Is insulin resistance the Eminence Grise of aging and noncommunicable chronic diseases?

Dzilda Velickiene^1*Izabela Szymczak-Pajor²Aivaras Ratkevicius³

• ¹Institute of Endocrinology, Lithuanian University of Health Sciences, Kaunas, Lithuania, Lietuvos sveikatos mokslu universitetas Medicinos akademija, Kaunas, Lithuania
• ²Uniwersytet Medyczny w Lodzi, Łódź, Poland
• ³Queen Mary University of London, London, United Kingdom

Insulin resistance (IR) is recognized as a central mechanism in metabolic dysfunction, with its influence extending far beyond glucose regulation. Increasingly, IR is recognized as the Eminence Grisethe unseen but powerful driverbehind many non-communicable chronic diseases (NCDs) and the biological processes of aging. The research topic "Is insulin resistance the Eminence Grise of aging and NCDs?" brings together 12 original investigations and reviews that collectively expand our understanding of IR as a systemic, multi-organ phenomenon. These studies explore IR not only as a metabolic hallmark but as a unifying pathophysiological thread linking cardiovascular, renal, hepatic, respiratory, neurological, and psychological disorders across the lifespan. The reviewed studies explored various accessible, non-insulin-based surrogate indices (Triglyceride-Glucose [TyG], Estimated Glucose Disposal Rate [eGDR]) across aging-related diseases. Although the hyperinsulinemic-euglycemic clamp remains the most accurate method for assessing IR, its application is often limited by the complexity and constraints of clinical settings. Decades of research have established that IR contributes to a wide range of metabolic and degenerative diseases. It plays a fundamental role in the development of type 2 diabetes, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), and atherosclerosis (1,2). Mechanistically, IR arises from the interplay between genetic susceptibility, ectopic lipid accumulation, mitochondrial dysfunction, chronic inflammation, and altered adipokine signaling (3). Beyond classical metabolic organs, impaired insulin signaling affects endothelial cells, neurons, and immune responses, contributing to vascular stiffness, neurodegeneration, and systemic low-grade inflammationhallmarks of aging (1-5). However, despite this well-established framework, several aspects remain underexplored. While the molecular basis of IR has been elucidated in skeletal muscle, liver, and adipose tissue, much less is known about its role in non-traditional target organs such as the lungs, kidneys, or brain. Moreover, there remains a gap in understanding the predictive and diagnostic value of emerging non-insulinbased IR indices, their relevance in acute settings, and their relationship with mental health and cognitive decline. Gaps also persist regarding pharmacological modulation, adipose-immune crosstalk, and longitudinal mechanistic studies integrating omics and imaging biomarkers. 37The papers in this address several of these gaps, validate surrogate markers, and deepen our 38 understanding of IR. 39 The interplay between IR and cardiovascular disease (CVD) remains a subject of persistent inquiry.