MASLD and ectopic fat in prediabetes

Abstract

Prediabetes represents an early stage of the cardiometabolic continuum, in which insulin resistance and adipose tissue dysfunction play a key role. The interaction between genetic and environmental factors favors the pathological expansion of adipose tissue, which begins with adipocyte hypertrophy, hypoxia, and endoplasmic reticulum stress, triggering the activation of inflammatory pathways. As a consequence, the release of adipokines and proinflammatory cytokines increases, promoting macrophage recruitment and perpetuating a state of chronic low-grade inflammation and insulin resistance.

Insulin resistance in adipose tissue increases lipolysis and the flow of free fatty acids to organs not specialized in lipid storage, such as the liver, skeletal muscle, pancreas, heart, and vascular bed. The accumulation of ectopic fat in these tissues constitutes a central mechanism of lipotoxicity, metabolic impairment, multi-organ dysfunction, progression to type 2 diabetes, and cardiovascular disease.

In this scenario, the liver acts as a metabolic sensor of dysfunctional adipose tissue and as the main target of this lipotoxic state, which explains the close association between steatotic liver disease associated with metabolic dysfunction (MASLD), prediabetes, and insulin resistance. Increased hepatic delivery of free fatty acids promotes steatosis and hypersecretion of very low-density lipoproteins (VLDL), leading to the atherogenic dyslipidemia characteristic of insulin resistance states, with hypertriglyceridemia, decreased HDL cholesterol, and a predominance of small, dense LDL particles—alterations closely related to an increased cardiovascular risk.

Treatment has evolved from a strategy focused exclusively on weight loss to a comprehensive approach aimed at improving adipose tissue function, reducing ectopic fat, and reversing metabolic dysfunction. Intensive lifestyle modifications remain the cornerstone of treatment. However, pioglitazone, GLP-1 receptor agonists, and dual GLP-1/GIP agonists have demonstrated benefits in improving insulin sensitivity, reducing liver fat, and enhancing the cardiometabolic profile. Understanding the role of dysfunctional adipose tissue allows us to integrate obesity, prediabetes, MASLD, and cardiovascular disease within a single pathophysiological continuum, where ectopic fat emerges as a relevant therapeutic target for modifying the course of these diseases.