The endothelin system: a potential target for the treatment of type 2 diabetes mellitus and associated cardiometabolic complications.

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance (IR), metabolic dysfunction, and cardiovascular (CV) and renal complications. Endothelin-1 (ET-1) receptors are widely expressed in insulin-sensitive tissues, including adipose tissue, skeletal muscle, and liver, which are both sources and targets of ET-1 action. Dysregulated ET-1 signaling promotes IR, altered glucose and lipid metabolism, inflammation, oxidative stress, and vascular dysfunction, contributing to obesity, CV complications, and multiorgan injury. In this review, we examine the role of ET-1 in T2DM complications, the indirect modulation of the ET system by established antidiabetic therapies, and the therapeutic potential of directly targeting ET-1 receptors and inhibiting ET-1 overproduction. We further discuss translational challenges and opportunities for combination therapies, biomarker-guided interventions, and precision ET-targeted approaches in cardiometabolic disease.