Biochemically Silent Sympathetic Paraganglioma, Pheochromocytoma, or Metastatic Disease in SDHD Mutation Carriers.

CONTEXT: Current guidelines do not consistently recommend imaging beyond the head and neck region in succinate dehydrogenase subunit D (SDHD) mutation carriers as long as catecholamine metabolite levels are within the reference range. PARTICIPANTS: We report a series of 10 patients carrying pathogenic variants in the SDHD gene from five tertiary referral centers for paraganglioma (PGL) in the Netherlands, who presented with a sympathetic PGL (sPGL), pheochromocytoma (PHEO), or metastases outside the head and neck region in the absence of excessive catecholamine production. Two of six patients with a biochemically silent sPGL/PHEO developed metastatic disease. Additionally, four patients were found to have metastases outside the head and neck region from head and neck PGL. The average interval between the initial diagnosis and discovery of the silent lesions was 10 (range, 0 to 32) years. CONCLUSIONS: The absence of excessive catecholamine production does not exclude the presence of manifestations of SDHD outside the head and neck region. These findings suggest that a more extensive imaging strategy in SDHD mutation carriers may be warranted for detection of biochemically silent lesions.

Retrospective Analysis of an Insulin-to-Liraglutide Switch in Patients with Type 2 Diabetes Mellitus.

INTRODUCTION: Insulin and the GLP-1 receptor agonist liraglutide are both effective in reaching glycemic targets. The efficacy of an insulin-to-liraglutide switch in an obese population with concurrent use of sulfonylurea and metformin is unknown. We assessed the efficacy and determinants of success of an insulin-to-liraglutide switch in these patients. METHODS: In a retrospective study we analyzed all patients that underwent an insulin-to-liraglutide switch during routine medical care (January 2009-February 2015). It was assessed if patients still continued liraglutide 12 months after the switch or discontinued because of poor glycemic control or side effects. Baseline characteristics were compared between the groups to establish determinants of success. RESULTS: A total of 104 patients made an insulin-to-liraglutide switch (43% male; mean age 57.2 ± 9.9 years; mean BMI 39.8 ± 5.4 kg/m2). Sixty patients still continued liraglutide after 12 months (58%) whereas 37 patients discontinued treatment because of poor glycemic control within 12 months (36%) and seven patients discontinued liraglutide because of intolerable side effects (7%). Insulin dose and insulin frequency at baseline were significantly lower in patients that continued liraglutide. Patients reaching HbA1c ≤ 7% (53 mmol/mol) showed lower baseline HbA1c levels, shorter duration of diabetes, and shorter duration of insulin therapy. CONCLUSION: The majority of patients continued liraglutide after a switch from insulin therapy with on average no change in glycemic control and decrease of body weight. HbA1c levels at baseline, duration of insulin therapy, and duration of diabetes were predictive of reaching glycemic control on liraglutide alone. In current practice this also indicates which patients on insulin can reduce their insulin dose after adding a GLP-1 receptor agonist. Plain language summary available for this article.

Higher TNF-α, IGF-1, and Leptin Levels are Found in Tasters than Non-Tasters.

Taste perception is controlled by taste cells that are present in the tongue that produce and secrete various metabolic hormones. Recent studies have demonstrated that taste receptors in tongue, gut, and pancreas are associated with local hormone secretion. The aim of this study was to determine whether there is a link between taste sensitivity and levels of circulating metabolic hormones in humans and whether taste sensitivity is potentially related to peripheral metabolic regulation. Thirty-one subjects were recruited and separated into tasters and non-tasters based on their phenol thiocarbamide (PTC) bitter taste test results. Fasting plasma and saliva were collected and levels of hormones and cytokines were assayed. We observed significant differences in both hormone levels and hormone-body mass index (BMI) correlation between tasters and non-tasters. Tasters had higher plasma levels of leptin (p = 0.05), tumor necrosis factor-α (TNF-α) (p = 0.04), and insulin-like growth factor 1 (IGF-1) (p = 0.03). There was also a trend toward increased IGF-1 levels in the saliva of tasters (p = 0.06). We found a positive correlation between plasma levels of glucose and BMI (R = 0.4999, p = 0.04) exclusively in non-tasters. In contrast, plasma C-peptide levels were found to be positively correlated to BMI (R = 0.5563, p = 0.03) in tasters. Saliva TNF-α levels were negatively correlated with BMI in tasters (R = -0.5908, p = 0.03). Our findings demonstrate that there are differences in circulating levels of leptin, TNF-α, and IGF-1 between tasters and non-tasters. These findings indicate that in addition to the regulation of food consumption, taste perception also appears to be tightly linked to circulating metabolic hormone levels. People with different taste sensitivity may respond differently to the nutrient stimulation. Further work investigating the link between taste perception and peripheral metabolic control could potentially lead to the development of novel therapies for obesity or Type 2 diabetes.

Pathogenesis of diabetic neuropathy: focus on neurovascular mechanisms.

Neuropathies of the peripheral and autonomic nervous systems affect up to half of all people with diabetes, and are major risk factors for foot ulceration and amputation. The aetiology is multifactorial: metabolic changes in diabetes may directly affect neural tissue, but importantly, neurodegenerative changes are precipitated by compromised nerve vascular supply. Experiments in animal models of diabetic neuropathy suggest that similar metabolic sequelae affect neurons and vasa nervorum endothelium. These include elevated polyol pathway activity, oxidative stress, the formation of advanced glycation and lipoxidation end products, and various pro-inflammatory changes such as elevated protein kinase C, nuclear factor κB and p38 mitogen activated protein kinase signalling. These mechanisms do not work in isolation but strongly interact in a mutually facilitatory fashion. Nitrosative stress and the induction of the enzyme poly (ADP-ribose) polymerase form one important link between physiological stressors such as reactive oxygen species and the pro-inflammatory mechanisms. Recently, evidence points to endoplasmic stress and the unfolded protein response as forming another crucial link. This review focuses on the aetiopathogenesis of neurovascular changes in diabetic neuropathy, elucidated in animal studies, and on putative therapeutic targets the majority of which have yet to be tested for efficacy in clinical trials.

More co-morbid depression in patients with Type 2 diabetes with multiple complications. An observational study at a specialized outpatient clinic.

AIMS: The impact of depression on patients with chronic medical illnesses such as diabetes is well documented. Depression is relatively common in diabetes patients with diabetes-related complications and they are more likely to be referred to specialized outpatient facilities. Only a few studies have addressed the association between depression and multiple diabetes-related complications at these specialized outpatient facilities. The aim of this study was to determine the association between diabetes with multiple complications and depression in patients with Type 2 diabetes at a specialized outpatient clinic. METHODS: After giving informed consent, 1194 patients were screened for depression using the Patient Health Questionnaire (PHQ-9). Additional data on the type of diabetes and complications were taken from the medical records. Logistic regression analysis was conducted, with complications as the predictor variable and the probability of depression as the dependent variable. RESULTS: A total of 596 (63%) patients with Type 2 diabetes participated in the study. The presence of two or more complications (OR 2.23, 95% CI 1.02­2.94) was significantly associated with depression. Neuropathy (OR 1.7, 95% CI 1.10­2.77) and nephropathy (OR 1.68, 95% CI 1.00­2.48) were especially related to depression. CONCLUSIONS: Patients with Type 2 diabetes with two or more complications, especially neuropathy or nephropathy, are at high risk of depression. Knowing this can help clinicians identify patients at risk for depression and facilitate timely and adequate treatment.

Growth hormone and selective attention: a review.

INTRODUCTION: The relation between growth hormone (GH) secretion and general cognitive function has been established. General cognitive functioning depends on core functions including selective attention, which have not been addressed specifically in relation to GH. The present review addresses current insights about specific effects of growth hormone deficiency (GHD) on varieties of selective attention, as well as effects of GH suppletion. MATERIALS AND METHODS: Studies investigating relationships between GH status and valid measures of selective or divided attention were reviewed. RESULTS AND DISCUSSION: There are no indications that GHD is characterized by impaired attribute selection, interference control, or attentional switching. In contrast, a few studies point to a deficit in integrated processing of multiple dimensions, as well as speed of information processing. There is also weak evidence for beneficial effects of GH replacement in the opposite direction in these domains. CONCLUSIONS: The function of integrated processing of multiple stimulus dimensions may be based on neural mechanisms in the anterior cingulate cortex and its extensive connections to the hippocampus, the latter being known to be rich in GH receptors.

Effects of growth hormone substitution therapy on cognitive functioning in growth hormone deficient patients: a functional MRI study.

Patients with childhood-onset growth hormone (GH) deficiency (GHD) show impairments in mood and cognitive functioning which may resolve following GH substitution. Brain functional magnetic resonance imaging (fMRI) during performance of a memory task was used to assess the cerebral activity of such patients. Thirteen childhood-onset GHD patients (mean age 27.3 +/- 6.9 years) were included in a double-blind, placebo-controlled study. The effects of 6 months of GH replacement or placebo therapy were studied using neuropsychological tests and fMRI. One patient was excluded from the study due to noncompliance with the protocol. Six months of GH substitution in these GHD patients resulted in improved memory functioning, both for long-term and working memory. fMRI showed activations during the working memory task in prefrontal, parietal, motor, and occipital cortices, as well as in the right thalamus and anterior cingulate cortex. Decreased activation in the ventrolateral prefrontal cortex was observed after GH treatment as compared with placebo treatment, indicating decreased effort and more efficient recruitment of the neural system involved. It can be concluded that GH treatment for 6 months improved the long-term as well as the working memory in patients with GHD, and this was associated with decreased brain activation in the ventrolateral prefrontal cortex. GH substitution in GHD patients is beneficial for cognitive functioning, the effects of which can be visualized by means of neuroimaging.

Effect of obesity and morbid obesity on the growth hormone (GH) secretion elicited by the combined GHRH + GHRP-6 test.

OBJECTIVE: Obesity is characterized by low basal levels of growth hormone (GH) and impeded GH release. However, the main problem arises in the diagnosis of GH deficiency in adults, as all accepted cut-offs in the diagnostic tests of GH reserve are no longer valid in obese subjects. In this work, the role of obesity in the GH response elicited by the GHRH + GHRP-6 test was assessed in a large population of obese and nonobese subjects. PATIENTS: GHRH + GHRP-6-induced GH peaks were evaluated in 542 subjects. One hundred and five were healthy obese, 50 were morbid obese, and 261 were nonobese (both normal weight and overweight). One hundred and seventy-six GH-deficient patients (obese and nonobese) were also studied. RESULTS: A regression analysis of the 366 subjects with normal pituitary function indicated that adiposity had a negative effect on the elicited GH peak (r = -0.503, P < 0.0001). A receiver operating characteristic (ROC) curve analysis showed that in subjects with a BMI < or =35, the currently accepted cut-offs of the GHRH + GHRP-6 test (GH peaks > or =20 microg/l: normal secretion; GH peaks < or =10 microg/l: GH deficiency), were fully operative. However, in subjects with a BMI > 35, normality was indicated by GH peaks > or =15 microg/l and GH deficiency by peaks < or =5 microg/l (1 microg/l = 2.6 mU/l). CONCLUSIONS: This study confirms: (a) that the combined provocative test is adequate to separate normal and GH-deficient subjects; (b) the negative effect of obesity on GH secretion; (c) that obesity accounts for 25% of the reduction of GH release; and (d) that present cut-off values are applicable to normal weight, overweight and grade I obesity subjects, whereas in obese subjects with a BMI exceeding 35, all the normative limits of the GHRH-GHRP +6 test must be reduced by 5 microg/l.

Growth hormone deficiency and memory functioning in adults visualized by functional magnetic resonance imaging.

Cognitive functioning, especially memory performance, is known to be impaired in patients with childhood-onset growth hormone deficiency (CO-GHD), and growth hormone substitution has been found to counteract this memory impairment. Neuropsychological and functional magnetic resonance imagining (fMRI) data acquired during a working memory task in 13 childhood-onset GH-deficient patients were compared with 13 age, sex and education level matched healthy controls. Results demonstrated that there is no difference in the quality of the performance in the working memory task between GH-deficient patients and control subjects. However, memory speed was found to be subnormal in patients. Concerning mood, patients reported more complaints of fatigue, and less vigor. Imaging data showed that patients had increased activity in dorsolateral/ventrolateral prefrontal cortex, anterior cingulate cortex, parietal cortex, supplementary motor and motor cortex, as well as in the thalamus and precuneus area. Increasing task load was also associated with an increase in brain activity in similar areas in patients compared to control subjects. In conclusion, this fMRI study shows that GH-deficient patients have a subnormal memory speed, but no impaired quality of memory performance, which may be due to compensatory recruitment of dorsal prefrontal brain regions. These findings indicate that the GH-IGF-1 axis contributes to prefrontal functioning in patients with CO-GHD.

The GHRH/GHRP-6 test for the diagnosis of GH deficiency in elderly or severely obese men.

OBJECTIVE AND DESIGN: Ageing and obesity result in decreased activity of the GH/IGF-I axis and concomitant impaired GH responses to secretory stimuli. We therefore determined the validity of the GH cut-off value of 15.0 microg/l in the GH-releasing hormone (GHRH)/GH releasing peptide-6 (GHRP-6) test for the diagnosis of GH deficiency in elderly or severely obese men. METHODS: We performed a combined GHRH/GHRP-6 test in ten elderly men (mean age 74 years; mean body mass index (BMI) 24.6 kg/m(2)), nine obese men (mean age 47 years; mean BMI 40.6 kg/m(2)) and seven healthy male controls (mean age 51 years, mean BMI 24.3 kg/m(2)). After assessment of fasting plasma GH, IGF-I and IGF-binding protein-3 (IGFBP-3), GHRH (100 microg) and GHRP-6 (93 microg) were given intravenously as a bolus injection. Repeated GH measurements were performed for two hours. RESULTS: Both peak GH levels and areas under the curve (AUC) were significantly lower in the obese than in the controls (peak 13.2 vs 53.4 microg/l, P = 0.001; AUC 707 vs 3250 microg/l x 120 min; P = 0.001). Mean GH response in the elderly was lower than in the controls (peak 35.0 microg/l; AUC 2274 microg/l x 120 min), but this was not statistically significant. In contrast, GH peak levels in seven obese men remained below the cut-off level of 15.0 microg/l associated with severe GH deficiency. All others had GH peak levels exceeding this threshold. IGFBP-3 levels were significantly lower in the elderly than in the controls (1.35 vs 2.05 mg/l, P = 0.001). Baseline GH or IGF-I did not differ significantly between groups. CONCLUSIONS: GH responses following GHRH/GHRP-6 administration were significantly reduced in severely obese men, but were not significantly reduced in elderly men, despite a negative trend. Our data indicate that the cut-off GH level of 15.0 microg/l after GHRH + GHRP-6 administration for the diagnosis of severe GH deficiency cannot be used in severely obese men.

Childhood-onset growth hormone deficiency, cognitive function and brain N-acetylaspartate.

Cognitive deficits have been reported in adults with childhood-onset growth hormone (GH) deficiency. We evaluated cognitive deficits simultaneously with parameters for neuronal integrity using (1)H magnetic resonance spectroscopy (MRS) in a cross-sectional design. We studied 11 adults (mean age 24.5 years) with childhood-onset GH deficiency, which persisted after reaching final height. All subjects were evaluated after interruption of GH supplementation for at least 3 months. We performed neuropsychological assessment (NPA) using tests evaluating memory, mental processing speed, reading ability and executive functioning. MRS was used to assess brain N-acetylaspartate (NAA)/choline ratios. Data were compared with an age-, sex- and education-matched control group (n=9, mean age 27.3 years). NPA demonstrated attenuated performance of the patients in the delayed verbal memory recall score (P<0.05) and the trail making A test (P<0.05), a measure of planning of behavior, processing speed and attention. Other neuropsychological tests were not affected. NAA/choline ratios were significantly reduced (P<0.01) in GH deficient subjects. Specific cognitive defects indicating affected memory and attention were found in patients with childhood-onset GH deficiency. These defects occur simultaneously with reduced neuronal integrity.

Neurocognitive function in adults with growth hormone deficiency.

The clinical condition of growth hormone deficiency (GHD) as a consequence of pituitary or hypothalamic disease has been associated with reduced cognitive performance. In several studies, neuropsychological assessment has been performed in adults with GHD both before and after growth hormone (GH) replacement therapy. Interpretation of the available data is complicated by the variation in patient selection as well as the neuropsychological tests used in such studies. Most of the available studies indicate that GHD can lead to small, but clinically relevant changes in memory, processing speed and attention. Some of these changes may be reversed by GH replacement, although the number of reliable intervention studies is limited. In addition to the possible clinical relevance of neuropsychological improvement following GH replacement in patients with GHD, the observed findings may be of interest for studies in neurocognitive performance in other conditions associated with changes in the activity of the somatotrophic axis, and in the understanding of underlying pathophysiological mechanisms.

The role of the somatotropic system in cognition and other cerebral functions.

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) receptors can be found in several areas of the brain. GH receptors are mainly found in the choroid plexus, thalamus, hypothalamus, pituitary, putamen, and hippocampus, whereas IGF-1 receptors are mainly concentrated in the hippocampus and parahippocampal areas. In early life, GH and IGF-1 have an important role in the development and differentiation of the central nervous system. In the more developed central nervous system, GH and IGF-1 are thought to have a variety of functions such as a neuroprotective function, an appetite increasing function, various cognitive functions, and perhaps a blood flow-regulating function. In GH-deficient children and adults, improvement of cognitive functions was observed after the administration of GH. Furthermore, specific cognitive functions in healthy older subjects may improve after increasing GH or IGF-1 levels.

Insulin-like growth factor-I, cognition and brain aging.

Aging is associated with a decline in the activity of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. As aging also coincides with a decline in specific cognitive functions and as some of these dysfunctions are also observed in subjects with GH deficiency, it has been hypothesised that a causal relationship exists between the reduction in circulating GH and/or IGF-I and the observed cognitive deficits in the elderly. The present review summarises the available data concerning the possible relation between GH, IGF-I and cognitive performance, and regarding possible underlying pathophysiological mechanisms.

Upper gastrointestinal responses to intraduodenal nutrient in type 1 diabetes mellitus.

BACKGROUND: Abnormal nutrient-related small-intestinal feedback may contribute to disordered gastric motility and upper gastrointestinal symptoms in patients with diabetes. AIM: To evaluate the motor, sensory and incretin responses to intraduodenal nutrients in patients with type 1 diabetes and in controls. METHODS: Eight type 1 diabetes patients (two with autonomic neuropathy) and nine controls were studied during euglycaemia. A manometric catheter was positioned across the pylorus, and nutrient was infused intraduodenally (90 kcal over 30 min). Blood glucose and plasma glucagon-like peptide 1 and gastric inhibitory polypeptide were measured, and sensations were assessed with visual analogue questionnaires. RESULTS: During nutrient infusion, neither the number of antral waves nor the stimulation of phasic or basal pyloric pressures differed between patients and controls. Upper gut sensations and areas under the plasma incretin peptide curves did not differ between the groups. CONCLUSIONS: During euglycaemia, the upper gastrointestinal motor, sensory and incretin peptide responses to small-intestinal nutrient are comparable in patients with relatively uncomplicated type 1 diabetes and in healthy subjects.

High prevalence of fatigue in quiescent inflammatory bowel disease is not related to adrenocortical insufficiency.

OBJECTIVES: Inflammatory bowel disease (IBD) patients, with active as well as quiescent disease, frequently complain of fatigue. This often has consequences for patients' work and daily lives. The primary aim of this study was to assess the prevalence and severity of fatigue in IBD patients in remission. Furthermore, we studied the correlation between fatigue and disease activity, quality of life, and biochemical and hematological test results, and the role of (secondary) hypocortisolism. METHODS: Eighty subjects with proven IBD were included. Disease activity was assessed using the Clinical Activity Index for Ulcerative Colitis and the Crohn's Disease Activity Index. Quality of life was measured by the Inflammatory Bowel Disease Questionnaire, and fatigue was assessed using the Multidimensional Fatigue Inventory (MFI). Routine biochemical and hematological tests were performed, and basal cortisol was determined. To evaluate adrenocortical reserve in subjects with a cortisol level of <0.4 micromol/L, a low dose adrenocorticotrophin hormone test was performed. Healthy age- and sex-matched subjects (n = 67) served as controls. RESULTS: More than 40% of the IBD patients in remission suffered from fatigue. Mean MFI scores of the IBD patients were comparable to mean MFI scores reported in cancer patients. The Inflammatory Bowel Disease Questionnaire showed a negative correlation with the MFI (r = -0.735; p < 0.001). No correlation was found between fatigue and basal cortisol levels or other laboratory parameters. CONCLUSION: Fatigue is an important feature in IBD in remission, adversely affecting the quality of life. It does not, however, affect all patients, nor does it seem to be the result of hypocortisolism.

Diagnosis of growth hormone deficiency after pituitary surgery: the combined acipimox/GH-releasing hormone test.

OBJECTIVE: Reduction of plasma free fatty acids leads to enhanced GH response after stimulation by GH-releasing hormone (GHRH). We studied the clinical usefulness of combined administration of acipimox and GHRH for the diagnosis of GH deficiency. DESIGN: We evaluated 35 patients [mean age 53.0 years; mean body mass index (BMI) 26.7 kg/m2] after pituitary surgery. We compared GH responses after acipimox and GHRH with the GH response during an insulin tolerance test (ITT) and, in a subgroup of 12 patients, with the GHRH/arginine test. The acipimox/GHRH test was additionally performed in 21 control subjects (mean age 53.8 years; mean BMI 24.7 kg/m2). RESULTS: In the patients, the mean (+/- SEM) peak GH was almost four-fold higher after acipimox/GHRH (6.94 +/- 1.07 microg/l, range 0.46-23.1; P < 0.001) and after GHRH/arginine (8.32 +/- 1.23 microg/l, range 1.1-49.2; P < 0.001) than after ITT (1.84 +/- 0.46 microg/l, range 0.01-11.9). According to the ITT, 29 patients were severely GH deficient (peak GH < 3.0 microg/l). Peak GH levels after acipimox/GHRH in controls ranged from 7.5 to 78.4 microg/l (mean 29.3 +/- 3.5). GH peak values during the acipimox/GHRH test were significantly correlated with values from the ITT (r = 0.63, P < 0.01) and GHRH/arginine test (r = 0.87, P < 0.001). Areas under the curve were also correlated. According to generally accepted cut-off peak GH levels for the ITT and GHRH/arginine test, a GH peak exceeding 11.2 micro g/l excludes severe GH deficiency after acipimox/GHRH. Our control data indicate that the cut-off level is lower at older age. CONCLUSIONS: The acipimox/GHRH test leads to GH responses similar to those of the GHRH/arginine test, and to higher peak GH values if compared with the ITT. The acipimox/GHRH test is a potential additional tool to detect GH deficiency in patients with pituitary disease, in particular in patients with a perturbation of fatty acid metabolism.

Sequential ACTH and catecholamine secretion in a phaeochromocytoma.

OBJECTIVE: We describe a patient with an ACTH-producing phaeochromocytoma who initially presented with hypercortisolism and normal catecholamine concentrations, followed by near-normalisation of ACTH secretion and massive catecholamine secretion. In vitro studies were carried out on the tumour to evaluate the interaction between the tumour cells and normal adrenal cortex. METHODS AND RESULTS: A 30-year-old man initially presented with severe hypercortisolism, biochemical evidence of ectopic ACTH production, a tumour in the right adrenal gland without a hyperintense signal on the T2-weighted images at magnetic resonance imaging (MRI) scanning, and normal urinary metanephrine concentrations. After 6 months, ACTH production had almost completely resolved, but the patient developed severe hypertension and excess catecholamines. At repeated MRI-scanning, the T2-weighted images showed a hyperintense signal, in agreement with the diagnosis of phaeochromocytoma. Although the initial T1-weighted images suggested bleeding in the adrenal tumour, no signs of bleeding were observed after surgical removal. The diagnosis of ACTH-producing phaeochromocytoma was histologically and immunohistochemically confirmed. Cultured cell suspensions of the tumour secreted ACTH, which stimulated cortisol production in the ipsilateral adrenocortical cells. CONCLUSION: This case demonstrates that the biological activity of an ACTH-producing phaeochromocytoma can vary significantly in time, which may be the consequence of different stages of tumour differentiation.

Oxidative stress and diabetic neuropathy: pathophysiological mechanisms and treatment perspectives.

Increased oxidative stress is a mechanism that probably plays a major role in the development of diabetic complications, including peripheral neuropathy. This review summarises recent data from in vitro and in vivo studies that have been performed both to understand this aspect of the pathophysiology of diabetic neuropathy and to develop therapeutic modalities for its prevention or treatment. Extensive animal studies have demonstrated that oxidative stress may be a final common pathway in the development of diabetic neuropathy, and that antioxidants can prevent or reverse hyperglycaemia-induced nerve dysfunction. Most probably, the effects of antioxidants are mediated by correction of nutritive blood flow, although direct effects on endoneurial oxidative state are not excluded. In a limited number of clinical studies, antioxidant drugs including alpha-lipoic acid and vitamin E were found to reduce neuropathic symptoms or to correct nerve conduction velocity. These data are promising, and additional larger studies with alpha-lipoic acid are currently being performed.