Insulin resistance and coronary microvascular dysfunction: a complex interplay

Up to 40-60% of patients undergoing coronary angiography because of angina and/or evidence of inducible ischaemia on non-invasive stress testing are diagnosed with ischaemia and non-obstructive coronary artery disease (INOCA). The pathogenesis of this condition is primarily attributed to two mechanisms: coronary microvascular dysfunction (CMD) and coronary vasospasm. Notably, ischaemic heart disease is the leading cause of death in patients with type 2 diabetes mellitus (T2DM). Insulin resistance (IR), affecting 10-25% of the general adult population, plays a major role in the pathophysiology of T2DM, but can precede diabetes by years. IR is recognised as a major cardiovascular risk factor, involved in endothelial dysfunction and inflammation, two key processes leading to CMD and vasomotor dysfunction. Hyperinsulinaemia, dysglycaemia, and oxidative stress contribute to this complex relationship, yet the connection between IR, CMD and coronary vasospasm remains incompletely defined. Moreover, IR may represent a target for tailored therapies aimed at improving microvascular function and alleviating symptom burden. Although a few studies have investigated this relationship, the molecular mechanisms by which multiple pathways lead to different INOCA endotypes remain incompletely defined. The aim of this review is to summarise current evidence linking IR, CMD and coronary vasospasm, with emphasis on pathophysiological mechanisms and diagnostic approaches, and to highlight future research directions in this clinical setting.