Circular RNAs as diagnostic biomarkers in type 2 diabetes mellitus: implications in metabolic dysfunction and immune-inflammatory crosstalk

Figure 1. Biogenesis and types of circRNAs. The top part shows the back-splicing process of circRNA formation, highlighting the role of cis-acting elements, inverted repeats, and RNA-binding proteins. The bottom part categorizes the three main types of circRNAs: exonic circRNAs (ecircRNAs) function as miRNA sponges, intronic circRNAs (ciRNAs) regulate transcription, and exon-intron circRNAs (EIciRNAs) modulate gene expression through interactions with transcriptional machinery.

Figure 2. Functional modes of circRNAs. CircRNAs regulate gene expression through multiple mechanisms. In the cytoplasm, circRNAs act as miRNA sponges to modulate mRNA translation via competing endogenous RNA (ceRNA) networks, influencing metabolic and inflammatory pathways. CircRNAs can also interact with proteins as scaffolds or decoys to fine-tune regulatory signaling. In addition, a subset of circRNAs may undergo cap-independent translation to generate functional peptides in a context-dependent manner.

Figure 3. Circulating circRNAs for early detection and diagnosis of T2DM. Several circRNAs detectable in peripheral blood, including hsa_circ_0054633, hsa_circ_0063425, hsa_circ_0056891, and hsa_circ_0071336, exhibit progressive dysregulation from normoglycemia to impaired fasting glucose and overt T2DM. ROC analyses demonstrate strong diagnostic performance. These stable circulating circRNAs enable early detection, disease staging, and risk stratification, providing molecular information beyond conventional glycemic markers.

Figure 4. CircRNAs for disease stratification and metabolic complications in T2DM. Circulating and exosomal circRNAs enable stratification of patients with type 2 diabetes mellitus according to vascular complication risk. Peripheral blood hsa-circRNA11783–2 is associated with cardiovascular comorbidity, whereas serum exosomal hsa_circRNA_0001842 correlates with lower limb vascular disease. These compartment-specific circRNA signatures support multidimensional risk assessment and precision management beyond binary disease diagnosis.

Figure 5. circRNA-mediated regulation of insulin resistance and glucose uptake in T2DM. Hsa_circ_0071336 acts as a competing endogenous RNA by sponging miR-93-5p, thereby relieving miRNA-mediated repression of GLUT4. This circRNA–miRNA–mRNA axis enhances GLUT4 expression and membrane translocation through insulin signaling pathways, promoting glucose uptake in insulin-sensitive tissues. Dysregulation of this mechanism contributes to impaired insulin responsiveness and metabolic dysfunction in type 2 diabetes mellitus.

Figure 6. circRNA-mediated regulation of pancreatic β-cell function and survival in T2DM. Hsa_circ_0115355 functions as a competing endogenous RNA by sponging miR-145, thereby relieving miRNA-mediated repression of SIRT1. Activation of SIRT1 enhances insulin secretion, improves mitochondrial function, and protects β-cells from glucotoxicity, lipotoxicity, and oxidative stress. Dysregulation of this circRNA–miRNA–mRNA axis contributes to β-cell dysfunction and progressive β-cell loss in type 2 diabetes mellitus.

Figure 7. circRNA-mediated immune–metabolic crosstalk in T2DM. CircANKRD36 is upregulated in circulating immune cells of patients with type 2 diabetes mellitus and promotes chronic low-grade inflammation through ceRNA-mediated regulation of inflammatory signaling. Enhanced release of pro-inflammatory cytokines, including TNF-α and IL-6, amplifies systemic immune–metabolic crosstalk, contributing to insulin resistance and metabolic dysfunction across peripheral tissues.

Figure 8. circRNA-mediated vascular dysfunction and metabolic complications in T2DM. CircRNAs contribute to organ-specific complications in type 2 diabetes mellitus through ceRNA regulation. In endothelial cells, circHMGCS1 sponges miR-4521, exacerbating oxidative stress and vascular inflammation, leading to endothelial dysfunction. In hepatocytes, circ_0004535 sequesters miR-1827 to upregulate CASP8, promoting apoptosis and inflammatory signaling and accelerating T2DM-associated non-alcoholic fatty liver disease progression.

Figure 9. Exosomal circRNAs as compartment-specific biomarkers in T2DM. Exosome-encapsulated circRNAs exhibit enhanced stability and reflect tissue-specific pathological processes. Serum exosomal hsa_circRNA_0001842 is selectively enriched in patients with type 2 diabetes mellitus complicated by lower limb vascular disease and is associated with vascular pathology. These findings highlight exosomal circRNAs as non-invasive biomarkers for complication-specific risk stratification and precision assessment beyond bulk circulating RNAs.

Figure 10. circRNAs as therapeutic targets or response indicators in T2DM. CircRNAs may function as mechanistic modulators or indicators of treatment response in type 2 diabetes mellitus. CircPIP5K1A influences glucose and lipid metabolism and inflammatory pathways in experimental models, providing proof-of-concept for circRNA modulation. In parallel, therapeutic interventions can alter exosome-derived circRNA profiles, suggesting a role for circRNAs as exploratory biomarkers for monitoring biological responses rather than established therapeutic targets.