Molecular Pathways of Cardiometabolic Residual Risk in Type 2 Diabetes: Insulin Resistance, Metaflammation, and Liver-Kidney-Vascular Crosstalk

作者：Labate AM, Cimino E, Giacomelli L, Ettori S, Oladeji OA, Agosti B · 发表于：International journal of molecular sciences · 年份：2026 · DOI：10.3390/ijms27146170 · 被引用次数：91 · 研究领域：MASLD、biomarkers、cardiometabolic risk、diabetic kidney disease、endothelial dysfunction、insulin resistance、metaflammation、oxidative stress、residual risk、type 2 diabetes

Cardiometabolic residual risk in type 2 diabetes mellitus (T2D) persists despite major advances in glucose-lowering therapy, lipid management, blood pressure control, weight reduction, and organ-protective strategies. This residual burden should not be interpreted solely as the consequence of incomplete achievement of conventional therapeutic targets, but rather as the clinical expression of persistent molecular activity involving multiple interconnected organs and pathways. Insulin resistance, metaflammation, oxidative stress, mitochondrial dysfunction, lipotoxicity, endothelial impairment, hepatic metabolic dysregulation, renal inflammation, fibrotic remodeling, and metabolic memory interact within a dynamic network linking adipose tissue, liver, kidney, immune cells, and vasculature. In this review, we discuss the biochemical and molecular drivers of cardiometabolic residual risk in T2D, with particular emphasis on impaired insulin receptor substrate/PI3K/Akt signaling, stress-kinase activation, NLRP3 inflammasome priming and assembly, MASLD-related lipotoxicity and fibrogenesis, podocyte and tubular injury, endothelial nitric oxide synthase uncoupling, AGE-RAGE signaling, and thrombo-inflammatory vascular injury. These pathways explain why biological vulnerability may persist even when conventional clinical parameters appear adequately controlled. We also examine the role of translational biomarkers and simple clinical indices, including TyG-derived indices, adiposity mar...