Insulin resistance is a hallmark of multiple metabolic disorders, including type 2 diabetes, obesity, metabolic syndrome, and polycystic ovary syndrome. It arises from complex and multifactorial molecular and cellular alterations that impair insulin signaling and glucose homeostasis. These alterations affect key insulin-responsive tissues such as the liver, adipose tissue, skeletal muscle, and, increasingly recognized, the brain. Over the past decades, major signaling nodes –including insulin receptor substrates (IRS), the PI3K-Akt pathway, AS160, and GLUT4 translocation– have been identified as central regulators of insulin action. In parallel, the roles of chronic low-grade inflammation, lipotoxicity, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress have been shown to contribute significantly to the development of insulin resistance.

However, substantial gaps remain in our understanding of how these molecular events are orchestrated in a tissue-specific and time-dependent manner, how they interact under various physiological or disease-inducing stimuli, and how compensatory mechanisms modulate disease progression. Also, a deeper mechanistic insight is urgently needed to identify novel therapeutic targets and strategies that can reverse or mitigate insulin resistance in a personalized and tissue-targeted way.

This Research Topic aims to gather cutting-edge studies exploring the molecular and cellular mechanisms that drive insulin resistance using in vitro systems, in vivo animal models, and human-derived tissues. We encourage contributions that investigate insulin resistance induced by nutritional, hormonal, inflammatory, or genetic factors, as well as studies analyzing the inter-organ communication and tissue-specific responses. Emphasis will also be placed on work exploring the role of oxidative stress, inflammation, mitochondrial dysfunction, endoplasmic reticulum stress, and post-translational modifications in insulin signaling disruption. Furthermore, we welcome research focused on pharmacological approaches to dissect insulin resistance mechanisms, including the use of specific agonists, antagonists, or small-molecule inhibitors. Studies identifying novel therapeutic targets, describing off-target effects of current anti-diabetic drugs, or revealing adaptive resistance to pharmacological treatments are also highly relevant.

We are particularly interested in original research articles, reviews, mini-reviews, hypothesis and theory articles, perspectives, or general commentaries addressing the following themes:

• tissue-specific insulin signaling pathways

• the interplay between mitochondrial and endoplasmic reticulum stress

• inflammatory and oxidative stress pathways

• nutrient-induced dysfunction in insulin action

• pharmacological modulators of insulin action

Are you interested in contributing a manuscript to this Research Topic?

Insights into the Molecular and Cellular Mechanisms of Insulin Resistance