The Shifting Landscape of Insulin Resistance and Diabetes: Novel Targets, Tools and Translational Horizons

Diabetes mellitus has become one of the defining pandemics of the twenty-first century, affecting hundreds of millions of adults worldwide and projected to reach well over a billion by 2050, with insulin resistance representing a central early pathogenic feature, particularly in type 2 diabetes. Insulin resistance is a systems-level disorder that connects adipose-tissue dysfunction, ectopic lipid deposition, inflammation, altered inter-organ signaling and progressive pancreatic β-cell failure. This Special Issue brings together 37 original investigations, systematic reviews and narrative syntheses, accompanied by 4 Research Highlights, spanning molecular mechanisms, metabolic phenotyping, diabetes heterogeneity and complications, lifestyle and environmental determinants, and emerging therapeutic strategies. The contributions illustrate how immune-metabolic crosstalk, islet inflammation, the gut microbiome, skeletal muscle, adipose-tissue distribution and central nervous system adaptation shape metabolic risk. They also evaluate practical and low-cost markers such as triglyceride-glucose-derived indices, body composition and lipidomic signatures for earlier and more precise risk stratification. Clinical studies address monogenic and fulminant diabetes, kidney and bone disease, wound healing and metabolic liver disease, while intervention studies examine exercise, dietary compounds, botanical products, multi-agonist and incretin-based pharmacotherapy and once-weekly basal insulin. Collectively, the Special Issue underscores both the rapid expansion of translational opportunities and the persistent need for rigorous validation, standardized phenotyping, longer follow-up and equitable implementation before promising biomarkers or therapies can be incorporated into routine care, marking a decisive shift from a glucose-centric model toward integrated, mechanism-informed and personalized cardiometabolic medicine.