Abstract

Obesity-related type 2 diabetes (T2D) emerges from a chronic immuno-endocrine imbalance in which 
inflammatory cytokines and adipokines remodel insulin signaling, substrate partitioning, and β-cell resilience. 
Hypertrophic, hypoxic adipose tissue (AT) recruits and reprograms immune cells, driving secretion of tumor 
necrosis factor-α (TNF-α), interleukins (IL-1β, IL-6, IL-18), chemokines (e.g., CCL2/MCP-1), and alarmins 
that activate stress kinases (JNK/IKK), SOCS proteins, and the NLRP3 inflammasome. In parallel, the adipokine 
milieu shifts like adiponectin declines; leptin, resistin, RBP4, chemerin, and lipocalin-2 often rise, tilting systemic 
physiology toward insulin resistance (IR), dyslipidemia, and endothelial dysfunction. These signals converge 
across organs: in the liver, cytokine and lipid cues sustain gluconeogenesis and steatosis; in muscle, lipid-derived 
metabolites and cytokines blunt GLUT4 translocation; in islets, IL-1β, TNF-α, and leptin resistance impair 
insulin secretion and promote β-cell stress. Endocrine and paracrine crosstalk is bidirectional; adipokines 
modulate immune tone, while immune mediators reshape adipocyte function and adipogenesis. Therapeutically, 
weight loss, physical activity, and metabolic surgery attenuate metaflammation and normalize adipokines. 
Pharmacotherapies (metformin, thiazolidinediones, SGLT2 inhibitors, and incretin-based agents) indirectly and 
sometimes directly recalibrate cytokine/adipokine networks. Targeted immunometabolic approaches like IL-1 
pathway blockade, NLRP3 inhibition, chemokine-axis modulation, selective PPAR agonism, and experimental 
adiponectin receptor agonists offer precision opportunities but demand careful safety assessment. This review 
integrates mechanistic insights, tissue crosstalk, and translational evidence to map how cytokines and adipokines 
drive the path from obesity to T2D and to highlight practical levers to restore immuno-endocrine homeostasis