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■ AbstractThere is a global diabetes epidemic correlating with an increase in obesity. This coincidence may lead to a rise in the prevalence of type 2 diabetes. There is also an as yet unexplained increase in the incidence of type 1 diabetes, which is not related to adiposity. Whilst improved diabetes care has substantially improved diabetes outcomes, the disease remains a common cause of working age adult-onset blindness. Diabetic retinopathy is the most frequently occurring complication of diabetes; it is greatly feared by many diabetes patients. There are multiple risk factors and markers for the onset and progression of diabetic retinopathy, yet residual risk remains. Screening for diabetic retinopathy is recommended to facilitate early detection and treatment. Common biomarkers of diabetic retinopathy and its risk in clinical practice today relate to the visualization of the retinal vasculature and measures of glycemia, lipids, blood pressure, body weight, smoking, and pregnancy status. Greater knowledge of novel biomarkers and mediators of diabetic retinopathy, such as those related to inflammation and angiogenesis, has contributed to the development of additional therapeutics, in particular for late-stage retinopathy, including intra-ocular corticosteroids and intravitreal vascular endothelial growth factor inhibitors ('anti-VEGFs') agents. Unfortunately, in spite of a range of treatments (including laser photocoagulation, intraocular steroids, and anti-VEGF agents, and more recently oral fenofibrate, a PPAR-alpha agonist lipid-lowering drug), many patients with diabetic retinopathy do not respond well to current therapeutics. Therefore, more effective treatments for diabetic retinopathy are necessary. New analytical techniques, in particular those related to molecular markers, are accelerating progress in diabetic retinopathy research. Given the increasing incidence and prevalence of diabetes, and the limited capacity of healthcare systems to screen and treat diabetic retinopathy, there is need to reliably identify and triage people with diabetes. Biomarkers may facilitate a better understanding of diabetic retinopathy, and contribute to the development of novel treatments and new clinical strategies to prevent vision loss in people with diabetes. This article reviews key aspects related to biomarker research, and focuses on some specific biomarkers relevant to diabetic retinopathy.

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The mammalian pancreas is known to show a remarkable degree of regenerative ability. Several studies until now have demonstrated that the mammalian pancreas can regenerate in normal as well as diabetic conditions. These studies illustrate that pancreatic transcription factors that are seen to be expressed in a temporal fashion during development are re-expressed during regeneration. The only known exception to this is Neurogenin3 (NGN3). Though NGN3 protein, which marks all the pro-endocrine cells during development, is not seen during mouse pancreas regeneration, functional neo-islets are generated by 4 weeks after 70% pancreatectomy. We observed that pancreatic transcription factors upstream of ngn3 showed similar gene expression patterns during development and regeneration. However, gene transcripts of transcription factors immediately downstream of ngn3 (neuroD and nkx2.2) did not show such similarities in expression. Since NGN3 protein was not detected at any time point during regeneration, we reasoned that post-transcriptional silencing of ngn3 by microRNAs may be a possible mechanism. We carried out microRNA analysis of 283 known and validated mouse microRNAs during different stages of pancreatic development and regeneration and identified that 4 microRNAs; miR-15a, miR-15b, miR-16 and miR-195, which can potentially bind to ngn3 transcript, are expressed at least 200-fold higher in the regenerating mouse pancreas as compared to embryonic day (e) 10.5 or e 16.5 developing mouse pancreas. Inhibition of these miRNAs in regenerating pancreatic cells using anti-sense miRNA-specific inhibitors, induces expression of NGN3 and its downstream players: neuroD and nkx2.2. Similarly, overexpression of miRNAs targeting ngn3 during pancreas development shows reduction in the number of hormone-producing cells. It appears that during pancreatic regeneration in mice, increased expression of these microRNAs allows endocrine regeneration via an alternate pathway that does not involve NGN3 protein. Our studies on microRNA profiling of developing and regenerating pancreas provide us with better understanding of mechanisms that regulate post-natal islet neogenesis.