Hepatic serine and lipid metabolism drive diabetic peripheral neuropathy

Type 2 diabetes represents a disease spectrum in which chronic metabolic dysfunction damages multiple organ systems including liver, kidneys, and peripheral nerves1,2. While onset and progression of these co-morbidities are linked with insulin resistance, hyperglycaemia and dyslipidemia3-7, aberrant amino acid metabolism also contributes to pathogenesis of diabetes and potentially its complications8-10. Serine and glycine are closely related non-essential amino acids11,12 that are consistently reduced in patients with metabolic syndrome10,13-16, but the mechanistic drivers of serine deficiency and the downstream metabolic and phenotypic consequences remain unclear. Low systemic serine, a serine-opathy, is also emerging as a hallmark of macular and peripheral nerve disorders. Specifically, serine deficiency correlates positively with impaired visual acuity and peripheral neuropathy (PN)17-19. Here we demonstrate that aberrant serine homeostasis in the liver drives serine and glycine deficiencies in genetically obese and hyperglycaemic mice. This serine-opathy can be diagnosed with a serine tolerance test that quantifies systemic serine disposal. Mimicking these metabolic alterations via dietary serine/glycine restriction together with high fat intake dramatically accelerates thermal hypoalgesia in mice and reduces epidermal sensory nerve density, which are accompanied by extensive sciatic nerve lipid remodeling. These phenotypes were subsequently normalized by myriocin, linking serine-associated PN with sphingolipid biosynthesis. These findings identify systemic serine deficiency and dyslipidemia as novel risk factors for PN that may be exploited therapeutically.

Ultrasound Measurements of the Median Nerve at the Distal Wrist Crease Correlate With Electrodiagnostic Studies

Background: Carpal tunnel syndrome (CTS) is the most common nerve entrapment neuropathy and is commonly evaluated using electrodiagnostic studies (EDSs). Ultrasound (US) has emerged as a potentially easier and more comfortable alternative to EDSs. The purpose of this study is to evaluate whether measurements of the cross-sectional area (CSA) of the median nerve via US correlate with the severity rating of CTS based on EDSs. Methods: A retrospective review of patients aged 18 years or older who underwent US and EDSs of the median nerve for CTS was performed. Sensory nerve action potential, distal motor latency, and compound muscle action potential were measured, and severity was graded on American Association of Neuromuscular and Electrodiagnostic Medicine guidelines. Cross-sectional area of the median nerve was measured via US at the wrist crease. Results: There was a significant association between increasing CSA and increasing EDS severity ( P < .0001). The mean CSA for normal, mild, moderate, and severe CTS was 7.48 ± 2.00, 10.36 ± 2.53, 12.01 ± 3.64, and 14.34 ± 4.77 mm2, respectively. The area under the curve demonstrated the ability of median nerve CSA to discriminate between normal and abnormal EDSs with an optimal cutoff CSA of ≥10 mm2, as well as, the ability to discriminate between mild CTS and moderate to severe CTS at a cutoff CSA of greater than or equal to 12 mm2. Conclusions: The results of this study show that US measurements of the median nerve at the distal wrist crease discriminate between normal and abnormal EDSs, and between mild CTS and moderate to severe CTS.

Roles of Epithelial and Mesenchymal TRP Channels in Mediating Inflammatory Fibrosis

The maintenance of normal vision is dependent on preserving corneal transparency. For this to occur, this tissue must remain avascular and its stromal architecture needs to be retained. Epithelial transparency is maintained provided the uppermost stratified layers of this tissue are composed of terminally differentiated non-keratinizing cells. In addition, it is essential that the underlying stromal connective tissue remains avascular and scar-free. Keratocytes are the source of fibroblasts that are interspersed within the collagenous framework and the extracellular matrix. In addition, there are sensory nerve fibers whose lineage is possibly either neural crest or mesenchymal. Corneal wound healing studies have been undertaken to delineate the underlying pathogenic responses that result in the development of opacification following chemical injury. An alkali burn is one type of injury that can result in severe and long- lasting losses in ocular transparency. During the subsequent wound healing process, numerous different proinflammatory cytokines and proteolytic enzymes undergo upregulation. Such increases in their expression levels induce maladaptive expression of sustained stromal inflammatory fibrosis, neovascularization, and losses in the smooth optical properties of the corneal outer surface. It is becoming apparent that different transient receptor potential channel (TRP) isoforms are important players in mediating these different events underlying the wound healing process since injury upregulates both their expression levels and functional involvement. In this review, we focus on the involvement of TRPV1, TRPA1 and TRPV4 in mediating some of the responses that underlie the control of anterior ocular tissue homeostasis under normal and pathological conditions. They are expressed on both different cell types throughout this tissue and also on corneal sensory nerve endings. Their roles have been extensively studied as sensors and transducers of environmental stimuli resulting from exposure to intrinsic modulators and extrinsic ligands. These triggers include alteration of the ambient temperature and mechanical stress, etc., that can induce pathophysiological responses underlying losses in tissue transparency activated by wound healing in mice losses in tissue transparency. In this article, experimental findings are reviewed about the role of injury-induced TRP channel activation in mediating inflammatory fibrotic responses during wound healing in mice.

Cutaneous Nerve Fibers Participate in the Progression of Psoriasis by Linking Epidermal Keratinocytes and Immunocytes

Recent studies have illustrated that psoriatic lesions are innervated by dense sensory nerve fibers. Psoriatic plaques appeared to improve after central or peripheral nerve injury. Therefore, the nervous system may play a vital role in psoriasis. We aimed to clarify the expression of nerve fibers in psoriasis and their relationship with immune cells and keratinocytes, and to explore the effect of skin nerve impairment. Our results illustrated that nerve fibers in psoriatic lesions increased and were closely innervated around immune cells and keratinocytes. RNA-seq analysis showed that peripheral sensory nerve-related genes were disrupted in psoriasis. In spinal cord hemi-section mice, sensory impairment improved psoriasiform dermatitis and inhibited the abnormal proliferation of keratinocytes. Botulinum toxin A alleviated psoriasiform dermatitis by inhibiting the secretion of calcitonin gene-related peptide. Collectively, cutaneous nerve fibers participate in the progression of psoriasis by linking epidermal keratinocytes and immunocytes. Neurological intervention may be a new treatment strategy for psoriasis.

Cryoneurolysis for Digital Neuralgia in Professional Baseball Players: A Case Series

ObjectiveWe describe a non-surgical approach to refractory digital neuralgia using cryoneurolysis in a series of 3 professional baseball players.BackgroundThumb injuries are common in baseball players and can sometimes be challenging to effectively manage. Depending on the injury, current treatments include anti-inflammatories, immobilization, physical therapy, corticosteroid injections, and/or surgery. A subset of patients, however, fail nonoperative management yet do not have a clear indication for surgery. Cryoneurolysis or cyroanalgesia is an FDA-approved form of neuromodulation, which has been used safely and effectively on a variety of peripheral nerves. The mechanism of action involves percutaneous introduction of a small probe under local anesthetic to nerve tissue using ultrasound guidance. The probe is then cooled to −88°C using nitrous oxide, which results in secondary Wallerian degeneration. Axonal and myelin regeneration occurs completely in 3–6 months.Design/MethodsVisualization of the superficial radial sensory and ulnar digital nerve were obtained under ultrasound. The skin was prepared in sterile fashion. A 22-gauge 1-½ inch needle was then advanced with ultrasound guidance, and local anesthetic was applied. Both treatment sites were marked with skin marker. Cryoneurolysis was employed using a 5 mm tip. 60-second treatment cycles were performed at each site. Each of the cycles resulted in a 5 × 7 mm lesion visible as hypoechoic signal.ResultsAll 3 players endorsed significant and prolonged relief and were able to return to an elite level of play.ConclusionsThis manuscript is subject to all of the limitations of a case series, and larger rigorous studies are needed to illuminate causal inferences. Novel, complex technologies may also be more susceptible to placebo effect. Nonetheless, we are able to report marked efficacy and safety from cryoneurolysis of the ulnar digital nerve and the superficial radial sensory nerve in a small group of elite baseball players with refractory digital neuralgia.

Sensory axons induce epithelial lipid microdomain remodeling and determine the distribution of junctions in the epidermis

Epithelial cell properties are determined by the polarized distribution of membrane lipids, the cytoskeleton, and adhesive junctions. Epithelia are often profusely innervated, but little work has addressed how contact with neurites affects the polarized organization of epithelial components. In previous work, we found that basal keratinocytes in the larval zebrafish epidermis wrap around axons to enclose them in ensheathment channels sealed by autotypic cell junctions. In this study, we used live imaging to characterize how sensory axons remodel cell membranes, the actin cytoskeleton, and adhesive junctions in basal keratinocytes. At the apical surface of basal keratinocytes, axons promoted the formation of lipid microdomains quantitatively enriched in reporters for PI(4,5)P2 and liquid-ordered (Lo) membranes. Lipid microdomains supported the formation of cadherin-enriched F-actin protrusions, which wrapped around axons, likely initiating the formation of ensheathment channels. Lo reporters, but not reporters of liquid-disordered (Ld) membranes, became progressively enriched at axon-associated membrane domains as autotypic junctions matured at ensheathment channels. In the absence of axons, cadherin-enriched lipid microdomains still formed on basal cell membranes, but were not organized into the contiguous domains normally associated with axons. Instead, these isolated domains formed ectopic heterotypic junctions with overlying periderm cells, a distinct epithelial cell type in the epidermis. Thus, axons inhibit the formation of epithelial heterotypic junctions by recruiting cadherin-rich lipid microdomains to form autotypic junctions at ensheathment channels. These findings demonstrate that sensory nerve endings dramatically remodel polarized epithelial components and regulate the adhesive properties of the epidermis.