Diabetes and its associated complications are a worldwide and major health issue. Diabetic neuropathy is the most common complication which typically presents as a distal symmetrical polyneuropathy (DSPN). DSPN is a chronic, bilateral, length-dependent sensorimotor neuropathy that initially manifests itself as symptoms in the toes that often spread to the feet, lower legs, and eventually, fingers and hands. The symptoms often include numbness, tingling and pain, and weakness in later stages as DSPN preferentially targets sensory axons and to a lesser extent motor axons. DSPN symptoms often lead to sleep disorders and depression, especially, when neuropathic pain is present. Despite its importance, DSPN is often diagnosed late. Although extensive research has focused on DSPN in the lower limbs, very little is known about how diabetes affects the nerves that supply the hands. Moreover, why some people with DSPN develop neuropathic pain is unclear. This thesis aimed to gain insight in the peripheral nervous system’s function, structure, and mechanical properties in people with diabetes, with and without DSPN. The thesis focussed predominantly on how diabetes and DSPN affects the hands. A comprehensive assessment using non-invasive methods to assess (1) nerve structure (i.e., diffusion weighted imaging, and in vivo corneal confocal microscopy), (2) function (i.e., electrodiagnosis and quantitative sensory testing) and (3) mechanical properties (i.e., shear-wave elastography) was performed in healthy individuals and in people with diabetes, with and without DSPN. To achieve our aims, ‘The DIANE Project’ was set up and a systematic review was conducted. The DIANE Project consisted of a cross-sectional study in which the above assessments were conducted in four groups of participants: (1) healthy participants, (2) people with diabetes without DSPN, (3) people with DSPN in lower limbs but not upper limbs (DSPN FEET ONLY) and (4) people with DSPN in upper and lower limbs (DSPN HANDS & FEET). The diabetes groups contained people with type 1 and type 2 diabetes; and the DSPN groups contained people with painful and non-painful DSPN. For the majority of studies, DSPN was diagnosed based on clinical presentation, confirmed with electrodiagnosis and/or corneal confocal microscopy. Regarding the study of DSPN in hands, our findings indicated that people with DSPN who have symptoms in hands present with the most severe loss of sensation in their hands measured with quantitative sensory testing (Chapter 3). Similarly, diffusion weighted imaging analyses showed that the median nerve and to a lesser extent the ulnar nerve presented microstructural abnormalities in people with DSPN in hands (Chapter 4). Interestingly, early quantitative sensory testing and diffusion weighted imaging changes were detected in people with diabetes with DSPN in feet, and in people with diabetes without DSPN (Chapter 3 and Chapter 4). Shear-wave elastography revealed increased stiffness in the tibial nerve, and even more pronounced in the sural nerve, in line with the idea that sensory nerves are affected before mixed nerves in DSPN (Chapter 5). Regarding the assessment of neuropathic pain in DSPN, our systematic review and meta-analysis showed that people with non-painful and with painful DSPN had a reduction in painful detection thresholds, demonstrated with quantitative sensory testing (Chapter 7). To gain insight in possible differences between painful and non-painful DSPN, we rearranged the groups from The DIANE Project: we still compared healthy people and people with diabetes without DSPN, but the people with DSPN were reassigned to a group of people with non-painful DSPN and a group of people with painful DSPN, irrespective of the location of their painful symptoms (feet only or hands and feet). Using corneal confocal microscopy, we detected an overall progressive nerve fibre loss across the four groups (Chapter 8). The proportion of people with abnormal corneal epithelial microneuromas (i.e., nerve features that typically arise after mechanical trauma) and their number were increased in people with painful DSPN compared to all other groups, including non-painful DSPN. Microneuromas could be candidate biomarkers for painful DSPN. In conclusion, this thesis provides evidence for biological changes in the nerves that supply the hand in people with diabetes without and with DSPN in feet, and DSPN in hands and feet. It is noteworthy that the vastly different methods used in this thesis to assess nerve function, nerve morphology and the nerves’ mechanical properties revealed a remarkably similar pattern, and that these biological changes corresponded with neuropathy severity questionnaires and quality of life questionnaires. Although The DIANE Project is cross-sectional in nature, our findings are in line with DSPN being a progressive condition. Our studies illustrate that many people with diabetes without DSPN, and people with DSPN in feet only, already have subclinical signs of DSPN in hands. Longitudinal studies will need to reveal how worrying this possible trend may be. In the meantime, we believe patients, clinicians and the community should not underestimate the possible effects of diabetes on the nerves that supply the hands.