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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.

Introduction: The aim of our study was to evaluate the relative effect of diabetes and hypertension on heart rate variability., Research Design and Methods: Four age-matched groups including type 2 diabetic patients with and without hypertension, non-diabetic patients with essential hypertension and healthy control subjects were studied. Autonomic function was evaluated by the standard cardiovascular reflex tests and 24-hour heart rate variability measurement. Heart rate variability was characterized by the triangular index value and by the spectral components of the frequency domain analysis., Results: According to the two-way analysis of variance on ranks, all parameters were influenced negatively by diabetes (heart rate variability triangular index: p < 0.001; low-frequency component: p < 0.0001; high-frequency component: p < 0.001; and total power: p < 0.0001), whereas hypertension had a negative effect only on the low-frequency component (p < 0.05). The interaction between hypertension and diabetes was not significant, indicating that their effects on the heart rate variability parameters are additive. Beat-to-beat variation upon deep breathing, the most sensitive cardiovascular reflex test was also negatively influenced by both diabetes (p < 0.001) and hypertension, (p < 0.05), and their effects were additive., Conclusions: Diabetes appears to have a greater effect on autonomic dysfunction compared with hypertension. Patients suffering from both diabetes and hypertension are at the highest risk of reduced heart rate variability. Early assessment of the autonomic nerve function is suggested in diabetic patients with hypertension., (Copyright © 2013 John Wiley & Sons, Ltd.)

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.

Background: Cardiac autonomic neuropathy (CAN) is associated with significant morbidity and mortality in diabetes and the risk is even greater in those with hypertension., Aims: The aim of our study was to investigate the relationship between CAN and 24-h blood pressure profile in normoalbuminuric patients with Type 2 diabetes mellitus., Methods: Seventy patients with Type 2 diabetes (31 without CAN, 39 with CAN), who had no history of hypertension, and 29 healthy volunteers underwent five standard cardiovascular reflex tests to assess autonomic function and 24-h ambulatory blood pressure monitoring., Results: Twenty-four-hour mean systolic blood pressure, blood pressure load and hyperbaric impact values were significantly higher in diabetic patients with CAN compared with control subjects and diabetic patients without CAN (P < 0.05). In spite of normal clinic blood pressures, 54% of diabetic subjects with CAN and 29% without CAN were hypertensive (systolic blood pressure load > 20%, P < 0.05). In the diabetes group as a whole, Valsalva ratio, postural systolic blood pressure changes and diastolic blood pressure responses during sustained handgrip correlated significantly and negatively with 24-h mean systolic blood pressure (P < 0.01, P < 0.001, P < 0.05) and blood pressure load (P < 0.05, P < 0.001, P < 0.05)., Conclusions: Cardiovascular autonomic neuropathy is independently associated with hypertension in normoalbuminuric Type 2 diabetic patients with no history of hypertension. Relying on clinic blood pressures in subjects with CAN could lead to a failure to diagnose hypertension in over half of cases. All normotensive patients with CAN should be screened for hypertension using ambulatory blood pressure monitoring in order to institute early aggressive interventions to improve their long-term outlook.

The aim of the present study was to investigate peripheral sensory nerve function in diabetic children and adolescents without neurological symptoms. Ninety-two children and adolescents with Type 1 (insulin-dependent) diabetes mellitus (mean +/- SD age: 14.2 +/- 2.1 years, diabetes duration: 5.8 +/- 3.0 years) and 80 healthy control subjects (age: 13.8 +/- 2.2 years) matched for age, sex, body mass index, and height standard deviation score were involved in the study. Using a sine-wave transcutaneous stimulator, current perception threshold (CPT) testing at 2000, 250 and 5 Hz was performed on the left median and peroneal nerves. Diabetic children had increased CPT at 2000 Hz on both nerves as compared to the control group (median (interquartile range), median nerve: 2.43 (2.20-3.43) vs 1.80 (1.51-2.60) mA, p = 0.02; peroneal nerve: 3.51 (2.81-4.82) vs 2.70 (2.04-3.70) mA, p = 0.01). Twenty-one (23%) of patients had CPT values higher than that of any healthy individual. Of these, elevated CPT was observed in 9 (9.8%) patients on the median nerve, in 8 (8.7%) patients on the peroneal nerve, and in 4 (4.3%) patients on both median and peroneal nerves. Using multiple logistic regression analysis, worse long-term metabolic control and advanced puberty were independently predictive of peripheral sensory nerve dysfunction as the dependent variable (adjusted OR (95% CI): 3.4 (1.2-6.2), p = 0.01, and 2.8 (1.1-5.6), p = 0.03, respectively). In conclusion, evidence of peripheral sensory nerve dysfunction is not rare in children and adolescents with diabetes and can be demonstrated by CPT testing in asymptomatic patients. Poor metabolic control is a risk factor for such subclinical neuropathy, and pubertal development may be involved in the pathogenesis of diabetic peripheral neuropathy.