Role of insulin resistance in atherosclerosis: underlying mechanisms and emerging stem cell-based therapeutic strategies.

Atherosclerosis, a chronic inflammatory disease of the arteries, is the primary cause of ischemic heart disease and stroke, which are the leading drivers of global mortality and major contributors to disability. Important risk factors for atherosclerosis include insulin resistance (IR), hypertension and hyperlipidemia. IR-induced endothelial dysfunction, inflammation, dyslipidemia, vascular remodeling, and prothrombotic effects represent central mechanistic links between IR and atherosclerosis. In this review, these mechanisms are summarized and discussed by incorporating emerging mechanistic insights into IR-induced trained immunity, tissue-selective IR, and mitochondrial dysfunction, with an emphasis on their contributions to atherosclerosis. Furthermore, emerging therapeutic strategies using mesenchymal stem cells (MSCs) and their exosomes to improve IR are discussed, with a focus on their underlying mechanisms, as well as current challenges and outstanding issues in the field. While the current literature shows promising effects of MSCs and their exosomes in improving IR in cellular and animal models, clinical evidence remains limited. To harness the potential therapeutic benefits of MSCs and their exosomes, standardized manufacturing protocols and optimal routes of administration and dosing need to be determined.