Abstract
Diabetes mellitus is characterized by insulin secretion from pancreatic β cells that is insufficient to maintain blood glucose homeostasis. Autoimmune destruction of β cells results in type 1 diabetes mellitus, whereas conditions that reduce insulin sensitivity and negatively affect β-cell activities result in type 2 diabetes mellitus. Without proper management, patients with diabetes mellitus develop serious complications that reduce their quality of life and life expectancy. Biomarkers for early detection of the disease and identification of individuals at risk of developing complications would greatly improve the care of these patients. Small non-coding RNAs called microRNAs (miRNAs) control gene expression and participate in many physiopathological processes. Hundreds of miRNAs are actively or passively released in the circulation and can be used to evaluate health status and disease progression. Both type 1 diabetes mellitus and type 2 diabetes mellitus are associated with distinct modifications in the profile of miRNAs in the blood, which are sometimes detectable several years before the disease manifests. Moreover, circulating levels of certain miRNAs seem to be predictive of long-term complications. Technical and scientific obstacles still exist that need to be overcome, but circulating miRNAs might soon become part of the diagnostic arsenal to identify individuals at risk of developing diabetes mellitus and its devastating complications.
Key Points
-
New biomarkers are needed to improve the identification of individuals at risk of developing diabetes mellitus and its associated complications, monitor disease progression and assess the efficacy of therapeutic interventions
-
Circulating microRNAs (miRNAs) are attractive biomarker candidates as they can be easily collected, are stable under different storage conditions and can be measured using assays that are specific, sensitive and reproducible
-
Pioneering studies have identified characteristic changes in blood levels of miRNAs in samples from a range of cohorts of patients with diabetes mellitus
-
However, definitive miRNA signatures for type 1 diabetes mellitus, type 2 diabetes mellitus or their associated complications remain to be defined and agreed upon
-
Although measuring circulating miRNAs is a promising approach in individuals at risk of developing diabetes mellitus, several key issues still need to be addressed, including the determination of the most appropriate blood sampling protocols
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Whiting, D. R., Guariguata, L., Weil, C. & Shaw, J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res. Clin. Pract. 94, 311–321 (2011).
Li, R., Zhang, P., Barker, L. E., Chowdhury, F. M. & Zhang, X. Cost-effectiveness of interventions to prevent and control diabetes mellitus: a systematic review. Diabetes Care 33, 1872–1894 (2010).
Pirot, P., Cardozo, A. K. & Eizirik, D. L. Mediators and mechanisms of pancreatic beta-cell death in type 1 diabetes. Arq. Bras. Endocrinol. Metabol. 52, 156–165 (2008).
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 28 (Suppl. 1), S37–S42 (2005).
Prentki, M. & Nolan, C. J. Islet β cell failure in type 2 diabetes. J. Clin. Invest. 116, 1802–1812 (2006).
Stumvoll, M., Goldstein, B. J. & van Haeften, T. W. Type 2 diabetes: principles of pathogenesis and therapy. Lancet 365, 1333–1346 (2005).
Winter, W. E., Harris, N. & Schatz, D. Type 1 diabetes islet autoantibody markers. Diabetes Technol. Ther. 4, 817–839 (2002).
Orban, T. et al. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet 378, 412–419 (2011).
Sherry, N. et al. Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial. Lancet 378, 487–497 (2011).
Purohit, S. & She, J. X. Biomarkers for type 1 diabetes. Int. J. Clin. Exp. Med. 1, 98–116 (2008).
Schulze, M. B. et al. Use of multiple metabolic and genetic markers to improve the prediction of type 2 diabetes: the EPIC-Potsdam Study. Diabetes Care 32, 2116–2119 (2009).
Muller, G. Microvesicles/exosomes as potential novel biomarkers of metabolic diseases. Diabetes Metab. Syndr. Obes. 5, 247–282 (2012).
Kolberg, J. A. et al. Development of a type 2 diabetes risk model from a panel of serum biomarkers from the Inter99 cohort. Diabetes Care 32, 1207–1212 (2009).
Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993).
Wightman, B., Ha, I. & Ruvkun, G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75, 855–862 (1993).
Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).
miRBase. The microRNA database [online], (2013).
Flynt, A. S. & Lai, E. C. Biological principles of microRNA-mediated regulation: shared themes amid diversity. Nat. Rev. Genet. 9, 831–842 (2008).
Poy, M. N. et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432, 226–230 (2004).
Poy, M. N. et al. miR-375 maintains normal pancreatic α- and β-cell mass. Proc. Natl Acad. Sci. USA 106, 5813–5818 (2009).
Kumar, M., Nath, S., Prasad, H. K., Sharma, G. D. & Li, Y. MicroRNAs: a new ray of hope for diabetes mellitus. Protein Cell 3, 726–738 (2012).
Shantikumar, S., Caporali, A. & Emanueli, C. Role of microRNAs in diabetes and its cardiovascular complications. Cardiovasc. Res. 93, 583–593 (2012).
Guay, C., Roggli, E., Nesca, V., Jacovetti, C. & Regazzi, R. Diabetes mellitus, a microRNA-related disease? Transl. Res. 157, 253–264 (2011).
Roggli, E. et al. Involvement of microRNAs in the cytotoxic effects exerted by proinflammatory cytokines on pancreatic β-cells. Diabetes 59, 978–986 (2010).
Roggli, E. et al. Changes in microRNA expression contribute to pancreatic β-cell dysfunction in prediabetic NOD mice. Diabetes 61, 1742–1751 (2012).
Lovis, P. et al. Alterations in microRNA expression contribute to fatty acid-induced pancreatic β-cell dysfunction. Diabetes 57, 2728–2736 (2008).
Zhao, E. et al. Obesity and genetics regulate microRNAs in islets, liver, and adipose of diabetic mice. Mamm. Genome 20, 476–485 (2009).
Herrera, B. M. et al. Global microRNA expression profiles in insulin target tissues in a spontaneous rat model of type 2 diabetes. Diabetologia 53, 1099–1109 (2010).
Trajkovski, M. et al. MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 474, 649–653 (2011).
Jordan, S. D. et al. Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism. Nat. Cell Biol. 13, 434–446 (2011).
Kornfeld, J. W. et al. Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b. Nature 494, 111–115 (2013).
Gallagher, I. J. et al. Integration of microRNA changes in vivo identifies novel molecular features of muscle insulin resistance in type 2 diabetes. Genome Med. 2, 9 (2010).
Granjon, A. et al. The microRNA signature in response to insulin reveals its implication in the transcriptional action of insulin in human skeletal muscle and the role of a sterol regulatory element-binding protein 1c/myocyte enhancer factor 2C pathway. Diabetes 58, 2555–2564 (2009).
Kantharidis, P., Wang, B., Carew, R. M. & Lan, H. Y. Diabetes complications: the microRNA perspective. Diabetes 60, 1832–1837 (2011).
Natarajan, R., Putta, S. & Kato, M. MicroRNAs and diabetic complications. J. Cardiovasc. Transl. Res. 5, 413–422 (2012).
Arroyo, J. D. et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc. Natl Acad. Sci. USA 108, 5003–5008 (2011).
Gibbings, D. J., Ciaudo, C., Erhardt, M. & Voinnet, O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat. Cell Biol. 11, 1143–1149 (2009).
Vickers, K. C., Palmisano, B. T., Shoucri, B. M., Shamburek, R. D. & Remaley, A. T. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat. Cell Biol. 13, 423–433 (2011).
Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).
Kroh, E. M., Parkin, R. K., Mitchell, P. S. & Tewari, M. Analysis of circulating microRNA biomarkers in plasma and serum using quantitative reverse transcription-PCR (qRT-PCR). Methods 50, 298–301 (2010).
Mitchell, P. S. et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl Acad. Sci. USA 105, 10513–10518 (2008).
Mraz, M., Malinova, K., Mayer, J. & Pospisilova, S. MicroRNA isolation and stability in stored RNA samples. Biochem. Biophys. Res. Commun. 390, 1–4 (2009).
Weber, J. A. et al. The microRNA spectrum in 12 body fluids. Clin. Chem. 56, 1733–1741 (2010).
Gilad, S. et al. Serum microRNAs are promising novel biomarkers. PLoS ONE 3, e3148 (2008).
Keller, A. et al. Toward the blood-borne miRNome of human diseases. Nat. Methods 8, 841–843 (2011).
Chen, X. et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 18, 997–1006 (2008).
Lawrie, C. H. et al. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br. J. Haematol. 141, 672–675 (2008).
Alevizos, I. & Illei, G. G. MicroRNAs as biomarkers in rheumatic diseases. Nat. Rev. Rheumatol. 6, 391–398 (2010).
Wang, J. F. et al. Serum miR-146a and miR-223 as potential new biomarkers for sepsis. Biochem. Biophys. Res. Commun. 394, 184–188 (2010).
Zampetaki, A. et al. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ. Res. 107, 810–817 (2010).
Kong, L. et al. Significance of serum microRNAs in pre-diabetes and newly diagnosed type 2 diabetes: a clinical study. Acta Diabetol. 48, 61–69 (2011).
Karolina, D. S. et al. Circulating miRNA profiles in patients with metabolic syndrome. J. Clin. Endocrinol. Metab. 97, E2271–E2276 (2012).
Nielsen, L. B. et al. Circulating levels of microRNA from children with newly diagnosed type 1 diabetes and healthy controls: evidence that miR-25 associates to residual beta-cell function and glycaemic control during disease progression. Exp. Diabetes Res. 2012, 896362 (2012).
Sebastiani, G. et al. MicroRNA expression fingerprint in serum of type 1 diabetic patients. Diabetologia 55, S48 (2012).
Erener, S., Mojibian, M., Fox, J. K., Denroche, H. C. & Kieffer, T. J. Circulating miR-375 as a biomarker of β-cell death and diabetes in mice. Endocrinology 154, 603–608 (2013).
Salas-Perez, F. et al. MicroRNAs miR-21a and miR-93 are down regulated in peripheral blood mononuclear cells (PBMCs) from patients with type 1 diabetes. Immunobiology 218, 733–737 (2013).
Sebastiani, G. et al. Increased expression of microRNA miR-326 in type 1 diabetic patients with ongoing islet autoimmunity. Diabetes Metab. Res. Rev. 27, 862–866 (2011).
Winer, N. & Sowers, J. R. Epidemiology of diabetes. J. Clin. Pharmacol. 44, 397–405 (2004).
Fichtlscherer, S. et al. Circulating microRNAs in patients with coronary artery disease. Circ. Res. 107, 677–684 (2010).
Fish, J. E. et al. miR-126 regulates angiogenic signaling and vascular integrity. Dev. Cell 15, 272–284 (2008).
Wang, S. et al. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev. Cell 15, 261–271 (2008).
Caporali, A. et al. Deregulation of microRNA-503 contributes to diabetes mellitus-induced impairment of endothelial function and reparative angiogenesis after limb ischemia. Circulation 123, 282–291 (2011).
Creemers, E. E., Tijsen, A. J. & Pinto, Y. M. Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease? Circ. Res. 110, 483–495 (2012).
van Empel, V. P., De Windt, L. J. & da Costa Martins, P. A. Circulating miRNAs: reflecting or affecting cardiovascular disease? Curr. Hypertens. Rep. 14, 498–509 (2012).
Pambianco, G. et al. The 30-year natural history of type 1 diabetes complications: the Pittsburgh Epidemiology of Diabetes Complications Study experience. Diabetes 55, 1463–1469 (2006).
Parving, H. H., Lewis, J. B., Ravid, M., Remuzzi, G. & Hunsicker, L. G. Prevalence and risk factors for microalbuminuria in a referred cohort of type II diabetic patients: a global perspective. Kidney Int. 69, 2057–2063 (2006).
Thomas, M. C., Groop, P. H. & Tryggvason, K. Towards understanding the inherited susceptibility for nephropathy in diabetes. Curr. Opin. Nephrol. Hypertens. 21, 195–202 (2012).
Macisaac, R. J. & Jerums, G. Diabetic kidney disease with and without albuminuria. Curr. Opin. Nephrol. Hypertens. 20, 246–257 (2011).
Perkins, B. A. et al. Microalbuminuria and the risk for early progressive renal function decline in type 1 diabetes. J. Am. Soc. Nephrol. 18, 1353–1361 (2007).
Perkins, B. A. et al. Regression of microalbuminuria in type 1 diabetes. N. Engl. J. Med. 348, 2285–2293 (2003).
Martino, F. et al. Circulating microRNAs are not eliminated by hemodialysis. PLoS ONE 7, e38269 (2012).
Neal, C. S. et al. Circulating microRNA expression is reduced in chronic kidney disease. Nephrol. Dial. Transplant 26, 3794–3802 (2011).
Wang, G. et al. Elevated levels of miR-146a and miR-155 in kidney biopsy and urine from patients with IgA nephropathy. Dis. Markers 30, 171–179 (2011).
Wang, N. et al. Urinary microRNA-10a and microRNA-30d serve as novel, sensitive and specific biomarkers for kidney injury. PLoS ONE 7, e51140 (2012).
Alvarez, M. L. & Distefano, J. K. The role of non-coding RNAs in diabetic nephropathy: potential applications as biomarkers for disease development and progression. Diabetes Res. Clin. Pract. 99, 1–11 (2013).
Miranda, K. C. et al. Nucleic acids within urinary exosomes/microvesicles are potential biomarkers for renal disease. Kidney Int. 78, 191–199 (2010).
van Balkom, B. W., Pisitkun, T., Verhaar, M. C. & Knepper, M. A. Exosomes and the kidney: prospects for diagnosis and therapy of renal diseases. Kidney Int. 80, 1138–1145 (2011).
Beltrami, C., Clayton, A., Phillips, A. O., Fraser, D. J. & Bowen, T. Analysis of urinary microRNAs in chronic kidney disease. Biochem. Soc. Trans. 40, 875–879 (2012).
Argyropoulos, C. et al. Urinary microRNA profiling in the nephropathy of type 1 diabetes. PLoS ONE 8, e54662 (2013).
Zhao, C. et al. Early second-trimester serum miRNA profiling predicts gestational diabetes mellitus. PLoS ONE 6, e23925 (2011).
Chim, S. S. et al. Detection and characterization of placental microRNAs in maternal plasma. Clin. Chem. 54, 482–490 (2008).
McDonald, J. S., Milosevic, D., Reddi, H. V., Grebe, S. K. & Algeciras-Schimnich, A. Analysis of circulating microRNA: preanalytical and analytical challenges. Clin. Chem. 57, 833–840 (2011).
Bryant, R. J. et al. Changes in circulating microRNA levels associated with prostate cancer. Br. J. Cancer 106, 768–774 (2012).
Komatsu, S. et al. Circulating microRNAs in plasma of patients with oesophageal squamous cell carcinoma. Br. J. Cancer 105, 104–111 (2011).
Li, L. M. et al. Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma. Cancer Res. 70, 9798–9807 (2010).
Madhavan, D. et al. Circulating miRNAs as surrogate markers for circulating tumor cells and prognostic markers in metastatic breast cancer. Clin. Cancer Res. 18, 5972–5982 (2012).
Lee, H. S., Jeong, J. & Lee, K. J. Characterization of vesicles secreted from insulinoma NIT-1 cells. J. Proteome Res. 8, 2851–2862 (2009).
Palmisano, G. et al. Characterization of membrane-shed microvesicles from cytokine-stimulated β-cells using proteomics strategies. Mol. Cell Proteomics 11, 230–243 (2012).
Sheng, H. et al. Insulinoma-released exosomes or microparticles are immunostimulatory and can activate autoreactive T cells spontaneously developed in nonobese diabetic mice. J. Immunol. 187, 1591–1600 (2011).
Guay, C., Menoud, V., Gattesco, S. & Regazzi, R. MicroRNA transfer as a new cell-to-cell communication mode between pancreatic β cells. Diabetologia 55, S95 (2012).
Rodriguez, A., Griffiths-Jones, S., Ashurst, J. L. & Bradley, A. Identification of mammalian microRNA host genes and transcription units. Genome Res. 14, 1902–1910 (2004).
Lee, Y. et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 23, 4051–4060 (2004).
Cifuentes, D. et al. A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity. Science 328, 1694–1698 (2010).
Ruby, J. G., Jan, C. H. & Bartel, D. P. Intronic microRNA precursors that bypass Drosha processing. Nature 448, 83–86 (2007).
Doench, J. G. & Sharp, P. A. Specificity of microRNA target selection in translational repression. Genes Dev. 18, 504–511 (2004).
Trams, E. G., Lauter, C. J., Salem, N. Jr & Heine, U. Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. Biochim. Biophys. Acta 645, 63–70 (1981).
Pan, B. T., Teng, K., Wu, C., Adam, M. & Johnstone, R. M. Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J. Cell Biol. 101, 942–948 (1985).
Harding, C., Heuser, J. & Stahl, P. Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J. Cell Biol. 97, 329–339 (1983).
Vlassov, A. V., Magdaleno, S., Setterquist, R. & Conrad, R. Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim. Biophys. Acta 1820, 940–948 (2012).
Johnstone, R. M., Adam, M., Hammond, J. R., Orr, L. & Turbide, C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J. Biol. Chem. 262, 9412–9420 (1987).
Kosaka, N. et al. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J. Biol. Chem. 285, 17442–17452 (2010).
Zhang, Y. et al. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol. Cell 39, 133–144 (2010).
Acknowledgements
The authors are supported by grants from the Swiss National Science Foundation, from the European Foundation for the Study of Diabetes and from the Société Francophone du Diabète (SFD)-Servier. C. Guay is supported by a fellowship from Fonds de la Recherche en Santé du Québec, the SFD and the Canadian Diabetes Association.
Author information
Authors and Affiliations
Contributions
Both authors contributed equally to all aspects of this article.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Guay, C., Regazzi, R. Circulating microRNAs as novel biomarkers for diabetes mellitus. Nat Rev Endocrinol 9, 513–521 (2013). https://doi.org/10.1038/nrendo.2013.86
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrendo.2013.86
This article is cited by
-
Understanding molecular mechanisms and miRNA-based targets in diabetes foot ulcers
Molecular Biology Reports (2024)
-
The link between glycemic control measures and eye microvascular complications in a clinical cohort of type 2 diabetes with microRNA-223-3p signature
Journal of Translational Medicine (2023)
-
Human umbilical cord mesenchymal stromal cell small extracellular vesicle transfer of microRNA-223-3p to lung epithelial cells attenuates inflammation in acute lung injury in mice
Journal of Nanobiotechnology (2023)
-
Microvesicle-associated and circulating microRNAs in diabetic dyslipidemia: miR-218, miR-132, miR-143, and miR-21, miR-122, miR-155 have biomarker potential
Cardiovascular Diabetology (2023)
-
Treatment of type 2 diabetes mellitus with stem cells and antidiabetic drugs: a dualistic and future-focused approach
Human Cell (2023)