The impact of ncRNAs on type 2 diabetes: A comprehensive review covering molecular mechanisms to clinical applications

Abstract

Type 2 diabetes (T2D) is a complex metabolic disorder with rising global prevalence. This review examines the diverse roles of non-coding RNAs (ncRNAs) in T2D, focusing on their involvement in key biological processes such as insulin signaling, glucose metabolism, oxidative stress, and inflammation. We explore how ncRNAs interact with known T2D risk genes and contribute to epigenetic regulation associated with disease progression. Particular attention is given to the emerging potential of ncRNAs as biomarkers for early diagnosis and as targets for personalized therapeutic strategies. We also discuss current advances in modulating ncRNA expression, including findings from experimental models and clinical trials published between 1998 and 2025. Finally, the review considers how lifestyle factors and common comorbidities influence ncRNA expression, highlighting their wider implications in the context of T2D. Overall, the findings underscore the growing importance of ncRNAs in understanding, diagnosing, and treating T2D.

Keywords: MT: Non-coding RNAs; circRNA; epigenetics; genetic; lncRNA; miRNA; ncRNA; piRNA; siRNA; type 2 diabetes.

Graphical abstract

Figure 1

LncRNAs and small ncRNAs are the two categories into which ncRNAs are divided based on length Short ncRNAs are divided into functional: (snRNA) small nuclear RNA, (rRNA) ribosomal RNA, (tRNA) transfer RNA, (mRNA) messenger RNA, and regulatory: (piRNA) piwi RNA, (siRNA) small interfering RNA, and (miRNA) micro-RNA. Long ncRNAs can also be divided into three groups based on their structure, function, and genomic location. They are separated structurally into circular and linear RNAs: (CircRNA) circular RNA, (eRNA) enhancer-derived RNA, (lincRNA) long intergenic noncoding RNA, (LncRNA) and long non-coding RNAs and based on their regulatory function (ceRNA) competing endogenous RNA, (transRNA) trans-acting RNA, and (cisRNA) cis-acting RNA.

Figure 2

Schematic representation of the canonical miRNA pathway showing nuclear and cytoplasmic processing steps miRNA genes are transcribed by RNA polymerase II into pri-miRNAs, which are processed by Drosha-DGCR8 into pre-miRNAs and exported to the cytoplasm via Exportin-5. Dicer processes pre-miRNAs into duplexes, from which the guide strand is loaded into the RISC complex with Ago2 to mediate translation repression or mRNA degradation. Created in https://BioRender.com.

Figure 3

Primary biogenesis of piRNAs is the term used to describe this process First, RNA polymerase II transcribes single-stranded piRNA clusters to initiate piRNA synthesis. Yb bodies then transport the resulting piRNA transcripts to the outer mitochondrial membrane. Second, the Zucchini (zuc) endonuclease and related components located on the mitochondria then cleave it, producing a precursor piRNA (pre-piRNA) with the 5′ end uridine as the first nucleotide. Following its binding to PIWI proteins, pre-piRNA is further trimmed at the 3′ end by the exonuclease Trimmer, resulting in its maturation length. Following this, completely mature piRNA is produced when methyltransferase Hen1 methylates mature piRNAs. Created in https://BioRender.com.

Figure 4

An overview of the potential roles of long non-coding RNAs (lncRNAs), including their impact on chromatin and DNA modification, their role as scaffolds in promoting protein-protein interactions, and their influence on RNA function Created in https://BioRender.com.

Figure 5

CircRNA is created by backsplicing The backsplicing location of a transcript can produce distinct types of circular RNAs. Created in https://BioRender.com.