Search

Peripheral neuropathy (PN) is a severe and frequent complication of obesity, prediabetes, and type 2 diabetes characterized by progressive distal-to-proximal peripheral nerve degeneration. However, a comprehensive understanding of the mechanisms underlying PN, and whether these mechanisms change during PN progression, is currently lacking. Here, gene expression data were obtained from distal (sciatic nerve; SCN) and proximal (dorsal root ganglia; DRG) injury sites of a high-fat diet (HFD)-induced mouse model of obesity/prediabetes at early and late disease stages. Self-organizing map and differentially expressed gene analyses followed by pathway enrichment analysis identified genes and pathways altered across disease stage and injury site. Pathways related to immune response, inflammation, and glucose and lipid metabolism were consistently dysregulated with HFD-induced PN, irrespective of injury site. However, regulation of oxidative stress was unique to the SCN while dysregulated Hippo and Notch signaling were only observed in the DRG. The role of the immune system and inflammation in disease progression was supported by an increase in the percentage of immune cells in the SCN with PN progression. Finally, when comparing these data to transcriptomic signatures from human patients with PN, we observed conserved pathways related to metabolic dysregulation across species, highlighting the translational relevance of our mouse data. Our findings demonstrate that PN is associated with distinct site-specific molecular re-programming in the peripheral nervous system, identifying novel, clinically relevant therapeutic targets. [ABSTRACT FROM AUTHOR]

Abstract: We examined changes in intraepidermal nerve fibers (IENFs) to differentiate patients with diabetic neuropathy (DN) and diabetic neuropathic pain (DN-P) from those with DN without pain (DN-NOP). Punch skin biopsies were collected from the proximal thigh (PT) and distal leg (DL) of normal subjects, patients with type 2 diabetes without evidence of DN (DM), or DN-P and DN-NOP patients. Protein gene product 9.5-positive (PGP+) immunohistochemistry was used to quantify total IENF, and growth-associated protein 43 (GAP43) for regenerating IENF. Compared to normal subjects and patients with type 2 diabetes without evidence of DN, both DN-P and DN-NOP have reduced PGP+ IENF densities in DL and PT. Although GAP43+ IENF densities were also reduced in DL for both DN-P and DN-NOP, the GAP43+ IENF densities in PT of DN-P remained at the control levels. Higher GAP43/PGP ratios were detected in DN-P compared to DN-NOP in the DL and PT. In parallel, increased numbers of axonal swellings per PGP+ fiber (axonal swelling/PGP) were detected in DN-P compared to normal subjects, patients with type 2 diabetes without evidence of DN, and DN-NOP in the DL. These axonal swellings were positive for tropomyosin-receptor-kinase A and substance P, suggesting that they are associated with nociception. Perspective: Among patients with DN, the ratios of GAP43/PGP and axonal swelling/PGP are likely to differentiate painful from painless phenotypes. [Copyright &y& Elsevier]

Rationale and Objectives: To assess differences in excitatory (glutamate/glutamine or Glx) and inhibitory (γ-Aminobutyric acid or GABA) neurotransmitter levels using MR spectroscopy in pain processing regions of the brain in patients diabetic neuropathy (DN) and positive sensory symptoms and age-matched healthy control (HC) subjects. Materials and Methods: Seven diabetic patients (5 males, 2 females, mean age = 57.0 ± 8.5 years) with confirmed DN and positive sensory symptoms and 7 age and sex matched HC subjects (mean age = 57.7 ± 3.2 years) underwent 3 Tesla MR spectroscopy. Glx and GABA levels were quantified in the right anterior and posterior insula, anterior cingulate cortex and right thalamus. Results: Mean Glx levels were significantly higher and mean GABA levels were significantly lower within the posterior insula in the DN patients compared to HC (P = 0.005 and 0.012 respectively). Conclusions: This pilot data demonstrates an excitatory/inhibitory neurotransmitter imbalance in the brain of in patients with DN and positive sensory symptoms compared to pain free HC subjects. [Copyright &y& Elsevier]

Metabolic syndrome is a cluster of cardiovascular risk factors including obesity, diabetes and dyslipidemia. Insulin resistance (IR) is at the core of metabolic syndrome. In adipose tissue and muscle, IR results in decreased insulin signaling, primarily affecting downstream phosphatidylinositol 3-kinase (PI3K)/Akt signaling. It was recently proposed that neurons can develop hyperinsulinemia-induced IR, which in turn results in injury to the peripheral and central nervous systems and is probably pathogenic in common neurological disorders such as diabetic neuropathy and Alzheimer''s disease (AD). This review presents evidence indicating that, similarly to insulin-dependent metabolically active tissues such as fat and muscle, neurons also develop IR and thus cannot respond to the neurotrophic properties of insulin, resulting in neuronal injury, subsequent dysfunction and disease states. [Copyright &y& Elsevier]

Abstract: Aligned electrospun nanofibers direct neurite growth and may prove effective for repair throughout the nervous system. Applying nanofiber scaffolds to different nervous system regions will require prior in vitro testing of scaffold designs with specific neuronal and glial cell types. This would be best accomplished using primary neurons in serum-free media; however, such growth on nanofiber substrates has not yet been achieved. Here we report the development of poly(l-lactic acid) (PLLA) nanofiber substrates that support serum-free growth of primary motor and sensory neurons at low plating densities. In our study, we first compared materials used to anchor fibers to glass to keep cells submerged and maintain fiber alignment. We found that poly(lactic-co-glycolic acid) (PLGA) anchors fibers to glass and is less toxic to primary neurons than bandage and glue used in other studies. We then designed a substrate produced by electrospinning PLLA nanofibers directly on cover slips pre-coated with PLGA. This substrate retains fiber alignment even when the fiber bundle detaches from the cover slip and keeps cells in the same focal plane. To see if increasing wettability improves motor neuron survival, some fibers were plasma etched before cell plating. Survival on etched fibers was reduced at the lower plating density. Finally, the alignment of neurons grown on this substrate was equal to nanofiber alignment and surpassed the alignment of neurites from explants tested in a previous study. This substrate should facilitate investigating the behavior of many neuronal types on electrospun fibers in serum-free conditions. [Copyright &y& Elsevier]

Diabetic peripheral neuropathy (DPN) occurs in up to half of individuals with type 1 or type 2 diabetes. DPN results from the distal-to-proximal loss of peripheral nerve function, leading to physical disability and sometimes pain, with the consequent lowering of quality of life. Early diagnosis improves clinical outcomes, but many patients still develop neuropathy. Hyperglycaemia is a risk factor and glycaemic control prevents DPN development in type 1 diabetes. However, glycaemic control has modest or no benefit in individuals with type 2 diabetes, probably because they usually have comorbidities. Among them, the metabolic syndrome is a major risk factor for DPN. The pathophysiology of DPN is complex, but mechanisms converge on a unifying theme of bioenergetic failure in the peripheral nerves due to their unique anatomy. Current clinical management focuses on controlling diabetes, the metabolic syndrome, and pain, but remains suboptimal for most patients. Thus, research is ongoing to improve early diagnosis and prognosis, to identify molecular mechanisms that could lead to therapeutic targets, and to investigate lifestyle interventions to improve clinical outcomes. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease. The discovery of genes associated with amyotrophic lateral sclerosis, commencing with SOD1 in 1993, started fairly gradually. Recent advances in genetic technology have led to the rapid identification of multiple new genes associated with the disease, and to a new understanding of oligogenic and polygenic disease risk. The overlap of genes associated with amyotrophic lateral sclerosis with those of other neurodegenerative diseases is shedding light on the phenotypic spectrum of neurodegeneration, leading to a better understanding of genotype-phenotype correlations. A deepening knowledge of the genetic architecture is allowing the characterisation of the molecular steps caused by various mutations that converge on recurrent dysregulated pathways. Of crucial relevance, mutations associated with amyotrophic lateral sclerosis are amenable to novel gene-based therapeutic options, an approach in use for other neurological illnesses. Lastly, the exposome-the summation of lifetime environmental exposures-has emerged as an influential component for amyotrophic lateral sclerosis through the gene-time-environment hypothesis. Our improved understanding of all these aspects will lead to long-awaited therapies and the identification of modifiable risks factors. [ABSTRACT FROM AUTHOR]

The diagnosis of amyotrophic lateral sclerosis can be challenging due to its heterogeneity in clinical presentation and overlap with other neurological disorders. Diagnosis early in the disease course can improve outcomes as timely interventions can slow disease progression. An evolving awareness of disease genotypes and phenotypes and new diagnostic criteria, such as the recent Gold Coast criteria, could expedite diagnosis. Improved prognosis, such as that achieved with the survival model from the European Network for the Cure of ALS, could inform the patient and their family about disease course and improve end-of-life planning. Novel staging and scoring systems can help monitor disease progression and might potentially serve as clinical trial outcomes. Lastly, new tools, such as fluid biomarkers, imaging modalities, and neuromuscular electrophysiological measurements, might increase diagnostic and prognostic accuracy. [ABSTRACT FROM AUTHOR]

Abstract: Cardiac autonomic neuropathy (CAN) is a relatively common and often devastating complication of diabetes. The major clinical signs are tachycardia, exercise intolerance, and orthostatic hypotension, but the most severe aspects of this complication are high rates of cardiac events and mortality. One of the earliest manifestations of CAN is reduced heart rate variability, and detection of this, along with abnormal results in postural blood pressure testing and/or the Valsalva maneuver, are central to diagnosis of the disease. The treatment options for CAN, beyond glycemic control, are extremely limited and lack evidence of efficacy. The underlying molecular mechanisms are also poorly understood. Thus, CAN is associated with a poor prognosis and there is a compelling need for research to understand, prevent, and reverse CAN. In this review of the literature we examine the use and usefulness of animal models of CAN in diabetes. Compared to other diabetic complications, the number of animal studies of CAN is very low. The published studies range across a variety of species, methods of inducing diabetes, and timescales examined, leading to high variability in study outcomes. The lack of well-characterized animal models makes it difficult to judge the relevance of these models to the human disease. One major advantage of animal studies is the ability to probe underlying molecular mechanisms, and the limited numbers of mechanistic studies conducted to date are outlined. Thus, while animal models of CAN in diabetes are crucial to better understanding and development of therapies, they are currently under-used. [Copyright &y& Elsevier]

Abstract: Reactive oxygen species such as hydrogen peroxide (H2O2) are involved in many cellular processes that positively and negatively regulate cell fate. H2O2, acting as an intracellular messenger, activates phosphatidylinositol-3 kinase (PI3K) and its downstream target Akt, and promotes cell survival. The aim of the current study was to understand the mechanism by which PI3K/Akt signaling promotes survival in SH-SY5Y neuroblastoma cells. We demonstrate that PI3K/Akt mediates phosphorylation of the pro-apoptotic Bcl-2 family member Bax. This phosphorylation suppresses apoptosis and promotes cell survival. Increased survival in the presence of H2O2 was blocked by LY294002, an inhibitor of PI3K activation. LY294002 prevented Bax phosphorylation and resulted in Bax translocation to the mitochondria, cytochrome c release, caspase-3 activation, and cell death. Collectively, these findings reveal a mechanism by which H2O2-induced activation of PI3K/Akt influences post-translational modification of Bax and inactivates a key component of the cell death machinery. [Copyright &y& Elsevier]

Abstract: The National Institute of Diabetes and Digestive and Kidney Diseases sponsored a meeting recently to explore new ways to assess diabetic retinopathy and neuropathy, both in diabetic patients and in diabetic mice. The workshop compared current gold standards for assessment of retinopathy and neuropathy, new improvements of existing techniques, and new functional biomarkers measured with nontraditional technologies. Since the anatomical changes that comprise diabetic retinopathy and neuropathy take long to develop and have proven difficult to arrest once initiated, some talks highlighted the value of methods that are based on the pathophysiology that precedes, and might contribute to, the histopathology. In addition, a goal of the workshop was to produce a set of working criteria on phenotyping diabetic retinopathy and neuropathy that could be reviewed by the scientific community. [Copyright &y& Elsevier]

Focal adhesion kinase (FAK) prevents apoptosis in many cell types. We have reported that tyrosine residues in FAK are dephosphorylated and FAK is degraded during mannitol-induced apoptosis in human neuroblastoma cells. Several studies suggest that FAK dephosphorylation and degradation are separate events. The current study defines the relationship between FAK dephosphorylation and degradation in neuroblastoma cells using okadaic acid (OA). OA, a serine phosphatase inhibitor, promotes serine/threonine phosphorylation, which in turn blocks tyrosine phosphorylation. OA induced focal adhesion loss, actin cytoskeleton disorganization, and cellular detachment, which corresponded to a loss of FAK Tyr[sup397] phosphorylation. These changes preceded caspase-3 activation, Akt and MAP kinase activity loss, protein ubiquitination, and cellular apoptosis. Insulin-like growth factor-I prevented mannitol-induced, but not OA-induced, substrate detachment and FAK Tyr[sup397] dephosphorylation, and the effects of OA on FAK Tyr[sup397] phosphorylation were irreversible. The proteolytic degradation of FAK is temporally distinct from its tyrosine dephosphorylation, occurring when apoptotic pathways are already initiated and during a generalized destruction of signaling proteins. Therefore, agents resulting in the dephosphorylation of FAK may be beneficial for therapeutic treatment, irrespective of FAK protein levels, as this may result in apoptosis, which cannot be prevented by growth factor signaling. [ABSTRACT FROM AUTHOR]

• ALS involves a complex interplay between innate and adaptive immunity. • Animal model and patient data reveal a multi-phased immune response. • Several cell types contribute to immune mechanisms in ALS pathogenesis. • PET provides neuroinflammatory response monitoring and possible ALS biomarkers. • Clinical trials of emerging immune-targeted therapies provide hope in ALS. Amyotrophic lateral sclerosis (ALS) is a debilitating and rapidly fatal neurodegenerative disease. Despite decades of research and many new insights into disease biology over the 150 years since the disease was first described, causative pathogenic mechanisms in ALS remain poorly understood, especially in sporadic cases. Our understanding of the role of the immune system in ALS pathophysiology, however, is rapidly expanding. The aim of this manuscript is to summarize the recent advances regarding the immune system involvement in ALS, with particular attention to clinical translation. We focus on the potential pathophysiologic mechanism of the immune system in ALS, discussing local and systemic factors (blood, cerebrospinal fluid, and microbiota) that influence ALS onset and progression in animal models and people. We also explore the potential of Positron Emission Tomography to detect neuroinflammation in vivo, and discuss ongoing clinical trials of therapies targeting the immune system. With validation in human patients, new evidence in this emerging field will serve to identify novel therapeutic targets and provide realistic hope for personalized treatment strategies. [ABSTRACT FROM AUTHOR]

The high prevalence of obesity is associated with an enormous medical, social, and economic burden. The metabolic dysfunction, dyslipidaemia, and inflammation caused by obesity contribute to the development of a wide variety of disorders and effects on the nervous system. In the CNS, mild cognitive impairment can be attributed to obesity-induced alterations in hippocampal structure and function in some patients. Likewise, compromised hypothalamic function and subsequent defects in maintaining whole-body energy balance might be early events that contribute to weight gain and obesity development. In the peripheral nervous system, obesity-driven alterations in the autonomic nervous system prompt imbalances in sympathetic-parasympathetic activity, while alterations in the sensory-somatic nervous system underlie peripheral polyneuropathy, a common complication of diabetes. Pharmacotherapy and bariatric surgery are promising interventions for people with obesity that can improve neurological function. However, lifestyle interventions via dietary changes and exercise are the preferred approach to combat obesity and reduce its associated health risks. [ABSTRACT FROM AUTHOR]

Intraspinal stem cell (SC) transplantation represents a new therapeutic approach for amyotrophic lateral sclerosis (ALS) clinical trials. There are considerable difficulties in designing future efficacy trials, some related to the field of ALS and some that are specific to SCs or the mode of delivery. In October 2015, the most controversial points on SC transplantation were addressed during an international workshop intended to bring together international SC and ALS researchers in a public discussion on a topic for which expertise is limited. During the meeting, a discussion was started on the basic structure of the ideal clinical trial testing the efficacy and safety of SC transplantation. The current document includes a number of consensus points reflecting the design of phase II/III clinical trials. [ABSTRACT FROM AUTHOR]

Diabetic neuropathy (DN) remains arguably the most prevalent chronic complication in people with both type 1 and type 2 diabetes, including in youth, despite changes in the current standards of clinical care. Additionally, emerging evidence demonstrates that neuropathy affects a large proportion of people with undiagnosed diabetes and/or prediabetes, as well as those with obesity. Here we summarize the latest epidemiology of DN, recent findings regarding the pathophysiology of the disease, as well as current outcome measures for screening and diagnosis, in research and clinical settings. The authors discuss novel perspectives on the impact of social determinants of health in DN development and management, and the latest evidence on effective therapies, including pharmacological and nonpharmacological therapies for neuropathic pain. Throughout the publication, we identify knowledge gaps and the need for future funding to address these gaps, as well as needs to advocate for a personalized care approach to reduce the burden of DN and optimize quality of life for all affected individuals. [ABSTRACT FROM AUTHOR]

The world faces a pandemic-level prevalence of type 2 diabetes. In parallel with this massive burden of metabolic disease is the growing prevalence of dementia as the population ages. The two health issues are intertwined. The Lancet Commission on dementia prevention, intervention, and care was convened to tackle the growing global concern of dementia by identifying risk factors. It concluded, along with other studies, that diabetes as well as obesity and the metabolic syndrome more broadly, which are frequently comorbid, raise the risk of developing dementia. Type 2 diabetes is a modifiable risk factor; however, it is uncertain whether anti-diabetic drugs mitigate risk of developing dementia. Reasons are manifold but constitute a critical knowledge gap in the field. This review outlines studies of type 2 diabetes on risk of dementia, illustrating key concepts. Moreover, it identifies knowledge gaps, reviews strategies to help fill these gaps, and concludes with a series of recommendations to mitigate risk and advance understanding of type 2 diabetes and dementia. [ABSTRACT FROM AUTHOR]

Aims: Cardiovascular autonomic neuropathy (CAN) predicts clinical diabetic nephropathy (DN). We investigated the relationship between DN structural lesions and CAN.Methods: Sixty three Pima Indians with type 2 diabetes underwent kidney biopsies following a 6-year clinical trial testing the renoprotective efficacy of losartan vs. placebo. CAN was assessed a median 9.2years later. CAN variables included expiration/inspiration ratio (E/I), standard deviation of the normal R-R interval (sdNN), and low and high frequency signal power and their ratio (LF, HF, LF/HF); lower values reflect more severe neuropathy. Associations of CAN with renal structural variables were assessed by linear regression adjusted for age, sex, diabetes duration, blood pressure, HbA1c, glomerular filtration rate, and treatment assignment during the trial.Results: Global glomerular sclerosis was negatively associated with sdNN (partial r=-0.35, p=0.01) and LF (r=-0.32, p=0.02); glomerular basement membrane width was negatively associated with all measures of CAN except for LF/HF (r=-0.28 to -0.42, p<0.05); filtration surface density was positively associated with sdNN, LF, and HF (r=0.31 to 0.38, p<0.05); and cortical interstitial fractional volume was negatively associated with HF (r=-0.27, p=0.04).Conclusions: CAN associates with DN lesions. [ABSTRACT FROM AUTHOR]

Aims Cardiac autonomic dysfunction is a serious complication of diabetes. One consequence is disruption of the normal beat-to-beat regulation of heart rate (HR), i.e. HR variability (HRV). However, our understanding of the disease process has been limited by inconsistent HR/HRV data from previous animal studies. We hypothesized that differences in the method of measurement, time of day, and level of stress account for the differing results across studies. Thus, our aim was to systematically assess HR and HRV in two common diabetic mouse models. Methods ECG radiotelemetry devices were implanted into db / db (type-2 diabetic), STZ-treated db /+ (type-1 diabetic), and control db /+ mice (n = 4 per group). HR and HRV were analyzed over 24 h and during treadmill testing. Results 24 h analysis revealed that db / db mice had an altered pattern of circadian HR changes, and STZ-treated mice had reduced HR throughout. HRV measures linked to sympathetic control were reduced in db / db mice in the early morning and early afternoon, and partially reduced in STZ-treated mice. HR response to treadmill testing was blunted in both models. Conclusions It is important to consider both time of day and level of stress when assessing HR and HRV in diabetic mice. db / db mice may have altered circadian rhythm of sympathetic control of HR, whereas STZ-treated mice have a relative reduction. This study provides baseline data and a framework for HR analysis that may guide future investigations. [ABSTRACT FROM AUTHOR]

Aims: To identify a female mouse model of diabetic peripheral neuropathy (DPN), we characterized DPN in female BTBR ob/ob mice and compared their phenotype to non-diabetic and gender-matched controls. We also identified dysregulated genes and pathways in sciatic nerve (SCN) and dorsal root ganglia (DRG) of female BTBR ob/ob mice to determine potential DPN mechanisms.Methods: Terminal neuropathy phenotyping consisted of examining latency to heat stimuli, sciatic motor and sural sensory nerve conduction velocities (NCV), and intraepidermal nerve fiber (IENF) density. For gene expression profiling, DRG and SCN were dissected, RNA was isolated and processed using microarray technology and differentially expressed genes were identified.Results: Similar motor and sensory NCV deficits were observed in male and female BTBR ob/ob mice at study termination; however, IENF density was greater in female ob/ob mice than their male counterparts. Male and female ob/ob mice exhibited similar weight gain, hyperglycemia, and hyperinsulinemia compared to non-diabetic controls, although triglycerides were elevated more so in males than in females. Transcriptional profiling of nerve tissue from female mice identified dysregulation of pathways related to inflammation.Conclusions: Similar to males, female BTBR ob/ob mice display robust DPN, and pathways related to inflammation are dysregulated in peripheral nerve. [ABSTRACT FROM AUTHOR]

Objective Experimental studies have reported potential benefit of glucagon-like peptide-1(GLP-1) receptor agonists in preventing diabetic peripheral neuropathy (DPN). We therefore performed a proof-of-concept pilot study to evaluate the effect of exenatide, a GLP-1 agonist, on measures of DPN and cardiovascular autonomic neuropathy (CAN) in patients with type 2 diabetes (T2D). Research Design and Methods Forty-six T2D subjects (age 54 ± 10 years, diabetes duration 8 ± 5 years, HbA1c 8.2 ± 1.3%) with mild to moderate DPN at baseline were randomized to receive either twice daily exenatide (n = 22) or daily insulin glargine (n = 24). The subjects, with similar HbA1c levels, were followed for 18 months. The primary end point was the prevalence of confirmed clinical neuropathy (CCN). Changes in measures of CAN, other measures of small fiber neuropathy such as intra-epidermal nerve fiber density (IENFD), and quality of life were also analyzed. Results Glucose control was similar in both groups during the study. There were no statistically significant treatment group differences in the prevalence of CCN, IENFD, measures of CAN, nerve conductions studies, or quality of life indices. Conclusions In this pilot study of patients with T2D and mild to moderate DPN, 18 months of exenatide treatment had no significant effect on measures of neuropathy compared with glargine treatment. [ABSTRACT FROM AUTHOR]