Pancreas-enriched miRNAs are altered in the circulation of subjects with diabetes: a pilot cross-sectional study
Attila A Seyhan, Yury O Nunez Lopez, Hui Xie, Fanchao Yi, Clayton Mathews, Magdalena Pasarica, Richard E Pratley, Attila A Seyhan, Yury O Nunez Lopez, Hui Xie, Fanchao Yi, Clayton Mathews, Magdalena Pasarica, Richard E Pratley
Abstract
The clinical presentation of diabetes sometimes overlaps, contributing to ambiguity in the diagnosis. Thus, circulating pancreatic islet-enriched microRNAs (miRNAs) might be useful biomarkers of β-cell injury/dysfunction that would allow more accurate subtyping of diabetes. We measured plasma levels of selected miRNAs in subjects with prediabetes (n = 12), type 2 diabetes (T2D, n = 31), latent autoimmune diabetes of adults (LADA, n = 6) and type 1 diabetes (T1D, n = 16) and compared them to levels in healthy control subjects (n = 27). The study was conducted at the Translational Research Institute for Metabolism and Diabetes (TRI-MD), Florida Hospital. MiRNAs including miR-375 (linked to β-cell injury), miR-21 (associated with islet inflammation), miR-24.1, miR-30d, miR-34a, miR-126, miR-146, and miR-148a were significantly elevated in subjects with various forms of diabetes compared to healthy controls. Levels of several miRNAs were significantly correlated with glucose responses during oral glucose tolerance testing, HbA1c, β-cell function, and insulin resistance in healthy controls, prediabetes, and T2D. These data suggest that miRNAs linked to β-cell injury and islet inflammation might be useful biomarkers to distinguish between subtypes of diabetes. This information could be used to predict progression of the disease, guide selection of optimal therapy and monitor responses to interventions, thus improving outcomes in patients with diabetes.
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References
- Tuomi T. et al. The many faces of diabetes: a disease with increasing heterogeneity. Lancet 383, 1084–1094 (2014).
- Seyhan A. A. microRNAs with different functions and roles in disease development and as potential biomarkers of diabetes: progress and challenges. Mol Biosyst 11, 1217–1234 (2015).
- Carini C. & Seyhan A. A. In Clinical and Statistical Considerations in Personalized Medicine (eds Carini C. et al.) Ch. 1, 1–26 (CRC Press, 2014).
- Ziegler A. G. et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA 309, 2473–2479 (2013).
- Zampetaki A. & Mayr M. MicroRNAs in vascular and metabolic disease. Circ Res 110, 508–522 (2012).
- 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).
- Poy M. N. et al. miR-375 maintains normal pancreatic alpha- and beta-cell mass. Proc Natl Acad Sci USA 106, 5813–5818 (2009).
- Erener S., Mojibian M., Fox J. K., Denroche H. C. & Kieffer T. J. Circulating miR-375 as a biomarker of beta-cell death and diabetes in mice. Endocrinology 154, 603–608 (2013).
- Zhao H. et al. Up-regulated pancreatic tissue microRNA-375 associates with human type 2 diabetes through beta-cell deficit and islet amyloid deposition. Pancreas 39, 843–846 (2010).
- Krek A. et al. Combinatorial microRNA target predictions. Nat Genet 37, 495–500 (2005).
- Poy M. N. et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432, 226–230 (2004).
- El Ouaamari A. et al. miR-375 targets 3′-phosphoinositide-dependent protein kinase-1 and regulates glucose-induced biological responses in pancreatic beta-cells. Diabetes 57, 2708–2717 (2008).
- Yamada H., Itoh M., Hiratsuka I. & Hashimoto S. Circulating microRNAs in autoimmune thyroid diseases. Clin Endocrinol (Oxf) 81, 276–281 (2014).
- Guay C. & Regazzi R. Circulating microRNAs as novel biomarkers for diabetes mellitus. Nat Rev Endocrinol 9, 513–521 (2013).
- Guay C., Roggli E., Nesca V., Jacovetti C. & Regazzi R. Diabetes mellitus, a microRNA-related disease? Transl Res 157, 253–264 (2011).
- Melkman-Zehavi T. et al. miRNAs control insulin content in pancreatic beta-cells via downregulation of transcriptional repressors. EMBO J 30, 835–845 (2011).
- Curtale G. et al. An emerging player in the adaptive immune response: microRNA-146a is a modulator of IL-2 expression and activation-induced cell death in T lymphocytes. Blood 115, 265–273 (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).
- Mitchell P. S. et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA 105, 10513–10518 (2008).
- Ge Q. et al. miRNA in plasma exosome is stable under different storage conditions. Molecules 19, 1568–1575 (2014).
- American Diabetes. A. Standards of medical care in diabetes–2014. Diabetes Care 37 Suppl 1, S14–S80 (2014).
- Dube S., Errazuriz I., Cobelli C., Basu R. & Basu A. Assessment of insulin action on carbohydrate metabolism: physiological and non-physiological methods. Diabet Med 30, 664–670 (2013).
- Retnakaran R., Qi Y., Goran M. I. & Hamilton J. K. Evaluation of proposed oral disposition index measures in relation to the actual disposition index. Diabet Med 26, 1198–1203 (2009).
- Cikos S., Bukovska A. & Koppel J. Relative quantification of mRNA: comparison of methods currently used for real-time PCR data analysis. BMC Mol Biol 8, 113 (2007).
- Livak K. J. & Schmittgen T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25, 402–408 (2001).
- Vandesompele J. et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3, RESEARCH0034 (2002).
Source: PubMed