Nighttime may be a key window for treatment and lifestyle choices in fatty liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) involves fat accumulation in the liver, but less is known about whether the underlying metabolic defects vary across the day. Researchers tested whether differences between day and night in how the body handles sugar and fat could help explain why fat builds up in the liver.

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The study included 24 overweight adults: 12 with MASLD and 12 controls without MASLD. Participants did not have diabetes or advanced liver scarring, and each completed separate daytime and nighttime testing visits after 12 hours of fasting. Researchers used a two-step hyperinsulinemic euglycemic clamp, a method that infuses insulin while holding blood glucose steady, to assess insulin sensitivity, glucose production, glucose disposal, and fat metabolism. Insulin is a hormone that helps move sugar from the blood into cells for energy or storage, so good sensitivity means the body responds effectively, while resistance means cells do not respond well, leading to higher blood sugar and increased fat release into the bloodstream. Eleven MASLD participants were retested after a 12-week commercial weight-loss program focused on diet and lifestyle changes.

• Controls showed lower de novo lipogenesis (the liver's production of new fat from non-fat sources) at night, while MASLD participants kept this liver fat-making pathway elevated during nighttime testing.
• MASLD participants showed worse insulin sensitivity in the liver at night. During low-dose insulin infusion, their liver released more glucose at night, and the study also reported higher morning Hep-IR, a marker of insulin resistance in the liver, than evening Hep-IR.
• Blood sugar handling was also impaired. Glucose disposal was lower at night across all conditions tested, but MASLD participants had about 40% to 60% lower glucose disposal than controls overall, indicating poorer uptake of glucose into skeletal muscle.
• Nighttime fat release from body fat stores appeared higher in MASLD. During low-dose insulin infusion, the nighttime increase in free fatty acids in the blood was linked to higher levels of liver fat measured by an ultrasound-based test.
• Nighttime insulin levels were lower in MASLD even though the same amount of insulin was given during both the day and night tests. There was a more than 66% drop in the body's own insulin production at night in response to the infused insulin, compared with the daytime response, along with faster removal of insulin from the blood, so overall less insulin was available to do its job.
• After the 12-week lifestyle and weight-loss program, MASLD participants lost about 6.3% of their body weight and showed improvements in body composition, liver markers, and liver fat. Even so, many nighttime metabolic differences persisted.

Rather than pointing to a single defect, the findings suggest a nighttime imbalance in how the body handles fuel in MASLD. Normally, insulin helps coordinate how the liver, muscles, and body fat manage sugar and fat during fasting. Here, that coordination appeared weaker at night, so fuel remained in circulation while the liver continued converting it into fat. The researchers also analyzed proteins in the blood and in small samples of fat and muscle tissue to look for underlying biological signals. These patterns pointed to differences in how the body burns fat, produces ketones (an alternative fuel made from fat), and uses energy in muscle. However, this was just an additional exploratory analysis that does not prove that these processes are causing the observed effects.

Overall, the findings suggest that nighttime may be an important window for treatment in MASLD, including when people eat, exercise, or take medications, with large evening meals potentially placing greater metabolic stress. Larger studies need to confirm the resutts and are also needed to test whether changing the timing of these lifestyle behaviors improves outcomes. In Q&A #76, I explain how choline and creatine may help protect against fatty liver disease.