Molecular Aspects in the Potential of Vitamins and Supplements for Treating Diabetic Neuropathy

PURPOSE OF REVIEW: To discuss and provide evidence-based data on dietary supplements as part of treating diabetic neuropathy RECENT FINDINGS: Few randomized controlled trials are available, but some have shown beneficial efficacy of various dietary supplements on objective primary endpoints including nerve conduction velocities and axon potentials as well as subjective patient-reported outcomes. SUMMARY: No medical cure for diabetic neuropathy exists, and prevention is therefore crucial. Tight glucose control slows the progression of nerve damage in diabetes, but an unmet clinical need for effective interventions is warranted. Consequently, a growing number of patients turn to dietary supplements proposed to possess neuroprotective properties. However, the postulated effects are often not evidence-based as they have not been tested scientifically. Taken together, this review will focus on dietary supplements investigated in clinical trials for their potential capabilities in targeting the molecular mechanisms involved in the underlying pathogenesis of diabetic neuropathy

Recommendations for the management of opioid-induced constipation - how to improve usability in clinical practice

INTRODUCTION: Opioid-induced constipation remains undertreated despite effective and safe treatment options exists. Previous guidelines have only been partially effective in improving management, possibly due to their complexity, and studies suggest that a simple setup of concise and behaviorally-orientated steps improves usability.AREAS COVERED: This article introduces the concept of opioid-induced constipation and provides an overview of existing guidelines in this field. We also propose simplified recommendations for managing opioid-induced constipation, derived from a synthesis of current guidelines and the principles of optimal guideline design theory.EXPERT OPINION: Despite standard treatment with laxatives and fluid intake in patients with opioid-induced constipation, escalation of treatment is often needed where μ-opioid receptor antagonists or newer medications such as lubiprostone, linaclotide, or prucalopride are used. Previous guidelines have not been used sufficiently and thus management of the condition is often insufficient. We therefore propose simplified recommendations to management, which we believe can come into broader use. It was validated in primary care for credibility, clarity, relevance, usability, and overall benefit. We believe that this initiative can lead to better management of the substantial proportion of patients suffering from side effects of opioids.</p

Low-grade inflammation in type 2 diabetes:a cross-sectional study from a Danish diabetes outpatient clinic

OBJECTIVES: To investigate low-grade inflammation in type 2 diabetes and explore associations to clinical aspects as well as microvascular and macrovascular complications. DESIGN: Cross-sectional analysis. SETTING: The outpatient diabetes clinic at the Department of Endocrinology at Aalborg University Hospital, Denmark. PARTICIPANTS: 100 participants with type 2 diabetes confirmed by a haemoglobin A1c (HbA1c)≥6.5% for a minimum of 1 year and 21 healthy controls. OUTCOME MEASURES: Serum levels of 27 inflammation-related biomarkers measured by immunoassay. Associations with microvascular and macrovascular complications, body weight, glycaemic control, medication and sex were investigated in the diabetes cohort. RESULTS: Serum levels of tumour necrosis factor (TNF)-α and eotaxin were elevated in type 2 diabetes (p<0.05), while interleukin (IL)-7 was decreased (p<0.001). IL-12/IL-23p40, IL-15, macrophage-derived chemokine (MDC) and C reactive protein (CRP) levels were increased with body weight (p<0.05), while eotaxin and TNF-α were increased with elevated HbA1c levels (p<0.04). Dipeptidyl peptidase-4 inhibitor therapy was associated with lower levels of induced protein-10, MDC and thymus and activation regulated chemokine (p<0.02), while females had higher levels of MDC (p=0.027). Individuals with ≥3 diabetic complications had elevated levels of IL-6, IL-10, IL-12/IL-23p40, IL-15 and CRP compared with those with ≤3 (p<0.05). CONCLUSION: The level of low-grade inflammation in type 2 diabetes is associated with obesity, glycaemic regulation, therapeutical management, sex and complications. Our results underline the importance of addressing inflammatory issues in type 2 diabetes, as these may predispose for crippling comorbidities

Circulating Inflammatory Markers Are Inversely Associated with Heart Rate Variability Measures in Type 1 Diabetes

Introduction. A neuroimmune communication exists, and compelling evidence suggests that diabetic neuropathy and systemic inflammation are linked. Our aims were (1) to investigate biomarkers of the ongoing inflammation processes including cytokines, adhesion molecules, and chemokines and (2) to associate the findings with cardiovascular autonomic neuropathy in type 1 diabetes by measuring heart rate variability and cardiac vagal tone. Materials and Methods. We included 104 adults with type 1 diabetes. Heart rate variability, time domain, and frequency domains were calculated from a 24-hour Holter electrocardiogram, while cardiac vagal tone was determined from a 5-minute electrocardiogram. Cytokines (interleukin- (IL-) 1α, IL-4, IL-12p70, IL-13, IL-17, and tumor necrosis factor- (TNF-) α), adhesion molecules (E-selectin, P-selectin, and intercellular adhesion molecule- (ICAM-) 1), and chemokines (chemokine (C-C motif) ligand (CCL)2, CCL3, CCL4, and C-X-C motif chemokine (CXCL)10) were assessed using a Luminex multiplexing technology. Associations between concentrations of inflammatory biomarkers and continuous variables of heart rate variability and cardiac vagal tone were estimated using multivariable linear regression adjusting for age, sex, disease duration, and smoking. Results. Participants with the presence of cardiovascular autonomic neuropathy had higher systemic levels of IL-1α, IL-4, CCL2, and E-selectin than those without cardiovascular autonomic neuropathy. IL-1α, IL-4, IL-12, TNF-α, and E-selectin were inversely associated with both sympathetic and parasympathetic heart rate variability measures (p>0.01). Discussion. Our results show that several pro- and anti-inflammatory factors, believed to be involved in the progression of diabetic polyneuropathy, are associated with cardiovascular autonomic neuropathy, suggesting that these factors may also contribute to the pathogenesis of cardiovascular autonomic neuropathy. Our findings emphasize the importance of the neuroimmune regulatory system in the pathogenesis of neuropathy in type 1 diabetes

Study protocol for a multicentre, randomised, parallel group, sham-controlled clinical trial investigating the effect of transcutaneous vagal nerve stimulation on gastrointestinal symptoms in people with diabetes complicated with diabetic autonomic neuropathy:The DAN-VNS Study

Introduction A high proportion of people with diabetes experience gastrointestinal (GI) symptoms, which may be manifestations of diabetic autonomic neuropathy (DAN). The current treatment regime is ineffective and associated with major side effects. Transcutaneous vagal nerve stimulation (tVNS) is a new therapeutic option, which has been shown to increase GI motility and reduce inflammatory responses. As vagus is the main neuronal pathway for extrinsic coordination of GI secretion and motility, we hypothesise that tVNS will improve DAN-induced GI symptoms in subjects with diabetes.Methods and analysis The DAN-VNS study is a randomised multicentre clinical trial investigating the effect of short-term, high intensity as well as long-term, medium-intensity tVNS on GI symptom alleviation in 120 subjects with diabetes. The primary outcome consists of changes from baseline in subjective ratings of symptom severity. Secondary outcomes include changes in gastric motility and GI transit time measured by MRI and wireless motility capsule. Moreover, cardiovascular and sudomotor function, glycaemic control, brain sensory processing and presence of low-grade inflammation will be investigated as secondary outcome measures. Lastly, 15 responders of tVNS treatment will be included in an explorative, randomised, cross-over study, in which the acute endocrine and metabolic response to short-term tVNS will be investigated.Ethics and dissemination The study has been approved by the North Denmark Region Committee on Health Research Ethics (N-20190020). Results will be published in relevant international peer-reviewed journals.Trial registration number NCT04143269