a total of 8 samples.

Dataset Information

Development of a novel peripherally acting alpha2A- adrenergic receptor antagonist for anti-diabetic

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets