Human MASLD is a diurnal disease driven by multisystem insulin resistance and reduced insulin availability at night.

Summary

In human MASLD, nighttime metabolic dysfunction is pronounced: hepatic and peripheral insulin resistance, de novo lipogenesis, and NEFA exposure increase at night while plasma insulin availability falls due to both reduced secretion and increased clearance. These diurnal abnormalities persist even after weight-loss–induced reductions in liver fat, and multi-tissue proteomics highlight candidate targets. Findings support chrono-nutrition/exercise and time-of-day medication strategies.

Key Findings

• Nighttime hepatic and peripheral insulin resistance, de novo lipogenesis, and systemic NEFA exposure are elevated in MASLD.
• Plasma insulin availability is lower at night due to reduced secretion and increased clearance.
• Diurnal metabolic differences persist after weight loss with reduced liver fat, implicating chronobiology as a primary driver.
• Integrated proteomics across plasma, adipose, and muscle identified candidate molecular targets varying by time-of-day.

Clinical Implications

Counsel MASLD patients to concentrate energy intake earlier in the day, prioritize evening insulin-sensitizing activity, and consider time-of-day dosing of agents affecting DNL or insulin dynamics (e.g., GLP-1RA, SGLT2i, pioglitazone) pending trials.

Limitations

• Sample size and cohort breadth not specified in the abstract; generalizability requires confirmation
• Observational day–night design without interventional chronotherapy testing limits causal inference for timing strategies

Future Directions

Randomized chronotherapy trials in MASLD to test time-of-day-specific nutrition, exercise, and pharmacotherapy; validation in diverse populations and integration with wearable circadian metrics.