From In Silico to Clinic: Harnessing Noncoding RNAs for Diabetes Research and Therapy, a Step toward ncRNA Precision.

Diabetes mellitus (DM) represents a heterogeneous group of metabolic disorders characterized by chronic hyperglycemia and progressive metabolic dysregulation, arising from distinct but overlapping pathogenic mechanisms. Emerging evidence positions noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long ncRNAs (lncRNAs), circular RNAs (circRNAs), and P-element-induced WImpy testis-interacting RNAs (piRNAs), as central regulators of pancreatic β-cell integrity, insulin signaling, immune modulation, and metabolic homeostasis. This comprehensive review synthesizes current mechanistic and translational insights into ncRNA biogenesis, regulatory networks, and functional roles across diverse DM subtypes, including type 1, type 2, latent autoimmune diabetes in adults, gestational, monogenic, and the recently recognized type 5 diabetes. Through systematic in silico integration of curated databases (e.g., HMDD v4.0 and LncRNADisease) with experimental evidence, we map disease-specific ncRNA signatures and delineate their regulatory axes in β-cell dysfunction, insulin resistance, inflammatory signaling, and diabetic complications. Increasing data support the clinical relevance of distinct circulating and tissue-specific ncRNAs as minimally invasive biomarkers for early detection, subtype stratification, prognosis, and prediction of therapeutic response. Moreover, mechanistic studies highlight ncRNA-mediated pathways as actionable targets for RNA-based therapeutics and precision medicine strategies, particularly in autoimmune-driven β-cell destruction and metabolic insulin resistance. By bridging computational network analyses with molecular and clinical evidence, this review advances an integrated framework for ncRNA-guided diabetes diagnostics and targeted intervention. We further identify critical methodological and validation gaps that must be addressed to accelerate the translation of ncRNA discoveries from bench to bedside, underscoring their transformative potential in reshaping DM management.

diabetes, microRNAs, long ncRNAs, circular RNAs, piRNAs, in silico analysis

Diabetes mellitus (DM) is one of the chronic disease states in which the blood glucose levels are elevated beyond the reference values, with subsequent deleterious effects that involve the different tissues of the body. , It develops as a result of the inability of the β-cells of the pancreas to produce enough insulin or as a consequence of the inability of the target tissues to respond to insulin in a proper way. Therefore, DM has several types, each of which has its distinct causes, characteristics, and management strategies. These include type 1 DM (T1DM), type 2 DM (T2DM), latent autoimmune diabetes in adults (LADA) or type 1.5 DM, gestational diabetes, monogenic diabetes, and secondary diabetes. Type 1 DM (insulin-dependent DM or juvenile diabetes) is a type of DM that has an immunologic nature. The immune system was proven to form autoantibodies that attack and inappropriately destroy the β-cells of the pancreas, with almost complete inhibition of insulin secretion. This type of DM typically develops in childhood or adolescence, mostly after viral respiratory infections, but it can occur at any age. Patients with this type require lifelong insulin therapy to efficiently control their elevated blood glucose levels. On the other hand, T2DM (noninsulin-dependent DM) usually develops in adults more than 30 years old and is often associated with specific lifestyle characteristics including obesity, sedentary life with physical inactivity, and unhealthy dietary habits. Although the β-cells of the pancreas secrete insulin, its amount is insufficient to meet the body’s needs. This, in addition to the development of insulin resistance, leads to significant deterioration of glycemic control, with secondary changes in various body tissues leading to serious complications, including pancreatic cancer. − The management strategy of type 2 DM relies on lifestyle modifications and oral medications, in addition to insulin therapy. In the early years of the second millennium, LADA emerged as a distinct form of diabetes. Its precise classification remains unclear as it exhibits characteristics of both type 1 and type 2 diabetes, leading to its description as type 1.5 DM. A key clinical concern in the detection of LADA is the recognition that gradual autoimmune β-cell destruction can occur in adults, resulting in a prolonged period of diminished insulin secretion. Gestational DM (GDM) refers to a type of diabetes that occurs in pregnant females due to the inability of the insulin-synthesizing machinery of the body to cope with the increased requirements of both the mother and the developing fetus. Fortunately, this type of diabetes usually resolves after childbirth, but recent reports have detected an increased risk of developing type 2 DM for both the mother and the child later in life. Dietary changes, increased physical activity, and insulin therapy represent the basis of management of GDM. Monogenic diabetes is a specific form of DM that appears as a consequence of mutations in a single gene such as maturity-onset diabetes of the young and neonatal diabetes. Persistent hyperglycemia that occurs as a result of other medical conditions such as pancreatitis and cystic fibrosis or appears with the use of certain medications such as prolonged corticosteroid therapy is termed secondary diabetes, and its management plans depend primarily on elimination of the causative agent. It is worth mentioning that early management of DM is crucial to preventing cardiovascular and neurological complications. , Type 5 DM is a newly recognized form of diabetes that was previously known as malnutrition-related DM. It is strongly linked to chronic undernutrition, especially during childhood, which prevents the pancreas from developing properly. As a consequence, insufficient insulin is produced, leading to persistent high blood sugar levels. This condition is most prevalent in low- and middle-income countries, particularly in regions such as Southeast Asia and sub-Saharan Africa. Unlike other types of diabetes, type 5 has unique characteristics linked to nutritional deficiencies rather than autoimmunity or lifestyle factors alone. , The individuals affected often face additional health challenges, making management more difficult. Insulin therapy is usually required, but researchers are exploring oral medications as potential treatments. The International Diabetes Federation officially classified type 5 diabetes in 2025, marking an important step in global health equity (https://idf.org/news/new-type-5-diabetes-working-group). This recognition ensures that millions of people living with this condition are no longer overlooked. Ultimately, this type of diabetes highlights the complex interrelation among nutrition, poverty, and chronic disease. Noncoding RNAs (ncRNAs) represent a large group of diverse RNA molecules that play a fundamental role in the regulation of gene expression and the maintenance of cellular homeostasis. , As depicted in Figure , they include microRNAs (miRNAs), long ncRNAs (lncRNAs), circular RNAs (circRNAs), and P-element-induced WImpy testis (PIWI)-interacting RNAs (piRNAs), which have unique biogenic characteristics and peculiar functions within the different cells of the body. , miRNAs are small RNA molecules of approximately 22 nucleotides long. Their synthesis starts with the transcription of primary miRNA (pri-miRNA) with the aid of RNA polymerase II, which undergoes further processing to form mature miRNAs. These miRNA fragments bind to the complementary sequences in the target mRNAs, leading to their degradation or inhibition of translation. These events may represent the cornerstones in many biological processes, including cellular development, differentiation, and disease progression. LncRNAs are members of the ncRNA family that are longer than 200 nucleotides. , They have a wide range of diverse functions, being involved in chromatin remodeling, regulation of DNA transcription, and post-transcriptional processing. Also, they act as scaffolds for the formation of functional complexes from protein molecules and other RNAs, thereby regulating gene expression. circRNA is one of the ncRNAs that is synthesized via a process called backsplicing, in which a downstream splice donor site is joined to an upstream splice acceptor site. This creates a covalently closed loop structure that contributes to various regulatory functions, including sequestration of miRNAs and prevention of their binding to their target mRNAs. Also, circRNAs interact with RNA-binding proteins, thereby affecting RNA transcription and splicing. piRNAs are small ncRNA molecules that consist of about 24–31 nucleotides. Their primary location is in the germ cells, where their precursors are synthesized from the piRNA clusters. Then, they undergo a series of cleavage and modification processes that end in the formation of mature piRNAs. They play a key role in epigenetic regulation, the formation of heterochromatin, and the maintenance of genomic integrity in germ cells. Also, they guide the PIWI proteins to certain complementary sequences in transposon RNAs, leading to silencing of their transposable elements. , Figure illustrates biogenesis and functions of different classes of ncRNAs. Recently, the findings of the ongoing research have opened new horizons toward the exploration of the potential role that may be played by the different types of ncRNAs in the pathogenesis and management of DM. , This may be derived from the ability of ncRNAs to modulate insulin secretion, control inflammation, and influence the expression of the genes involved in glucose and lipid metabolism, insulin sensitivity, and the functions of the β-cells of the pancreas. , This review aims to systematically integrate current mechanistic and translational evidence to define how dysregulated ncRNAs contribute to DM pathogenesis, subtype differentiation, diagnostic stratification, and therapeutic targeting. Drawing on in silico analyses of curated databases (e.g., HMDD v4.0 and LncRNADisease) alongside experimental and clinical studies, we mapped disease-specific ncRNA signatures across the different types of diabetes. Additionally, we highlighted the key regulatory axes linking ncRNAs to β-cell survival, insulin signaling pathways, inflammatory cascades, and metabolic homeostasis. Moreover, by consolidating computational network mapping with molecular and clinical evidence, this review will provide a focused framework for advancing ncRNA-driven diagnostics and targeted interventions in diabetes, while identifying critical validation and translational challenges that must be addressed for clinical implementation.

and Search Strategy The objective of this review is to comprehensively explore the multiple roles of dysregulated ncRNAs and their interactions with some of their target molecules in diabetes pathogenesis and diagnosis and their potential use in precision medicine. Inclusion criteria: Studies reporting direct mechanistic evidence (e.g., target gene validation, pathway modulation, and functional assays), differential expression in human clinical samples, or in vivo/in vitro experimental confirmation were prioritized. Entries lacking primary literature support, computational predictions without validation, or nonhuman-only annotations without translational relevance were excluded. When multiple reports existed for the same ncRNA-disease association, the most recent and methodologically robust studies were retained. Data extraction included the ncRNA name, experimental model (human/animal), study design (in vivo/in vitro), validated targets, and reported functional relevance in diabetes-related pathways. Exclusion criteria included studies focusing solely on coding RNAs (e.g., mRNA) without any ncRNA analysis and studies focusing solely on diabetic complications. Editorials, letters, commentaries, or abstracts without full articles and articles with outdated hypotheses or disproven mechanisms were excluded. To minimize subjective selection bias, methodological rigor of the included studies was systematically evaluated prior to data extraction. “Poor methodology” was defined as studies lacking clear study design description, inadequate sample size reporting, absence of appropriate control groups, missing statistical analysis details, failure to report validation experiments, or reliance solely on predictive bioinformatic outputs without experimental confirmation. For animal studies, the methodological robustness was evaluated according to randomization, allocation concealment, blinding, and completeness of outcome data. In vitro studies were assessed on the basis of experimental reproducibility, presence of functional validation (e.g., knockdown/overexpression assays), and appropriate statistical reporting. In Silico Search and Analysis Entries retrieved from HMDD v4.0, LncRNADisease, and LncRNAWiki 2.0 were selected to ensure their relevance, reliability, and biological significance. Only experimentally validated associations between ncRNAs (miRNAs, lncRNAs, circRNAs, and piRNAs) and DM (T1DM, T2DM, LADA, GDM, monogenic, or type 5 diabetes) were included. Via the human miRNA disease database (HMDD v4.0), Tables – address miRs in type 1 and 2 DM and gestational diabetes, respectively, retrieved from the lncRNAdisease database (https://www.cuilab.cn/lncrnadisease) accessed September 26, 2023, and LncRNAWiki 2.0 Community curation of lincRNAs for integrating human lincRNAs with multiomics annotations (https://ngdc.cncb.ac.cn/lncbook/omics/expression) accessed May 7, 2025. 1. miRs in Type 1 DM . | miRNA | description | human/animal study | in vivo/in vitro study | ref | |---|---|---|---|---| | hsa-mir-21 | miR-21 targets BCL2 mRNA to increase apoptosis in rat and human β-cells | both | INS-1 832/13 β cellsin vitro; human isletsin vitro; NOD & STZ micein vivo | , | | hsa-mir-23a, hsa-mir-23b, hsa-mir-149 | miR-23a-3p, miR-23b-3p, and miR-149-5p regulate the expression of pro-apoptotic BH3-only proteins DP5 and PUMA in human pancreatic β-cells | human study | human pancreatic islets/β-cellsin vitro | | | hsa-mir-192 | miR-192, upregulated in T1DM, regulates pancreatic β-cell development and inhibits insulin secretion through suppressing GLP-1 expression | both | NIT-1 cells (mouse β-cell line)in vitro; human serumex vivo; STZ-induced ratsin vivo | Retrieved from the lncRNAdisease database (https://www.cuilab.cn/lncrnadisease) accessed September 26, 2023. 3. miRs in Gestational Diabetes Showing Causality Link to miRs. | miRNA | description | human/animal study | in vivo/in vitro study | ref | |---|---|---|---|---| | has-mir-101 | GDM impairs HUVEC function via miR-101 upregulation. The transcriptional inhibitor EZH2, a target gene of miR-101 in HUVECs, contributes to some of the miR-101-induced defects of GDM-HUVECs | human study | HUVECs from umbilical cord veinsex vivo/in vitro; HUVECs exposed to high or normal glucosein vitro | | | Has-mir-518d | miR-518d regulates PPARα protein expression in the placentas of females with GDM | human study | placentaex vivo; placental tissue from GDM patients tand controls | 2. miRs in Type 2 DM . | miRNA | PMID | description | human/animal study | in vivo/in vitro study | |---|---|---|---|---| | hsa-let-7a | 24105413 | expression of microRNA let-7a and let-7d, which are direct translational repressors of the IL-13 gene, was increased in skeletal muscle from T2DM patients | human study | skeletal muscle biopsiesex vivo; cultured myotubesin vitro | | hsa-let-7d | 24105413 | expression of microRNA let-7a and let-7d, which are direct translational repressors of the IL-13 gene, was increased in skeletal muscle from T2DM patients | human study | skeletal muscle biopsiesex vivo; cultured myotubesin vitro | | hsa-mir-17 | 29477089 | miR-17 improved inflammation-induced insulin resistance by suppressing ASK1 expression in macrophages | animal study | 3T3-L1 adipocytesin vitro; LPS-induced macrophagesin vitro | | hsa-mir-22 | 26193896 | miR-22-3p targets the Tcf7 role in diabetes pathogenesis by upregulating gluconeogenesis. Targeting miR-22/Tcf7/Wnt axis might hold therapeutic potential for the treatment of altered hepatic physiology during insulin resistance and type 2 diabetes | both | HepG2 cellsin vitro; db/db mice liverin vivo | | hsa-mir-24 | 23761103 | microRNA-24/MODY gene regulatory pathway mediates pancreatic β-cell dysfunction | both | MIN6 cells (mouse β-cells)in vitro; primary mouse and human isletsin vitro/in vivo | | hsa-mir-26a | 26208605 | Mir-26a suppresses autoimmune diabetes in NOD mice in part through promoting regulatory T cells (Tregs) expression | animal study | NOD micein vivo; isolated splenocytes/Tregsin vitro | | hsa-mir-26a | 25961460 | miR-26a as a regulator of liver metabolism, to be explored as a potential target for the treatment of T2D | both | human liver biopsiesex vivo; liver of obese micein vivo; primary hepatocytes/cell linesin vitro | | hsa-mir-96 | 28036389 | miR-96 induction by dietary saturated fatty acids exacerbates hepatic insulin resistance through INSR and IRS-1 suppression | animal study | palmitate-treated hepatocytes (primary hepatocytes)in vitro; liver of HFD-fed micein vivo | | hsa-mir-124a | 25408296 | silencing miR-124a in T2D islets resulted in an increased expression of β-cell function target genes, whose overexpression impaired glucose-stimulated insulin secretion and β-cell dysfunction in type 2 diabetes | human study | human pancreatic isletsex vivo; MIN6 pseudoisletsin vitro | | hsa-mir-125b | 29319168 | hepatic miR-125b inhibits insulin signaling pathway by targeting PIK3CD | both | liver, HepG2 cells, L02 cells, primary hepatocytesin vitro; liver of HFD, ob/ob, db/db micein vivo | | hsa-mir-128 | 30341898 | MiR-128-3p accelerates cardiovascular calcification and insulin resistance through the ISL1-dependent Wnt pathway in T2DM rats | animal study | islet β-cells/pancreas, bloodin vivo (T2DM rats) and ex vivo (isolated islets) | | hsa-mir-132 | 26218441 | overexpression of miR-132 or miR-212 enhances glucose and GLP-1-stimulated insulin secretion | both | pancreatic β-cells, INS-1 832/3, INS-1 832/13 cells, isolated rat/mouse/human isletsin vitro; GLP-1 infusion in micein vivo | | hsa-mir-144 | 21829658 | miR-144 impairs insulin signaling by inhibiting the expression of IRS-1 in T2DM | both | pancreas, liver, adipose, skeletal muscle, bloodin vivo (T2D rat model)/human blood samples; in vitro | | hsa-mir-187 | 24149837 | miR-187 role in blunting of insulin secretion, regulating HIPK3, during the pathogenesis of T2DM | both | pancreatic islets, INS-1 cells, primary rat isletsin vitro; human islets from T2D patientsex vivo | | hsa-mir-199a | 25084986 | MiR-199a is overexpressed in plasma of T2DM patients which contributes to T2D by targeting GLUT4 | human study | HEK293T cells, L6 myoblastsin vitro; plasma from T2D patients | | hsa-mir-200 | 25985365 | miR-200 family regulates pancreatic β-cell survival in T2DM | animal study | pancreatic β cellsin vivo (β cell-specific overexpression/knockout in diabetic mice) | | hsa-mir-200b | 25814674 | inflammation underlying nonhealing wounds in patients with T2DM influences plasma miRNA concentrations; miR-191 modulates cellular migration and angiogenesis via paracrine regulation of zonula occludens-1 to delay the tissue repair process | human study | plasma, endothelial cells, fibroblastsex vivo/in vitro | | hsa-mir-205 | 30174230 | miR-205-5p gain-of-function increases AKT phosphorylation and decreases SHIP2 in primary hepatocytes, resulting in FOXO inhibition | animal study | primary hepatocytesin vitro; liver of Foxo 1,3a,4 knockout micein vivo | | hsa-mir-212 | 26218441 | overexpression of miR-132 or miR-212 enhances glucose and GLP-1-stimulated insulin secretion | both | INS-1 832/3 and 832/13 cells, isolated rat/mouse/human isletsin vitro; GLP-1 infusion in micein vivo | | hsa-mir-223 | 20080987 | miR-223 role in GLUT4 regulation and glucose metabolism in the heart reveal the pleiotropic effects of miRNAs across tissues and show that miRNAs can upregulate target genes in terminally differentiated cardiomyocytes | both | neonatal rat cardiomyocytesin vitro; left ventricular biopsies from T2D patientsex vivo | | hsa-mir-375 | 25408296 | miR-124a hyperexpression in T2D islets, whose silencing resulted in increased expression of target genes of major importance for β-cell function and whose overexpression impaired glucose-stimulated insulin secretion, leading to the hypothesis that an altered miR-124a expression may contribute to β cell dysfunction in T2D | human study | MIN6 pseudoisletsin vitro; human pancreatic isletsex vivo | | hsa-mir-423 | 28411267 | NFE2 induces miR-423-p to promote gluconeogenesis and hyperglycemia by repressing the hepatic FAM3A-ATP-Akt pathway | both | cultured hepatocytesin vitro; liver of obese diabetic mice and NAFLD patientsin vivo/ex vivo | | hsa-mir-696 | 27432632 | miR-696 plays a role in hepatic gluconeogenesis development and IR through PGC-1α inhibition of translation in the liver | animal study | primary hepatocytes from C57BL/6 and ob/ob micein vitro and in vivo | | hsa-mir-1271 | 27613089 | miR-1271 upregulated by saturated fatty acid palmitate provokes impaired insulin signaling by repressing INSR and IRS-1 expression in HepG2 cells | both | HepG2 cellsin vitro; palmitate-treated hepatocytesin vitro | | hsa-mir-4463 | 30244253 | downregulation of miRNA-4463 attenuates high-glucose- and hypoxia-induced endothelial cell injury by targeting PNUTS | human study | HUVECsin vitro; vascular tissues from T2D patients with ASOex vivo | Retrieved from lncRNAdisease database (https://www.cuilab.cn/lncrnadisease) accessed September 26, 2023. Figure demonstrates disease network analysis of DM (2A) to lung cancer, thyroid cancer, chronic hepatitis C, hypertension, and pulmonary disease, as well as lymphoma. A special focus on type 2 diabetes (Figure B) disease network connection analysis, from the HMDD disease-network module (http://www.cuilab.cn/hmdd), highlighted kidney failure and Helicobacter pylori, atrial fibrillation, sepsis, hepatitis, and specific cancer types connection. Figure C plot quantifies disease similarity to diabetes, showing relative associations of various disorders with diabetes across the disease spectrum. The strongest positive association is observed with follicular thyroid carcinoma, followed by H. pylori infection, type 2 DM, chronic hepatitis C, and small-cell lung carcinoma. Additional positive links are seen with prolactinoma, head and neck squamous cell carcinoma, gastrointestinal neoplasms, thyroid neoplasms, and adrenal cortex carcinoma. Conversely, negative associations are observed under conditions such as pulmonary hypertension, diffuse large B-cell lymphoma, hepatitis B, esophageal neoplasms, laryngeal neoplasms, salivary gland neoplasms, periodontitis, endometriosis, and colorectal neoplasms. Involvement of ncRNAs in DM Development/Pathogenesis Type 1 DM The early detection of T1DM is now possible through the identification of multiple autoantibodies, enabling the prediction of future disease development. According to the American Diabetes Association (ADA), the updated staging system classifies individuals based on the presence of autoantibodies rather than solely on symptoms, identifying at-risk, presymptomatic patients before they progress to stage 3, characterized by overt symptoms and clinical diagnosis. While β-cell function remains critical for evaluating treatment efficacy, more precise biomarkers are needed to identify high-risk individuals. Recent evidence has highlighted the pivotal role of ncRNAs in autoimmune diseases, including T1DM, suggesting their potential as biomarkers for disease progression and diagnostic specificity. , Various types of ncRNAs, including miRNAs, lncRNAs, and piRNAs, are highly expressed in pancreatic islets and β-cells. circRNAs have also been detected at elevated levels in the plasma of newly diagnosed T1DM patients. These findings have prompted investigations into the roles of ncRNAs in pancreatic development and their potential contribution to the pathogenesis of T1DM. For example, the inactivation of the miRNA-processing enzyme Dicer1 impairs pancreatic development, reduces β-cell mass, and leads to β-cell dysfunction. Additionally, Dicer1 deletion results in decreased insulin content and secretion, ultimately contributing to the onset of T1DM with age. Specific ncRNAssuch as miR-7 and lncRNAs like HI-LNC-78have been implicated in pancreatic development, regulation of insulin content, and modulation of gene expression in pathways that control insulin secretion. − More targeted studies have confirmed that several miRNAs are involved in the development of T1DM. Although their altered expression profiles may serve as valuable biomarkers for early diagnosis, understanding their mechanistic roles in modulating gene expression could provide deeper insights into disease pathogenesis. Notably, miR-146a was found to be elevated in T1DM and is known to target key inflammation-associated genes such as tumor necrosis factor receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1), potentially intensifying the inflammatory response and contributing to β-cell destruction, in addition to the observation that miR-146a may also interfere with genes essential for β-cell survival and functionality. , Similarly, miR-375 is upregulated in T1DM and has been shown to suppress genes involved in insulin synthesis, thereby impairing glucose homeostasis. Recent evidence suggests that lncRNAs play crucial roles in the regulation of β-cell function and survival. Several lncRNAs located within the T1DM-associated genetic loci appear to influence chromatin structure and gene expression in islet cells. Through interactions with regulatory variants and enhancer elements, these lncRNAs may serve as key cis- or trans-acting modulators of β-cell transcriptional activity, contributing to epigenetic remodeling that underlies autoimmune-mediated β-cell dysfunction. One specific lncRNA, maternally expressed gene 3 (MEG3), has been shown to be downregulated in pancreatic islets of the female nonobese diabetic (NOD) T1DM mouse model. Experimental knockdown of MEG3 in vitro led to reduced insulin synthesis and secretion and increased β-cell apoptosis. These findings indicate that MEG3 supports normal β-cell function and survival, and its reduced expression may contribute to β-cell failure during the early stages of T1DM. In a study using the MIN6B1 β-cell line, exposure to pro-inflammatory cytokines altered the expression of several lncRNAs, with similar changes confirmed in islets from control and prediabetic NOD mice. Four lncRNAs were upregulated in response to cytokines and during insulitis progression. Their overexpression in MIN6 cells and primary islet cells promoted β-cell apoptosis without affecting insulin synthesis or secretion. Notably, lncRNA-1 (Gm5970) enhanced the nuclear translocation of nuclear factor κ B (NFκB). These findings suggest that cytokine-regulated lncRNAs contribute to early β-cell dysfunction in T1DM. LncRNA MALAT1 contributes to β-cell dysfunction in T1DM by epigenetically downregulating pancreatic and duodenal homeobox 1 (PDX-1), also known as insulin promoter factor 1, a key transcription factor essential for insulin gene expression. In NOD mouse islets and interleukin (IL)-1β-stimulated MIN6 cells, MALAT1 levels were elevated, whereas PDX-1 expression declined in an age- or time-dependent manner. MALAT1 reduced H3 histone acetylation at the PDX-1 promoter and suppressed its transcription and protein production. Knockdown of MALAT1 restored PDX-1 levels and insulin secretion, suggesting that MALAT1 plays a pathogenic role in T1DM by impairing β-cell function through the epigenetic regulation of PDX-1. These collective findings underscore the contributing role of ncRNAs in the onset of T1DM and highlight this as a promising area for further investigation. Type 2 DM T2DM is characterized by insulin resistance, chronic hyperglycemia, and relative impairment in insulin secretion that progressively worsens over time. Unlike T1DM, the development of T2DM is a gradual process that unfolds over several years and is driven by well-established risk factors. This fundamental difference in pathogenesis between T1DM and T2DM highlights the need to explore how ncRNAs function differently in each condition. For example, recent studies have shown that ncRNAs play a key role in modulating various cellular pathways such as β-cell function and peripheral insulin signaling, which are closely linked to the onset and progression of insulin resistance and T2DM. In addition to their regulatory roles, ncRNAs also hold promise as diagnostic biomarkers and potential therapeutic targets for T2DM. A growing body of evidence suggests that variations in miRNA genes may contribute to T2DM development by altering either miRNA expression or binding sites within mRNA regulatory regions. Several miRNAs have been implicated in β-cell functions and insulin regulation. For instance, miR-103 and miR-107 negatively regulated insulin sensitivity by targeting caveolin-1, a key component of insulin signaling. Their upregulation in the livers of diet-induced obese mice was associated with impaired glucose uptake. In contrast, silencing of these miRNAs enhanced caveolin-1 expression, improved insulin signaling, and reduced adipocyte size. Additionally, miR-107 has been shown to inhibit fatty acid oxidation in both obese mouse models and individuals with fatty liver disease, linking its activity to metabolic dysfunction in diabetes. If this could be linked to metabolic hormones with or without inflammation − or signaling pathways, it would be a point to be explored. Beyond its established role in impairing insulin signaling, miR-29 has also been linked to β-cell mitochondrial dysfunction, providing the first experimental evidence of its direct impact on mitochondrial regulation of insulin secretion. Silencing miR-29 enhanced insulin release by improving mitochondrial metabolism in β-cells, highlighting its potential as a therapeutic target to support β-cell function and meet the elevated insulin demands in T2DM. Obesity and a high intake of saturated fatty acids, such as palmitate, contribute to insulin resistance and T2DM by disrupting hepatic insulin signaling. , Recent studies have identified miR-15b as a key mediator of this process. In response to obesity and palmitate exposure, miR-15b directly targeted the 3′ untranslated region of insulin receptor mRNA, suppressing its protein expression. This downregulation of insulin receptor impaired insulin signaling and reduced glycogen synthesis in hepatocytes, highlighting a mechanistic link between saturated fatty acid-induced obesity, miR-15b upregulation, and hepatic insulin resistance. MiR-543 has been identified as a regulator of sirtuin 1 (SIRT1). Its expression was significantly elevated in tumor necrosis factor-α (TNF-α)-induced insulin-resistant HepG2 cells. Overexpression of miR-543 suppressed both the mRNA and protein levels of SIRT1, thereby promoting insulin resistance. Conversely, miR-543 inhibition restored SIRT1 expression and improved insulin sensitivity. Notably, SIRT1 overexpression counteracted the insulin-desensitizing effects of miR-543, confirming the role of the miR-543/SIRT1 axis in the pathogenesis of insulin resistance. Insulin exerts its metabolic effects through the activation of insulin receptor substrate-1 (IRS-1), which initiates a downstream signaling cascade involving phosphoinositide 3-kinase (PI3K), phosphorylation of protein kinase B (PKB/AKT), and translocation of glucose transporter 4 (GLUT4) to the plasma membrane, facilitating glucose uptake. Dysregulation of this pathway has been linked to several ncRNAs. For instance, miR-29 overexpression impaired glucose metabolism in skeletal muscle by downregulating IRS-1 and PI3K, thereby inhibiting insulin signaling. miR-499-5p plays a regulatory role in hepatic insulin signaling by targeting phosphatase and tensin homologue (PTEN), a negative regulator of the PI3K/AKT/glycogen synthase kinase (GSK) pathway. The downregulation of miR-499-5p, as seen in diabetic mouse models, impaired this signaling cascade, leading to reduced glycogen synthesis and a disrupted insulin response. Conversely, restoration of miR-499-5p levels enhanced insulin sensitivity and improved both glucose and insulin tolerance in high-fat-diet-fed mice. These findings highlight the regulatory role of miR-499-5p in hepatic glucose metabolism and its contribution to insulin resistance via PTEN suppression. Another miRNA that exerts a comparable effect on insulin resistance is miR-301a. It contributes to IL-6-induced insulin resistance by directly targeting PTEN, thereby disrupting the AKT/GSK signaling pathway and impairing glycogenesis. miR-802 contributed to hepatic insulin resistance by promoting oxidative stress and disrupting insulin-signaling pathways. Its overexpression elevated reactive oxygen species (ROS) and lipid peroxidation while reducing antioxidant enzyme activity, collectively intensifying hepatic oxidative stress. Mechanistically, miR-802 activated the stress kinases Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPK) (p38MAPK), which, in turn, impaired IRS-1 function and reduced AKT phosphorylation, ultimately dampening insulin signal transduction. These alterations underscore the pathogenic role of miR-802 in mediating insulin resistance via the JNK/p38MAPK axis and oxidative stress amplification. MiR-592 was found to be significantly downregulated in the liver of obese mice and humans. Its inhibition in lean mice led to elevated blood glucose, increased gluconeogenesis, and reduced insulin sensitivity, whereas hepatic overexpression improved metabolic parameters in obese mice. Mechanistically, the forkhead box O1 transcription factor (FOXO1) was identified as a direct target of miR-592, which suppresses its expression by binding to the 3′-UTR of FOXO1 mRNA. These results suggest that the obesity-related decline in miR-592 contributed to insulin resistance, and restoring its levels may offer therapeutic benefits for improving glucose and lipid metabolism, and hence insulin sensitivity. Similar to miRNAs, lncRNAs have been closely linked to dysregulated blood glucose and insulin resistance in T2DM, positioning them as key contributors to disease progression and as potential therapeutic targets for managing diabetes and its complications. Several lncRNAs have been implicated in the development of hepatic insulin resistance through modulation of FOXO1 expression and activity. In both high-fat-diet-fed and ob/ob mice, as well as in hepatocytes exposed to fatty acids such as palmitate, oleate, and linoleate, the expression of lncRNA MEG3 was found to be significantly elevated. This upregulation enhanced the transcription of FOXO1 and its downstream gluconeogenic genes G6PC and PEPCK, thereby increasing gluconeogenesis and impairing insulin-stimulated glycogen storage. , In this context, histone acetylation has been proposed as a mechanism that promotes MEG3 transcription. Similarly, lncRNA Gomafu was shown to contribute to hepatic insulin resistance via FOXO1 regulation. Elevated Gomafu levels in obese mice act as molecular sponges for miR-139-5p, effectively lifting the brakes on FOXO1 expression. This derepression of FOXO1 led to increased gluconeogenic gene expression and disrupted insulin signaling, whereas FOXO1 knockdown abolished the effects of Gomafu overexpression. These findings highlight the central role of the MEG3/FOXO1 and Gomafu/miR-139-5p/FOXO1 axes in promoting hepatic insulin resistance. In addition to FOXO1 regulation, MEG3 exerts additional diabetogenic effects through its alternative mechanisms. It has been reported to function as a competing endogenous RNA for miR-185-5p, resulting in the upregulation of early growth response 2, a transcription factor known to impair insulin signaling by negatively regulating the IRS. Clinical evidence supports these molecular findings, with increased MEG3 expression observed in patients with T2DM, further emphasizing its pathogenic relevance and potential as a therapeutic target. MALAT1 has also been implicated in the development of insulin resistance through its regulatory effect on oxidative stress pathways. Mechanistically, MALAT1 modulated the transcriptional activity of nuclear factor erythroid 2-related factor 2 (Nrf2), a key antioxidant response factor, thereby influencing cellular responses to reactive ROS. Elevated ROS levels impair insulin signaling by activating the JNK pathway, which inhibits IRS-1 and reduces AKT phosphorylation. In MALAT1-deficient models, insulin signaling was enhanced due to reduced JNK activation, which restored IRS-1 function and AKT phosphorylation. Overall, MALAT1 contributes to insulin resistance by promoting oxidative stress-induced JNK activity, disrupting the IRS-1/Akt signaling pathway, and positioning it as a potential target for managing diabetes linked to oxidative stress. Latent Autoimmune Diabetes in Adults Although several studies have identified the differential expression patterns of ncRNAs in LADA, their functional roles in disease development remain largely unexplored. In particular, Pengyu et al., Ning et al., and Sorgjerd et al. reported distinct profiles of lncRNAs, circRNAs, and small RNAs in LADA compared to T2DM and healthy controls. These findings suggest the potential utility of ncRNAs as diagnostic biomarkers for distinguishing LADA from other forms of diabetes. However, the current evidence does not clarify whether these altered ncRNAs contribute mechanistically to the autoimmune or metabolic features of LADA. This highlights a significant knowledge gap and underscores the need for future research to unravel the regulatory roles of ncRNAs in the LADA pathogenesis. Gestational DM GDM is different from other forms of diabetes, as affected women may have been normal or had underlying insulin resistance or impaired glucose regulation prior to pregnancy, yet the overt diagnosis typically becomes evident between the 24th and 28th weeks of gestation. Whether this condition resolves or progresses to permanent diabetes is determined within 1–3 months postpartum (American Diabetes Association Professional Practice Committee, 2024). While insulin resistance and β-cell dysfunction remain central to the pathogenesis of GDM, additional factors, such as placental dysfunction, endothelial abnormalities, and an altered adiponectin/TNF-α ratio, have also been implicated. , This raises an important inquiry into whether ncRNAs contribute to the development of GDM through mechanisms distinct from those in classical types of diabetes. Investigating the specific roles of ncRNAs in GDM pathogenesis is therefore an enticing and valuable area of research that remains largely uncharted. Several placenta-derived miRNAs have been implicated in the pathogenesis of GDM. Among them, both miR-518d and miR-21 expressed in the placentas of GDM patients were shown to negatively regulate peroxisome proliferator-activated receptor α (PPARα), a key transcription factor involved in placental development, lipid metabolism, and inflammatory regulation. , According to Qiu et al., this suppression of PPARα activates the nuclear translocation of NFκB and promotes the phosphorylation of associated signaling proteins, thereby triggering an inflammatory cascade that contributes to the development of GDM. In contrast, Guan et al. reported that miR-21 expression is downregulated in the placentas of GDM patients, while PPARα expression is upregulatedfindings that suggest impaired placental function due to reduced cell proliferation and trophoblast invasion. Emerging evidence highlights the role of miR-657 in the development of GDM. A previous study reported that miR-657 is upregulated in patients with GDM, in contrast to the downregulation of its target, IL-37. At the molecular level, miR-657 enhanced the proliferation of mononuclear macrophages and promoted the production of pro-inflammatory cytokines such as IL-6 and TNF-α, along with activation of the NFκB signaling pathway. These effects were attenuated by exogenous IL-37, underscoring the involvement of the miR-657/IL-37/NFκB axis in mediating placental inflammation and contributing to GDM pathogenesis. miR-143 was reported to be significantly downregulated in placentas from pharmacologically treated GDM patients compared to diet-treated and control groups. This downregulation was associated with upregulation of glycolytic enzymes such as GLUT1, hexokinase-2 (HK-2), phosphofructokinase, and lactate dehydrogenase. The study also reported that miR-143 directly targeted HK-2, and its overexpression in trophoblast cells helped rescue mitochondrial function and normalize glycolytic enzyme expression. Similarly, both miR-9 and miR-22 were found to be significantly downregulated in the placental tissues from GDM patients. This reduction was associated with an increased expression of the glycolytic enzymes GLUT1 and HK2 despite unchanged mRNA levels. Specifically, GLUT1 was identified as a direct target of both miR-9 and miR-22, whereas HK2 was targeted by miR-9 alone. Functional inhibition of these miRNAs led to enhanced glucose uptake and lactate secretion. Thus, the upregulation of GLUT1 and HK2 due to miR-9 and miR-22 suppression likely contributes to impaired glucose homeostasis in GDM, highlighting their relevance in the pathogenesis of the disease. Previous findings indicated that miR-503 plays a key role in the pathogenesis of GDM. Its expression was significantly upregulated in both placental tissue and peripheral blood of GDM patients and correlated with elevated blood glucose levels. Functionally, miR-503 impaired pancreatic β-cell activity by reducing insulin secretion and promoting apoptosis. These effects were mediated through direct targeting of the mammalian target of rapamycin (mTOR), a key regulator of β-cell growth and function, as silencing mTOR reversed the beneficial outcomes of miR-503 knockdown. Similarly, miR-770-5p was upregulated in GDM and contributed to β-cell dysfunction by directly targeting P53-regulated inhibitor of apoptosis 1 (TRIAP1). Inhibition of miR-770-5p enhanced insulin secretion, promoted β-cell proliferation, and reduced apoptosiseffects that were reversed by TRIAP1 silencing. Mechanistically, miR-770-5p exerted its pro-apoptotic influence through the apoptotic peptidase activating factor 1 signaling pathway, further linking this miRNA dysregulation to the development of GDM. Another important miRNA involved in GDM is miR-98. The study of Cao et al. showed that enhanced expression of miR-98 in placental tissues affected glucose uptake by modulating DNA methylation and directly inhibiting methyl CpG binding protein 2 (Mecp2) expression, which in turn negatively influenced the expression of canonical transient receptor potential 3 (Trpc3), a regulator of insulin-mediated glucose uptake. Inversely, both miR-96 and miR-221 were found to be significantly downregulated in GDM, with their expression levels inversely correlating with blood glucose levels. These miRNAs directly target p21-activated kinase 1 (PAK1), a molecule known to impair β-cell function. Under normal conditions, miR-96 and miR-221 enhance β-cell viability and insulin secretion by repressing PAK1. However, their downregulation in GDM leads to increased PAK1 expression, promoting β-cell apoptosis and functional decline, thereby contributing to the progression of GDM through compromised insulin production. , Regarding the role of lncRNAs in GDM, reduced expression of the lncRNA PVT1 was found to be associated with GDM, potentially through its regulatory effects on human trophoblast cell function. In placental tissues from pregnant females, PVT1 levels were significantly lower compared to healthy controls, which may contribute to trophoblast dysfunction. Mechanistically, PVT1 influenced the PI3K/AKT signaling pathway; its knockdown suppressed AKT phosphorylation, whereas its overexpression enhanced it. Since inhibition of the PI3K/AKT pathway in rat models of GDM has been shown to reduce oxidative stress and improve glycemic control, these findings suggest that downregulation of PVT1 may impair this signaling axis, thereby contributing to the development of GDM through compromised placental function. Mounting evidence points to the critical role for the lncRNA MALAT1 in the development of GDM. Placental tissues from GDM patients showed significantly elevated MALAT1 expression compared to those from healthy pregnant females. Silencing MALAT1 in trophoblastic cells via siRNA results in reduced cell proliferation, migration, and invasion, alongside decreased secretion of pro-inflammatory cytokines TNF-α and IL-6. Furthermore, MALAT1 knockdown downregulated transforming growth factor β (TGF-β) and NFκB expression, suggesting that its pathogenic influence may be mediated through activation of the TGF-β/NFκB signaling pathway. These findings implicate MALAT1 as a key driver of trophoblast dysfunction and placental inflammation in GDM. LncRNA–miRNA crosstalk also plays a pivotal role in GDM pathogenesis. Upregulation of miR-33a-5p has been associated with impaired β-cell function in GDM, correlating positively with blood glucose levels. Its overexpression suppressed proliferation and insulin secretion in the rat insulinoma cell line, INS-1 cells, by directly targeting ATP-binding cassette transporter A1 (ABCA1). The lncRNA DANCR mitigated these effects by functioning as a molecular sponge for miR-33a-5p, thereby restoring ABCA1 expression and promoting β-cell viability. This lnc-DANCR/miR-33a-5p/ABCA1 regulatory axis underscores a key molecular mechanism contributing to β-cell dysfunction in GDM development. Further highlighting the role of lncRNA–miRNA networks in GDM, elevated levels of lncRNA MEG3 were observed in both the blood and placental villous tissues of GDM patients. MEG3 exerted its effects by targeting miR-345-3p, which is notably downregulated in GDM. Functional assays in the human chorionic trophoblast cell line revealed that MEG3 overexpression impaired cell viability, migration, and invasion while promoting apoptosis. Conversely, MEG3 knockdown reversed these effects, and silencing miR-345-3p abrogated the protective impact of MEG3 inhibition. These findings suggest that the MEG3/miR-345-3p axis modulates trophoblast function and contributes to GDM pathogenesis. Among circRNAs implicated in GDM, hsa_circ_0005243 has been shown to play a regulatory role in placental function and inflammation. Its expression was significantly reduced in both the placenta and plasma of GDM patients. Functional studies demonstrated that silencing this circRNA in trophoblast cells impaired cell proliferation and migration, while simultaneously elevating the secretion of pro-inflammatory cytokines TNF-α and IL-6. Mechanistically, hsa_circ_0005243 depletion led to reduced β-catenin expression and enhanced nuclear translocation of NFκB p65, implicating its involvement in both placental dysfunction and inflammation. These results position hsa_circ_0005243 as a novel molecular player in the pathogenesis of GDM through modulation of the β-catenin and NFκB signaling pathways. Oncogenic and Tumor Suppressor ncRNAs in Diabetes Several ncRNAs have dual roles dependent upon the tissue and disease environment, which elucidate the contradictory findings regarding their function in diabetes. In recent years, ncRNAs have emerged as key mediators in numerous pathological states, playing substantial roles in both DM and cancer. They exert their roles by controlling gene expression, RNA processing, and other regulatory activities. , Generally, ncRNAs could be considered oncogenes (OGs) or TSs according to their expression levels and roles inside the cell. Associations between diabetes and cancer risk have been established; such associations could be attributed to common molecular pathways with common ncRNAs. Exploring molecular linkages between both DM and cancer provides useful insights for further understanding disease etiologies and sets new paths for management and treatment. , Considering lncRNAs with oncogenic properties in DM, nuclear-enriched abundant transcript 1 (NEAT1) is a major carcinogenic ncRNA in the context of diabetes and its complications since it has multiple roles as a profibrotic and proapoptotic factor. NEAT1 promotes high-glucose-induced hypertrophy in mesangial cells in diabetic nephropathy by regulating miR-222-3p and CDKN1B. Furthermore, NEAT1’s oncogenic character is further demonstrated by its role in increasing fibrosis, inflammation, proliferation, and oxidative stress in diabetic nephropathy by modifying the miR-423/5p and GLIPR2 pathways. , ANRIL, identified as an OG, was also found to be overexpressed in the case of hyperglycemia. It was found that it promotes glycolysis and glucose metabolism in the tumor microenvironment, leading to proliferation of colon cancer through sponging miR-186-5p. Moreover, another widely classified as an OG is the lncRNA HOTAIR, which is emerging as a novel biomarker for cancer. Diabetic serum levels of HOTAIR were also reported to be elevated, and its higher levels were associated with the development of diabetes complications such as kidney dysfunction and retinopathy. , MALAT1 could sponge miR-142-3p to promote the invasion and proliferation of malignant cells. It is also one of the overexpressed lncRNAs strongly associated with DM and is proposed as a marker for diagnosis and a therapeutic target for diabetes and its complications. Regarding MALAT1, its loss is implicated in β-cell dysfunction and apoptosis, also reducing insulin secretion. It directly binds and stabilizes PTBP1, alters the PKM1/PKM2 isoform ratio, and is transcriptionally controlled by Pdx1. Moreover, MALAT1 sequesters tumor-suppressive miRNAs, therefore releasing their targets and enhancing the expression of genes that facilitate epithelial–mesenchymal transition, invasion, and stemness mainly through PI3K/Akt and Wnt/β-catenin pathways. LncRNA TUG1 has multifaceted roles depending on the specific cellular context and target pathways. For instance, TUG1 is elevated in T2DM and could be considered to have diagnostic potential. It is also associated with endoplasmic reticulum stress in DM. On the other hand, in cancers, TUG1 is irregularly expressed and is correlated with carcinogenesis via controlling invasion, cell proliferation, metastasis, apoptosis, and drug resistance. LncRNAs ANRIL, MIAT, RNCR3, and PLUTO were associated with T2DM and linked to levels of hemoglobin A1c. Despite the fact that their precise oncogenic or tumor-suppressive activities were not well established in the search results, their correlation with diabetes development years before illness start shows potential relevance in the diabetes–cancer relationship that warrants additional investigation. Various ncRNAs appear in blood and urine as well as exosomes; they present potential diagnostic/prognostic promise in various diseases, including cancer , and diabetes. Considering miRNAs with OG properties, miR-21 demonstrates remarkable carcinogenic characteristics under diabetes-related conditions. Its expression is markedly increased in the serum of patients with T1DM and in the urine exosomes of T2DM associated with nephropathy. Additionally, miR-21 significantly contributes to the chemoresistance of colon cancer cells to 5-fluorouracil (5-FU) and correlates with the downregulation of repair genes, possibly acting as a biomarker for therapeutic efficacy in colorectal cancer. Thus, its dual function in diabetic complications and cancer chemoresistance establishes it as a pivotal oncogenic miRNA that connects them. Moreover, oncogenic miR-17-5p was elevated in DM and under persistent high glucose levels; miR-17-5p targets MAPK protein levels and is also implicated in diabetic retinopathy. In colorectal cancer, miR-17-5p expression was inversely correlated with survival. Another miRNA implicated in chemoresistance in colorectal cancer is miR-10b, which plays a critical role in DM progression. On the other hand, several ncRNAs widely accepted as TSs were dysregulated in DM with multiple roles in the pathogenesis. For instance, growth arrest-specific 5 (GAS5) has various effects in quenching tumor proliferation by modulating the PI3K/AKT/mTOR pathway. GAS5 exhibits typical tumor-suppressor characteristics but assumes detrimental, proinflammatory functions in specific diabetes scenarios, especially in wound healing. GAS5 overexpression in diabetic wounds alters macrophage polarization toward a sustained pro-inflammatory phenotype, hindering healing and normal tissue repair. Despite GAS5 being predominantly characterized as a TS, its overexpression in diabetic wounds exacerbates inflammation. Moreover, in DM, GAS5 promoted fibrosis in renal tubular epithelial cells by inhibiting miR-96-5p. One of the miRs linked to DM is miR-375, which participates in the regulation of insulin secretion by suppressing exocytosis. Its levels were inversely related to β-cell mass in mice and elevated significantly with diabetes complications. Moreover, miR-375 was reported to diminish the stemness in breast and gastric cancers, making it a predominant TS. , Identification of OG and TS ncRNAs implicated in DM will pose significant strategies for both disease management and cancer prevention. Figure and Table both illustrate the role of various ncRNAs in the context of diabetes, categorizing them into two main groups based on their expression and function, either oncogenic or TS ones being up- or down-regulated in DM. Figure demonstrates how imbalanced regulation of oncogenic and TS ncRNAs influences inflammatory and oxidative stress pathways, ultimately contributing to the development and progression of DM. 4. Oncogenic and TS ncRNAs in DM. | ncRNA | name | level | OG/TS | functional role | human/animal study | in vivo/in vitro study | ref | |---|---|---|---|---|---|---|---| | lncRNA | NEAT1 | ↑ | OG | fibrosis, inflammation, proliferation, and oxidative stress | review | review | , | | ANRIL | ↑ | OG | modifies glucose metabolism (increased glycolysis enzyme synthesis) | human study | colon tissueex vivo; Caco2 and SW620 cell linesin vitro (high glucose treatment) | || | HOTAIR | ↑ | OG | endorsing insulin transcription-related genes | human study | serumex vivo (T2DM patients and healthy controls) | – | | | MALAT1 | ↑ | OG | promotes glucose-induced inflammatory cytokines | human study | cervical cancer cell linesin vitro (metformin treatment) | , | | | GAS5 | ↑ | TS | cell growth arrest, proliferation, apoptosis, and autophagy | both | HK-2 cellsin vitro; HDF/STZ mouse kidneysin vivo (renal fibrosis/DKD model) | || | TUG1 | ↑ | OG | increased risk of T2DM | human study | peripheral bloodex vivo (T2DM patients and controls) | || | ANRIL, MIAT, RNCR3, PLUTO | ↑ | OG/TS | involved in the progressive loss of glucose homeostasis | human study | serumex vivo (prospective cohort study, older adults) | || | miRNA | miR-21 | ↑ | OG | PPARα inhibition | review | review | | | miR-17-5p | ↑ | OG | pancreatic β-cell proliferation and adaptation | human study | serum, colorectal tumor tissues, and colorectal cancer cell lines (SW480)ex vivo and in vitro | , | | | miR-10b | ↑ | OG | insulin signaling pathway | human study | serum microvesiclesex vivo (prediabetic individuals in PREDAPS cohort) | || | miR-375 | ↑ | TS | inhibiting insulin exocytosis | human study | serumex vivo (T2D patients with and without coronary artery disease, CAD) | Involvement of ncRNAs in Insulin Resistance By altering insulin sensitivity, β-cell function, inflammation, and metabolic balance, ncRNAs, such as circRNAs, lncRNAs, and miRNAs, significantly contribute to insulin resistance. Through their modulation of insulin sensitivity, inflammation, and glucose metabolism, miRNAs are important regulators of diabetic insulin resistance, especially in T2DM. For instance, insulin resistance is tightly associated with miRs-103 and -107. Serum levels of miR-103 exhibit a high correlation with fasting blood glucose, HbA1c, triglycerides, cholesterol, and insulin resistance indices (HOMA-IR, QUICKI), according to studies on the protein in T2DM patients. In animal models, anti-miR therapies that target miR-103/107 increased insulin sensitivity and glucose tolerance, suggesting that these molecules may be used as therapeutic targets to alleviate insulin resistance. Modulating these miRNAs has been shown to impact insulin sensitivity, glucose tolerance, and adipogenesis in experimental animals. For instance, downregulating the Let-7 family restored insulin sensitivity in muscle and liver tissues, and anti-miR-208a therapy improved glucose homeostasis in mice fed a high-fat diet. Furthermore, miR-122 was found to be a biomarker that predicts cardiovascular risk and insulin resistance in obese children, indicating its involvement in early mechanisms of diabetes insulin resistance. Furthermore, it was discovered that miR-21 increased vulnerability to oxidative stress brought on by glucose oscillations, connecting it to insulin resistance and oxidative damage associated with diabetes. Recent research showed that obese individuals’ gene expression of seven miRNAs, including let-7f-5p, miR-335-5p, miR-15b-5p, miR-7-5p, let-7i-5p, miR-205-5p, and miR-320c, changed before, during, and after bariatric surgery. Remarkably, these miRNAs target T2DM-related functional pathways and genes that contribute to insulin resistance. According to Lozano-Bartolome et al., insulin resistance was inversely correlated with the downregulation of miR-23a-3p and miR-181a-5p in the adipose tissue of obese people. By altering the expression of important components of the insulin signaling cascade, including PTEN and p70S6K, these miRNAs can prevent TNF-α-stimulated insulin resistance in adipocytes. Therefore, targeting signaling cascades in adipocytes would be beneficial as a treatment option. , Additionally, it was noted that the livers of obese mice and humans had reduced expression of miR-592, which resulted in increased gluconeogenesis, hyperglycemia, insulin resistance, and hepatic lipid buildup. By binding to the 3′-UTR of FOXO1, overexpression of this miRNA in obese mice improves glucose metabolism in hepatic cells. Therefore, miRNAs are intriguing indicators and therapeutic targets to improve insulin resistance because they influence glucose metabolism. In preclinical animals, experimental anti-miR treatments have the potential to improve glucose tolerance and insulin sensitivity. In target tissues such as the liver, skeletal muscle, and adipose tissue, lncRNAs alter the insulin signaling pathways. For instance, MEG3 is elevated in the liver of diabetic and high-fat mice, which increases the expression of FOXO1, a crucial regulator of lipid metabolism and gluconeogenesis, and contributes to hepatic insulin resistance. Similarly, via stabilization of SREBP-1c, a transcription factor implicated in lipid synthesis, MALAT1 increases hepatic insulin resistance. Insulin sensitivity may be enhanced, and hyperglycemia may be decreased by targeting these lncRNAs. It is interesting to note that GAS5 has been suggested as a predictive biomarker that has a high sensitivity and specificity for differentiating between those with diabetes and those without. Additionally, lncSHGL and H19 control lipid and glucose metabolism, which affects insulin sensitivity. Additionally, lncSHGL has been shown to affect lipid and glucose metabolism, which in turn controls insulin signaling in the muscle and liver. Furthermore, lncRNAs impact insulin signaling pathways such as IRS-1/2, PI3K/AKT, and GLUT4 by controlling gene expression at the epigenetic, transcriptional, and post-transcriptional levels. Additionally, they control fibrosis and inflammation, both of which are important factors in the development of diabetic resistance. To address insulin resistance, therapeutic approaches that target lncRNAs such as gene knock-in and RNA interference are being investigated. Many lncRNAs are still poorly understood, and further research is required to determine the exact biochemical pathways behind their roles in diabetes resistance. To convert these discoveries into clinical uses, better RNA sequencing and functional research are necessary. CircRNAs are becoming more widely acknowledged as significant modulators of insulin resistance. Two of the most researched circRNAs in diabetes are ciRS-7/CDR1as and ciHIPK3. By regulating important β-cell genes and acting as a sponge for miR-124-3p and miR-338-3p, circHIPK3 promotes insulin production and β-cell proliferation. Diabetes progresses when circHIPK3 is silenced because it reduces insulin production and β-cell proliferation. Similarly, ciRS-7 promotes β-cell activity and proliferation by sponging up miR-7, which inhibits insulin production. The complicated control of both circRNAs and their potential as therapeutic targets is highlighted by the fact that they are elevated in the peripheral blood of T2DM patients but lowered in the islets of diabetic mouse models. A number of circRNAs, such as hsa_circ_0054633, hsa_circ_0063425, and hsa_circ_0056891, exhibit changed expression in the plasma of patients with prediabetes and T2DM. These circRNAs can differentiate these patients from healthy controls with high diagnostic accuracy and are associated with insulin resistance and glycemic status. ncRNA in Diabetes Prognosis As predictive indicators for diabetes and its consequences, including diabetic retinopathy and cardiovascular disease, miRNAs have been thoroughly investigated. Important findings include the identification of miR-146a, miR-21, and miR-34a as predictive and diagnostic biomarkers in diabetes, with altered expression linked to problems such as diabetic retinopathy and the advancement of the disease. Insulin secretion, insulin resistance, and β-cell activity are all associated with circulating miRNAs like miR-126 and miR-375. For instance, miR-375 regulates β-cell mass and vascular dysfunction, whereas lower circulating miR-126 is a strong predictor of endothelial dysfunction and the progression of diabetes. Some miRNAs are useful for predicting cardiovascular issues in diabetes because they correlate with cardiovascular risk factors in diabetic patients such as blood pressure, blood glucose, and lipid abnormalities. It has been demonstrated that in patients with coronary heart disease receiving nutritional therapy, miR-let7b-3p, miR-141-5p, miR-182, and miR-192 predict the remission of T2DM. Remission with a low-fat diet is predicted by low baseline plasma levels of miR-let7b-3p, but remission with a Mediterranean diet is predicted by high baseline levels of miR-141-5p, miR-182, and miR-192. Additionally, circulating miRNAs have been confirmed to be predictive indicators for diabetic retinopathy, and some of these miRNAs may be pharmaceutical targets to stop or reduce the progression of the disease. As biomarkers for diabetic retinopathy stage classification, hsa-miR-195-5p, hsa-miR-20a-5p, hsa-miR-20b-5p, hsa-miR-27b-3p, and hsa-miR-451a were confirmed. Furthermore, it was demonstrated that individuals with severe diabetic nephropathy had differential expression of miRNAs; miR-21-3p and miR-378-3p were found to be elevated, while miR-16-5p and miR-29a-3p were downregulated. miR-21 and miR-378a-3p have been recently considered potential contributors to renal tubulointerstitial injury and fibrosis in different animal models of kidney injury. , Diabetic foot is one of the life-threatening diabetic complications that mandates better glycemic control. The formation of diabetic foot ulcers and elevated glucose levels were closely linked to the expression of miR-17, miR-191, and miR-121, which have long been implicated in diabetic wound healing. Since variations in lncRNA expression are common as diabetes and its complications progress, they hold potential as novel biomarkers for diabetes prognosis. They have better selectivity than proteins because of their distinct structure, which also makes them more stable and detectable. ANRIL, LINC-PINT, MALAT-1, LIPCAR, SENCR, and MIAT are among the lncRNAs whose expression has been assessed in T2DM patients with cardiovascular problems and may be able to predict these cardiovascular events. Similarly, the development of diabetic kidney disease is influenced by lncRNAs. They alter a number of processes in diverse kidney cell types, such as fibrosis, inflammation, and vascular growth. Some, like lncPVT1 and lncRNA MALAT1, are elevated in diabetic nephropathy. By controlling the buildup of ECM, PVT1 may be involved in the origin and progression of diabetic nephropathy. By improving serine/arginine splicing factor 1, MALAT1 may facilitate the translocation of β-catenin into the nucleus. Nuclear accumulation of β-catenin can harm podocytes and ultimately result in diabetic nephropathy. Other lncRNAs, including lncRNA MIAT and lncRNA TUG1, are down-regulated in diabetic nephropathy. TUG1 can reduce ECM buildup and cytokine release by acting as an endogenous sponge of miR-377 and downregulating miR-377 expression levels. By maintaining the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), the primary molecule of cellular defense against oxidative stress and genotoxicity of cells brought on by elevated blood glucose, MIAT can control the viability of proximal convoluted tubule cells. Additionally, Nrf2 can both functionally and pathologically shield the kidney from diabetes injury. Similar to this, lncRNAs GAS5 promote wound healing in diabetic foot ulcers by binding to TAF15, a part of RNA polymerase II, and activating the HIF1A/VEGF pathway. Both T2DM and coronary artery disease groups exhibit decreased circRNA expression of hsa-circRNA11783-2, which suggests that hsa-circRNA11783-2 may be associated with diabetic heart failure. In animal models of diabetic nephropathy, circ_0123996 expression was elevated, and lowering circ_0123996 levels reduced the expression of proteins linked to fibrosis. Furthermore, circ_0123996 participates in diabetic nephropathy by acting as a sponge of miR-149-5p. Certain circRNAs may have pathogenic significance for the development of diabetic retinopathy since they affect retinopathy by acting as neovascularization stimulators or inhibitors. For instance, human retinal microvascular endothelial cells and the retinal proliferative fibrovascular membranes of diabetic retinopathy patients have markedly elevated levels of hsa_circ_0002570. Additionally, the diabetic foot samples showed higher levels of hsa_circ_0084443, which is found in the cytoplasm of the human epidermal keratinocytes. This reduces the keratinocytes’ ability to migrate through the PI3K, EGFR, and ERK signaling pathways. Figure demonstrates the distinct profiles of ncRNAs linked to the prognosis of different diabetic complications, suggesting their potential use as specific biomarkers for monitoring disease progression. Diagnostic Significance of ncRNAs in DM According to the diagnostic criteria established by the World Health Organization (WHO) and endorsed by the American Diabetes Association (ADA), DM is diagnosed on the basis of the measurement of blood glucose levels or glycated hemoglobin (HbA1c) levels. While these established methods are reliable for diagnosing, they often identify the disease at a stage where significant pancreatic β-cell dysfunction or insulin resistance has already occurred. Furthermore, current diagnostic markers may not fully capture the complex heterogeneity of diabetes or predict individual disease progression. This underscores a critical need for novel, sensitive, and noninvasive biomarkers for earlier detection, more precise stratification of diabetes subtypes, and improved prognostic capabilities. In this context, ncRNAs have emerged as promising candidates. In recent years, ncRNAs, particularly miRNAs, lncRNAs, and circRNAs, have emerged as promising biomarkers for the pathogenesis of several diseases, including diabetes. ,, ncRNAs are involved in key DM-related pathways, including glucose homeostasis, insulin secretion, insulin sensitivity, β-cell function, and inflammation, making them sensitive indicators of disease states. Moreover, their high stability in bodily fluids such as blood, urine, and saliva makes them excellent candidates for noninvasive diagnostic tools. Numerous studies have observed altered expression levels of circulating miRNA, lncRNA, and circRNA in individuals with diabetes compared to those in healthy controls. , Although much of the early research in this area predominantly focused on circulating miRNAs, investigations into the diagnostic potential of lncRNAs and circRNAs are gaining momentum. Figure demonstrates the emerging diagnostic molecular biomarkers for DM. miRNAs as Precision Biomarkers for Early Detection miRNAs are among the most extensively studied ncRNAs for DM diagnosis due to their regulatory roles in insulin signaling, β-cell function, and inflammation. Their small size, stability in circulation, and detectability in biofluids make them ideal for noninvasive testing. Their dysregulated expression is widely documented in patients with both T1 and T2DM and is thought to contribute to the underlying pathological mechanisms of the disease and its complications. , Early research indicates that circulating miRNAs have the potential to predict DM and its related vascular complications, as these changes were evident several years before the onset of the disease. Zampetaki and colleagues were the first to identify a unique blood miRNA expression profile associated with DM. In their prospective study, the researchers analyzed blood samples from over 800 participants. They discovered a subset of five miRNAs, miR-15a, miR-28-3p, miR-29b, miR-126, and miR-223, that showed significant dysregulation in 80 individuals who were either prediabetic or diabetic. Among the miRNA-related characteristic changes observed, lower levels of miR-126 exhibited the highest association with DM, as well as the incidence of subclinical and overt arterial disorders. In the context of T1DM, several miRNAs have been identified with aberrant expression profiles. For instance, serum levels of miR-148a and miR-21-5p have been reported to be increased in the serum of T1DM patients compared to nondiabetic individuals. These miRNAs correlate with markers of bone strength and metabolism, serving as potential biomarkers for detecting bone fragility in T1DM patients, offering insights into disease progression, and possible therapeutic interventions. A study analyzing blood samples from T1DM patients identified 41 differentially expressed miRNAs, with 36 downregulated and five upregulated compared to those of healthy controls, highlighting their potential as biomarkers. Specific miRNAs like miR-326 have been found to have increased expression in T1DM patients with ongoing islet autoimmunity. Baseline levels of specific miRNAs, such as miR-3187-3p and miR-4302, were found to predict future C-peptide decline in newly diagnosed T1DM patients. For T2DM, numerous studies have also demonstrated dysregulated miRNA expression, suggesting their involvement in the pathological mechanisms underlying the disease and their potential as biomarkers. Circulating miRNAs associated with T2DM have been identified in various studies. A meta-analysis of miRNA expression profiling identified eight circulating miRNAsmiR-29a, miR-34a, miR-375, miR-103, miR-107, miR-132, miR-142-3p, and miR-144as promising biomarker candidates for T2DM. These miRNAs are known to regulate crucial processes related to T2DM, such as insulin secretion and signaling, and adipogenesis. Studies focusing on glucose metabolism, inflammation, platelet reactivity, and endothelial dysfunction in T2DM have highlighted the utility of circulating miRNAs like miR-30a-5p, miR-30d-5p, and miR-30c-5p as biomarkers for disease detection and progression. miRNAs have also been explored for their potential in diagnosing prediabetes, a state preceding T2DM. Identifying biomarkers for prediabetes is crucial for implementing early interventions to prevent or delay the onset of T2DM and its complications. In the study by Sidorkiewicz et al. 2020, using NanoString technology, researchers analyzed the expression levels of 798 miRNAs and identified three miRNAs, miR-491-5p, miR-1307-3p, and miR-298, that were upregulated in individuals who later developed T2DM. Pathway analysis linked these miRNAs to neuronal NO synthase signaling, amyloid processing, and hepatic cholestasis. The study found a strong predictive value for these miRNAs, with miR-491-5p showing an area under the curve (AUC) of 94.0%. Validation through qRT-PCR confirmed the findings, suggesting that these miRNAs could serve as early biomarkers to assess the T2DM risk in prediabetic patients, enabling preventive measures to mitigate disease progression. In a longitudinal observational study assessing whether circulating miRNAs predict improvements in fasting blood glucose, it was found that circulating miRNAs such as let-7c, miR-363, and miR-374b are significant predictors of changes in fasting blood glucose over time. LncRNAs as Diagnostic Biomarkers in Diabetes LncRNAs have emerged as promising biomarkers for the diagnosis and prognosis of diabetes and its complications. Their unique expression patterns in diabetic patients suggest potential utility in early detection, disease monitoring, and risk assessment for both types of diabetes, as well as related complications such as diabetic nephropathy and diabetic retinopathy. LncRNAs are recognized for their diverse functional roles, acting as signals, decoys, guides, or scaffolds to influence gene expression. Consequently, they are linked to pancreatic β-cell dysfunction, insulin resistance, and epigenetic regulation in diabetes. Several systematic reviews and meta-analyses have been conducted to evaluate the diagnostic utility of lncRNAs in identifying T2DM and associated comorbidities. , One meta-analysis included 17 relevant studies with a total of 4685 participants. The analysis of pooled data indicated that lncRNAs had a diagnostic AUC of 0.84 (95% CI: 0.80–0.87), along with a sensitivity of 0.79 (95% CI: 0.74–0.83) and a specificity of 0.75 (95% CI: 0.69–0.80). For the diagnosis of prediabetes, lncRNAs demonstrated an AUC of 0.65, with a sensitivity of 82% and a specificity of 65%. These results suggest a significant association between abnormal lncRNA expression and diagnostic outcomes in cases of T2DM. Specific lncRNAs have been associated with diabetes and its complications. For example, serum lncRNA HOTAIR has shown diagnostic significance for T2DM and predictive value for chronic complications, and serum lncRNA CASC2 is clinically significant for predicting chronic renal failure in patients with T2DM. MALAT1, a well-studied lncRNA, has been implicated in various diseases, , including diabetes-related complications, including retinopathy, cardiomyopathy, and kidney disease. MALAT1 was detected to be upregulated in the urine of T1DM patients. Moreover, MALAT1 expression in PBMC was significantly upregulated in T2DM and DKD groups when compared to control individuals. Although lncRNAs show promise as biomarkers, further research is necessary to fully understand their functional significance and to confirm their potential as diagnostic biomarkers. It is important to standardize lncRNA detection methods, validate findings in larger cohorts, and clarify their roles in the pathogenesis and complications of diabetes. circRNAs as Emerging Diagnostic Biomarkers in Diabetes CircRNAs are a unique type of single-stranded ncRNA, distinguished by a covalently closed-loop structure that contributes to their high biological stability. This stability, along with their conservation, abundance, and tissue specificity, makes circRNAs particularly promising candidates for novel biomarkers under pathological conditions, including DM. Functionally, circRNAs can act as “sponges” that bind to miRNAs and RNA-binding proteins, serve as protein scaffolds, maintain mRNA stability, and regulate gene transcription and translation. Studies have demonstrated that alterations in circRNA expression are strongly associated with the initiation and progression of various types of DMs and their complications. Differential expression profiles of circRNAs have been observed across different types of diabetes, supporting their potential role as promising biomarkers. For T1DM, circulating circRNAs show potential as diagnostic biomarkers. A study comparing circRNAs in the plasma of new-onset T1DM patients and controls identified 68 differentially expressed circRNAs, where 61 were upregulated and seven were downregulated, suggesting their use as diagnostic and therapeutic biomarkers. Using independent samples, the study confirmed that plasma hsa_circRNA_085129, hsa_circRNA_100332, hsa_circRNA_101062, and hsa_circRNA_103845 were significantly upregulated in T1DM patients, differentiating them from control individuals. In T2DM, various circRNAs that are differentially expressed have been identified as promising diagnostic biomarkers. For example, hsa_circ_0054633 has been recognized as a diagnostic biomarker for both prediabetes and T2DM, demonstrating potential diagnostic capability. Serum levels of has_circ_CCNB1 increased significantly, while circ_0009024 decreased in T2DM patients, showing high diagnostic accuracy for early detection of abnormal insulin signaling and prediction of pre-T2DM. A combination of has_circ_0071106 with lncRNA TUG1 and hsa-miR-607 showed promising diagnostic values for T2DM with 75.2% sensitivity and 100.0% specificity. Reduced levels of circ_0063425 and hsa_circ_0056891 are strongly linked to impaired fasting glucose and insulin resistance, exhibiting significant diagnostic accuracy for T2DM detection, with an AUC value for circ_0063425 (0.837) and hsa_circ_0056891 (0.719) displaying significant diagnostic accuracy for the detection of T2DM. While there is substantial evidence supporting the potential of ncRNAs as diagnostic biomarkers for DM and its complications, current research has yet to identify a universally accepted “gold standard” ncRNA biomarker. Further investigation is required to thoroughly understand the intricate molecular mechanisms involving ncRNAs and their interactions with the pathogenesis of DM. Further research is also needed to establish their utility in clinical practice, including standardizing blood sampling protocols and determining if detected changes are specific to diabetes or also occur in other conditions. The potential influence of sex on ncRNA biomarkers is also an area of ongoing exploration. Additionally, developing artificial intelligence-based prediction models that incorporate various types of ncRNAs, their expression levels, and patient information could aid in identifying valuable biomarkers for the prediction of DM and its complications. Table presents a summary of promising ncRNAs, including miRNAs, lncRNAs, and circRNAs, identified as potential diagnostic biomarkers for type 1 and 2 DM. 5. Emerging ncRNAs; miRNAs, lncRNAs, and circRNAs, Identified as Potential Diagnostic Molecular Biomarkers for T1DM and T2DM. | ncRNA | specific ncRNA | expression level | sample and study type | human/animal study | potential diagnostic value/association | ref | |---|---|---|---|---|---|---| | Type 1 Diabetes Mellitus | |||||| | miRNA | miR-21 | higher | plasmaT1DM patients (5 years), healthy controlsex vivo | human | associated with renal dysfunction | , | | miRNA | miR-126 | lower | urineT2DM patients with and without DN, healthy volunteersex vivo | human | associated with endothelial dysfunction in the kidney and diabetic retinopathy | , | | miRNA | miR-29b | higher | urine of DKD patients; podocytes in vitro; ADR nephropathy and db/db miceex vivo and in vivo | both | associated with diabetic kidney disease | | | miRNA | miR-30e-5p | lower | plasma and urineTDM patients with DKD (moderate/severe) vs controlsex vivo | human | associated with diabetic kidney disease | | | miRNA | miR-146a-5p | lower | serumT1D patientsex vivo | human | associated with retinopathy and cardiovascular diseases | , | | miRNA | miR-518d-3p, miR-618 | higher | serumT1D patientsex vivo | human | associated with endothelial dysfunction | | | miRNA | miR-204 | higher | serumT1D children and adults; INS-1 cells; human islets; diabetic miceex vivo/in vitro/in vivo | both | associated with T1DM-associated β-cell loss | | | miRNA | miR-487a-3p | higher | PBMCnewly diagnosed pediatric T1Dex vivo/in vitro | human | associated with the severity of disease onset | | | miRNA | miR-20a, miR-326 | higher | PBMCT1D patients vs healthy controlsex vivo | human | potential for detection of T1DM | | | miRNA | miR-146 | lower | PBMCnewly diagnosed T1Dex vivo | human | associated with an autoimmune imbalance | | | miRNA | miR-424 | higher | urinary exosomesT1D children vs healthy controlsex vivo | human | potential for prediction and detection of T1DM in children | | | miRNA | miRNA-377, miRNA-216a, miR-145, miR-155, miR-424 | miRNA-377, miR-145 higher; miRNA-216a, miR-155, miR-424 lower | urineT1DM children/adolescents; normoalbuminuric and microalbuminuricex vivo | human | biomarkers of nephropathy in children with T1DM | | | miRNA | miR-16-5p, miR-574-5p, miR-302d-3p, miR-191-5p | lower | plasma-derived exosomesT1DM vs controlsex vivo/in vitro | human | potential biomarkers for T1DM onset and progression | | | miRNA | miR-375 | lower | serumT1D children at onset vs controls; human isletsex vivo/in vitro | human | possible biomarker of inflammation associated with newly diagnosed T1DM in children | | | lncRNA | HOTAIR | lower | myocardial tissue and serumdiabetic cardiomyopathy; AC16 cardiomyocytesex vivo/in vitro | human | effectively distinguish patients with diabetic cardiomyopathy from healthy controls | | | lncRNA | MALAT1 | higher | PBMCrecent-onset T1D patientsex vivo | human | potential biomarker for endothelial cell dysfunction, islet β-cell dysfunction; potential biomarker for diabetic kidney disease | , | | lncRNA | CASC15 | higher | plasmaDCRF patients; CIHP-1 podocytesex vivo/in vitro | human | potential biomarker for chronic renal failure | | | lncRNA | MIAT | higher | plasma and kidney tissueDN patients; podocytes in vitro; Miat-KO miceex vivo/in vitro/in vivo | both | potential biomarker for reflecting the development of diabetic retinopathy | | | lncRNA | 162 differentially expressed exosomal lncRNAs | differentially expressed (e.g., MYL6-208 lower, CCT5-212 higher) | plasma-derived exosomesT1DM vs controlsex vivo | human | potential involvement in T1DM development. Inaugural exploration of lncRNA profiles in T1DM plasma exosomes | | | circRNA | hsa_circ_085129, hsa_circ_100332, hsa_circ_101062, hsa_circ_103845 | higher | plasmanew onset T1DM patients vs healthy controlsex vivo | human | potentially associated with the onset of T1DM | | | circRNA | hsa_circ_0002202 | higher | PBMC/macrophagesT1DM; inhibition in vitroex vivo/in vitro | human | potential biomarker associated with T1DM | | | circRNA | hsa_circ0005630 | higher | plasma-derived exosomesT1DM vs controlsex vivo | human | involved in the progression of T1DM | | | circRNA | hsa_circPPM1F | higher | PBMC/monocytesT1DM children; streptozocin-induced diabetic miceex vivo/in vitro/in vivo | both | associated with pancreatic islet injury | | | circRNA | hsa_circRNA_100632 | higher | PBMCFT1D and T1D vs controlsex vivo | human | diagnostic marker of fulminant T1DM. Predicted diagnostic marker for fulminant T1DM with an AUC = 0.846, 75.0% sensitivity, and 79.1% specificity | | | circRNA | hsa_circ_0071224, hsa_circ_0002437, hsa_circ_0084429, hsa_circ_0072697, hsa_circ_0000787 | hsa_circ_0071224, hsa_circ_0002437, hsa_circ_0084429, hsa_circ_0000787 higher expressed/hsa_circ_0072697, lower expressed | peripheral bloodT1D vs controlsex vivo | human | associated withT1DM development | | | circRNA | circHIPK3 | lower | plasmadiabetic cardiomyopathy, DM without complications, healthy controls; AC16 cardiomyocytesex vivo/in vitro | human | potential for diagnosis of T1DM and further correlated to diabetic cardiomyopathy | | | Type 2 Diabetes Mellitus | |||||| | miRNA | miR-15a, miR-28-3p, miR-29b, miR-126, miR-223 | deregulated | plasmaT2DM patients; hyperglycemic Lep(ob) miceex vivo/in vivo | both | suggested as a blood miRNA signature for T2DM | | | miRNA | miR-9, -29a, -30d, -34a | deregulated | serumnewly diagnosed T2D (n-T2D), prediabetes, T2D-susceptible normal glucose tolerance (s-NGT)ex vivo | human | found in prediabetes and newly diagnosed T2DM | | | miRNA | miR-103, miR-28-3p, miR-29a, miR-9, miR-30a-5p, miR-150 | low (miR-103, miR-28-3p, miR-29a, miR-9) and high (miR-30a-5p, miR-150) | plasmanondiabetic patients at baseline; follow-up for T2DM developmentex vivo | human | added to HbA1c, it showed greater predictive value in early diagnosis of T2DM (AUC = 0.8342) than HbA1c alone (AUC = 0.6950). Low levels of the first four and high levels of the last two are associated with higher risk of T2DM development | | | miRNA | miR-30a-5p, miR-30d-5p, miR-30c-5p | differentially expressed | platelets/circulationT2DM patients vs controlsex vivo | human | utility as biomarkers for detection and progression of T2DM. Associated with glucose metabolism and inflammation | | | miRNA | miR-103, miR-107, miR-132, miR-144, miR-142-3p, miR-29a, miR-34a, miR-375 | differentially expressed | multiple tissues: pancreas (miR-199a-3p, miR-223), liver (miR-199a-3p), plasma/serum, unspecified tissuesex vivo/in vivo | both | identified as promising biomarkers in a meta-analysis. Regulate processes like insulin secretion and signaling | , | | lncRNA | pooled lncRNAs | differentially expressed | serum/plasmaT2DM and prediabetes patients vs healthy controlsex vivo | human | diagnostic value for T2DM vs healthy controls: AUC = 0.73, sensitivity 0.71, specificity 0.66. Serve as promising indicators for the diagnostic evaluation of T2DM patients | | | lncRNA | GAS5 | lower | serumT2DM patients and nondiabeticex vivo | human | potential diagnostic biomarker for prediabetes and T2DM. Levels correlated to the prevalence of T2DM | | | lncRNA | ENST00000550337.1 | increased linearly | peripheral bloodhealthy, prediabetes, and T2DM cohortsex vivo | human | potential diagnostic biomarker for prediabetes and T2DM. Levels increased linearly from control to prediabetes to T2D. Showed the highest AUC for diagnosis. AUC for prediabetes is 0.714, and that for T2DM is 0.701. May differentiate between prediabetes and T2DM | | | circRNA | hsa_circHIPK3CDR1as | significantly elevated | peripheral bloodT2DM, prediabetes, and controlsex vivo | human | correlated with DM initiation/development. Able to distinguish T2DM from controls. Potential for diagnosis of islet dysfunction-related diabetes | | | circRNA | hsa_circ_0054633 | significantly elevated | peripheral bloodT2DM, prediabetes, and controlsex vivo | human | diagnostic biomarker for prediabetes and T2DM | | | circRNA | hsa_circ_0071106 (combined with lncRNA TUG1 and hsa-miR-607) | combined with other ncRNAs | peripheral bloodT2DM vs healthy controlsex vivo | human | the combined panel showed promising diagnostic values for T2DM (75.2% sensitivity, 100.0% specificity) | | | circRNA | has_circ_CCNB1 has_circ_0009024 | has_circ_CCNB1 increased and circ_0009024 decreased | serumT2DM patients vs healthy volunteersex vivo | human | preferred biomarker for early detection of abnormal insulin signaling and prediction of pre-T2DM (AUC = 0.9255) | | | circRNA | circANKRD36 | upregulated | peripheral bloodT2DM patients with CKD vs controlsex vivo | human | potential biomarker of chronic inflammation in DM patients. Associated with chronic inflammation in T2DM | | | circRNA | hsa-circRNA11806-28, hsa-circRNA11783-2, hsa-circRNA6510-1 | significantly reduced | peripheral bloodT2DM, coronary artery disease, and controlsex vivo | human | considered promising biomarkers for T2DM and closely related to coronary artery disease | Clinical Trials Involving ncRNAs in DM In recent years, several clinical trials have been initiated to explore the diagnostic and therapeutic potential of ncRNAs in patients with DM. These studies aimed to evaluate the clinical relevance of circulating ncRNAs, their association with disease progression, and the effectiveness of ncRNA-based interventions. Table summarizes the current clinical trials investigating the role of ncRNAs in DM, highlighting their objectives and clinical applications, retrieved from https://clinicaltrials.gov. 6. Clinical Trials Investigating the Role of ncRNAs in DM and Its Complications . | trial title | CT reference | study type | population | aim | clinical application | |---|---|---|---|---|---| | miRNA | ||||| | miRNA and FGF21 profile in first trimester and gestational diabetes prediction | NCT05632055 | observational | healthy pregnant women with single alive fetus, subgrouped by 100 g OGTT results | compare miRNA and FGF21 profiles in pregnancies with and without GDM | prediction of GDM | | dynamic parameters of glucose control in relation to biomarkers in serum and intraocular fluid in patients with diabetes | NCT05944640 | observational | adults with T1DM or T2DM, with or without diabetic retinopathy, undergoing ocular surgery | determine biomarkers (miRNA and cytokines) in blood/intraocular fluid in diabetic patients | biomarker discovery for ocular diabetic complications | | determining serum and urinary levels of miRNA 192 and miRNA 25 in patients with and without type 2 diabetes | NCT04176276 | observational | 300 patients: 200 with T2DM, 100 without diabetes | association between urinary/serum levels of miRNA 192/25 and kidney function in T2DM | diagnosis and monitoring of diabetic kidney disease | | correlation between vitamin D levels and ADAMTS13, VWF and microRNA expression in diabetic hemodialysis patients | NCT02245633 | observational | hemodialysis patients with diabetes | investigate effects of vitamin D on inflammation, coagulation, and miRNAs in diabetic hemodialysis patients | understanding pathophysiology and potential therapeutic targets | | profiling of original cellular and humoral biomarkers of type 1 diabetes | NCT01042301 | interventional | patients with T1DM (recent, long-term, latent), at-risk individuals, T1DM graft recipients, healthy controls | identify T cell and miRNA profiles relevant to T1D pathogenesis and immune monitoring | biomarker profiling for T1DM diagnosis and monitoring | | urine extracellular vesicles: noninvasive biomarkers of β-cell function and novel therapeutic agents in diabetes | NCT06832215 | observational | children/adolescents at CHUC, with T1DM, genetic risk or general endocrine evaluation | develop noninvasive miRNA biomarkers in urine for early T1DM identification | early diagnosis and prevention of T1D | | macrophage phenotype in type 2 diabetics after myocardial infarction and the potential role of miRNAs secreted | NCT02768935 | interventional | T2DM patients postmyocardial infarction | to identify miRNAs and vesicles that promote monocyte differentiation to anti-inflammatory macrophages | potential future therapy to restore monocyte differentiation using targeted miRNA delivery | | expression analysis of urinary exosome in type 2 diabetic kidney disease and evaluation of its clinical diagnostic value | NCT06123871 | observational | hospitalized patients with clinically confirmed T2DM | to analyze urinary exosomal miR-136-5p expression and assess its value in diagnosing diabetic nephropathy | noninvasive biomarker for early diagnosis of diabetic kidney disease | | effect of microvesicles and exosomes therapy on β-cell mass in T1DM | NCT02138331 | interventional phase 2/phase 3 | 20 T1DM patients (age 18–60) with >50% reduction in C-peptide, C-peptide >0.8 ng/mL, insulin ≥0.4 IU/kg/day | to evaluate whether umbilical cord-derived MSC microvesicle therapy reduces inflammation and improves β-cell mass and glycemic control | potential regenerative therapy for T1DM via MSC-derived extracellular vesicles | | circulating microRNAs for discriminating obese preschoolers at risk of diabetes | NCT02843139 | observational | children categorized by BMI (obese, overweight, normal) based on WHO standards; some adult T2DM patients for validation | to identify circulating miRNAs associated with progression from childhood obesity to adult T2DM using a multiphase study design | early detection of children at risk for T2DM using circulating miRNA biomarkers | | effect of exercise on miR-126 in individuals with prediabetes (EMiR-126-PD) | NCT06809257 | interventional | adults aged 18–60 with newly diagnosed prediabetes, physically inactive, eligible for exercise, stable weight (±2.5 kg in last 6 months) | to assess how structured exercise influences miR-126 expression in individuals with prediabetes | evaluate miR-126 as a potential biomarker for exercise-induced metabolic improvement in prediabetes | | lncRNA | ||||| | role of LncRNA H19 in the regulation of IGF-1R expression | NCT04767750 | observational | the study included 101 patients divided into 4 groups: Group I: 24 HCC patients Group II: 26 T2DM patients Group III: 24 HCC & T2DM patients Group IV: 27 age and gender-matched healthy control volunteers | to investigate the link between HCC and T2DM by analyzing the relationship between lncRNA H19 and IGF-1R mRNA in patient blood samples | discovering a correlation between H19 and IGF-1R could support new therapies for HCC and T2DM, such as using them as biomarkers or targets for RNA-based treatments | | effect of circulating lncRNAs on type 2 diabetic peripheral neuropathy | NCT04638556 | observational | the normal group consisted of healthy adults without any diseases. The T2DM group included patients with uncomplicated T2DM. The diabetic peripheral neuropathy group included patients with T2DM combined with diabetic peripheral neuropathy | to investigate the role of circulating lncRNAs in the inflammatory response and pathogenesis of diabetic peripheral neuropathy, particularly through regulation of miR-146a | to evaluate the potential of target lncRNAs as circulating biomarkers for diabetic peripheral neuropathy diagnosis or progression monitoring, which may aid in early detection and personalized treatment strategies | Retrieved from https://clinicaltrials.gov. Expert Recommendations for the Sustainable Use of ncRNAs in DM Precision Medicine The focus on precision treatment holds a promising future for DM treatment. A particular focus on ncRNAs paves the way for such a future through their profiling and creation of comprehensive molecular profiles that could be used for precise, individualized therapies. , Looking to the future, the sustainable application of ncRNAs in DM treatment will likely involve combining ncRNA biomarkers with other omics data (genomics, proteomics, and metabolomics) to create comprehensive molecular profiles for precise and individualized therapies. The context-dependent functions of specific ncRNAs further exemplify the intricacy of their regulatory networks. The identification of these unique ncRNAs and their functional activities offers significant insights into the discovery of innovative biomarkers for diagnosis and therapeutic targets for diabetes management and cancer prevention techniques. Also, a continuous challenge facing ncRNAs is their stability in drug delivery systems; thus, with the emergence of nanotechnology systems, such challenges are tackled, providing them with more stability and targeted delivery while minimizing side effects. , Therefore, new trends in targeting or treating diseases utilizing natural or small synthetic molecules should be considered. In addition, the newly categorized type 5 diabetes, with its link to childhood malnutrition and consequences of extreme insulin deficit, should be extensively studied to identify implicated ncRNAs that could discriminate type 5 from other diabetes types. Also, we understand the underlying mechanisms that malnutrition poses on the pancreatic function. Furthermore, the application of ncRNAs as liquid biopsy indicators for the real-time assessment of disease development and therapeutic response presents significant potential. Ongoing interdisciplinary research, encompassing in vitro and in vivo validation as well as meticulously designed clinical trials, will be essential to integrating these advancements into standard clinical practice, thereby revolutionizing diabetes management through precision medicine. Future Perspectives and Translational Challenges Future research should prioritize rigorous experimental validation, mechanistic studies, and the development of standardized protocols for ncRNA analysis. Addressing these limitations will be essential for translating ncRNA discoveries into clinically actionable strategies, ultimately improving outcomes for individuals with DM. Moreover, future research should prioritize large-scale, multicenter validation studies to confirm the reproducibility and clinical robustness of ncRNA signatures across diverse populations and diabetes subtypes. Standardization of sampling procedures, normalization strategies, and quantification platforms is essential to ensure comparability and regulatory acceptance. Mechanistically, deeper functional interrogation using genome editing, single-cell transcriptomics, and spatial multiomics will be critical to clarify tissue-specific roles and causal relationships. Translationally, major challenges remain, including targeted and safe RNA delivery systems, minimization of off-target effects, long-term safety evaluation, and interindividual variability in ncRNA expression. Addressing these barriers will be pivotal for transitioning ncRNA-based diagnostics and therapeutics from experimental promise to clinically actionable precision medicine strategies in diabetes care. Summary and Conclusion DM is a worldwide health issue marked by chronic metabolic dysregulation, which requires most patients to take medication for the rest of their lives. The increasing body of evidence supports the concept that ncRNAs are critical regulators of numerous biological processes that contribute to the development of DM and its complications. These ncRNAs serve as epigenetic regulators of gene expression, affecting all stages of RNA processing (splicing/translation/stability), with causal implications for β-cell malfunction and insulin resistance as demonstrated in preclinical studies. This comprehensive review explores the multifaceted roles of ncRNAs, including miRNAs, lncRNAs, circRNAs, and piRNAs, in the pathogenesis, diagnosis, and potential treatment of DM across its diverse subtypes. Diabetes, a complex metabolic disorder, manifests as type 1, type 2, LADA or type 1.5, gestational, monogenic, secondary, and recently recognized type 5 diabetes, each with unique etiologies and clinical features, along with distinct pathophysiological mechanisms. Through a systematic in silico approach utilizing databases such as HMDD v4.0 and lncRNAdisease, this review catalogued dysregulated ncRNAs associated with various DM subtypes, mapping their interactions with key genes and signaling pathways implicated in pancreatic β-cell development, insulin secretion, immune modulation, and metabolic homeostasis. Experimental evidence was integrated to underscore the regulatory impact of specific ncRNAs on insulin synthesis, glucose metabolism, and inflammatory responses, as well as their potential to preserve genomic stability of pancreatic β-cells. The review further emphasized the emerging value of ncRNAs as biomarkers for early diagnosis, disease staging, and therapeutic targeting, particularly in contexts of autoimmunity and insulin resistance. Herein, we focused on both in silico analyses and experimental validation, providing a robust foundation for the translational potential of ncRNA research in diabetes. We also addressed the expanding landscape of ncRNA-based precision medicine, advocating for the integration of ncRNA profiling into individualized DM management strategies. However, one of the detected limitations is the functional role of many identified ncRNAs that remains incompletely understood, and the causal relationships between ncRNA dysregulation and DM pathogenesis often require further mechanistic and clinical investigation. Additionally, the review highlighted a lack of standardized methodologies for ncRNA detection and quantification, which can impede reproducibility and comparability across studies. In conclusion, this review established that ncRNAs are integral to the molecular landscape of DM, influencing disease onset, progression, and therapeutic response. The identification of specific ncRNAs as candidate biomarkers and therapeutic targets holds significant promise for advancing precision medicine in the treatment of DM. Acknowledgments Glossary List of Abbreviations - ABCA1 ATP-binding cassette transporter A1 - ADA American Diabetes Association - ADAMTS13 a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13 - AKT protein kinase B - APAF1 apoptotic peptidase activating factor - BMI body mass index - ceRNA competing endogenous RNA - circRNA circular RNA - DGCR8 DiGeorge syndrome critical region 8 - DICER double-stranded RNA-specific endoribonuclease - DM diabetes mellitus - EGR2 early growth response 2 - FGF21 fibroblast growth factor-21 - FOXO1 FOrkhead boX O1 transcription factor - GAS5 growth arrest-specific 5 - GDM gestational diabetes mellitus - GLUT4 GLUcose transporter 4 - GSK glycogen synthase kinase - HbA1c hemoglobin A1c - HCC hepatocellular carcinoma - HK-2 hexokinase-2 - IGF-1R insulin-like growth factor 1 receptor - IL interleukin - IPF1 insulin promoter factor 1 - IRAK1 interleukin-1 receptor-associated kinase 1 - IRS-1 insulin receptor substrate-1 - JNK Jun N-terminal kinase - LADA latent autoimmune diabetes in adults - LDH lactate dehydrogenase - lncRNA long noncoding RNA - MAPK mitogen-activated protein kinases - MCP-1 monocyte chemoattractant protein-1 - Mecp2 methyl cpG binding protein 2 - MEG3 maternally expressed gene 3 - miRNA microRNA - MSC mesenchymal stem cell - mTOR mammalian target of rapamycin - ncRNA noncoding RNA - NEAT1 nuclear-enriched abundant transcript 1 - NFκB nuclear factor κ B-cell - NGT normal glucose tolerance - NOD non-obese diabetic - Nrf2 nuclear factor erythroid 2-related factor 2 - OG oncogenes - OGTT oral glucose tolerance test - p38MAPK p38 mitogen-activated protein kinases - PAK1 P21-activated kinase 1 - PDX-1 pancreatic and duodenal homeoboX 1 - PFK phospho-fructoKinase - PI3K phospho-inositide 3-kinase - piRNAs PIWI-interacting RNAs - PIWI P-element induced WImpy testis - PPARα peroxisome proliferator-activated receptor-α - PTEN phosphatase and TENsin homologue - ROS reactive oxygen species - SIRT1 sirtuin 1 - T1DM type 1 diabetes mellitus - T2DM type 2 diabetes mellitus - TGF-β transforming growth factor-β - TNF-α tumor necrosis factor-α - TRAF6 TNF receptor-associated factor 6 - TRIAP1 tissue p53 regulated inhibitor of apoptosis 1 - Trpc3 canonical transient receptor potential 3 - TS tumor suppressor - TUG1 taurine upregulated gene 1 - UTRs un-translated regions - VEGF vascular endothelial growth factor - VWF von Willebrand factor All the data obtained and/or analyzed during the current study are available from the corresponding authors upon reasonable request. All the authors contributed equally to conceptualization, resource methodology, data curation, writingoriginal draft preparation, and writingreview and editing. Supervision, project administration, software, in silico search, and bioinformatics analysis by N.M.H. All the authors have read and agreed to the published version of the manuscript. All the authors have agreed to the submission of this manuscript. The authors declare no competing financial interest.

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