Increased ADORA1 expression in pancreatic islets coincides with insulin secretory defects in human type 2 diabetes

Adenosine receptors (ADORAs) are G-protein coupled receptors that critically modulate cell function, yet their specific roles in regulating insulin and glucagon secretion remain incompletely understood. While RNA sequencing of isolated human islets, confirmed by qPCR, revealed that only ADORA1 and ADORA2A transcripts are abundantly expressed, mouse islets express all four receptor subtypes (Adora1, Adora2a, Adora2b, Adora3). Confocal immunofluorescence demonstrated ADORA1 protein localization in both islet β- and α-cells. Transcriptome correlation analysis of human islets identified 87 genes strongly associated with ADORA1 expression, enriched in pathways regulating carbohydrate and lipid metabolism, cell cycle, apoptosis, proliferation, endocrine system development, and metabolic disease. ADORA1 mRNA levels were positively correlated with HbA1c and elevated in islets of type 2 diabetes (T2D) donors, implicating ADORA1 in β-cell dysfunction. In ob/ob mouse islets, reduced Adora1 expression coincided with enhanced pulsatile insulin secretion, while the control islets showed a biphasic with a weaker second phase insulin secretory response. Adenosine efficiently suppressed insulin secretion in both ob/ob and control islets. ADORA1 antagonist DPCPX attenuated adenosine-induced suppression of insulin release. Adora1-KD mice exhibited a restored, pulsatile second-phase insulin response absent in controls. In human islets, adenosine suppressed both glucose-stimulated insulin secretion and cAMP generation, effects prevented by DPCPX. Adenosine also impaired β-cell viability and proliferation, which were rescued by ADORA1 inhibition. Collectively, our findings identify ADORA1 as a key inhibitory modulator of β-cell function under diabetogenic stress, thereby a promising therapeutic target to preserve insulin secretory capacity in early T2D.