Metabolic state switches between morning and evening in association with circadian clock in people without diabetes.
Level 2 - randomized trial
Individual randomized crossover physiological trial in humans
PubMed 35429128 · doi:10.1111/jdi.13810
What was done
Individuals without diabetes were enrolled in two separate randomized crossover cohorts: 14 completed a 75-g oral glucose tolerance test (OGTT) and 10 completed a hyperinsulinemic-euglycemic clamp, both performed at 08:00 and 20:00 in random order. Hair follicle samples were collected prior to testing to analyze circadian clock gene expression (Per2, E4bp4). In parallel, protein kinase B (Akt) phosphorylation was assessed in liver and muscle tissue of mice via western blotting.
What was found
Glucose tolerance was superior at 08:00, driven by higher 1-hour insulin secretion on the OGTT and greater skeletal muscle insulin sensitivity on the clamp. Conversely, hepatic insulin sensitivity (estimated via the hepatic insulin resistance index) was higher at 20:00. The 1-hour insulin secretion and hepatic insulin resistance index correlated significantly with Per2 mRNA expression. The morning-to-evening difference in glucose infusion rate correlated significantly with the change in non-esterified fatty acids (NEFA), but not with clock gene expression. NEFA changes correlated significantly with E4bp4 mRNA expression and cortisol variation. Mouse muscle and liver Akt phosphorylation mirrored these tissue-specific time-of-day differences. The abstract reported no exact numerical values or effect sizes.
Why it matters
This study demonstrates distinct, tissue-specific circadian shifts in glucose handling, showing that morning metabolic advantage is driven by skeletal muscle sensitivity and early insulin secretion while hepatic sensitivity is higher in the evening.
Limits
The human sample size was very small (n=14 and n=10 across separate protocols), and the abstract provides no specific numerical values, confidence intervals, or p-values. Hepatic insulin sensitivity was estimated from an OGTT proxy rather than measured directly with tracer methods during the clamp. The findings are restricted to individuals without diabetes and may not reflect metabolic regulation in impaired states.
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