Abstract

Circadian timekeeping aligns cellular metabolism with daily cycles of light, feeding, and activity. In 
obesity-linked type 2 diabetes (T2D), misalignment between endogenous clocks and behavior via shift work, 
social jetlag, evening eating, short/fragmented sleep, insomnia, or sleep-disordered breathing exacerbates 
insulin resistance (IR), impairs β-cell function, and worsens glycemic variability. Molecular clocks (CLOCK, 
BMAL1, PER, CRY) coordinate transcriptional oscillations in liver, skeletal muscle, adipose tissue, pancreas, 
and gut; disruption alters glucose production, lipid handling, adipokine release, mitochondrial quality control, 
and inflammatory tone. Acute sleep restriction reduces insulin sensitivity within days through sympathetic and 
HPA-axis activation, increased evening cortisol, GH, and catecholamine shifts, and elevated free fatty acids; 
chronic restriction sustains ectopic fat and endothelial dysfunction. Obstructive sleep apnea (OSA) adds 
intermittent hypoxia and arousal-driven surges in sympathetic activity, raising nocturnal glucose and blood 
pressure and aggravating NAFLD. Meal timing interacts with clocks: late eating increases postprandial 
glycemia and decreases diet-induced thermogenesis; early time-restricted eating improves fasting glucose and 
HOMA-IR independent of large weight loss. Interventions: sleep hygiene, cognitive behavioral therapy for 
insomnia (CBT-I), positive airway pressure for OSA, light management, melatonin timing in circadian disorders, 
exercise timing, and chrononutrition restore alignment and augment pharmacotherapy (GLP-1 receptor 
agonists, SGLT2 inhibitors, TZDs) and surgery when indicated. Precision strategies combine chronotype, 
actigraphy/polysomnography, continuous glucose monitoring (CGM), and metabolomics to tailor timing 
prescriptions and medication dosing. This review synthesizes mechanisms linking circadian/sleep disruption to 
diabesity, evaluates disease-specific sleep disorders, and outlines pragmatic, scalable, and equitable 
chronobiology-informed care.