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Research Article Volume 18 Issue 4
Insulin resistance and coronary microvascular dysfunction: molecular mechanisms, clinical evidence, and therapeutic perspectives
Ömer Burak ÇELİK, Macit KALÇIK, Mucahit YETİM, Muhammet Cihat ÇELİK, Lütfü BEKAR, Yusuf KARAVELİOĞLU
Received: October 13, 2025 | Published: October 24, 2025
Citation: ÇELİK OB, KALÇIK M, YETİM M, et al. Insulin resistance and coronary microvascular dysfunction: molecular mechanisms, clinical evidence, and therapeutic perspectives. J Cardiol Curr Res. 2025;18(4):197-206. DOI: 10.15406/jccr.2025.18.00632
Abstract
Coronary microvascular dysfunction (CMD) represents a pathological impairment in the regulation of coronary microcirculatory blood flow, occurring in the absence of obstructive epicardial coronary artery disease. Insulin resistance (IR), a central feature of cardiometabolic disorders such as type 2 diabetes mellitus and metabolic syndrome, plays a pivotal role in vascular pathology. IR impairs insulin signaling via the IRS/PI3K/ Akt pathway, reducing nitric oxide bioavailability while enhancing vasoconstrictive and pro-inflammatory signaling through the MAPK pathway. These alterations promote endothelial dysfunction, oxidative stress, inflammation, and structural remodeling of the coronary microvasculature. Clinical and experimental evidence consistently demonstrate an association between IR and CMD, even in the absence of overt diabetes, underscoring the role of IR as an early mediator of microvascular disease. Importantly, CMD is increasingly recognized as a mechanistic link between metabolic abnormalities and adverse cardiovascular outcomes, including heart failure with preserved ejection fraction (HFpEF) and microvascular angina. Therapeutic interventions aimed at improving insulin sensitivity, such as lifestyle modification, metformin, GLP-1 receptor agonists, and SGLT2 inhibitors, have shown promising effects on endothelial function and microvascular health. However, diagnostic challenges persist, and IR-related CMD remains underrepresented in clinical trials. This review summarizes current knowledge on the pathophysiological mechanisms linking IR and CMD, the clinical evidence supporting their association, and potential therapeutic strategies. Understanding these interactions may enable earlier identification and intervention in at-risk patients, ultimately reducing the burden of cardiometabolic disease.
Keywords: coronary microvascular dysfunction, insulin resistance, endothelial dysfunction, oxidative stress, heart failure with preserved ejection fraction (HFpEF)
©2025 ÇELİK, et al. This is an open access article distributed under the terms of the, which permits unrestricted use, distribution, and build upon your work non-commercially.