Targeting the ADA/ADO Axis Rescues β-Cell Failure in Type 2 Diabetes.

Abstract

Challenging the view that elevated circulating adenosine deaminase (ADA) is merely a secondary phenomenon, this study defines its pathogenic role in linking dyslipidemia to β-cell failure and establishes adenosine (ADO) homeostasis restoration as a disease-remitting therapy. We identify tissue-specific compensatory ADA upregulation that paradoxically fails to prevent systemic ADO accumulation, with elevated adenosine selectively inducing apoptosis in immune and pancreatic β-cells. We establish a novel systemic clearance-local decompression therapeutic mechanism in which exogenous ADA reduces circulating ADO, normalizes compensatory tissue ADA hyperactivity, and rescues islet function. This work redefines plasma ADA from a diagnostic marker to a therapeutic target, providing the rationale for an ADA-based therapy that uniquely combines immune modulation with metabolic correction to halt β-cell failure progression.