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Circulating microRNAs (miRNAs) have emerged as novel biomarkers of diabetes. The current study focuses on the role of circulating miRNAs in patients with type 1 diabetes and their association with diabetic retinopathy. A total of 29 miRNAs were quantified in serum samples (n = 300) using a nested case-control study design in two prospective cohorts of the DIabetic REtinopathy Candesartan Trial (DIRECT): PROTECT-1 and PREVENT-1. The PREVENT-1 trial included patients without retinopathy at baseline; the PROTECT-1 trial included patients with nonproliferative retinopathy at baseline. Two miRNAs previously implicated in angiogenesis, miR-27b and miR-320a, were associated with incidence and with progression of retinopathy: the odds ratio per SD higher miR-27b was 0.57 (95% CI 0.40, 0.82; P = 0.002) in PREVENT-1, 0.78 (0.57, 1.07; P = 0.124) in PROTECT-1, and 0.67 (0.50, 0.92; P = 0.012) combined. The respective odds ratios for higher miR-320a were 1.57 (1.07, 2.31; P = 0.020), 1.43 (1.05, 1.94; P = 0.021), and 1.48 (1.17, 1.88; P = 0.001). Proteomics analyses in endothelial cells returned the antiangiogenic protein thrombospondin-1 as a common target of both miRNAs. Our study identifies two angiogenic miRNAs, miR-320a and miR-27b, as potential biomarkers for diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Background: In REMOVAL (NCT01483560), adjunct metformin treatment in adults with type 1 diabetes reduced body weight and LDL cholesterol (secondary outcomes) and progression of averaged maximal carotid intima-media thickness (tertiary outcome). Here, we report effects of metformin on tissue plasminogen activator antigen (tPA), soluble E-selectin (sE-selectin) and soluble intracellular-adhesion molecule 1 (sICAM-1) (tertiary outcomes) as well as other exploratory biomarkers. Methods: Samples were available at 0, 12, 24 and 36 months from 428 men and women with type 1 diabetes randomly assigned to metformin 1000 mg or matching placebo twice daily for three years: (mean±SD) age 55±8·5 years, HbA1c 8·0±0·82%, BMI 28·4±4·3 kg/m2, duration of diabetes 34±10·8 years, 82% on statin therapy. Commercial ELISA kits were used for tPA, sE-selectin, and sICAM-1 and automated platforms for apolipoproteins (Apo) A-1 and B, C-reactive protein (CRP), and high sensitivity cardiac troponin T (cTnT). Results: Metformin reduced tPA (22.2%, p<0.001; tertiary outcome), CRP (15.8%, p=0.041), and Apo B (4.6%, p=0.012) but did not affect sE-selectin, sICAM-1, Apo A-1 or cTnT (repeated measures ANCOVA). Conclusion: The reductions in tPA and CRP observed with metformin in type 1 diabetes indicate modest antithrombotic and anti-inflammatory effects consistent with previous studies in type 2 diabetes. Disclosure: P. Welsh: Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH. N. Greenlaw: None. H. Colhoun: Advisory Panel; Self; Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Sanofi-Aventis. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Regeneron Pharmaceuticals, Roche Pharma, Sanofi-Aventis. Speaker's Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. N. Chaturvedi: Advisory Panel; Self; AstraZeneca. I. Ford: None. I. Hramiak: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Insulet Corporation, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; Merck & Co., Inc. A.D. Hughes: Advisory Panel; Spouse/Partner; AstraZeneca. A. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. B.E.K. Klein: None. R. Klein: None. M. Brouwers: None. P. Rossing: Advisory Panel; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp. Other Relationship; Self; Novartis AG, Novo Nordisk A/S. C.D. Stehouwer: None. N. Sattar: Advisory Panel; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S. Consultant; Self; NAPP Pharmaceuticals Limited. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Amgen Inc., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Roche Diagnostics France, Sanofi. J.R. Petrie: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Research Support; Self; Itamar Medical Ltd., Merck KGaA. Other Relationship; Self; Applied Clinical Intelligence, LLC, Boehringer Ingelheim International GmbH, Diabetes UK, Quintiles. Funding: JDRF (17-2011-272) [ABSTRACT FROM AUTHOR]