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Sun C, Wen X, Chu X, Yuan F, Chen Y, Peng C, Qian M, Mei J, Wang J, Jiang Y, Xu S, Wang C, Li W, Zhang J. Adipocyte exosome miR-4472 inhibits glucose uptake in skeletal muscle through downregulation of MEF2D. J Diabetes Investig 2025. [PMID: 40342203 DOI: 10.1111/jdi.70054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Revised: 04/11/2025] [Accepted: 04/16/2025] [Indexed: 05/11/2025] Open
Abstract
AIMS/INTRODUCTION Previous studies have found that miR-4472 is overexpressed in the serum of individuals with obesity and type 2 diabetes mellitus (T2DM), which may participate in the process of obesity-induced T2DM. However, a role for miR-4472 in the process has not been demonstrated. Here, we aim to investigate whether the increased content of miR-4472 in adipose tissue derived from exosomes inhibits glucose uptake in skeletal muscle by downregulating the expression of its target gene. MATERIALS AND METHODS In vitro C2C12 and 3T3-L1 cells, and in vivo diet-induced obesity mouse models and AT-Dicer KO mice were used to assess the impact of miR-4472 on glucose uptake and insulin sensitivity. We also evaluated the effects of serum exosomes from normal and obese individuals on insulin sensitivity in mice and the expression of miR-4472 and target genes in skeletal muscle. RESULTS miR-4472 exhibits a strong positive correlation with BMI, waist circumference, hip circumference, and FPG. The content of miR-4472 derived from adipose tissue exosomes increases in the circulation in a state of obesity, which can induce insulin resistance by targeting the expression of MEF2D/GLUT4, inhibiting the glucose consumption and uptake ability of skeletal muscle cells. Both exosome inhibitors and miR-4472 inhibitors can reverse the inhibitory effect of miR-4472 on MEF2D/GLUT4 expression and glucose intake and uptake ability. Additionally, they can improve insulin resistance caused by increased miR-4472 levels in mice with obesity. CONCLUSIONS Adipocyte exosome miR-4472 inhibits glucose uptake in skeletal muscle through downregulating the expression of MEF2D/GLUT4.
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Affiliation(s)
- Chaoyue Sun
- Ministry of Education Key Laboratory of Xinjiang Endemic and Ethnic Disease, Shihezi, Xinjiang, China
| | - Xin Wen
- Medical College of Shihezi University, Shihezi, Xinjiang, China
| | - Xiaolong Chu
- Medical College of Shihezi University, Shihezi, Xinjiang, China
- Medical College of Tarim University, Alaer, Xinjiang, China
| | - Fangyuan Yuan
- Medical College of Shihezi University, Shihezi, Xinjiang, China
| | - Yao Chen
- Medical College of Shihezi University, Shihezi, Xinjiang, China
| | - Chaoling Peng
- Medical College of Shihezi University, Shihezi, Xinjiang, China
| | - Meiyu Qian
- Medical College of Shihezi University, Shihezi, Xinjiang, China
| | - Jin Mei
- Medical College of Shihezi University, Shihezi, Xinjiang, China
| | - Juan Wang
- Medical College of Shihezi University, Shihezi, Xinjiang, China
| | - Yidan Jiang
- Medical College of Shihezi University, Shihezi, Xinjiang, China
| | - Shibo Xu
- Medical College of Shihezi University, Shihezi, Xinjiang, China
| | - Cuizhe Wang
- Medical College of Shihezi University, Shihezi, Xinjiang, China
| | - Wei Li
- Medical College of Shihezi University, Shihezi, Xinjiang, China
- The First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang, China
| | - Jun Zhang
- Ministry of Education Key Laboratory of Xinjiang Endemic and Ethnic Disease, Shihezi, Xinjiang, China
- Medical College of Shihezi University, Shihezi, Xinjiang, China
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Ajadee A, Mahmud S, Ali MA, Mollah MMH, Ahmmed R, Mollah MNH. In-silico discovery of type-2 diabetes-causing host key genes that are associated with the complexity of monkeypox and repurposing common drugs. Brief Bioinform 2025; 26:bbaf215. [PMID: 40370100 PMCID: PMC12078936 DOI: 10.1093/bib/bbaf215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 04/11/2025] [Accepted: 04/21/2025] [Indexed: 05/16/2025] Open
Abstract
Monkeypox (Mpox) is a major global human health threat after COVID-19. Its treatment becomes complicated with type-2 diabetes (T2D). It may happen due to the influence of both disease-causing common host key genes (cHKGs). Therefore, it is necessary to explore both disease-causing cHKGs to reveal their shared pathogenetic mechanisms and candidate drugs as their common treatments without adverse side effect. This study aimed to address these issues. At first, 3 transcriptomics datasets for each of Mpox and 6 T2D datasets were analyzed and found 52 common host differentially expressed genes (cHDEGs) that can separate both T2D and Mpox patients from the control samples. Then top-ranked six cHDEGs (HSP90AA1, B2M, IGF1R, ALD1HA1, ASS1, and HADHA) were detected as the T2D-causing cHKGs that are associated with the complexity of Mpox through the protein-protein interaction network analysis. Then common pathogenetic processes between T2D and Mpox were disclosed by cHKG-set enrichment analysis with biological processes, molecular functions, cellular components and Kyoto Encyclopedia of Genes and Genomes pathways, and regulatory network analysis with transcription factors and microRNAs. Finally, cHKG-guided top-ranked three drug molecules (tecovirimat, vindoline, and brincidofovir) were recommended as the repurposable common therapeutic agents for both Mpox and T2D by molecular docking. The absorption, distribution, metabolism, excretion, and toxicity and drug-likeness analysis of these drug molecules indicated their good pharmacokinetics properties. The 100-ns molecular dynamics simulation results (root mean square deviation, root mean square fluctuation, and molecular mechanics generalized born surface area) with the top-ranked three complexes ASS1-tecovirimat, ALDH1A1-vindoline, and B2M-brincidofovir exhibited good pharmacodynamics properties. Therefore, the results provided in this article might be important resources for diagnosis and therapies of Mpox patients who are also suffering from T2D.
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Affiliation(s)
- Alvira Ajadee
- Bioinformatics Lab (Dry), Department of Statistics, University of Rajshahi, Rajshahi 6205, Bangladesh
| | - Sabkat Mahmud
- Bioinformatics Lab (Dry), Department of Statistics, University of Rajshahi, Rajshahi 6205, Bangladesh
| | - Md Ahad Ali
- Bioinformatics Lab (Dry), Department of Statistics, University of Rajshahi, Rajshahi 6205, Bangladesh
- Department of Chemistry, University of Rajshahi, Rajshahi 6205, Bangladesh
| | - Md Manir Hossain Mollah
- Department of Physical Sciences, Independent University Bangladesh, Bashundhara Residential Area, Dhaka 1245, Bangladesh
| | - Reaz Ahmmed
- Bioinformatics Lab (Dry), Department of Statistics, University of Rajshahi, Rajshahi 6205, Bangladesh
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi 6205, Bangladesh
| | - Md Nurul Haque Mollah
- Bioinformatics Lab (Dry), Department of Statistics, University of Rajshahi, Rajshahi 6205, Bangladesh
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Al-Rawaf HA, Gabr SA, Alghadir T, Alghadir F, Iqbal A, Alghadir AH. Correlation between circulating microRNAs and vascular biomarkers in type 2 diabetes based upon physical activity: a biochemical analytic study. BMC Endocr Disord 2025; 25:55. [PMID: 40016689 PMCID: PMC11866858 DOI: 10.1186/s12902-025-01855-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 01/21/2025] [Indexed: 03/01/2025] Open
Abstract
BACKGROUND This research investigated how physical activity (PA) might impact the expression of several microRNAs, specifically miR-126, miR-146a, miR-34a, miR-124a, miR-155, and miR-221, in the blood of elderly individuals with type 2 diabetes (T2D). Additionally, the study examined the relationship between these microRNAs and markers of vascular endothelial dysfunction, including vascular endothelial growth factor (VEGF), apolipoprotein A-I (apoA-I), and apolipoprotein B (apoB), to assess their potential in the prevention, early detection, and treatment of diabetes. METHODS This correlational observational study involved 100 male participants, aged between 18 and 65 years, all of whom had been living with type 2 diabetes (T2D) for over six years. The participants were divided into three groups: inactive, moderate, and active, depending on their level of physical activity (PA). Real-time PCR and immunoassays were employed to measure the expression of selected miRNAs, as well as VEGF, apoA-I, apoB, and diabetic management indicators. PA levels were determined using ACTi graph GT1M accelerometer (model WAM 7164; Fort Walton Beach, FL) and energy expenditure was measured in the form of metabolic equivalent (MET) by indirect calorimetry method. RESULTS The expression levels of miR-146a, miR-34a, and miR-124a were significantly higher in patients with higher physical activity, while no such increase was observed for the other miRNAs in less active participants. Additionally, PA-active individuals showed a more pronounced decrease in fasting blood sugar (FBS), insulin resistance (IR), fasting insulin (FINS), HOMA-IR, HbA1c (%), and levels of VEGF, apoAI, apoB, and the apoB/apoA-I ratio. The alteration in miRNA expression was positively associated with physical activity, VEGF, apoAI, apoB, the apoB/apoA-I ratio, and diabetes-related metrics, while being inversely related to BMI. CONCLUSIONS In diabetic patients with higher physical activity levels, circulating miR-146a, miR-34a, and miR-124a showed elevated expression, accompanied by a notable decrease in vascular biomarkers, including apoAI, apoB, and the apoB/apoA-I ratio. The findings revealed a strong correlation between these vascular biomarkers and the physiological responses of miR-146a, miR-34a, and miR-124a, though larger studies are required to validate these results further. TRIAL REGISTRATION Not applicable.
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Affiliation(s)
- Hadeel A Al-Rawaf
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, 11433, Saudi Arabia
- Rehabilitation Research Chair, Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh, 11433, Saudi Arabia
| | - Sami A Gabr
- Rehabilitation Research Chair, Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh, 11433, Saudi Arabia
| | - Talal Alghadir
- College of Medicine, King Saud University, Riyadh, 11433, Saudi Arabia
| | - Faisal Alghadir
- College of Medicine, King Saud University, Riyadh, 11433, Saudi Arabia
| | - Amir Iqbal
- Rehabilitation Research Chair, Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh, 11433, Saudi Arabia.
| | - Ahmad H Alghadir
- Rehabilitation Research Chair, Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh, 11433, Saudi Arabia
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Drago L, De La Motte LR, Deflorio L, Sansico DF, Salvatici M, Micaglio E, Biazzo M, Giarritiello F. Systematic review of bidirectional interaction between gut microbiome, miRNAs, and human pathologies. Front Microbiol 2025; 16:1540943. [PMID: 39973938 PMCID: PMC11835932 DOI: 10.3389/fmicb.2025.1540943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 01/21/2025] [Indexed: 02/21/2025] Open
Abstract
MicroRNAs (miRNAs) and the gut microbiome are key regulators of human health, with emerging evidence highlighting their complex, bidirectional interactions in chronic diseases. miRNAs, influence gene expression and can modulate the composition and function of the gut microbiome, impacting metabolic and immune processes. Conversely, the microbiome can affect host miRNA expression, influencing inflammatory pathways and disease susceptibility. This systematic review examines recent studies (2020-2024) focusing exclusively on human subjects, selected through rigorous inclusion and exclusion criteria. Studies were included if they investigated the interaction between miRNAs and the gut microbiome in the context of gastrointestinal diseases, obesity, autoimmune diseases, cognitive and neurodegenerative disorders, and autism. In vitro, in vivo and in silico analyses were excluded to ensure a strong translational focus on human pathophysiology. Notably, miRNAs, stable and abundant in patients, are emerging as promising biomarkers of microbiome-driven inflammation. This systematic review provides an overview of miRNAs, their regulatory effects on bacterial strains, and their associations with specific diseases. It also explores therapeutic advances and the potential of miRNA-based therapies to restore microbial balance and reduce inflammation.
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Affiliation(s)
- Lorenzo Drago
- UOC Laboratory of Clinical Medicine with Specialized Areas, IRCCS MultiMedica, Milan, Italy
- Clinical Microbiology and Microbiome Laboratory, Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | | | - Loredana Deflorio
- UOC Laboratory of Clinical Medicine with Specialized Areas, IRCCS MultiMedica, Milan, Italy
| | | | - Michela Salvatici
- UOC Laboratory of Clinical Medicine with Specialized Areas, IRCCS MultiMedica, Milan, Italy
| | | | | | - Fabiana Giarritiello
- UOC Laboratory of Clinical Medicine with Specialized Areas, IRCCS MultiMedica, Milan, Italy
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, Campobasso, Italy
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Hemedan AA, Satagopam V, Schneider R, Ostaszewski M. Cohort-specific boolean models highlight different regulatory modules during Parkinson's disease progression. iScience 2024; 27:110956. [PMID: 39429779 PMCID: PMC11489052 DOI: 10.1016/j.isci.2024.110956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 07/02/2024] [Accepted: 09/10/2024] [Indexed: 10/22/2024] Open
Abstract
Parkinson's disease (PD) involves complex molecular interactions and diverse comorbidities. To better understand its molecular mechanisms, we employed systems medicine approaches using the PD map, a detailed repository of PD-related interactions and applied Probabilistic Boolean Networks (PBNs) to capture the stochastic nature of molecular dynamics. By integrating cohort-level and real-world patient data, we modeled PD's subtype-specific pathway deregulations, providing a refined representation of its molecular landscape. Our study identifies key regulatory biomolecules and pathways that vary across PD subtypes, offering insights into the disease's progression and patient stratification. These findings have significant implications for the development of targeted therapeutic interventions.
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Affiliation(s)
- Ahmed Abdelmonem Hemedan
- Bioinformatics Core Unit, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Venkata Satagopam
- Bioinformatics Core Unit, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Reinhard Schneider
- Bioinformatics Core Unit, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Marek Ostaszewski
- Bioinformatics Core Unit, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
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Tu C, Wu Q, Wang J, Chen P, Deng Y, Yu L, Xu X, Fang X, Li W. miR-486-5p-rich extracellular vesicles derived from patients with olanzapine-induced insulin resistance negatively affect glucose-regulating function. Biochem Pharmacol 2024; 225:116308. [PMID: 38788961 DOI: 10.1016/j.bcp.2024.116308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 05/02/2024] [Accepted: 05/21/2024] [Indexed: 05/26/2024]
Abstract
A high risk of glucometabolic disorder severely disturbs compliance and limits the clinical application of olanzapine. MicroRNAs (miRNAs) in extracellular vesicles (EVs) have been reported as emerging biomarkers in glucolipid metabolic disorders. A total of 81 individuals with continuous olanzapine treatment over 3 months were recruited in this study, and plasma EVs from these individuals were isolated and injected into rats via the tail vein to investigate the glucose-regulating function in vivo. Moreover, we performed a miRNA profiling assay by high through-put sequencing to clarify the differentiated miRNA profiles between two groups of patients who were either susceptible or not susceptible to olanzapine-induced insulin resistance (IR). Finally, we administered antagomir and cocultured them with adipocytes to explore the mechanism in vitro. The results showed that individual insulin sensitivity varied in those patients and in olanzapine-administered rats. Furthermore, treatment with circulating EVs from patients with olanzapine-induced IR led to the development of metabolic abnormalities in rats and adipocytes in vitro through the AKT-GLUT4 pathway. Deep sequencing illustrated that the miRNAs of plasma EVs from patients showed a clear difference based on susceptibility to olanzapine-induced IR, and miR-486-5p was identified as a notable gene. The adipocyte data indicated that miR-486-5p silencing partially reversed the impaired cellular insulin sensitivity. Collectively, this study confirmed the function of plasma EVs in the interindividual differences in olanzapine-induced insulin sensitivity.
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Affiliation(s)
- Chuyue Tu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Wu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Wang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peiru Chen
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yahui Deng
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lixiu Yu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaojin Xu
- Affiliated Wuhan Mental Health Center, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Xiangming Fang
- Department of Psychiatry, Wuhan Youfu Hospital, Wuhan, China
| | - Weiyong Li
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Singh S, Sarma DK, Verma V, Nagpal R, Kumar M. Unveiling the future of metabolic medicine: omics technologies driving personalized solutions for precision treatment of metabolic disorders. Biochem Biophys Res Commun 2023; 682:1-20. [PMID: 37788525 DOI: 10.1016/j.bbrc.2023.09.064] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 09/13/2023] [Accepted: 09/21/2023] [Indexed: 10/05/2023]
Abstract
Metabolic disorders are increasingly prevalent worldwide, leading to high rates of morbidity and mortality. The variety of metabolic illnesses can be addressed through personalized medicine. The goal of personalized medicine is to give doctors the ability to anticipate the best course of treatment for patients with metabolic problems. By analyzing a patient's metabolomic, proteomic, genetic profile, and clinical data, physicians can identify relevant diagnostic, and predictive biomarkers and develop treatment plans and therapy for acute and chronic metabolic diseases. To achieve this goal, real-time modeling of clinical data and multiple omics is essential to pinpoint underlying biological mechanisms, risk factors, and possibly useful data to promote early diagnosis and prevention of complex diseases. Incorporating cutting-edge technologies like artificial intelligence and machine learning is crucial for consolidating diverse forms of data, examining multiple variables, establishing databases of clinical indicators to aid decision-making, and formulating ethical protocols to address concerns. This review article aims to explore the potential of personalized medicine utilizing omics approaches for the treatment of metabolic disorders. It focuses on the recent advancements in genomics, epigenomics, proteomics, metabolomics, and nutrigenomics, emphasizing their role in revolutionizing personalized medicine.
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Affiliation(s)
- Samradhi Singh
- ICMR- National Institute for Research in Environmental Health, Bhopal Bypass Road, Bhouri, Bhopal, 462030, Madhya Pradesh, India
| | - Devojit Kumar Sarma
- ICMR- National Institute for Research in Environmental Health, Bhopal Bypass Road, Bhouri, Bhopal, 462030, Madhya Pradesh, India
| | - Vinod Verma
- Stem Cell Research Centre, Department of Hematology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow, 226014, Uttar Pradesh, India
| | - Ravinder Nagpal
- Department of Nutrition and Integrative Physiology, College of Health and Human Sciences, Florida State University, Tallahassee, FL, 32306, USA
| | - Manoj Kumar
- ICMR- National Institute for Research in Environmental Health, Bhopal Bypass Road, Bhouri, Bhopal, 462030, Madhya Pradesh, India.
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Afsharmanesh MR, Mohammadi Z, Mansourian AR, Jafari SM. A Review of micro RNAs changes in T2DM in animals and humans. J Diabetes 2023; 15:649-664. [PMID: 37329278 PMCID: PMC10415875 DOI: 10.1111/1753-0407.13431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 04/22/2023] [Accepted: 05/24/2023] [Indexed: 06/19/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) and its associated complications have become a crucial public health concern in the world. According to the literature, chronic inflammation and the progression of T2DM have a close relationship. Accumulated evidence suggests that inflammation enhances the insulin secretion lost by islets of Langerhans and the resistance of target tissues to insulin action, which are two critical features in T2DM development. Based on recently highlighted research that plasma concentration of inflammatory mediators such as tumor necrosis factor α and interleukin-6 are elevated in insulin-resistant and T2DM, and it raises novel question marks about the processes causing inflammation in both situations. Over the past few decades, microRNAs (miRNAs), a class of short, noncoding RNA molecules, have been discovered to be involved in the regulation of inflammation, insulin resistance, and T2DM pathology. These noncoding RNAs are specifically comprised of RNA-induced silencing complexes and regulate the expression of specific protein-coding genes through various mechanisms. There is extending evidence that describes the expression profile of a special class of miRNA molecules altered during T2DM development. These modifications can be observed as potential biomarkers for the diagnosis of T2DM and related diseases. In this review study, after reviewing the possible mechanisms involved in T2DM pathophysiology, we update recent information on the miRNA roles in T2DM, inflammation, and insulin resistance.
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Affiliation(s)
- Mohammad Reza Afsharmanesh
- Metabolic Disorders Research CenterGolestan University of Medical SciencesGorganIran
- Department of Biochemistry and Biophysics, School of MedicineGolestan University of Medical SciencesGorganIran
| | - Zeinab Mohammadi
- Metabolic Disorders Research CenterGolestan University of Medical SciencesGorganIran
- Department of Biochemistry and Biophysics, School of MedicineGolestan University of Medical SciencesGorganIran
| | - Azad Reza Mansourian
- Metabolic Disorders Research CenterGolestan University of Medical SciencesGorganIran
- Department of Biochemistry and Biophysics, School of MedicineGolestan University of Medical SciencesGorganIran
| | - Seyyed Mehdi Jafari
- Metabolic Disorders Research CenterGolestan University of Medical SciencesGorganIran
- Department of Biochemistry and Biophysics, School of MedicineGolestan University of Medical SciencesGorganIran
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Macvanin MT, Gluvic Z, Bajic V, Isenovic ER. Novel insights regarding the role of noncoding RNAs in diabetes. World J Diabetes 2023; 14:958-976. [PMID: 37547582 PMCID: PMC10401459 DOI: 10.4239/wjd.v14.i7.958] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 05/01/2023] [Accepted: 05/22/2023] [Indexed: 07/12/2023] Open
Abstract
Diabetes mellitus (DM) is a group of metabolic disorders defined by hyperglycemia induced by insulin resistance, inadequate insulin secretion, or excessive glucagon secretion. In 2021, the global prevalence of diabetes is anticipated to be 10.7% (537 million people). Noncoding RNAs (ncRNAs) appear to have an important role in the initiation and progression of DM, according to a growing body of research. The two major groups of ncRNAs implicated in diabetic disorders are miRNAs and long noncoding RNAs. miRNAs are single-stranded, short (17-25 nucleotides), ncRNAs that influence gene expression at the post-transcriptional level. Because DM has reached epidemic proportions worldwide, it appears that novel diagnostic and therapeutic strategies are required to identify and treat complications associated with these diseases efficiently. miRNAs are gaining attention as biomarkers for DM diagnosis and potential treatment due to their function in maintaining physiological homeostasis via gene expression regulation. In this review, we address the issue of the gradually expanding global prevalence of DM by presenting a complete and up-to-date synopsis of various regulatory miRNAs involved in these disorders. We hope this review will spark discussion about ncRNAs as prognostic biomarkers and therapeutic tools for DM. We examine and synthesize recent research that used novel, high-throughput technologies to uncover ncRNAs involved in DM, necessitating a systematic approach to examining and summarizing their roles and possible diagnostic and therapeutic uses.
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Affiliation(s)
- Mirjana T Macvanin
- Department of Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
| | - Zoran Gluvic
- Department of Endocrinology and Diabetes, Clinic for Internal Medicine, Zemun Clinical Hospital, School of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Vladan Bajic
- Department of Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
| | - Esma R Isenovic
- Department of Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
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Abstract
Type 2 diabetes mellitus (T2DM) is a worldwide disease with rapidly increasing prevalence. This complex disorder caused by interplay between genetic predisposition factors, early developmental elements, diet and inactive lifestyle. Several researches have shown impact of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in the pathogenesis of this disorder. Several miRNAs such as miR-126, miR-222-3p, miR-182, let-7b-5p, and miR-1-3p have been down-regulated in different biological sources of patients with T2DM. Some other miRNAs including miR-21, miR-30d, miR-148a-3p, miR-146b and miR-486 have the opposite trends. In addition, a number of lncRNAs such as LY86-AS, HCG27_201, VIM-AS1, CTBP1-AS2, CASC2, GAS5, LINC-PINT, and MALAT1 have been altered in the peripheral blood, serum samples or tissues obtained from patients with T2DM. Taken together, both miRNAs and lncRNAs contribute to the development of T2DM and might be applied as markers or therapeutic molecules for this disorder.
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Affiliation(s)
- Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reyhane Eghtedarian
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mir Davood Omrani
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Szydełko J, Matyjaszek-Matuszek B. MicroRNAs as Biomarkers for Coronary Artery Disease Related to Type 2 Diabetes Mellitus-From Pathogenesis to Potential Clinical Application. Int J Mol Sci 2022; 24:ijms24010616. [PMID: 36614057 PMCID: PMC9820734 DOI: 10.3390/ijms24010616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/23/2022] [Accepted: 12/24/2022] [Indexed: 12/31/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with still growing incidence among adults and young people worldwide. Patients with T2DM are more susceptible to developing coronary artery disease (CAD) than non-diabetic individuals. The currently used diagnostic methods do not ensure the detection of CAD at an early stage. Thus, extensive research on non-invasive, blood-based biomarkers is necessary to avoid life-threatening events. MicroRNAs (miRNAs) are small, endogenous, non-coding RNAs that are stable in human body fluids and easily detectable. A number of reports have highlighted that the aberrant expression of miRNAs may impair the diversity of signaling pathways underlying the pathophysiology of atherosclerosis, which is a key player linking T2DM with CAD. The preclinical evidence suggests the atheroprotective and atherogenic influence of miRNAs on every step of T2DM-induced atherogenesis, including endothelial dysfunction, endothelial to mesenchymal transition, macrophage activation, vascular smooth muscle cells proliferation/migration, platelet hyperactivity, and calcification. Among the 122 analyzed miRNAs, 14 top miRNAs appear to be the most consistently dysregulated in T2DM and CAD, whereas 10 miRNAs are altered in T2DM, CAD, and T2DM-CAD patients. This up-to-date overview aims to discuss the role of miRNAs in the development of diabetic CAD, emphasizing their potential clinical usefulness as novel, non-invasive biomarkers and therapeutic targets for T2DM individuals with a predisposition to undergo CAD.
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12
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Dysregulation of Mir-193B and Mir-376A as a Biomarker of Prediabetes in Offspring of Gestational Diabetic Mice. Processes (Basel) 2022. [DOI: 10.3390/pr10122551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is a type of diabetes initiated during pregnancy and is characterized by maternal hyperglycemia that induces complications in mothers and children. In the current study, we used a GDM mouse model (through i.p. injection of a single dose of streptozocin, STZ, 60 mg/kg/bw) to investigate the biochemical and immunological changes in the blood and brain of diabetic mothers and their offspring relative to their appropriate controls. In addition, we estimated the expression levels of a set of microRNAs (miRNAs) to link between the dysregulation in the levels of miRNAs and the exposure to oxidative stress during embryonic development, as well as metabolic changes that occur after birth and during puberty in offspring (5-weeks-old). At the biochemical level, newborn pups appeared mostly to suffer from the same oxidative stress conditions of their mothers as shown by the significant increase in nitric oxide (NO) and malondialdehyde (MDA) in blood and brain of diabetic mothers and their pups. However, the 5-week-old offspring showed a significant increase in proinflammatory cytokines, IL-1β, IL-6, and TNF-α, and based on their blood glucose levels, could be considered as prediabetic (with glucose mean value of 165 mg/dl). In the meantime, the tested miRNAs, especially miR-15b, miR-146a, and miR-138 showed mostly similar expression levels in diabetic mothers and newborn pups. In this regard, miR-15a and -15b, miR-146a, and miR-138 are downregulated in diabetic mothers and their newborn pups relative to their appropriate controls. However, in offspring of diabetic mothers at puberty age, these miRNAs displayed different expression levels relative to mothers and control offspring. Interestingly, miR-193 and miR-763 expression levels were significantly lower in diabetic mothers but upregulated in their 5-week-old offspring, suggesting that miR-193 and miR-763 could be used as biomarkers to differentiate between prediabetes and diabetes.
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Ormazabal V, Nair S, Carrión F, Mcintyre HD, Salomon C. The link between gestational diabetes and cardiovascular diseases: potential role of extracellular vesicles. Cardiovasc Diabetol 2022; 21:174. [PMID: 36057662 PMCID: PMC9441052 DOI: 10.1186/s12933-022-01597-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 08/05/2022] [Indexed: 11/25/2022] Open
Abstract
Extracellular vesicles are critical mediators of cell communication. They encapsulate a variety of molecular cargo such as proteins, lipids, and nucleic acids including miRNAs, lncRNAs, circular RNAs, and mRNAs, and through transfer of these molecular signals can alter the metabolic phenotype in recipient cells. Emerging studies show the important role of extracellular vesicle signaling in the development and progression of cardiovascular diseases and associated risk factors such as type 2 diabetes and obesity. Gestational diabetes mellitus (GDM) is hyperglycemia that develops during pregnancy and increases the future risk of developing obesity, impaired glucose metabolism, and cardiovascular disease in both the mother and infant. Available evidence shows that changes in maternal metabolism and exposure to the hyperglycemic intrauterine environment can reprogram the fetal genome, leaving metabolic imprints that define life-long health and disease susceptibility. Understanding the factors that contribute to the increased susceptibility to metabolic disorders of children born to GDM mothers is critical for implementation of preventive strategies in GDM. In this review, we discuss the current literature on the fetal programming of cardiovascular diseases in GDM and the impact of extracellular vesicle (EV) signaling in epigenetic programming in cardiovascular disease, to determine the potential link between EV signaling in GDM and the development of cardiovascular disease in infants.
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Affiliation(s)
- Valeska Ormazabal
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine + Biomedical Sciences, The University of Queensland, Building 71/918, Herston, QLD, 4029, Australia.,Faculty of Biological Sciences, Pharmacology Department, University of Concepcion, Concepción, Chile
| | - Soumyalekshmi Nair
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine + Biomedical Sciences, The University of Queensland, Building 71/918, Herston, QLD, 4029, Australia
| | - Flavio Carrión
- Departamento de Investigación, Postgrado y Educación Continua (DIPEC), Facultad de Ciencias de la Salud, Universidad del Alba, Santiago, Chile
| | - H David Mcintyre
- Mater Research, Faculty of Medicine, University of Queensland, Mater Health, South Brisbane, Australia
| | - Carlos Salomon
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine + Biomedical Sciences, The University of Queensland, Building 71/918, Herston, QLD, 4029, Australia. .,Departamento de Investigación, Postgrado y Educación Continua (DIPEC), Facultad de Ciencias de la Salud, Universidad del Alba, Santiago, Chile.
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14
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De Sousa RAL, Improta-Caria AC. Regulation of microRNAs in Alzheimer´s disease, type 2 diabetes, and aerobic exercise training. Metab Brain Dis 2022; 37:559-580. [PMID: 35075500 DOI: 10.1007/s11011-022-00903-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 01/03/2022] [Indexed: 12/11/2022]
Abstract
Alzheimer's disease (AD) is the most common type of dementia. The evolution and aggregation of amyloid beta (β) oligomers is linked to insulin resistance in AD, which is also the major characteristic of type 2 diabetes (T2D). Being physically inactive can contribute to the development of AD and/or T2D. Aerobic exercise training (AET), a type of physical exercise, can be useful in preventing or treating the negative outcomes of AD and T2D. AD, T2D and AET can regulate the expression of microRNAs (miRNAs). Here, we review some of the changes in miRNAs expression regulated by AET, AD and T2D. MiRNAs play an important role in the gene regulation of key signaling pathways in both pathologies, AD and T2D. MiRNA dysregulation is evident in AD and has been associated with several neuropathological alterations, such as the development of a reactive gliosis. Expression of miRNAs are associated with many pathophysiological mechanisms involved in T2D like insulin synthesis, insulin resistance, glucose intolerance, hyperglycemia, intracellular signaling, and lipid profile. AET regulates miRNAs levels. We identified 5 miRNAs (miR-21, miR-29a/b, miR-103, miR-107, and miR-195) that regulate gene expression and are modulated by AET on AD and T2D. The identified miRNAs are potential targets to treat the symptoms of AD and T2D. Thus, AET is a non-pharmacological tool that can be used to prevent and fight the negative outcomes in AD and T2D.
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Affiliation(s)
- Ricardo Augusto Leoni De Sousa
- Programa Multicêntrico de Pós-Graduação Em Ciências Fisiológicas- Sociedade Brasileira de Fisiologia (SBFis), Universidade Federal Dos Vales Do Jequitinhonha E Mucuri (UFVJM), Campus JK, Rodovia MGT 367, Km 583, Alto da Jacuba, nº 5000, Diamantina, Minas Gerais, CEP 39100-000, Brazil.
| | - Alex Cleber Improta-Caria
- Post-Graduate Program in Medicine and Health, Faculty of Medicine, Federal University of Bahia, Bahia, Brazil
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15
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Padilla-Martinez F, Wojciechowska G, Szczerbinski L, Kretowski A. Circulating Nucleic Acid-Based Biomarkers of Type 2 Diabetes. Int J Mol Sci 2021; 23:ijms23010295. [PMID: 35008723 PMCID: PMC8745431 DOI: 10.3390/ijms23010295] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 12/25/2021] [Accepted: 12/26/2021] [Indexed: 11/23/2022] Open
Abstract
Type 2 diabetes (T2D) is a deficiency in how the body regulates glucose. Uncontrolled T2D will result in chronic high blood sugar levels, eventually resulting in T2D complications. These complications, such as kidney, eye, and nerve damage, are even harder to treat. Identifying individuals at high risk of developing T2D and its complications is essential for early prevention and treatment. Numerous studies have been done to identify biomarkers for T2D diagnosis and prognosis. This review focuses on recent T2D biomarker studies based on circulating nucleic acids using different omics technologies: genomics, transcriptomics, and epigenomics. Omics studies have profiled biomarker candidates from blood, urine, and other non-invasive samples. Despite methodological differences, several candidate biomarkers were reported for the risk and diagnosis of T2D, the prognosis of T2D complications, and pharmacodynamics of T2D treatments. Future studies should be done to validate the findings in larger samples and blood-based biomarkers in non-invasive samples to support the realization of precision medicine for T2D.
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Affiliation(s)
- Felipe Padilla-Martinez
- Clinical Research Centre, Medical University of Bialystok, 15276 Białystok, Poland; (F.P.-M.); (L.S.); (A.K.)
| | - Gladys Wojciechowska
- Clinical Research Centre, Medical University of Bialystok, 15276 Białystok, Poland; (F.P.-M.); (L.S.); (A.K.)
- Correspondence:
| | - Lukasz Szczerbinski
- Clinical Research Centre, Medical University of Bialystok, 15276 Białystok, Poland; (F.P.-M.); (L.S.); (A.K.)
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15276 Białystok, Poland
| | - Adam Kretowski
- Clinical Research Centre, Medical University of Bialystok, 15276 Białystok, Poland; (F.P.-M.); (L.S.); (A.K.)
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15276 Białystok, Poland
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16
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Kim JM, Joung KH, Lee JC, Choung S, Kang SM, Kim HJ, Ku BJ. Soluble LRIG2 is a potential biomarker for type 2 diabetes mellitus. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1612. [PMID: 34926656 PMCID: PMC8640903 DOI: 10.21037/atm-21-3272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 09/12/2021] [Indexed: 12/22/2022]
Abstract
Background Early diagnosis and treatment of type 2 diabetes can delay the onset of microvascular and macrovascular complications. Therefore, the identification of a novel biomarker for diagnosing diabetes is necessary. In the present study, the role of serum soluble leucine-rich repeats and immunoglobulin like domains 2 (sLRIG2) was investigated as a diagnostic biomarker of type 2 diabetes. Methods A total of 240 subjects with newly diagnosed type 2 diabetes (n=80), prediabetes (n=80), or normal glucose tolerance (NGT; n=80) were included in this study. The fasting serum sLRIG2 level was measured using a quantitative sandwich enzyme immunoassay technique with an enzyme-linked immunosorbent assay (ELISA). Serum sLRIG2 levels were compared among the three groups, and the associations of serum sLRIG2 levels with clinical variables were investigated. Results Serum sLRIG2 levels were significantly higher in subjects with type 2 diabetes (16.7±8.0 ng/mL) than in subjects without diabetes (NGT group: 12.3±5.3 ng/mL, P<0.001; prediabetes group: 13.2±5.8 ng/mL, P=0.002). Glycosylated hemoglobin (HbA1c: r=0.378, P<0.001) and blood glucose (fasting: r=0.421, P<0.001; 2-hour postprandial: r=0.433, P<0.001) correlated more strongly with sLRIG2 than any other clinical variables. Conclusions The serum sLRIG2 levels correlated with glucose parameters; thus, sLRIG2 might be a novel diagnostic biomarker for type 2 diabetes.
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Affiliation(s)
- Ji Min Kim
- Department of Endocrinology, Chungnam National University Sejong Hospital, Sejong, Republic of Korea.,Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Kyong Hye Joung
- Department of Endocrinology, Chungnam National University Sejong Hospital, Sejong, Republic of Korea.,Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Jun Choul Lee
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Sorim Choung
- Department of Medical Science, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Seon Mee Kang
- Department of Internal Medicine, Busan Paik Hospital, College of Medicine, Inje University, Busan, South Korea
| | - Hyun Jin Kim
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Bon Jeong Ku
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Republic of Korea.,Department of Medical Science, Chungnam National University College of Medicine, Daejeon, Republic of Korea
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Luís C, Baylina P, Soares R, Fernandes R. Metabolic Dysfunction Biomarkers as Predictors of Early Diabetes. Biomolecules 2021; 11:1589. [PMID: 34827587 PMCID: PMC8615896 DOI: 10.3390/biom11111589] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 10/26/2021] [Accepted: 10/26/2021] [Indexed: 12/23/2022] Open
Abstract
During the pathophysiological course of type 2 diabetes (T2D), several metabolic imbalances occur. There is increasing evidence that metabolic dysfunction far precedes clinical manifestations. Thus, knowing and understanding metabolic imbalances is crucial to unraveling new strategies and molecules (biomarkers) for the early-stage prediction of the disease's non-clinical phase. Lifestyle interventions must be made with considerable involvement of clinicians, and it should be considered that not all patients will respond in the same manner. Individuals with a high risk of diabetic progression will present compensatory metabolic mechanisms, translated into metabolic biomarkers that will therefore show potential predictive value to differentiate between progressors/non-progressors in T2D. Specific novel biomarkers are being proposed to entrap prediabetes and target progressors to achieve better outcomes. This study provides a review of the latest relevant biomarkers in prediabetes. A search for articles published between 2011 and 2021 was conducted; duplicates were removed, and inclusion criteria were applied. From the 29 studies considered, a survey of the most cited (relevant) biomarkers was conducted and further discussed in the two main identified fields: metabolomics, and miRNA studies.
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Affiliation(s)
- Carla Luís
- FMUP–Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal;
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal;
- LABMI-PORTIC, Laboratory of Medical & Industrial Biotechnology, Porto Research, Technology and Innovation Center, Porto Polytechnic, 4200-375 Porto, Portugal;
| | - Pilar Baylina
- LABMI-PORTIC, Laboratory of Medical & Industrial Biotechnology, Porto Research, Technology and Innovation Center, Porto Polytechnic, 4200-375 Porto, Portugal;
- IPP–Escola Superior de Saúde, Instituto Politécnico do Porto, 4200-072 Porto, Portugal
| | - Raquel Soares
- FMUP–Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal;
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal;
- Biochemistry Unit, Department of Biochemistry, FMUP, Faculty of Medicine, University of Porto, Al Prof Hernani Monteiro, 4200-319 Porto, Portugal
| | - Rúben Fernandes
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal;
- LABMI-PORTIC, Laboratory of Medical & Industrial Biotechnology, Porto Research, Technology and Innovation Center, Porto Polytechnic, 4200-375 Porto, Portugal;
- IPP–Escola Superior de Saúde, Instituto Politécnico do Porto, 4200-072 Porto, Portugal
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18
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González-Sánchez LE, Ortega-Camarillo C, Contreras-Ramos A, Barajas-Nava LA. miRNAs as biomarkers for diagnosis of type 2 diabetes: A systematic review. J Diabetes 2021; 13:792-816. [PMID: 33576054 DOI: 10.1111/1753-0407.13166] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 01/02/2021] [Accepted: 02/07/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND This systematic review summarizes results of studies that evaluated the expression of microRNAs (miRs) in prediabetes or type 2 diabetes (T2D). METHODS The information was obtained from PubMed, EMBL-EBI, Wanfang, Trip Database, Lilacs, CINAHL, Human microRNA Disease Database (HMDD) v3.0, and Google. A qualitative synthesis of the results was performed and miRs frequency was graphically represented. From 1893 identified studies, only 55 fulfilled the inclusion criteria. These 55 studies analyzed miRs in T2D, and of them, 13 also described data of prediabetes. RESULTS In diabetics, 122 miRs were reported and 35 miRs for prediabetics. However, we identified that five miRs (-122-5p, 144-3p, 210, 375, and -126b) were reported more often in diabetics and four (144-3p, -192, 29a, and -30d) in prediabetics. CONCLUSIONS Circulating miRs could be used as biomarkers of T2D. However, it is necessary to validate these microRNAs in prospective and multicenter studies with different population subgroups, considering age, gender, and risk factors.
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Affiliation(s)
- Luis Edgar González-Sánchez
- Laboratory of Developmental Biology Research and Experimental Teratogenicity, Hospital Infantil de México Federico Gómez (HIMFG), Mexico City, Mexico
| | - Clara Ortega-Camarillo
- Medical Research Unit in Biochemistry, Specialties Hospital, National Medical Center SXXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Alejandra Contreras-Ramos
- Laboratory of Developmental Biology Research and Experimental Teratogenicity, Hospital Infantil de México Federico Gómez (HIMFG), Mexico City, Mexico
| | - Leticia Andrea Barajas-Nava
- Evidence-Based Medicine Research Unit, Hospital Infantil de México Federico Gómez (HIMFG), Mexico City, Mexico
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19
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Tonyan ZN, Nasykhova YA, Mikhailova AA, Glotov AS. MicroRNAs as Potential Biomarkers of Type 2 Diabetes Mellitus. RUSS J GENET+ 2021. [DOI: 10.1134/s1022795421060107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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MicroRNA Sequences Modulated by Beta Cell Lipid Metabolism: Implications for Type 2 Diabetes Mellitus. BIOLOGY 2021; 10:biology10060534. [PMID: 34203703 PMCID: PMC8232095 DOI: 10.3390/biology10060534] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 12/23/2022]
Abstract
Alterations in lipid metabolism within beta cells and islets contributes to dysfunction and apoptosis of beta cells, leading to loss of insulin secretion and the onset of type 2 diabetes. Over the last decade, there has been an explosion of interest in understanding the landscape of gene expression which influences beta cell function, including the importance of small non-coding microRNA sequences in this context. This review sought to identify the microRNA sequences regulated by metabolic challenges in beta cells and islets, their targets, highlight their function and assess their possible relevance as biomarkers of disease progression in diabetic individuals. Predictive analysis was used to explore networks of genes targeted by these microRNA sequences, which may offer new therapeutic strategies to protect beta cell function and delay the onset of type 2 diabetes.
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21
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Zeinali F, Aghaei Zarch SM, Jahan-Mihan A, Kalantar SM, Vahidi Mehrjardi MY, Fallahzadeh H, Hosseinzadeh M, Rahmanian M, Mozaffari-Khosravi H. Circulating microRNA-122, microRNA-126-3p and microRNA-146a are associated with inflammation in patients with pre-diabetes and type 2 diabetes mellitus: A case control study. PLoS One 2021; 16:e0251697. [PMID: 34077450 PMCID: PMC8171947 DOI: 10.1371/journal.pone.0251697] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 04/30/2021] [Indexed: 01/21/2023] Open
Abstract
The prevalence of type 2 diabetes mellitus (T2DM) is increasing dramatically worldwide. Dysregulation of microRNA (miRNA) as key regulators of gene expression, has been reported in numerous diseases including diabetes. The aim of this study was to investigate the expression levels of miRNA-122, miRNA-126-3p and miRNA-146a in diabetic and pre-diabetic patients and in healthy individuals, and to determine whether the changes in the level of these miRNAs are reliable biomarkers in diagnosis, prognosis, and pathogenesis of T2DM. Additionally, we examined the relationship between miRNA levels and plasma concentrations of inflammatory factors including tumor necrosis factor alpha (TNF-α) and interleukin 6 (Il-6) as well as insulin resistance. In this case-control study, participants (n = 90) were allocated to three groups (n = 30/group): T2DM, pre-diabetes and healthy individuals as control (males and females, age: 25–65, body mass index: 25–35). Expression of miRNA was determined by real-time polymerase chain reaction (RT-PCR). Furthermore, plasma concentrations of TNF-α, IL-6 and fasting insulin were measured by enzyme-linked immunosorbent assay. Homeostatic model assessment for insulin resistance (HOMA-IR) was calculated as an indicator of insulin resistance. MiRNA-122 levels were higher while miRNA-126-3p and miRNA-146a levels were lower in T2DM and pre-diabetic patients compared to control (p<0.05). Furthermore, a positive correlation was found between miRNA-122 expression and TNF-α (r = 0.82), IL-6 (r = 0.83) and insulin resistance (r = 0.8). Conversely, negative correlations were observed between miRNA-126-3p and miRNA-146a levels and TNF-α (r = -0.7 and r = -0.82 respectively), IL-6 (r = -0.65 and r = -0.78 respectively) as well as insulin resistance (r = -0.67 and r = -0.78 respectively) (all p<0.05). Findings of this study suggest the miRNAs can potentially contribute to the pathogenesis of T2DM. Further studies are required to examine the reproducibility of these findings.
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Affiliation(s)
- Fahime Zeinali
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Seyed Mohsen Aghaei Zarch
- Department of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Alireza Jahan-Mihan
- Department of Nutrition and Dietetics, University of North Florida, Jacksonville, FL, United States of America
| | - Seyed Mehdi Kalantar
- Department of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Yazd Clinical and Research Center of Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | | | - Hossein Fallahzadeh
- Department of Biostatistics and Epidemiology, Research Center of Prevention and Epidemiology of Non-Communicable Disease, School of Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mahdieh Hosseinzadeh
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Masoud Rahmanian
- Yazd Diabetic Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hassan Mozaffari-Khosravi
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Yazd Diabetic Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- * E-mail:
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22
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Lu J, Pang L, Zhang B, Gong Z, Song C. Silencing circANKRD36 inhibits streptozotocin-induced insulin resistance and inflammation in diabetic rats by targeting miR-145 via XBP1. Inflamm Res 2021; 70:695-704. [PMID: 33978765 DOI: 10.1007/s00011-021-01467-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 04/19/2021] [Accepted: 04/28/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diabetes mellitus (DM) is defined as a group of metabolic diseases characterized by hyperglycemia, which results from a deficiency in insulin secretion and/or insulin action. In diabetic patients, type 2 diabetes mellitus (T2DM) is in the majority. We explored the effects of circANKRD36 on streptozotocin (STZ)-induced insulin resistance and inflammation in diabetic rats with the aim of uncovering the underlying mechanism. METHODS STZ was used to induce the in vivo T2DM rat model. After circANKRD36 interference, blood glucose, insulin and adiponectin were respectively detected. Hematoxylin and eosin (H&E), enzyme-linked immunosorbent assay (ELISA) and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) were conducted to examine inflammation and apoptosis in T2DM rats, and western blot was used for detecting apoptosis-related proteins. The binding relationships among circANKRD36, miR-145 and XBP1 were examined by luciferase reporter assay. RESULTS Results showed that circANKRD36 was expressed at a high level in T2DM rats, while silencing circANKRD36 led to decreased blood glucose and insulin, accompanied by increased adiponectin level, and ameliorating insulin resistance. Silencing circANKRD36 alleviated the inflammation and suppressed cell apoptosis in the pancreatic tissues of T2DM rats, which was abated by miR-145 inhibitor. The binding of miR-145 to XBP1 was then confirmed. Additionally, miR-145 inhibitor increased the level of XBP1 in T2DM rats, which was decreased in the presence of circANKRD36 silencing. CONCLUSION This study is the first to prove that silencing circANKRD36 inhibits STZ-induced insulin resistance and inflammation in diabetic rats by targeting miR- 145 via XBP1. The results warrant the importance of circRNAs as drug target and thereby pave way for the development of newer therapeutic measures for T2DM.
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MESH Headings
- Animals
- Cytokines/blood
- Diabetes Mellitus, Experimental/blood
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/immunology
- Diabetes Mellitus, Experimental/pathology
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/immunology
- Diabetes Mellitus, Type 2/pathology
- Inflammation/genetics
- Insulin Resistance/genetics
- Male
- MicroRNAs
- Pancreas/metabolism
- Pancreas/pathology
- RNA, Circular
- Rats, Sprague-Dawley
- Up-Regulation
- X-Box Binding Protein 1/genetics
- X-Box Binding Protein 1/metabolism
- Rats
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Affiliation(s)
- Jinger Lu
- Department of Endocrinology, The Affiliated People's Hospital of Ningbo University, Ningbo, 315040, Zhejiang, China
| | - Linrong Pang
- Department of Chemoradiotherapy Centre, The Affiliated People's Hospital of Ningbo University, Ningbo, 315040, Zhejiang, China
| | - Bo Zhang
- Department of Infectious Disease, The Affiliated People's Hospital of Ningbo University, Ningbo, 315040, Zhejiang, China
| | - Zhigang Gong
- College of Physical Education, Jiangxi Normal University, Nanchang, 330022, Jiangxi, China
| | - Chunhui Song
- College of Life Sciences, Jiangxi Normal University, No. 99 Ziyang Avenue, Nanchang, 330022, Jiangxi, China.
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Zhang Z, Liang X, Zhou J, Meng M, Gao Y, Yi G, Fu M. Exosomes in the pathogenesis and treatment of ocular diseases. Exp Eye Res 2021; 209:108626. [PMID: 34087205 DOI: 10.1016/j.exer.2021.108626] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 05/09/2021] [Accepted: 05/12/2021] [Indexed: 12/12/2022]
Abstract
Exosomes have diverse functions and rich content and are involved in intercellular communication, immune regulation, viral infection, tissue regeneration, and the occurrence, development and metastasis of tumours. Notably, various stem cell-derived exosomes are expected to become new therapeutic approaches for inflammatory diseases and tumours and have good clinical application prospects. However, few studies have examined exosomes in ophthalmic diseases. Therefore, based on the functions of exosomes, this paper summarizes progress in the possible use of exosomes as treatment for specific ophthalmic diseases, aiming to determine the pathogenesis of exosomes to achieve more effective clinical diagnosis and treatment of these diseases.
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Affiliation(s)
- Zhihan Zhang
- Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaotian Liang
- Southern Medical University, Guangzhou, Guangdong, China
| | - Jing Zhou
- Southern Medical University, Guangzhou, Guangdong, China
| | - Meijun Meng
- Southern Medical University, Guangzhou, Guangdong, China
| | - Ya Gao
- Southern Medical University, Guangzhou, Guangdong, China
| | - Guoguo Yi
- Department of Ophthalmology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
| | - Min Fu
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
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24
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Ramzan F, Vickers MH, Mithen RF. Epigenetics, microRNA and Metabolic Syndrome: A Comprehensive Review. Int J Mol Sci 2021; 22:ijms22095047. [PMID: 34068765 PMCID: PMC8126218 DOI: 10.3390/ijms22095047] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/06/2021] [Accepted: 05/07/2021] [Indexed: 12/13/2022] Open
Abstract
Epigenetics refers to the DNA chemistry changes that result in the modification of gene transcription and translation independently of the underlying DNA coding sequence. Epigenetic modifications are reported to involve various molecular mechanisms, including classical epigenetic changes affecting DNA methylation and histone modifications and small RNA-mediated processes, particularly that of microRNAs. Epigenetic changes are reversible and are closely interconnected. They are recognised to play a critical role as mediators of gene regulation, and any alteration in these mechanisms has been identified to mediate various pathophysiological conditions. Moreover, genetic predisposition and environmental factors, including dietary alterations, lifestyle or metabolic status, are identified to interact with the human epigenome, highlighting the importance of epigenetic factors as underlying processes in the aetiology of various diseases such as MetS. This review will reflect on how both the classical and microRNA-regulated epigenetic changes are associated with the pathophysiology of metabolic syndrome. We will then focus on the various aspects of epigenetic-based strategies used to modify MetS outcomes, including epigenetic diet, epigenetic drugs, epigenome editing tools and miRNA-based therapies.
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25
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Suneja S, Gangopadhyay S, Saini V, Dawar R, Kaur C. Emerging Diabetic Novel Biomarkers of the 21st Century. ANNALS OF THE NATIONAL ACADEMY OF MEDICAL SCIENCES (INDIA) 2021. [DOI: 10.1055/s-0041-1726613] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
AbstractDiabetes is a growing epidemic with estimated prevalence of infected to reach ~592 million by the year 2035. An effective way to approach is to detect the disease at a very early stage to reduce the complications and improve lifestyle management. Although several traditional biomarkers including glucated hemoglobin, glucated albumin, fructosamine, and 1,5-anhydroglucitol have helped in ease of diagnosis, there is lack of sensitivity and specificity and are inaccurate in certain clinical settings. Thus, search for new and effective biomarkers is a continuous process with an aim of accurate and timely diagnosis. Several novel biomarkers have surged in the present century that are helpful in timely detection of the disease condition. Although it is accepted that a single biomarker will have its inherent limitations, combining several markers will help to identify individuals at high risk of developing prediabetes and eventually its progression to frank diabetes. This review describes the novel biomarkers of the 21st century, both in type 1 and type 2 diabetes mellitus, and their present potential for assessing risk stratification due to insulin resistance that will pave the way for improved clinical outcome.
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Affiliation(s)
- Shilpa Suneja
- Department of Biochemistry, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India
| | - Sukanya Gangopadhyay
- Department of Biochemistry, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India
| | - Vandana Saini
- Department of Biochemistry, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India
| | - Rajni Dawar
- Department of Biochemistry, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India
| | - Charanjeet Kaur
- Department of Biochemistry, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India
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26
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Wang H. MicroRNAs, Parkinson's Disease, and Diabetes Mellitus. Int J Mol Sci 2021; 22:ijms22062953. [PMID: 33799467 PMCID: PMC8001823 DOI: 10.3390/ijms22062953] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/08/2021] [Accepted: 03/09/2021] [Indexed: 02/07/2023] Open
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder that affects 1% of the population over the age of 60. Diabetes Mellitus (DM) is a metabolic disorder that affects approximately 25% of adults over the age of 60. Recent studies showed that DM increases the risk of developing PD. The link between DM and PD has been discussed in the literature in relation to different mechanisms including mitochondrial dysfunction, oxidative stress, and protein aggregation. In this paper, we review the common microRNA (miRNA) biomarkers of both diseases. miRNAs play an important role in cell differentiation, development, the regulation of the cell cycle, and apoptosis. They are also involved in the pathology of many diseases. miRNAs can mediate the insulin pathway and glucose absorption. miRNAs can also regulate PD-related genes. Therefore, exploring the common miRNA biomarkers of both PD and DM can shed a light on how these two diseases are correlated, and targeting miRNAs is a potential therapeutic opportunity for both diseases.
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Affiliation(s)
- Hsiuying Wang
- Institute of Statistics, National Yang Ming Chiao Tung University, Hsinchu 30010, Taiwan
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27
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Al-Kafaji G, Al-Muhtaresh HA, Salem AH. Expression and clinical significance of miR-1 and miR-133 in pre-diabetes. Biomed Rep 2021; 14:33. [PMID: 33585035 DOI: 10.3892/br.2021.1409] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 01/22/2021] [Indexed: 12/11/2022] Open
Abstract
Pre-diabetes represents an intermediate state of altered glucose metabolism between normal glucose levels and type 2 diabetes mellitus (T2D), and is considered a significant risk factor for the development of T2D and related complications. Early detection of pre-diabetes may allow for the use of timely and effective treatment strategies to prevent its progression. Circulating microRNAs (miRNAs/miRs) that reflect changes in diabetes-related tissues, including the pancreas, liver, skeletal and heart muscle, and adipose tissue are promising biomarkers of disease progression. In our previous study, it was demonstrated that the cardiac and skeletal muscle specific miR-1 and miR-133 are upregulated in the blood of patients with T2D and cardiovascular disease. Since both miRNAs have been shown to be implicated in insulin resistance, an important feature of pre-diabetes, we hypothesised that their expression may be increased prior to clinical diagnosis of T2D, and may thus serve as biomarkers for pre-diabetes. The expression levels of circulating miRNAs were evaluated by reverse transcription-quantitative PCR in whole blood samples from 55 subjects, including 28 pre-diabetes individuals with impaired fasting glucose (FG) and impaired glucose tolerance, and 27 healthy controls. The individuals with pre-diabetes exhibited significantly higher expression levels of miR-1 and miR-133 compared with the controls (P<0.05). Target prediction search revealed that both miR-1 and miR-133 target several pathways involved in the pathophysiology of diabetes. Pearson's correlation analysis revealed that the two miRNAs were positively correlated with blood glucose parameters, including FG, 2-h oral glucose tolerance test and glycated haemoglobin A1c levels, as well as with insulin resistance (P<0.05). Multivariate logistic regression analysis revealed that the two miRNAs were significantly and directly associated with pre-diabetes, and this association remained significant after adjustment for several confounding variables (P<0.05). Moreover, linear regression analysis showed that the Homeostatic Model Assessment-Insulin Resistance was the only significant predictor to be significantly associated with both miRNAs (P<0.05). In discriminating pre-diabetes individuals from healthy controls, the area under the curves (AUCs) of the receiver operating characteristic curves (ROCs) were 0.813 and 0.810 for miR-1 and miR-133 respectively (P<0.05). Despite the relatively small number of participants, the present study showed for the first time that circulating levels of miR-1 and miR-133 were increased in individuals with pre-diabetes, and they were associated with important features of pre-diabetes. Thus, they may serve as clinical biomarkers for the early-stages of T2D.
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Affiliation(s)
- Ghada Al-Kafaji
- Department of Molecular Medicine/Al-Jawhara Centre for Molecular Medicine, Genetics, and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama 26671, Kingdom of Bahrain
| | - Haifa Abdulla Al-Muhtaresh
- Department of Molecular Medicine/Al-Jawhara Centre for Molecular Medicine, Genetics, and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama 26671, Kingdom of Bahrain
| | - Abdel Halim Salem
- Department of Anatomy, College of Medicine and Medical Sciences, Arabian Gulf University, Manama 26671, Kingdom of Bahrain
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28
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Li L, Li C, Lv M, Hu Q, Guo L, Xiong D. Correlation between alterations of gut microbiota and miR-122-5p expression in patients with type 2 diabetes mellitus. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1481. [PMID: 33313226 PMCID: PMC7729379 DOI: 10.21037/atm-20-6717] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Background To investigate the correlation between gut microbiota and circulating microRNAs (miRNAs) in patients with primary diagnosis of type 2 diabetes mellitus (T2DM) and to explore the possible mechanisms of miRNA-gut microbiota crosstalke network in the regulation of the insulin signaling pathway and glucose homeostasis in T2DM. Methods T2DM patients and normal controls were recruited. Fasting plasma and fecal samples were collected from the subjects, and their biochemical indexes including fasting blood glucose (FBG), glycated hemoglobin (HbAlc), cholesterol (TC), total triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and insulin were recorded. The variations in intestinal microbiota in the two groups were analyzed using 16S rRNA third-generation sequencing technology, and the differential expression of miRNAs between the groups was screened using miRNA high-throughput sequencing. The correlation and association between specifically changed intestinal microbiota and miRNA expressions were analyzed using a combination of bioinformatics analysis and statistical methods. Finally, 16S functional gene prediction analysis and target gene enrichment pathway analysis were carried out to predict relevant gut microbiota and miRNAs. Results Compared with normal controls, the biochemical indexes of HAlbc, FBG, TG, TC, LDL, HDL, and insulin were significantly different in T2DM patients (P<0.001, P<0.001, P=0.0125, P=0.98, P<0.001 P=0.022, and P=0.0013, respectively). The two groups also showed significantly different intestinal microbiota distribution and miRNA expression characteristics, including in the counts of Bacteriodes. uniformis and Phascolarctobacterium. Faecium (P=0.023, 0.031), which were negatively correlated (P=0.014, FC = -2.36) with the expression levels of serum miR-122-5p (r=−0.68, −0.60, P=0.01, 0.01). Conclusions This study discovered specific gut microbiota and miRNA characteristics in patients with a primary diagnosis of T2DM. A negative correlation between miR-122-5p and the intestinal bacteria Bacteriodes. uniformis and Phascolarctobacterium. Faecium was also revealed, suggesting that the crosstalke between miRNA and gut microbiota may regulate the insulin secretion and signal transduction by controling key genes of glucose metabolism during the development of T2DM.
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Affiliation(s)
- Lisha Li
- Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.,College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chaomin Li
- Endocrinology Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Meijun Lv
- College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiongying Hu
- Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lixuan Guo
- Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Daqian Xiong
- Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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S.V. A, Pratibha M, Kapil B, M.K. S. Identification of circulatory miRNAs as candidate biomarkers in prediabetes - A systematic review and bioinformatics analysis. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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30
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Sun Q, Zeng J, Liu Y, Chen J, Zeng QC, Chen YQ, Tu LL, Chen P, Yang F, Zhang M. microRNA-9 and -29a regulate the progression of diabetic peripheral neuropathy via ISL1-mediated sonic hedgehog signaling pathway. Aging (Albany NY) 2020; 12:11446-11465. [PMID: 32544883 PMCID: PMC7343507 DOI: 10.18632/aging.103230] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 02/25/2020] [Indexed: 12/13/2022]
Abstract
In this study, we tested the hypothesis that overexpression of miR-9 and miR-29a may contribute to DPN development and progression. We performed a meta-analysis of miR expression profile studies in human diabetes mellitus (DM) and the data suggested that miR-9 and miR-29a were highly expressed in patients with DM, which was further verified in serum samples collected from 30 patients diagnosed as DM. Besides, ISL1 was confirmed to be a target gene of miR-9 and miR-29a. Lentivirus-mediated forced expression of insulin gene enhancer binding protein-1 (ISL1) activated the sonic hedgehog (SHH) signaling pathway, increased motor nerve conduction velocity and threshold of nociception, and modulated expression of neurotrophic factors in sciatic nerves in rats with DM developed by intraperitoneal injection of 0.45% streptozotocin, suggesting that ISL1 could delay DM progression and promote neural regeneration and repair after sciatic nerve damage. However, lentivirus-mediated forced expression of miR-9 or miR-29a exacerbated DM and antagonized the beneficial effect of ISL1 on DPN. Collectively, this study revealed potential roles of miR-9 and miR-29a as contributors to DPN development through the SHH signaling pathway by binding to ISL1. Additionally, the results provided an experimental basis for the targeted intervention treatment of miR-9 and miR-29a.
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Affiliation(s)
- Qin Sun
- Department of Geriatrics, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, P. R. China
| | - Jun Zeng
- Chengdu Medical College, Chengdu 610500, P. R. China
| | - Yang Liu
- Department of Geriatrics, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, P. R. China
| | - JingYan Chen
- Department of Geriatrics, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, P. R. China
| | - Qing-Cui Zeng
- Department of Geriatrics, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, P. R. China
| | - Yan-Qiu Chen
- Department of Neurology, People's Hospital of Chongqing Yubei, Chongqing 401120, P. R. China
| | - Li-Li Tu
- Department of Geriatrics, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, P. R. China
| | - Ping Chen
- Department of Geriatrics, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, P. R. China
| | - Fan Yang
- Department of General Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, P. R. China
| | - Min Zhang
- Department of Geriatrics, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, P. R. China
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Zeinali F, Aghaei Zarch SM, Vahidi Mehrjardi MY, Kalantar SM, Jahan-mihan A, Karimi-Nazari E, Fallahzadeh H, Hosseinzadeh-Shamsi-Anar M, Rahmanian M, Fazeli MR, Mozaffari-Khosravi H. Effects of synbiotic supplementation on gut microbiome, serum level of TNF-α, and expression of microRNA-126 and microRNA-146a in patients with type 2 diabetes mellitus: study protocol for a double-blind controlled randomized clinical trial. Trials 2020; 21:324. [PMID: 32290852 PMCID: PMC7158024 DOI: 10.1186/s13063-020-04236-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Accepted: 03/09/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The dramatic increase in the prevalence of type 2 diabetes mellitus (T2DM) is a global major challenge to health. Circulating microRNAs have been suggested as promising biomarkers for different disorders such as diabetes. Imbalances in the gut microbiome have been revealed to contribute to the progression of multiple diseases including T2DM. Recently, the consumption of probiotics and synbiotics in the treatment of various diseases has shown a substantial growth. The anti-diabetes and anti-inflammatory effects of synbiotics have been indicated, which may be due to their beneficial effects on the gut microbiome. However, further research is needed to assess the effects of synbiotics on the microbiota and their impacts on expression of microRNAs relating to T2DM. Thus, we will aim to assess the effects of synbiotics on microbiota, serum level of tumor necrosis factor-α (TNF-α), and expression of microRNA-126 and microRNA-146a in patients with T2DM. METHODS Seventy-two patients with T2DM will be recruited in this double-blind randomized parallel placebo-controlled clinical trial. After block matching based on age and sex, participants will be randomly assigned to receive 1000 mg/day synbiotic (Familact) or placebo for 12 weeks. The microRNA-126 and microRNA-146a expression levels will be measured by real-time polymerase chain reaction and serum TNF-α level will be assessed by enzyme-linked immunosorbent assay kit at the beginning and at the end of the study. Determination of the gut microbiota will be done by quantitative polymerase chain reaction methods at baseline and at the end of the trial. Biochemical assessments (glycemic and lipid profiles) will also be conducted at onset and end of the study. DISCUSSION This is the first randomized controlled trial that will determine the effect of synbiotic supplementation on the gut microbiota and its probable impacts on serum levels of TNF-α and expression of related microRNAs in patients with T2DM. TRIAL REGISTRATION Iranian Registry of Clinical Trials: IRCT20180624040228N2. Registered on 27 March 2019. http://www.irct.ir/trial/38371.
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Affiliation(s)
- Fahime Zeinali
- grid.412505.70000 0004 0612 5912Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- grid.412505.70000 0004 0612 5912Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Seyed Mohsen Aghaei Zarch
- grid.412505.70000 0004 0612 5912Department of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | | | - Seyed Mehdi Kalantar
- grid.412505.70000 0004 0612 5912Department of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- grid.412505.70000 0004 0612 5912Yazd Clinical and Research Center of infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Alireza Jahan-mihan
- grid.266865.90000 0001 2109 4358Department of Nutrition and Dietetics, University of North Florida, Jacksonville, FL USA
| | - Elham Karimi-Nazari
- grid.412505.70000 0004 0612 5912Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hossein Fallahzadeh
- grid.412505.70000 0004 0612 5912Department of Biostatistics and Epidemiology, Research Center of Prevention and Epidemiology of Non-Communicable Disease, School of Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mahdieh Hosseinzadeh-Shamsi-Anar
- grid.412505.70000 0004 0612 5912Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- grid.412505.70000 0004 0612 5912Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Masoud Rahmanian
- grid.412505.70000 0004 0612 5912Yazd Diabetic Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mohammad Reza Fazeli
- grid.411705.60000 0001 0166 0922Department of Drug and Food Control, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Hassan Mozaffari-Khosravi
- grid.412505.70000 0004 0612 5912Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- grid.412505.70000 0004 0612 5912Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- grid.412505.70000 0004 0612 5912Yazd Diabetic Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Luo M, Xu C, Luo Y, Wang G, Wu J, Wan Q. Circulating miR-103 family as potential biomarkers for type 2 diabetes through targeting CAV-1 and SFRP4. Acta Diabetol 2020; 57:309-322. [PMID: 31583475 DOI: 10.1007/s00592-019-01430-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 09/23/2019] [Indexed: 12/13/2022]
Abstract
AIMS MicroRNA-103 (miR-103) family plays important roles in regulating glucose homeostasis in type 2 diabetes mellitus (DM2). However, the underlying mechanisms remain poorly characterized. The objective of this study was to test the hypothesis that circulating miR-103a and miR-103b, which regulate CAV-1 and SFRP4, respectively, are novel biomarkers for diagnosis of DM2. METHODS We determined the predictive potential of circulating miR-103a and miR-103b in pre-DM subjects (pre-DM), noncomplicated diabetic subjects, and normal glucose-tolerance individuals (control) using bioinformatic analysis, qRT-PCR, luciferase assays, and ELISA assays. RESULTS We found that both miR-103a and miR-103b had high complementarity and conservation, modulated reporter gene expression through seed sequences in the 3'UTRs of CAV-1 and SFRP4 mRNA, and negatively regulated their mRNA and protein levels, respectively. We also found that increased miR-103a and decreased miR-103a in plasma were significantly and negatively correlated with reduced CAV-1 levels and elevated SFRP4 levels in pre-DM and DM2, respectively, and were significantly associated with glucose metabolism, HbA1c levels, and other DM2 risk factors for progression from a normal individual to one with pre-DM. Furthermore, we demonstrated that the reciprocal changes in circulating miR-103a and miR-103b not only provided high sensitivity and specificity to differentiate the pre-DM population but also acted as biomarkers for predicting DM2 with high diagnostic value. CONCLUSIONS These findings suggest that circulating miR-103a and miR-103b may serve as novel biomarkers for diagnosis of DM2, providing novel insight into the mechanisms underlying pre-DM.
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Affiliation(s)
- Mao Luo
- Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, China
- Laboratory for Cardiovascular Pharmacology of Department of Pharmacology, The School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
| | - Chunrong Xu
- Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, China
- Laboratory for Cardiovascular Pharmacology of Department of Pharmacology, The School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
| | - Yulin Luo
- GCP Center, Affiliated Hospital (T.C.M) of Southwest Medical University, Luzhou, Sichuan, China
| | - Gang Wang
- Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, China
- Laboratory for Cardiovascular Pharmacology of Department of Pharmacology, The School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
| | - Jianbo Wu
- Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, China
- Laboratory for Cardiovascular Pharmacology of Department of Pharmacology, The School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
| | - Qin Wan
- Department of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China.
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Sadeghzadeh S, Dehghani Ashkezari M, Seifati SM, Vahidi Mehrjardi MY, Dehghan Tezerjani M, Sadeghzadeh S, Ladan SAB. Circulating miR-15a and miR-222 as Potential Biomarkers of Type 2 Diabetes. Diabetes Metab Syndr Obes 2020; 13:3461-3469. [PMID: 33061506 PMCID: PMC7537850 DOI: 10.2147/dmso.s263883] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 08/04/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND In recent years, considerable attention has been paid to the role of microRNAs (miRs) as biomarkers in type 2 diabetes (T2D). The aim of the study was to evaluate the expression levels of miR-15a and miR-222 in diabetic, pre-diabetic, and healthy individuals. MATERIALS AND METHODS Ninety individuals, who were referred to the Yazd diabetic center, were enrolled in this study and then classified into three groups as healthy, pre-T2D, and diabetic based on the clinical manifestations. Real-time PCR was performed to explore miRs expression in the plasma samples of the studied population. The correlation between the biochemical characteristic and the expression of these miRs as well as specificity and sensitivity of different clinical markers in healthy and pre-diabetic groups was evaluated. RESULTS miR-222 expression was significantly upregulated in the pre-T2D cases compared to the control subjects (P<0.001), while no significant difference was found between the pre-T2D and T2D groups (P<0.05). The expression of miR-15a was statistically downregulated in the pre-T2D and T2D subjects (P<0.05). The receiver operating characteristic (ROC) curve analysis of miR-15a expression with a cutoff point of 1.12 resulted in the area under the curve (AUC) of 85% (95% CI 0.865-0.912; P<0.001) with 84% and 85% sensitivity and specificity, respectively. Similarly, for miR-222, the cutoff point of 4.03 and AUC of 86% (95% CI 0.875-0.943; P<0.001) discriminated against the pre-T2D and control subjects via the sensitivity and specificity of 86% and 87%, respectively. Moreover, miR-15a values showed a negative correlation with FG (R=-0.32, P=0.005); however, miR-222 values were positively correlated with FG (R=0.25, P=0.03) in the pre-T2D group. Furthermore, miR-222 values were correlated with OGTT in the pre-T2D group (R=0.27, P=0.001). In addition, LDL-C had a negative correlation with miR-222 values in the pre-T2D group (R=-0.23, P=0.02). CONCLUSION This study indicated that the plasma expression levels of miR-222 and miR-15a can be considered as non-invasive, fast tools to separate the pre-T2D individuals from their healthy counterparts. Accordingly, this information could be used to predict the development of the disease as well as a direction for optimal therapy, thus refining outcomes in patients with diabetes.
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Affiliation(s)
- Salman Sadeghzadeh
- Medical Biotechnology Research Center, Ashkezar Branch, Islamic Azad University, Ashkezar, Yazd, Iran
| | - Mahmood Dehghani Ashkezari
- Medical Biotechnology Research Center, Ashkezar Branch, Islamic Azad University, Ashkezar, Yazd, Iran
- Correspondence: Mahmood Dehghani Ashkezari Medical Biotechnology Research Center, Ashkezar Branch, Islamic Azad University, Ashkezar, Yazd, Iran Email
| | - Seyed Morteza Seifati
- Medical Biotechnology Research Center, Ashkezar Branch, Islamic Azad University, Ashkezar, Yazd, Iran
| | - Mohammad Yahya Vahidi Mehrjardi
- Diabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Department of Genetics, Medical School, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Masoud Dehghan Tezerjani
- Abortion Research Center, Yazd Institute of Reproductive Sciences, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Sara Sadeghzadeh
- Department of Physiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Seyed Amir Behtash Ladan
- Medical Biotechnology Research Center, Ashkezar Branch, Islamic Azad University, Ashkezar, Yazd, Iran
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34
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Sangalli E, Tagliabue E, Sala LL, Prattichizzo F, Uccellatore A, Spada D, Lorino F, de Candia P, Lupini S, Cantone L, Favero C, Madeddu P, Bollati V, Genovese S, Spinetti G. Circulating MicroRNA-15a Associates With Retinal Damage in Patients With Early Stage Type 2 Diabetes. Front Endocrinol (Lausanne) 2020; 11:254. [PMID: 32390950 PMCID: PMC7192007 DOI: 10.3389/fendo.2020.00254] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 04/06/2020] [Indexed: 11/30/2022] Open
Abstract
Circulating microRNAs are potential biomarkers of type 2 diabetes mellitus (T2DM) and related complications. Here, we investigated the association of microRNA-15a with early retinal damage in T2DM. A cohort of untreated subjects screened for intermediate/high risk of T2DM, according to a score assessment questionnaire, and then recognized to have a normal (NGT) or impaired (IGT) glucose tolerance or T2DM was studied. The thickness of the ganglion cell complex (GCC), an early marker of retinal degeneration anteceding overt retinopathy was assessed by Optical Coherence Tomography. Total and extracellular vesicles (EV)-associated microRNA-15a quantity was measured in plasma by real time PCR. MicroRNA-15a level was significantly higher in subjects with IGT and T2DM compared with NGT. MicroRNA-15a abundance was correlated to body mass index and classical diabetes biomarkers, including fasting glucose, HbA1c, insulinemia, and HOMA-IR. Moreover, GCC thickness was significantly reduced in IGT and T2DM subjects compared with NGT controls. Importantly, total microRNA-15a correlated with GCC in IGT subjects, while in T2DM subjects, EV-microRNA-15a negatively correlated with GCC, suggesting that microRNA-15a may monitor initial retinal damage. The assessment of plasma microRNA-15a may help refining risk assessment and secondary prevention in patients with preclinical T2DM.
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Affiliation(s)
| | | | | | | | - AnnaChiara Uccellatore
- Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | | | | | | | - Silvia Lupini
- Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Laura Cantone
- EPIGET Lab, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Chiara Favero
- EPIGET Lab, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Paolo Madeddu
- Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Valentina Bollati
- EPIGET Lab, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | | | - Gaia Spinetti
- IRCCS MultiMedica, Milan, Italy
- *Correspondence: Gaia Spinetti
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35
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Jin Z, Ren J, Qi S. RETRACTED: Human bone mesenchymal stem cells-derived exosomes overexpressing microRNA-26a-5p alleviate osteoarthritis via down-regulation of PTGS2. Int Immunopharmacol 2020; 78:105946. [PMID: 31784400 DOI: 10.1016/j.intimp.2019.105946] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 09/24/2019] [Accepted: 09/26/2019] [Indexed: 12/19/2022]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. Concern was raised about the reliability of the Western blot results in Figures 2E, 3D and F, 4B, E+G, 5D+I, and 6D+F, which appear to have a similar phenotype as contained in many other publications, detailed here: https://pubpeer.com/publications/73C0A79F5EDF9ECC9818CE2D9B2A09; and here: https://docs.google.com/spreadsheets/d/1r0MyIYpagBc58BRF9c3luWNlCX8VUvUuPyYYXzxWvgY/edit#gid=262337249. The provenance of the flow cytometry data in Figure 5A was also questioned, as it appeared to have histograms that were hand drawn. The journal requested the corresponding author comment on these concerns and provide the raw data. The authors did not respond to this request and therefore the Editor-in-Chief decided to retract the article.
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Affiliation(s)
- Zhe Jin
- Department of Orthopaedics, the First Hospital of China Medical University, Shenyang 110001, PR China.
| | - Jiaan Ren
- Department of Orthopaedics, the First Hospital of China Medical University, Shenyang 110001, PR China
| | - Shanlun Qi
- Department of Orthopaedics, Dashiqiao Central Hospital, Yingkou 115100, PR China
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36
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Rosado JA, Diez-Bello R, Salido GM, Jardin I. Fine-tuning of microRNAs in Type 2 Diabetes Mellitus. Curr Med Chem 2019; 26:4102-4118. [PMID: 29210640 DOI: 10.2174/0929867325666171205163944] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 11/23/2017] [Accepted: 11/23/2017] [Indexed: 12/13/2022]
Abstract
Type 2 diabetes mellitus is a metabolic disease widely spread across industrialized countries. Sedentary lifestyle and unhealthy alimentary habits lead to obesity, boosting both glucose and fatty acid in the bloodstream and eventually, insulin resistance, pancreas inflammation and faulty insulin production or secretion, all of them very well-defined hallmarks of type 2 diabetes mellitus. miRNAs are small sequences of non-coding RNA that may regulate several processes within the cells, fine-tuning protein expression, with an unexpected and subtle precision and in time-frames ranging from minutes to days. Since the discovery of miRNA and their possible implication in pathologies, several groups aimed to find a relationship between type 2 diabetes mellitus and miRNAs. Here we discuss the pattern of expression of different miRNAs in cultured cells, animal models and diabetic patients. We summarize the role of the most important miRNAs involved in pancreas growth and development, insulin secretion and liver, skeletal muscle or adipocyte insulin resistance in the context of type 2 diabetes mellitus.
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Affiliation(s)
- Juan A Rosado
- Institute of Molecular Pathology Biomarkers & Department of Physiology (Cell Physiology Research Group), University of Extremadura, 10003-Caceres, Spain
| | - Raquel Diez-Bello
- Institute of Molecular Pathology Biomarkers & Department of Physiology (Cell Physiology Research Group), University of Extremadura, 10003-Caceres, Spain
| | - Ginés M Salido
- Institute of Molecular Pathology Biomarkers & Department of Physiology (Cell Physiology Research Group), University of Extremadura, 10003-Caceres, Spain
| | - Isaac Jardin
- Institute of Molecular Pathology Biomarkers & Department of Physiology (Cell Physiology Research Group), University of Extremadura, 10003-Caceres, Spain
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37
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Guo Y, Li G, Li H, Huang C, Liu Q, Dou Y, Yin X, Dong L, Yang N, Han Z. MicroRNA-15a Inhibits Glucose Transporter 4 Translocation and Impairs Glucose Metabolism in L6 Skeletal Muscle Via Targeting of Vesicle-Associated Membrane Protein-Associated Protein A. Can J Diabetes 2019; 44:261-266.e2. [PMID: 31594761 DOI: 10.1016/j.jcjd.2019.07.151] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 07/13/2019] [Accepted: 07/22/2019] [Indexed: 12/15/2022]
Abstract
OBJECTIVES MicroRNAs have been reported to participate in various important cell biological processes, such as glucose metabolism. The aim of this study was to explore the roles of microRNA-15a (miR-15a) in regulating insulin sensitivity. METHODS In L6 rat skeletal muscle cells, we observed the effect of miR-15a on glucose metabolism and glucose transporter 4 (GLUT4) translocation by targeting vesicle-associated membrane protein-associated protein A (VAP-A) after insulin treatment. Luciferase reporter assays were performed to demonstrate a direct interaction between miR-15a and the 3'-untranslated region of VAP-A microRNA. RESULTS We identified miR-15a as an extremely important regulator of GLUT4 translocation via targeting of VAP-A. Additionally, knockdown of endogenous miR-15a or overexpression of VAP-A could increase extracellular glucose by inhibiting the translocation of GLUT4 to the cell membrane after insulin treatment. However, overexpression of miR-15a or knockdown of VAP-A had no significant effect on glucose metabolism. CONCLUSIONS These findings reveal the following: 1) VAP-A is a marker of skeletal muscle glucose disposal and 2) a novel mechanism for GLUT4 translocation by miR-15a.
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Affiliation(s)
- Ying Guo
- Department of Obstetrics and Gynecology, Maternity and Child Health Hospital of Qinhuangdao, Qinhuangdao, Hebei, China.
| | - Gang Li
- Department of Obstetrics and Gynecology, Maternity and Child Health Hospital of Qinhuangdao, Qinhuangdao, Hebei, China
| | - Huiqing Li
- Department of Obstetrics and Gynecology, Maternity and Child Health Hospital of Qinhuangdao, Qinhuangdao, Hebei, China
| | - Chunlan Huang
- Department of Obstetrics and Gynecology, Maternity and Child Health Hospital of Qinhuangdao, Qinhuangdao, Hebei, China
| | - Qiao Liu
- Department of Psychology and Dentistry, Health School of Qinhuangdao, Qinhuangdao, Hebei, China
| | - Yifei Dou
- Department of Obstetrics and Gynecology, Maternity and Child Health Hospital of Qinhuangdao, Qinhuangdao, Hebei, China
| | - Xiurong Yin
- Department of Obstetrics and Gynecology, Maternity and Child Health Hospital of Qinhuangdao, Qinhuangdao, Hebei, China
| | - Lixia Dong
- Department of Obstetrics and Gynecology, Maternity and Child Health Hospital of Qinhuangdao, Qinhuangdao, Hebei, China
| | - Na Yang
- Department of Obstetrics and Gynecology, Maternity and Child Health Hospital of Qinhuangdao, Qinhuangdao, Hebei, China
| | - Zhonghou Han
- Department of Obstetrics and Gynecology, Maternity and Child Health Hospital of Qinhuangdao, Qinhuangdao, Hebei, China
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38
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Kim M, Zhang X. The Profiling and Role of miRNAs in Diabetes Mellitus. JOURNAL OF DIABETES AND CLINICAL RESEARCH 2019; 1:5-23. [PMID: 32432227 PMCID: PMC7236805 DOI: 10.33696/diabetes.1.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Diabetes mellitus (DM), a complex metabolic disease, has become a global threat to human health worldwide. Over the past decades, an enormous amount of effort has been devoted to understand how microRNAs (miRNAs), a class of small non-coding RNA regulators of gene expression at the post-transcriptional level, are implicated in DM pathology. Growing evidence suggests that the expression signature of a specific set of miRNAs has been altered in the progression of DM. In the present review, we summarize the recent investigations on the miRNA profiles as novel DM biomarkers in clinical studies and in animal models, and highlight recent discoveries on the complex regulatory effect and functional role of miRNAs in DM.
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Affiliation(s)
- Michael Kim
- Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY, USA
| | - Xiaokan Zhang
- Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY, USA
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39
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Mononen N, Lyytikäinen LP, Seppälä I, Mishra PP, Juonala M, Waldenberger M, Klopp N, Illig T, Leiviskä J, Loo BM, Laaksonen R, Oksala N, Kähönen M, Hutri-Kähönen N, Raitakari O, Lehtimäki T, Raitoharju E. Whole blood microRNA levels associate with glycemic status and correlate with target mRNAs in pathways important to type 2 diabetes. Sci Rep 2019; 9:8887. [PMID: 31222113 PMCID: PMC6586838 DOI: 10.1038/s41598-019-43793-4] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 04/29/2019] [Indexed: 12/25/2022] Open
Abstract
We analyzed the associations between whole blood microRNA profiles and the indices of glucose metabolism and impaired fasting glucose and examined whether the discovered microRNAs correlate with the expression of their mRNA targets. MicroRNA and gene expression profiling were performed for the Young Finns Study participants (n = 871). Glucose, insulin, and glycated hemoglobin (HbA1c) levels were measured, the insulin resistance index (HOMA2-IR) was calculated, and the glycemic status (normoglycemic [n = 534]/impaired fasting glucose [IFG] [n = 252]/type 2 diabetes [T2D] [n = 24]) determined. Levels of hsa-miR-144-5p, -122-5p, -148a-3p, -589-5p, and hsa-let-7a-5p associated with glycemic status. hsa-miR-144-5p and -148a-3p associated with glucose levels, while hsa-miR-144-5p, -122-5p, -184, and -339-3p associated with insulin levels and HOMA2-IR, and hsa-miR-148a-3p, -15b-3p, -93-3p, -146b-5p, -221-3p, -18a-3p, -642a-5p, and -181-2-3p associated with HbA1c levels. The targets of hsa-miR-146b-5p that correlated with its levels were enriched in inflammatory pathways, and the targets of hsa-miR-221-3p were enriched in insulin signaling and T2D pathways. These pathways showed indications of co-regulation by HbA1c-associated miRNAs. There were significant differences in the microRNA profiles associated with glucose, insulin, or HOMA-IR compared to those associated with HbA1c. The HbA1c-associated miRNAs also correlated with the expression of target mRNAs in pathways important to the development of T2D.
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Affiliation(s)
- Nina Mononen
- Department of Clinical Chemistry, Pirkanmaa Hospital District, Fimlab Laboratories, and the Finnish Cardiovascular Research Center, Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Leo-Pekka Lyytikäinen
- Department of Clinical Chemistry, Pirkanmaa Hospital District, Fimlab Laboratories, and the Finnish Cardiovascular Research Center, Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Ilkka Seppälä
- Department of Clinical Chemistry, Pirkanmaa Hospital District, Fimlab Laboratories, and the Finnish Cardiovascular Research Center, Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Pashupati P Mishra
- Department of Clinical Chemistry, Pirkanmaa Hospital District, Fimlab Laboratories, and the Finnish Cardiovascular Research Center, Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Markus Juonala
- Division of Medicine, Turku University Hospital, and Department of Medicine, University of Turku, Turku, Finland
| | - Melanie Waldenberger
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum, German Research Center for Environmental Health, Munich, Germany
| | - Norman Klopp
- Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.,Institute for Human Genetics, Hannover Medical School, Hanover, Germany
| | - Thomas Illig
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum, German Research Center for Environmental Health, Munich, Germany.,Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.,Institute for Human Genetics, Hannover Medical School, Hanover, Germany
| | - Jaana Leiviskä
- Department of Clinical Chemistry, University of Helsinki and Helsinki University Hospital HUSLAB, Helsinki, Finland
| | - Britt-Marie Loo
- Joint Clinical Biochemistry Laboratory of the University of Turku and Turku University Central Hospital and Department of Chronic Disease Prevention, National Institute for Health and Welfare, Turku, Finland
| | - Reijo Laaksonen
- Department of Clinical Chemistry, Pirkanmaa Hospital District, Fimlab Laboratories, and the Finnish Cardiovascular Research Center, Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Niku Oksala
- Department of Clinical Chemistry, Pirkanmaa Hospital District, Fimlab Laboratories, and the Finnish Cardiovascular Research Center, Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Centre for Vascular Surgery and Interventional Radiology, Tampere University Hospital, Tampere, Finland
| | - Mika Kähönen
- Department of Clinical Physiology, Tampere University Hospital, and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Nina Hutri-Kähönen
- Department of Pediatrics, Tampere University and Tampere University Hospital, Tampere, Finland
| | - Olli Raitakari
- Research Centre for Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.,Department of Clinical Physiology and Nuclear Medicine and Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Pirkanmaa Hospital District, Fimlab Laboratories, and the Finnish Cardiovascular Research Center, Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Emma Raitoharju
- Department of Clinical Chemistry, Pirkanmaa Hospital District, Fimlab Laboratories, and the Finnish Cardiovascular Research Center, Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
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Houshmand-Oeregaard A, Schrölkamp M, Kelstrup L, Hansen NS, Hjort L, Thuesen ACB, Broholm C, Mathiesen ER, Clausen TD, Vaag A, Damm P. Increased expression of microRNA-15a and microRNA-15b in skeletal muscle from adult offspring of women with diabetes in pregnancy. Hum Mol Genet 2019. [PMID: 29528396 DOI: 10.1093/hmg/ddy085] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Offspring of women with diabetes in pregnancy exhibit skeletal muscle insulin resistance and are at increased risk of developing type 2 diabetes, potentially mediated by epigenetic mechanisms or changes in the expression of small non-coding microRNAs. Members of the miR-15 family can alter the expression or function of important proteins in the insulin signalling pathway, affecting insulin sensitivity and secretion. We hypothesized that exposure to maternal diabetes may cause altered expression of these microRNAs in offspring skeletal muscle, representing a potential underlying mechanism by which exposure to maternal diabetes leads to increased risk of cardiometabolic disease in offspring. We measured microRNA expression in skeletal muscle biopsies of 26- to 35-year-old offspring of women with either gestational diabetes (O-GDM, n = 82) or type 1 diabetes (O-T1DM, n = 67) in pregnancy, compared with a control group of offspring from the background population (O-BP, n = 57) from an observational follow-up study. Expression of both miR-15a and miR-15b was increased in skeletal muscle obtained from O-GDM (both P < 0.001) and O-T1DM (P = 0.024, P = 0.005, respectively) compared with O-BP. Maternal 2 h post OGTT glucose levels were positively associated with miR-15a expression (P = 0.041) in O-GDM after adjustment for confounders and mediators. In all groups collectively, miRNA expression was significantly positively associated with fasting plasma glucose, 2 h plasma glucose and HbA1c. We conclude that fetal exposure to maternal diabetes is associated with increased skeletal muscle expression of miR-15a and miR-15b and that this may contribute to development of metabolic disease in these subjects.
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Affiliation(s)
- Azadeh Houshmand-Oeregaard
- Department of Obstetrics, Center for Pregnant Women with Diabetes, Rigshospitalet, 2100 Copenhagen, Denmark.,Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, 2100 Copenhagen, Denmark.,Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Maren Schrölkamp
- Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, 2100 Copenhagen, Denmark
| | - Louise Kelstrup
- Department of Obstetrics, Center for Pregnant Women with Diabetes, Rigshospitalet, 2100 Copenhagen, Denmark.,Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Ninna S Hansen
- Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, 2100 Copenhagen, Denmark.,Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Line Hjort
- Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, 2100 Copenhagen, Denmark.,Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.,Danish Diabetes Academy, 5000 Odense, Denmark
| | - Anne Cathrine B Thuesen
- Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, 2100 Copenhagen, Denmark
| | - Christa Broholm
- Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, 2100 Copenhagen, Denmark
| | - Elisabeth R Mathiesen
- Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.,Department of Endocrinology, Center for Pregnant Women with Diabetes, Rigshospitalet, 2100 Copenhagen, Denmark
| | - Tine D Clausen
- Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.,Department of Gynecology and Obstetrics, Nordsjaellands Hospital, University of Copenhagen, 3400 Hilleroed, Denmark
| | - Allan Vaag
- Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, 2100 Copenhagen, Denmark.,Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.,Cardiovascular and Metabolic Disease (CVMD) Translational Medicine Unit, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
| | - Peter Damm
- Department of Obstetrics, Center for Pregnant Women with Diabetes, Rigshospitalet, 2100 Copenhagen, Denmark.,Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
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Upregulation of Circulating Cardiomyocyte-Enriched miR-1 and miR-133 Associate with the Risk of Coronary Artery Disease in Type 2 Diabetes Patients and Serve as Potential Biomarkers. J Cardiovasc Transl Res 2019; 12:347-357. [PMID: 30610670 DOI: 10.1007/s12265-018-9857-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 12/10/2018] [Indexed: 12/21/2022]
Abstract
Circulating miRNAs are increasingly suggested as clinical biomarker for diseases. We evaluated the expression of circulating cardiomyocyte-enriched miR-1 and miR-133 by real-time PCR in blood from patients with type 2 diabetes (T2D) without and with coronary artery disease (CAD) and healthy controls, investigated their association with the risk of CAD risk and their potential as biomarkers. The two miRNAs were upregulated in patients with T2D and CAD compared with controls, associated with CAD risk and remained significant after adjustment for multiple confounders. LDL-C was a positive predictor for miR-1 and miR-133, and mean blood pressure was also a positive predictor for miR-133. Both miRNAs strongly distinguished CAD from controls. miR-1 significantly distinguished CAD from T2D with higher diagnostic ability than miR-133, whereas the miR-1/miR-133 combination improved the diagnostic value. Upregulation of circulating miR-1 and miR-133 associate with the risk of CAD in T2D patients and may serve as diagnostic biomarkers.
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42
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Goody D, Pfeifer A. MicroRNAs in brown and beige fat. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:29-36. [DOI: 10.1016/j.bbalip.2018.05.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 02/05/2018] [Accepted: 05/04/2018] [Indexed: 12/27/2022]
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43
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A plasma circulating miRNAs profile predicts type 2 diabetes mellitus and prediabetes: from the CORDIOPREV study. Exp Mol Med 2018; 50:1-12. [PMID: 30598522 PMCID: PMC6312530 DOI: 10.1038/s12276-018-0194-y] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 09/03/2018] [Accepted: 09/19/2018] [Indexed: 12/22/2022] Open
Abstract
We aimed to explore whether changes in circulating levels of miRNAs according to type 2 diabetes mellitus (T2DM) or prediabetes status could be used as biomarkers to evaluate the risk of developing the disease. The study included 462 patients without T2DM at baseline from the CORDIOPREV trial. After a median follow-up of 60 months, 107 of the subjects developed T2DM, 30 developed prediabetes, 223 maintained prediabetes and 78 remained disease-free. Plasma levels of four miRNAs related to insulin signaling and beta-cell function were measured by RT-PCR. We analyzed the relationship between miRNAs levels and insulin signaling and release indexes at baseline and after the follow-up period. The risk of developing disease based on tertiles (T1-T2-T3) of baseline miRNAs levels was evaluated by COX analysis. Thus, we observed higher miR-150 and miR-30a-5p and lower miR-15a and miR-375 baseline levels in subjects with T2DM than in disease-free subjects. Patients with high miR-150 and miR-30a-5p baseline levels had lower disposition index (p = 0.047 and p = 0.007, respectively). The higher risk of disease was associated with high levels (T3) of miR-150 and miR-30a-5p (HRT3-T1 = 4.218 and HRT3-T1 = 2.527, respectively) and low levels (T1) of miR-15a and miR-375 (HRT1-T3 = 3.269 and HRT1-T3 = 1.604, respectively). In conclusion, our study showed that deregulated plasma levels of miR-150, miR-30a-5p, miR-15a, and miR-375 were observed years before the onset of T2DM and pre-DM and could be used to evaluate the risk of developing the disease, which may improve prediction and prevention among individuals at high risk for T2DM. Tiny RNA molecules circulating in the blood could give early warning of type 2 diabetes risk. MicroRNAs help regulate the expression of other genes, and recent research has linked irregularities in these molecules to many different diseases. Researchers led by José López Miranda of the University of Córdoba in Spain monitored a cohort of 462 patients for several years to assess how plasma levels of certain microRNAs are deregulated before the onset and progression of diabetes. They observed a striking ‘signature’ of altered expression in four microRNAs for patients who developed diabetes over the course of the study. Intriguingly, patients with markedly elevated blood sugar—state known as prediabetes—exhibited a similar signature, but with more modest alteration in the gene expression levels, indicating that these microRNAs could help clinicians track and prevent disease onset.
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Lin Y, Wu W, Sun Z, Shen L, Shen B. MiRNA-BD: an evidence-based bioinformatics model and software tool for microRNA biomarker discovery. RNA Biol 2018; 15:1093-1105. [PMID: 30081733 DOI: 10.1080/15476286.2018.1502590] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs with the potential as biomarkers for disease diagnosis, prognosis and therapy. In the era of big data and biomedical informatics, computer-aided biomarker discovery has become the current frontier. However, most of the computational models are highly dependent on specific prior knowledge and training-testing procedures, very few are mechanism-guided or evidence-based. To the best of our knowledge, untill now no general rules have been uncovered and applied to miRNA biomarker screening. In this study, we manually collected literature-reported cancer miRNA biomarkers and analyzed their regulatory patterns, including the regulatory modes, biological functions and evolutionary characteristics of their targets in the human miRNA-mRNA network. Two evidences were statistically detected and used to distinguish biomarker miRNAs from others. Based on these observations, we developed a novel bioinformatics model and software tool for miRNA biomarker discovery ( http://sysbio.suda.edu.cn/MiRNA-BD/ ). In contrast to routine methods that focus on miRNA synergic functions, our method searches for vulnerable sites in the miRNA-mRNA network and considers the independent regulatory power of miRNAs, i.e., single-line regulations between miRNAs and mRNAs. The performance comparison demonstrates the generality and precision of our model, which identifies miRNA biomarkers for cancers as well as other complex diseases without training or specific prior knowledge.
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Affiliation(s)
- Yuxin Lin
- a Center for Systems Biology , Soochow University , Suzhou, Jiangsu , China
| | - Wentao Wu
- a Center for Systems Biology , Soochow University , Suzhou, Jiangsu , China
| | - Zhandong Sun
- a Center for Systems Biology , Soochow University , Suzhou, Jiangsu , China
| | - Li Shen
- a Center for Systems Biology , Soochow University , Suzhou, Jiangsu , China.,b Department of Genetics & Systems Biology Institute , Yale University School of Medicine , West Haven , CT USA
| | - Bairong Shen
- a Center for Systems Biology , Soochow University , Suzhou, Jiangsu , China.,c Center for Translational Biomedical Informatics , Guizhou University School of Medicine , Guiyang , China.,d Institute for Systems Genetics, West China Hospital , Sichuan University , Chengdu , China
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Al-Kafaji G, Said HM, Alam MA, Al Naieb ZT. Blood-based microRNAs as diagnostic biomarkers to discriminate localized prostate cancer from benign prostatic hyperplasia and allow cancer-risk stratification. Oncol Lett 2018; 16:1357-1365. [PMID: 30061955 DOI: 10.3892/ol.2018.8778] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Accepted: 05/14/2018] [Indexed: 12/15/2022] Open
Abstract
Prostate cancer (PCa) is the second most diagnosed malignancy, and the leading cause of cancer-associated mortality among males. Prostate-specific antigen (PSA) has long been used for the detection of PCa. However, PSA levels increase in PCa and benign prostatic hyperplasia (BPH), and are associated with a poor disease outcome. Circulating microRNAs (miRNAs) have been determined to be highly stable in the circulation, and could be utilized as biomarkers to improve disease diagnosis and management. In the present study, the effectiveness of four PCa-associated miRNAs in the discrimination of PCa from BPH and the risk-stratification of PCa was assessed. The study included 100 participants: 35 patients with localized PCa, 35 patients with BPH and 30 healthy subjects. Patients with PCa were categorized based on their tumor stage (T), PSA level and Gleason score (GS) into low-(T 1/2, PSA <10 ng/ml or GS ≤7) and high-risk groups (T 3/4, PSA >20 ng/ml or GS ≥8). Reverse transcription-quantitative polymerase chain reaction was employed to assess the miRNA expression in peripheral blood samples. Significantly reduced expression of miR-15a, miR-126, miR-192 and miR-377 was observed in patients with PCa compared with patients with BPH and healthy subjects. In addition, the expression of the four miRNAs was lower in high-risk PCa patients than in low-risk PCa patients, with miR-126 being the most downregulated. The expression of the four miRNAs was also significantly and independently associated with PCa. Receiver operating characteristic curve analysis revealed a significant ability of the miRNAs to distinguish patients with PCa from those with BPH, patients with PCa from controls and low-risk PCa from high-risk PCa. These data suggested that expression of these miRNAs in the blood circulation may be promising, non-invasive biomarkers for the early detection of localized PCa, and for PCa risk stratification. Further validations of the clinical implementation of these results are warranted in a larger cohort.
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Affiliation(s)
- Ghada Al-Kafaji
- Department of Molecular Medicine and Al-Jawhara Centre for Molecular Medicine, Genetics and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama 329, Kingdom of Bahrain
| | - Harun Muayad Said
- Department of Molecular Medicine, Graduate School of Health Sciences, Dokuz Eylul University, Izmir 35220, Turkey
| | - Mahmood Abduljalil Alam
- Department of Molecular Medicine and Al-Jawhara Centre for Molecular Medicine, Genetics and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama 329, Kingdom of Bahrain
| | - Ziad Tarraq Al Naieb
- Department of Surgery, College of Medicine and Medical Sciences, Arabian Gulf University, Manama 329, Kingdom of Bahrain
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Al-Kafaji G, Al-Muhtaresh HA. Expression of microRNA‑377 and microRNA‑192 and their potential as blood‑based biomarkers for early detection of type 2 diabetic nephropathy. Mol Med Rep 2018; 18:1171-1180. [PMID: 29845236 DOI: 10.3892/mmr.2018.9040] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Accepted: 03/08/2018] [Indexed: 11/06/2022] Open
Abstract
The increased incidence of diabetic nephropathy (DN) in type 2 diabetes (T2D) requires novel markers for the early detection of DN. Previously, microRNAs (miRs) have been demonstrated to be promising disease biomarkers. The present study evaluated the biomarker potential of DN‑associated miR‑377 and miR‑192 in the early stages of DN. The study included 85 participants: 55 patients with T2D (30 without DN and 25 with DN) and 30 healthy controls. The patients with T2D were classified according to albumin‑to‑creatinine ratio and were split into three groups: Normoalbuminuric group (n=30), microalbuminuric group (n=15) and macroalbuminuric group (n=10). Reverse transcription‑quantitative polymerase chain reaction analysis was used to evaluate blood miR expression. It was observed that there was higher miR‑377 expression and lower miR‑192 expression in T2D patients with and without DN compared with healthy controls (P<0.05). miR‑377 was higher in the normoalbuminuric group and gradually increased in the microalbuminuric and macroalbuminuric groups (P<0.05), whereas miR‑192 was lower in the macroalbuminuric group compared with the normoalbuminuric group (P<0.05). Regression analysis revealed direct associations between the two miRs and albuminuria (P<0.05). miR‑377 was independently associated with DN risk, even following multivariable adjustment, and albuminuria was the only predictor of miR‑377 (P<0.001). In discriminating overall patients from healthy subjects, ROC analysis revealed areas under the curve (AUCs) of 0.851 for miR377 and 0.774 for miR‑192 (P<0.001). In discriminating the normoalbuminuric group from the microalbuminuric/macroalbuminuric groups, the AUCs were 0.711 (P=0.008) and 0.70 (P=0.049) for miR‑377 and miR‑192, respectively. In patients with microalbuminuria and macroalbuminuria, miR‑377 correlated positively with albuminuria and negatively with renal function, whereas miR‑192 correlated negatively with albuminuria and positively with renal function (P=0.001), and the two miRs were correlated with known risk factors of DN (P<0.05). The results suggested that blood‑based miR‑377 and miR‑192 may serve as potential biomarkers for early detection of DN. Further validation studies are required with larger sample sizes.
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Affiliation(s)
- Ghada Al-Kafaji
- Department of Molecular Medicine and Al‑Jawhara Centre for Molecular Medicine, Genetics and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
| | - Haifa Abdulla Al-Muhtaresh
- Department of Molecular Medicine and Al‑Jawhara Centre for Molecular Medicine, Genetics and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
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Evaluation of Two-Diabetes Related microRNAs Suitability as Earlier Blood Biomarkers for Detecting Prediabetes and type 2 Diabetes Mellitus. J Clin Med 2018; 7:jcm7020012. [PMID: 29373500 PMCID: PMC5852428 DOI: 10.3390/jcm7020012] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Revised: 01/17/2018] [Accepted: 01/23/2018] [Indexed: 12/12/2022] Open
Abstract
Increased the incidence of prediabetes and type 2 diabetes (T2D) worldwide raises an urgent need to develop effective tools for early disease detection to facilitate future preventive interventions and improve patient’s care. We evaluated the suitability of diabetes-related miR-375 and miR-9 as earlier biomarkers for detecting prediabetes and T2D.TaqMan-based RT-qPCR was used to quantify the expression of miRNAs in peripheral blood of 30 prediabetes patients, 30 T2D patients and 30 non-diabetic healthy controls. Compared to controls, miR-375 and miR-9 were expressed at higher levels in prediabetes patients and progressively more enriched in T2D patients. Both miRNAs were directly associated with the presence of prediabetes and T2D independently of known risk factors to T2D and miR-375 was independently associated with the development of T2D. Both miRNAs were positively correlated with the glycemic status and other T2D risk factors. The ROC analysis indicated good diagnostic abilities for miR-375 to distinguish overall patients from control and prediabetes from T2D patients. Whereas, miR-9 showed lower values and borderline significance in discriminating the subject groups. The combination of miRNAs enhanced the predictability to discriminate patients from control. These results suggest that miR-375 and miR-9 are associated with the susceptibility to developing T2D and miR-375 alone or in combination with miR-9 could serve as biomarkers for early detection of prediabetes and T2D.
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Jiang Y, Liu L, Steinle JJ. miRNA15a regulates insulin signal transduction in the retinal vasculature. Cell Signal 2018; 44:28-32. [PMID: 29339083 DOI: 10.1016/j.cellsig.2018.01.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 01/10/2018] [Accepted: 01/11/2018] [Indexed: 02/06/2023]
Abstract
We previously reported that tumor necrosis factor alpha (TNFα) could inhibit insulin signal transduction in retinal cells. We recently found that miR15a/16 also reduced TNFα in retinal endothelial cells (REC) and in vascular specific miR15a/16 knockout mice. Since in silico programs suggested that miR15a could directly bind the insulin receptor, we wanted to determine whether miR15a altered insulin signal transduction. We used a luciferase-based binding assay to determine whether miR15a directly bound the insulin receptor. We then used Western blotting, ELISA, and qPCR to investigate whether miR15a altered insulin signaling proteins in REC and in both miR15a/16 endothelial cell knockout and overexpressing mice. We also treated some REC with resveratrol to determine if resveratrol could increase miR15a expression, since resveratrol is protective to the diabetic retina. We found that miR15a directly bound the 3'UTR of the insulin receptor. Treatment with resveratrol increased miR15a expression in REC grown in high glucose. While total insulin receptor levels were not altered, insulin signal transduction was reduced in REC grown in high glucose and was restored with treatment with resveratrol. miR15a knockout mice had reduced insulin receptor phosphorylation and Akt2 levels, with increased insulin receptor substrate 1 (IRS-1) phosphorylation on serine 307, a site known to inhibit insulin signaling. In contrast, overexpression of miR15a increased insulin signal transduction. Taken together, these data suggest that miR15a binds the insulin receptor and indirectly regulates insulin receptor actions. It also offers an additional mechanism by which resveratrol is protective to the diabetic retina.
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Affiliation(s)
- Youde Jiang
- Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, United States
| | - Li Liu
- Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, United States
| | - Jena J Steinle
- Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, United States; Department of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, United States.
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Morais Junior GS, Souza VC, Machado-Silva W, Henriques AD, Melo Alves A, Barbosa Morais D, Nóbrega OT, Brito CJ, dos Santos Silva RJ. Acute strength training promotes responses in whole blood circulating levels of miR-146a among older adults with type 2 diabetes mellitus. Clin Interv Aging 2017; 12:1443-1450. [PMID: 28979106 PMCID: PMC5608226 DOI: 10.2147/cia.s141716] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) consists of a set of metabolic and endocrine disorders which evolve into deficiency in insulin action and hyperglycemia. Physical exercise is considered the main intervention to prevent and control T2DM. Literature has suggested that circulating microRNAs (miRs) help to understand responses to physical activity among diabetic patients. Thus, the aim of this study was to analyze the acute effect of two interventions (strength and cardiovascular) on the total, whole blood circulating concentrations of miR-126, miR-146a and miR-155 in older adults with and without T2DM. A total of 23 male and female older adults (68.2±5.3 years) participated in the trial, 13 of whom presented with controlled T2DM and 10 were nondiabetics. They underwent both interventions separately, performed with intensity from 60% to 70% of reserve heart rate. Glucose and miRs levels were quantified and compared across groups with baseline titers as covariables. Diabetic patients showed more reduction in serum blood glucose than nondiabetics, with a great magnitude of reduction after the strength training intervention, which was paralleled by a positive change of the whole blood circulating levels of miR-146a, but not of the other miRs. Our report supports evidence that miR-146a levels in peripheral blood leukocytes are negatively associated with a state of insulin resistance, which is suggested as a novel marker to trace response to antidiabetic interventions.
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Affiliation(s)
| | | | | | | | | | | | | | - Ciro José Brito
- Universidade Federal de Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil
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