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Published on: November 11, 2016
Diurnal Insulin Clearance and Circadian Metabolic Gene Signatures in MASLD: Integrative Multi-Dataset Physiological
Lin Guo1, Yimin Yin1, Yanyan Sun1
1Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
Background/Objectives:
Insulin clearance is a key determinant of circulating insulin availability, but its diurnal variation and relationship with circadian metabolic programs in metabolic dysfunction associated steatotic liver disease (MASLD) remain unclear. This study aimed to explore diurnal insulin clearance in humans and examine associated metabolic gene signatures in MASLD.
Methods:
A single-subject pilot assessment was performed to explore daytime-nighttime differences in insulin clearance rate (ICR) surrogate index, followed by evaluation using public hyperinsulinemic-euglycemic clamp datasets from healthy individuals and patients with MASLD. Public circadian transcriptomic datasets, spatial transcriptomic data, and a time course high-fat diet (HFD)-induced mouse dataset were integrated. A predefined panel of insulin clearance-related and circadian genes, including carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), insulin receptor (INSR), insulin-degrading enzyme (IDE), clock circadian regulator (CLOCK), basic helix-loop-helix ARNT like 1 (BMAL1), nuclear receptor subfamily 1 group D member 1/2 (NR1D1/2), period circadian regulator 1/2 (PER1/2), and cryptochrome 1/2 (CRY1/2), was analyzed.
Results:
The pilot assessment showed higher nighttime than daytime ICR, and independent clamp datasets showed a similar pattern in healthy individuals. In MASLD, nighttime ICR remained relatively higher, whereas overall insulin clearance was reduced compared with controls. Human blood-based circadian transcriptomic datasets identified rhythmic expression patterns of selected genes involved in insulin clearance and circadian regulation, including CEACAM1, CLOCK, NR1D1, CRY1, PER1, and PER2. MASLD liver datasets showed reduced expression of insulin clearance-related and circadian genes, while spatial transcriptomics suggested altered lobular distribution of these signatures. In HFD mouse model, rhythmic expression of selected genes was attenuated.
Conclusions:
These integrative findings suggest that insulin clearance may exhibit diurnal variation and may be linked to circadian metabolic gene signatures across systemic and hepatic datasets in MASLD. Larger controlled human studies are needed to validate the temporal regulation of insulin clearance and its metabolic relevance.
