Impact of Core Circadian Gene Variants on Glycemic Parameters and Insulin Resistance in Type 2 Diabetes: A Systematic Review
Abstract
Circadian rhythm disruption is increasingly implicated in the pathophysiology of type 2 diabetes mellitus (T2DM). Variants in core circadian clock genes - CLOCK (circadian locomotor output cycles kaput), BMAL1/ARNTL (brain and muscle ARNT-like protein 1), CRY1/2 (cryptochrome 1 and 2), PER1-3 (period 1-3), and NR1D1 (REV-ERBα) - and associated melatonin receptor genes may influence glycaemic homeostasis and insulin resistance. This systematic review synthesises evidence published between 2020 and 2025 on associations between these variants and key glycaemic parameters. A systematic search of PubMed/MEDLINE, Embase, Web of Science, and the Cochrane Library was performed following PRISMA 2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Studies published from January 2020 to December 2025 that examined circadian gene variants or expression in T2DM or at-risk human populations and reported glycaemic or insulin-resistance outcomes were included. Risk of bias was independently assessed using the Newcastle-Ottawa Scale (NOS). Owing to substantial heterogeneity, a narrative synthesis following the Synthesis Without Meta-analysis (SWiM) framework was undertaken; no meta-analysis, formal heterogeneity (I²) metric, or GRADE certainty rating was performed. Six studies of diverse design (case control, cross-sectional, narrative review, and systematic review with meta-analysis) from China, South Africa, Croatia/multi-ethnic, and Spain, collectively…
How strong is the evidence?
Evidence Hub reads this as a systematic review. Its evidence level is 1 of 5 (Highest · pooled evidence). Pooled evidence from several studies sits at the top of the evidence pyramid. Reported size: 18,000 participants or records.
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