Background: Diabetic peripheral neuropathy (DPN) is traditionally divided into large and small fibre neuropathy (SFN). Damage to the large fibres can be detected using nerve conduction studies (NCS) and often results in a significant reduction in sensitivity and loss of protective sensation, while damage to the small fibres is hard to reliably detect and can be either asymptomatic, associated with insensitivity to noxious stimuli, or often manifests itself as intractable neuropathic pain. Objective: To describe the recent advances in both detection, grading, and treatment of DPN as well as the accompanying neuropathic pain. Methods: A review of relevant, peer-reviewed, English literature from MEDLINE, EMBASE and Cochrane Library between January 1st 1967 and January 1st 2020 was used. Results: We identified more than three hundred studies on methods for detecting and grading DPN, and more than eighty randomised-controlled trials for treating painful diabetic neuropathy. Conclusion: NCS remains the method of choice for detecting LFN in people with diabetes, while a gold standard for the detection of SFN is yet to be internationally accepted. In the recent years, several methods with huge potential for detecting and grading this condition have become available including skin biopsies and corneal confocal microscopy, which in the future could represent reliable endpoints for clinical studies. While several newer methods for detecting SFN have been developed, no new drugs have been accepted for treating neuropathic pain in people with diabetes. Tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors and anticonvulsants remain first line treatment, while newer agents targeting the proposed pathophysiology of DPN are being developed.

OBJECTIVE: Diabetic peripheral neuropathy (DPN) and neuropathic pain impacts quality of life (QoL) and mental health negatively. This cross-sectional survey study aimed to 1) elucidate the associations between painful and painless DPN and QoL, mental health, and socioeconomic factors, 2) assess the prevalence of sensory pain descriptors, and 3) evaluate the association between descriptors and the above factors. RESEARCH DESIGN AND METHODS: Participants were grouped into people with (n = 1,601) and without (n = 5,359) DPN based on the Michigan Neuropathy Screening Instrument questionnaire. Participants with DPN were subsequently divided into people with (n = 1,085) and without (n = 516) concomitant neuropathic pain based on the modified Douleur Neuropathique en 4 Questions-interview. RESULTS: The study showed diminished QoL (36-item Short Form Health Survey [SF-36]: 55.1 [interquartile range 36.7, 73.6], 82.2 [63.6, 90.9]) and poorer mental health (Hospital Anxiety and Depression Scale, subscale for anxiety [HADS-A]: 5.00 [2, 9], 2.00 [1, 5]; HADS-subscale for depression [HADS-D]: 4.00 [1, 8], 1.00 [0, 3]) in participants with DPN compared with participants without DPN. The addition of pain diminished QoL (SF-36: 50.7 [34.8, 69.8]) and mental health (HADS-A: 6 [3, 10], HADS-D: 4 [1, 8]) further. The most prevalent pain descriptor in participants with painful DPN were burning pain (73%), while the most prevalent sensory descriptor was pins-and-needles (93%). An interesting finding is the high prevalence of itch (44%). Weak associations with mental health and QoL were present for cold pain, electric pain, and itch. CONCLUSIONS: An increased focus on differences in QoL, mental health, and pain phenotypes is of importance to move the field forward toward more interdisciplinary, personalized treatment.

OBJECTIVE: In this study we aimed to investigate the functional connectivity of brain regions involved in sensory processing in diabetes with and without painful and painless diabetic peripheral neuropathy (DPN) and the association with peripheral nerve function and pain intensity.RESEARCH DESIGN AND METHODS: In this cross-sectional study we used resting-state functional MRI (fMRI) to investigate functional brain connectivity of 19 individuals with type 1 diabetes and painful DPN, 19 with type 1 diabetes and painless DPN, 18 with type 1 diabetes without DPN, and 20 healthy control subjects. Seed-based connectivity analyses were performed for thalamus, postcentral gyrus, and insula, and the connectivity z scores were correlated with peripheral nerve function measurements and pain scores.RESULTS: Overall, compared with those with painful DPN and healthy control subjects, subjects with type 1 diabetes without DPN showed hyperconnectivity between thalamus and motor areas and between postcentral gyrus and motor areas (all P ≤ 0.029). Poorer peripheral nerve functions and higher pain scores were associated with lower connectivity of the thalamus and postcentral gyrus (all P ≤ 0.043). No connectivity differences were found in insula (all P ≥ 0.071).CONCLUSIONS: Higher functional connectivity of thalamus and postcentral gyrus appeared only in diabetes without neuropathic complications. Thalamic/postcentral gyral connectivity measures demonstrated an association with peripheral nerve functions. Based on thalamic connectivity, it was possible to group the phenotypes of type 1 diabetes with painful/painless DPN and type 1 diabetes without DPN. The results of the current study support that fMRI can be used for phenotyping, and with validation, it may contribute to early detection and prevention of neuropathic complications.

Background: Diabetic peripheral neuropathy (DPN) is a prevalent and debilitating complication of diabetes, often leading to severe neuropathic pain. Although other diabetes-related complications have witnessed a surge of emerging treatments in recent years, DPN has seen minimal progression. This stagnation stems from various factors, including insensitive diagnostic methods and inadequate treatment options for neuropathic pain. Methods: In this comprehensive review, we highlight promising novel diagnostic techniques for assessing DPN, elucidating their development, strengths, and limitations, and assessing their potential as future reliable clinical biomarkers and endpoints. In addition, we delve into the most promising emerging pharmacological and mechanistic treatments for managing neuropathic pain, an area currently characterized by inadequate pain relief and a notable burden of side effects. Results: Skin biopsies, corneal confocal microscopy, transcutaneous electrical stimulation, blood-derived biomarkers, and multi-omics emerge as some of the most promising new techniques, while low-dose naltrexone, selective sodium-channel blockers, calcitonin gene-related peptide antibodies, and angiotensin type 2 receptor antagonists emerge as some of the most promising new drug candidates. Conclusion: Our review concludes that although several promising diagnostic modalities and emerging treatments exist, an ongoing need persists for the further development of sensitive diagnostic tools and mechanism-based, personalized treatment approaches.

Aim: To investigate the trends in non‐traumatic lower limb amputation in people with and without diabetes.Methods: From the Danish National Patient Register, all people with either type 1 or type 2 diabetes (n = 462 743) as well as a group of people without diabetes from the general population (n = 1 388 886) were identified and separated into three groups based on diabetes type. Among these, 17 265 amputations were identified between 1997 and 2017 and stratified into trans‐femoral amputations, trans‐tibial amputations and amputations below the ankle using surgical codes. Annual changes were described using least‐squares linear regression.Results: The yearly mean decrease in incidence rate of amputation per 1000 person‐years was −0.032 [95% CI: −0.062, −0.001], −0.022 [−0.032, −0.012] and −0.006 [−0.009, −0.003] for trans−femoral amputation, −0.072 [−0.093, −0.052], −0.090 [−0.102, −0.078] and −0.015 [−0.016, −0.013] for trans‐tibial amputation, and −0.055 [−0.080, −0.020], −0.075 [−0.090, −0.060] and −0.011 [−0.014, −0.007] for amputation below the ankle in people with type 1 diabetes, people with type 2 diabetes and people without diabetes, respectively.Conclusions: Over recent decades, the incidence of amputation has decreased significantly in people with diabetes and in the general population without diabetes.

It remains unknown why some people with diabetes develop painful neuropathies while others experience no pain. This study aimed to validate a novel method for assessing the function of small sensory nerves in diabetes to further elucidate this phenomenon. The function of large and small nerves was assessed using a novel perception threshold tracking technique in 3 well-characterized groups (n = 60) with type 1 diabetes, namely, (1) painful diabetic peripheral neuropathy (T1DM + PDPN), (2) painless diabetic peripheral neuropathy (T1DM + DPN), and (3) no neuropathy (T1DM − DPN), and healthy controls (n = 20). Electrical currents with different shapes, duration, and intensities were applied by 2 different skin electrodes activating large and small fibers, respectively. The minimal current needed to activate the fibers were analyzed as the rheobase of the stimulus–response function. Nerve fiber selectivity was measured by accommodation properties of stimulated nerves. The rheobase of both fiber types were highest for T1DM + PDPN, followed by T1DM + DPN, T1DM − DPN, and healthy controls, indicating that the nerve properties are specific in individuals with diabetes and pain. There was an overall significant difference between the groups (P < 0.01). The accommodation properties of stimulated fibers were different between the 2 electrodes (P < 0.05) apart from in the group with T1DM + PDPN, where both electrodes stimulated nerves displaying properties similar to large fibers. Perception threshold tracking reveals differences in large and small nerve fiber function between the groups with and without diabetes, DPN, and pain. This indicates that the methods have potential applications in screening DPN and explore further the features differentiating painful from nonpainful DPN.