Screening, diagnosis and management of diabetic sensorimotor polyneuropathy in clinical practice: International expert consensus recommendations.

Diabetic sensorimotor polyneuropathy (DSPN) affects around one third of people with diabetes and accounts for considerable morbidity, increased risk of mortality, reduced quality of life, and increased health care costs resulting particularly from neuropathic pain and foot ulcers. Painful DSPN is encountered in 13-26% of diabetes patients, while up to 50% of patients with DSPN may be asymptomatic. Unfortunately, DSPN still remains inadequately diagnosed and treated. Herein we provide international expert consensus recommendations and algorithms for screening, diagnosis, and treatment of DSPN in clinical practice derived from a Delphi process. Typical neuropathic symptoms include pain, paresthesias, and numbness particularly in the feet and calves. Clinical diagnosis of DSPN is based on neuropathic symptoms and signs (deficits). Management of DSPN includes three cornerstones: (1) lifestyle modification, optimal diabetes treatment aimed at near-normoglycemia, and multifactorial cardiovascular risk intervention, (2) pathogenetically oriented pharmacotherapy (e.g. α-lipoic acid and benfotiamine), and (3) symptomatic treatment of neuropathic pain including analgesic pharmacotherapy (antidepressants, anticonvulsants, opioids, capsaicin 8% patch and combinations, if required) and non-pharmacological options. Considering the individual risk profile, pain management should not only aim at pain relief, but also allow for improvement in quality of sleep, functionality, and general quality of life.

Skin autofluorescence: Correlation with measures of diabetic sensorimotor neuropathy.

OBJECTIVE: Advanced glycation end products (AGE) contribute to the development of diabetes complications. Their accumulation in skin can be non-invasively assessed by measurement of skin autofluorescence (SAF). Our study investigated whether SAF correlates with measures of diabetic peripheral neuropathy (DPN). METHODS: In a multi-center study (8 centers), 497 consecutive individuals with diabetes mellitus were investigated. Forearm SAF was measured using the AGE Reader (Groningen, The Netherlands). DPN was assessed using the Toronto Clinical Neuropathy Score (TCNS), the Neuropathy Symptoms Score (NSS) and the Neuropathy Disability Score (NDS). RESULTS (MEAN ±â€¯SD): According to the TCNS, SAF (arbitrary units - AU) was increased in individuals with DPN (TCNS > 5): 2.59 ±â€¯0.56 AU compared with those without DPN (TCNS ≤ 5): 2.45 ±â€¯0.53 AU, (p = 0.04) and significantly increased with the severity of DPN (p = 0.028). Higher SAF was detected in individuals with neuropathic deficits (NDS > 2): 2.58 ±â€¯0.56 AU vs. those without deficits (NDS ≤ 2): 2.45 ±â€¯0.53 AU, (p = 0.009) as well as in individuals with symptoms (NSS > 2): 2.54 ±â€¯0.56 AU vs. those without symptoms (NSS ≤ 2): 2.40 ±â€¯0.47 AU, (p = 0.022). CONCLUSIONS: Accumulation of AGE in skin is increased in individuals with DPN and progresses with the severity of DPN. Therefore, SAF measurement, an easy-to-use, quick and non-invasive method, might help in identifying subjects at high risk for having DPN.

Advances in the management of diabetic neuropathy.

The authors review current advances in the therapy of diabetic neuropathy. The role of glycemic control and management of cardiovascular risk factors in the prevention and treatment of neuropathic complications are discussed. As further options of pathogenetically oriented treatment, recent knowledge on benfotiamine and alpha-lipoic acid is comprehensively reviewed. Alpha-lipoic acid is a powerful antioxidant and clinical trials have proven its efficacy in ameliorating neuropathic signs and symptoms. Benfotiamine acts via the activation of transketolase and thereby inhibits alternative pathways triggered by uncontrolled glucose influx in the cells comprising polyol, hexosamine, protein-kinase-C pathways and formation of advanced glycation end products. Beyond additional forms of causal treatment, choices of symptomatic treatment will be summarized. The latter is mostly represented by the anticonvulsive agents pregabalin and gabapentin as well as duloxetine widely acknowledged as antidepressant. Finally, non-pharmacological therapeutic alternatives are summarized. The authors conclude that combination therapy should be more often suggested to our patients; especially the combination of pathogenetic and symptomatic agents.

A randomised, active- and placebo-controlled, three-period crossover trial to investigate short-term effects of the dipeptidyl peptidase-4 inhibitor linagliptin on macro- and microvascular endothelial function in type 2 diabetes.

BACKGROUND: Studies of dipeptidyl peptidase (DPP)-4 inhibitors report heterogeneous effects on endothelial function in patients with type 2 diabetes (T2D). This study assessed the effects of the DPP-4 inhibitor linagliptin versus the sulphonylurea glimepiride and placebo on measures of macro- and microvascular endothelial function in patients with T2D who represented a primary cardiovascular disease prevention population. METHODS: This crossover study randomised T2D patients (n = 42) with glycated haemoglobin (HbA1c) ≤7.5%, no diagnosed macro- or microvascular disease and on stable metformin background to linagliptin 5 mg qd, glimepiride 1-4 mg qd or placebo for 28 days. Fasting and postprandial macrovascular endothelial function, measured using brachial flow-mediated vasodilation, and microvascular function, measured using laser-Doppler on the dorsal thenar site of the right hand, were analysed after 28 days. RESULTS: Baseline mean (standard deviation) age, body mass index and HbA1c were 60.3 (6.0) years, 30.3 (3.0) kg/m2 and 7.41 (0.61)%, respectively. After 28 days, changes in fasting flow-mediated vasodilation were similar between the three study arms (treatment ratio, gMean [90% confidence interval]: linagliptin vs glimepiride, 0.884 [0.633-1.235]; linagliptin vs placebo, 0.884 [0.632-1.235]; glimepiride vs placebo, 1.000 [0.715-1.397]; P = not significant for all comparisons). Similarly, no differences were seen in postprandial flow-mediated vasodilation. However, under fasting conditions, linagliptin significantly improved microvascular function as shown by a 34% increase in hyperaemia area (P = 0.045 vs glimepiride), a 34% increase in resting blow flow (P = 0.011 vs glimepiride, P = 0.003 vs placebo), and a 25% increase in peak blood flow (P = 0.009 vs glimepiride, P = 0.003 vs placebo). There were no significant differences between treatments in postprandial changes. Linagliptin had no effect on heart rate or blood pressure. Rates of overall adverse events with linagliptin, glimepiride and placebo were 27.5, 61.0 and 35.0%, respectively. Fewer hypoglycaemic events were seen with linagliptin (5.0%) and placebo (2.5%) than with glimepiride (39.0%). CONCLUSIONS: Linagliptin had no effect on macrovascular function in T2D, but significantly improved microvascular function in the fasting state. Trial registration ClinicalTrials.gov identifier-NCT01703286; registered October 1, 2012.

Vascular Effects of Dietary Advanced Glycation End Products.

Evidence has accumulated lately demonstrating that advanced glycation end products (AGEs) play an important role in the development of diabetic and cardiovascular complications as well as the development of other chronic diseases. AGEs originating from diet have a significant contribution to the AGEs body pool and therefore dietary interventions aiming at reducing AGEs load are believed to exert health promoting effects. This review summarizes the evidence from clinical studies regarding effects of dietary AGEs on the vascular system, highlighting also the different aspects of vascular tests. It also advocates an extension of dietary recommendations towards the promotion of cooking methods that reduce dietary AGEs in consumed foods.

Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment.

In the nervous system, NMDA receptors (NMDARs) participate in neurotransmission and modulate the viability of neurons. In contrast, little is known about the role of NMDARs in pancreatic islets and the insulin-secreting beta cells whose functional impairment contributes to diabetes mellitus. Here we found that inhibition of NMDARs in mouse and human islets enhanced their glucose-stimulated insulin secretion (GSIS) and survival of islet cells. Further, NMDAR inhibition prolonged the amount of time that glucose-stimulated beta cells spent in a depolarized state with high cytosolic Ca(2+) concentrations. We also noticed that, in vivo, the NMDAR antagonist dextromethorphan (DXM) enhanced glucose tolerance in mice, and that in vitro dextrorphan, the main metabolite of DXM, amplified the stimulatory effect of exendin-4 on GSIS. In a mouse model of type 2 diabetes mellitus (T2DM), long-term treatment with DXM improved islet insulin content, islet cell mass and blood glucose control. Further, in a small clinical trial we found that individuals with T2DM treated with DXM showed enhanced serum insulin concentrations and glucose tolerance. Our data highlight the possibility that antagonists of NMDARs may provide a useful adjunct treatment for diabetes.

Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on C-peptide kinetics.

Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves indices of ß-cell function estimated based on circulating C-peptide and glucose concentrations (e.g., Homeostasis Model Assessment [HOMA2-%B], meal tolerance test-based indices). However, use of these ß-cell function indices assumes C-peptide kinetics are not altered by canagliflozin. This 2-period crossover study assessed the effect of a single canagliflozin 300-mg dose on C-peptide kinetics in 10 healthy participants. Two hours after receiving canagliflozin or placebo, participants received intravenous somatostatin infusion to suppress endogenous C-peptide secretion and 1 hour later received a bolus injection of synthetic human C-peptide 150 µg. Serum C-peptide was measured over 3 hours and urinary glucose and C-peptide excretion were measured. C-peptide kinetic parameters, including total clearance (CLtotal ) and renal clearance (CLrenal ), were calculated. Serum C-peptide profiles were similar following canagliflozin or placebo treatment. C-peptide CLtotal was slightly lower with canagliflozin versus placebo (mean (SD) of 190 (37) vs. 197 (30) mL/min; canagliflozin/placebo ratio [90% CI] = 96.1% [93.0%; 99.3%]). Other kinetic parameters, including CLrenal , were generally similar between treatments. Results indicate canagliflozin 300 mg does not meaningfully alter C-peptide clearance or other kinetic parameters; therefore, C-peptide-based measurements of insulin secretion are appropriate for assessing ß-cell function in canagliflozin-treated participants.

Microvascular dysfunction in the context of diabetic neuropathy.

Microvascular dysfunction in diabetes plays a crucial role in the development of diabetic complications. The skin, as one of the most accessible organs, serves as a model for the investigation of microvascular dysfunction. Several non-invasive, mostly laser-Doppler-based methods have been developed lately to assess microvascular function in the skin. Microvascular functional changes occur even in the prediabetic state and become more complex with overt diabetes, being exacerbated by the presence of peripheral and/or autonomic diabetic neuropathy. The present article aims at shedding light on the implication of endothelial and neurovascular dysfunction in microvascular changes in diabetes, highlighting the contribution of different forms of diabetic neuropathy.

Measurement of Lens Autofluorescence for Diabetes Screening.

Many efforts have been made lately to develop cost-effective, simple, and reproducible tests for diabetes screening besides the already established fasting plasma glucose, the oral glucose tolerance test, and the glycated hemoglobin A1c. Several tests have been proposed lately, based on the measurement of the so-called advanced glycation endproducts (AGEs). AGEs production is exacerbated during hyperglycemia, and their accumulation in different tissues reflects the degree and duration of dysglycemia. The human lens represents a tissue where AGEs accumulation can be particularly well assessed. The present article comments on the article by Cahn et al. published in this issue of the Journal of Diabetes Science and Technology. Cahn and coauthors tested a new scanning confocal biomicroscope for its accuracy to detect noninvasively subjects with diabetes or at risk for developing diabetes.

Vascular effects of advanced glycation endproducts: Clinical effects and molecular mechanisms.

The enhanced generation and accumulation of advanced glycation endproducts (AGEs) have been linked to increased risk for macrovascular and microvascular complications associated with diabetes mellitus. AGEs result from the nonenzymatic reaction of reducing sugars with proteins, lipids, and nucleic acids, potentially altering their function by disrupting molecular conformation, promoting cross-linking, altering enzyme activity, reducing their clearance, and impairing receptor recognition. AGEs may also activate specific receptors, like the receptor for AGEs (RAGE), which is present on the surface of all cells relevant to atherosclerotic processes, triggering oxidative stress, inflammation and apoptosis. Understanding the pathogenic mechanisms of AGEs is paramount to develop strategies against diabetic and cardiovascular complications.

Skin Autofluorescence - A Non-invasive Measurement for Assessing Cardiovascular Risk and Risk of Diabetes.

The results of the Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) study have strengthened the 'glycaemic memory' concept, postulating that the quality of metabolic control over several years predicts the development of diabetic complications. To mirror long-term metabolic control, the degree of glycated haemoglobin (HbA1c) might not represent the optimal biomarker. Other substances with a longer persistence, like the so-called advanced glycation end-products (AGEs), which probably form the substrate of the glycaemic memory, might perform better. Newly developed methods such as the assessment of skin autofluorescence (SAF), enable fast, uncomplicated and non-invasive AGEs assessment. SAF was validated for diabetes screening and shows a good predictive value for the development of diabetic and cardiovascular complications. This article deals with the theoretical background and with available clinical data on this new variable.

Noninvasive skin fluorescence spectroscopy for diabetes screening.

The development of cost-effective, simple, and reproducible tests for diabetes screening represents a priority of modern medicine in light of the increasing prevalence of diabetes mellitus. Besides fasting plasma glucose, the oral glucose tolerance test, and glycated hemoglobin A1c, several tests have been proposed, among them the assessment of skin fluorescence spectroscopy (SFS). This article comments on the article by Olson and coauthors published in this issue of Journal of Diabetes Science and Technology and comprehensively reviews related available information. Overall, SFS seems to represent an easy-to-use, noninvasive tool that adds value to existing tests for diabetes screening.

Variability of skin autofluorescence measurement over 6 and 12 weeks and the influence of benfotiamine treatment.

BACKGROUND: Measurements of skin autofluorescence (SAF) allow for a simple and noninvasive quantification of tissue advanced glycation end-products (AGEs), a marker linked to the risk of diabetes complications. The aim of this study was to test the repeatability of SAF over 6 and 12 weeks and to test whether benfotiamine, a thiamine prodrug suggested to reduce AGEs formation under hyperglycemic conditions, is able to attenuate SAF when administered over 6 weeks. PATIENTS AND METHODS: In a double-blind, placebo-controlled, randomized, crossover study, 22 patients with type 2 diabetes mellitus (T2DM) received 900 mg/day benfotiamine or placebo for 6 weeks (washout period of 6 weeks between). At the beginning and at the end of each treatment period, SAF was assessed in the fasting state, as well as 2, 4, and 6 h following a mixed test meal. RESULTS: The respective intra-individual and inter-individual variability of fasting SAF was 6.9% and 24.5% within 6 weeks and 10.9% and 23.1% within 12 weeks. The respective variability calculated for triplicate comparisons was 9.9% and 27.7%. A short-term therapy with benfotiamine did not influence SAF significantly, nor did we find a significant postprandial SAF increase. CONCLUSIONS: In patients with T2DM, repeated, timely spaced SAF measurements have an intra-subject variability of below 11%. Using these data, sample sizes were calculated for interventional studies aiming at reducing SAF. Benfotiamine treatment for 6 weeks did not significantly influence SAF; for this, a longer-term therapy is probably needed.

Current options and perspectives in the treatment of diabetic neuropathy.

We aimed to summarise recent advances in the therapy of diabetic neuropathy. Although all therapeutic choices in the treatment of diabetes mellitus itself are based on clear pathophysiological basis, this approach is less present in the treatment of the "forgotten complication", diabetic neuropathy. As part of pathogenetic oriented treatment, the role of glycemic control and cardiovascular risk factors are reviewed. The mode of action of benfotiamine is based on inhibition of key alternative pathways, including the polyol, hexosamine, protein-kinase-C pathways, and inhibition of advanced glycation end products formation, just as on activation of transketolase. Alpha- lipoic-acid is considered as the most potent antioxidant. Other forms of pathogenetic oriented treatment, including actovegin, will be summarised. The anticonvulsants gabapentin and pregabalin, as well as the antidepressant duloxetine represent the most important new drugs among agents for symptomatic relief. Most likely, we should offer combination treatment to our patients much more often, first of all combination of pathogenetic and symptomatic drugs. Finally, the broad spectrum of non-pharmacological treatment will be reviewed.

Acute macrovascular dysfunction in patients with type 2 diabetes induced by ingestion of advanced glycated ß-lactoglobulins.

OBJECTIVE: Recent evidence indicates that heat-enhanced food advanced glycation end products (AGEs) adversely affect vascular function. The aim of this study was to examine the acute effects of an oral load of heat-treated, AGE-modified ß-lactoglobulins (AGE-BLG) compared with heat-treated, nonglycated BLG (C-BLG) on vascular function in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: In a double-blind, controlled, randomized, crossover study, 19 patients with T2DM received, on two different occasions, beverages containing either AGE-BLG or C-BLG. We measured macrovascular [brachial ultrasound of flow-mediated dilatation (FMD)] and microvascular (laser-Doppler measurements of reactive hyperemia in the hand) functions at baseline (T0), 90 (T90), and 180 (T180) min. RESULTS: Following the AGE-BLG, FMD decreased at T90 by 80% from baseline and remained decreased by 42% at T180 (P < 0.05 vs. baseline, P < 0.05 vs. C-BLG at T90). By comparison, following C-BLG, FMD decreased by 27% at T90 and 51% at T180 (P < 0.05 vs. baseline at T180). A significant decrease in nitrite (T180) and nitrate (T90 and T180), as well as a significant increase in N(ε)-carboxymethyllisine, accompanied intake of AGE-BLG. There was no change in microvascular function caused by either beverage. CONCLUSIONS: In patients with T2DM, acute oral administration of a single AGE-modified protein class significantly though transiently impaired macrovascular function in concert with decreased nitric oxide bioavailability. These AGE-related changes were independent of heat treatment.

Benfotiamine counteracts smoking-induced vascular dysfunction in healthy smokers.

Background. Smoking induces endothelial dysfunction (ED) mainly by exacerbating oxidative stress (OS) and inflammation. Benfotiamine, a thiamine prodrug with high bioavailability, prevents nicotine-induced vascular dysfunction in rats. It remained unknown whether this effect also occurs in humans. Methods. Therefore, 20 healthy volunteers (mean age: 38 years) were investigated twice, 7-10 days apart in a randomized, cross-over, and investigator-blinded design. Vascular function was assessed by flow-mediated vasodilatation (FMD) of the brachial artery and by measurements of the soluble vascular cell adhesion molecule (sVCAM)-1. Investigations were performed after an overnight fast as well as 20 minutes after one cigarette smoking. On another day, the same procedure was applied following a 3-day oral therapy with benfotiamine (1050 mg/day). Ten patients were randomized to start with smoking alone, and ten started with benfotiamine. Results. Results are expressed as (mean ± SEM). Smoking acutely induced a decrease in FMD by 50% ((∗∗)P < 0.001 versus baseline) an effect significantly reduced by benfotiamine treatment to 25%(∗§) ((∗)P < 0.05 versus baseline, (§)P < 0.05 versus smoking alone). Smoking-induced elevation in sVCAM-1 was also prevented by benfotiamine. The endothelium-independent vasodilatation remained unaltered between days. Conclusion. In healthy volunteers, smoking blunts vascular function mirrored by a decrease in FMD and an increase in sVCAM-1. Short-term treatment with benfotiamine significantly reduces these effects, showing protective vascular properties.

[The role of AGEs and ROS in atherosclerosis]. / Die Bedeutung von AGEs und ROS bei Atherosklerose.

Advanced glycation end products (AGEs) are among the "newcomers" of metabolic research during the last 2-3 decades. Also known as Maillard products, they have belonged to the everyday life of food research for a long time, but their role in the development of diabetes and cardiovascular complications has been suggested only recently. Even though multiple studies have recently dealt with the role of AGEs and their receptors in mediating pathomechanisms, we are still far from understanding them completely and maybe even farther from developing effective therapeutic approaches. Nevertheless, the present article attempts to offer an overview of known associations between AGEs and vascular complications, in order to draw attention to a less known subject--the AGEs--and, maybe, to stimulate further research in this very exciting field.

Effects of n-3 fatty acids on macro- and microvascular function in subjects with type 2 diabetes mellitus.

BACKGROUND: Recent evidence supports the protective effects of n-3 (omega-3) fatty acids (n-3 FAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on vascular function. OBJECTIVE: We investigated the effects of EPA and DHA on postprandial vascular function in subjects with type 2 diabetes mellitus. DESIGN: In a double-blind, placebo-controlled, randomized, crossover manner, 34 subjects with type 2 diabetes mellitus received daily either 2 g purified EPA/DHA (termed n-3 FAs) or olive oil (placebo) for 6 wk. At the end of this period, we measured macrovascular (brachial ultrasound of flow-mediated dilatation; FMD) and microvascular [laser-Doppler measurements of reactive hyperemia (RH) of the hand] function at fasting and 2, 4, and 6 h after a high-fat meal (600 kcal, 21 g protein, 41 g carbohydrates, 40 g fat). RESULTS: Fasting vascular function remained unchanged after n-3 FAs and placebo. Postprandial FMD decreased from fasting after placebo, with a maximum decrease (38%) at 4 h-an effect that was significantly reduced (P = 0.03 for time x treatment interaction) by n-3 FA supplementation (maximum decrease in FMD was at 4 h: 13%). RH remained unchanged after placebo, whereas it improved significantly (P = 0.04 for time x treatment interaction) after n-3 FA supplementation (maximum increase was at 2 h: 27%). CONCLUSIONS: In subjects with type 2 diabetes mellitus, 6 wk of supplementation with n-3 FAs reduced the postprandial decrease in macrovascular function relative to placebo. Moreover, n-3 FA supplementation improved postprandial microvascular function. These observations suggest a protective vascular effect of n-3 FAs.