Introduction‘It feels like the prickling sensation you get as your skin warms up when coming inside after being out on a really cold day.’ This feeling is recognizable for many people and is generally described as an unpleasant sensation. It is also one of the many ways patients describe the symptoms of diabetic peripheral neuropathy, a frequently occurring microvascular complication of diabetes.1 Despite the fact that pain is one of the main manifestations, the pathophysiological mechanisms of diabetic peripheral neuropathy are still not fully clear.2 However, there is growing evidence showing the role of microRNAs in the pathophysiological mechanisms of diabetic microvascular complications.3 Because of the increasing prevalence of diabetes and its complications, there is a growing need for effective therapeutics and also for biomarkers that are reliable to pinpoint the onset and monitor the progression of diabetic peripheral neuropathy.4 In this essay, I aim to explore the potential role of circulating microRNAs as diagnostic tool or therapeutic target for painful diabetic peripheral neuropathy. Diabetic neuropathyFurther knowledge of diabetic neuropathy is necessary to understand the subjects explained in this essay. The most common presentation of diabetic neuropathy is distal symmetrical polyneuropathy, better known as diabetic peripheral neuropathy (DPN).5 DPN develops due to long term hyperglycaemia, which leads to damaged axons and derangements of the small vessels that supply the nerves.6 Loss of vibration sense, tactile sensitivity and kinaesthesia in the lower limbs are often seen in patients with DPN.7 DPN frequently contributes to the development of foot ulcers and these ulcerations are an important cause of lower limb amputations.6 One phenotype of DPN is painful diabetic peripheral neuropathy (PDPN). According to the International Association for the Study of Pain (IASP), the definition of PDPN is ‘pain arising as a direct...