Reduced growth hormone secretion after cranial irradiation contributes to neurocognitive dysfunction.

The objective of this study was to investigate the relation between growth hormone (GH) and attentional electro-cortical responses to task-relevant stimuli (N2b), target detections, speed of responding, P300 latencies, and performance on neuropsychological tests in 19 patients who received external beam radiation therapy for brain tumors in adulthood. In addition, we studied the association between IGF-I and activation of the motor cortex responses (lateralized readiness potential, LRP). Brain function was assessed using event-related potentials (ERPs) during a go/no go selective-attention task, including N2b, P300 and selective motor preparation as reflected in the LRP. Correlations were calculated between peak GH levels after a standardized growth hormone-releasing hormone (GHRH)-arginine test, plasma IGF-I, and cognitive functions. We separately studied four patients who were diagnosed with GHD according to the GHRH-arginine test. Performance on WAIS digit span backward and the Rey-Osterrieth complex figure test correlated positively with GH peak. GHD patients performed worse than non-GHD patients on Stroop interference, trail making B/A attentional shifting and Rey-Osterrieth complex figure test. At trend-level significance, trails A performance was better in patients with lower GH levels and higher radiation doses, and GHD participants detected fewer targets in the go/no go selective attention task. N2b was not significantly altered by GH status. Furthermore, plasma IGF-I was positively correlated with the sum of digit span forward and backward. No relations with P300 were observed. In this study only 21% (4/19) of the patients who received fractionated radiotherapy for a non-endocrine brain tumor were diagnosed with GHD. GHD in these patients was associated with impaired interference control, attentional shifting, and visual long-term memory. The results for interference control and attentional shifting suggest an additional effect of the radiation history.

Cognitive performance in older males is associated with growth hormone secretion.

Decreases in GH secretion with age may contribute to cognitive changes associated with aging. We evaluated the relation between GH secretion and cognition in elderly males by assessing correlations between GH secretion and performance on cognitive tests in conjunction with recording of event-related potentials (ERPs) to assess underlying neurophysiological mechanisms. GH secretion of 17 elderly male participants was assessed by a GHRH-GHRP-6 test. Standardized neuropsychological tests were used to assess cognitive function. EEG/ERPs were recorded to assess on-line electrocortical correlates of sensory-cortical processing and selective attention. GH secretion was significantly correlated with target detections and speed of responding in the selection-potential task. Furthermore, GH peak was significantly correlated with the performance letter-digit span test. The present data confirm that cognitive performance in elderly males is associated with GH secretion, with respect to target detection and speed of responding in conditions of selective attention, short-term memory, and basic processing speed.

alpha-Tocopherol levels in plasma in new-onset, insulin-dependent diabetes mellitus.

BACKGROUND: Diabetic complications have been related to increased oxidative stress. Plasma antioxidant levels may be affected by hyperglycemia-induced oxidative stress as well as by insulin therapy. We evaluated the immediate effect of insulin treatment and improved metabolic control on the important antioxidant alpha-tocopherol plasma (vitamin E) levels in new-onset, insulin-dependent diabetes mellitus. METHODS: The study was performed in 15 consecutive patients, aged 20-67 years, with new-onset diabetes mellitus requiring acute insulin treatment. Plasma alpha-tocopherol levels were measured before the start of intensive insulin treatment and monthly for 6 months thereafter. Simultaneously, we studied plasma malondialdehyde (MDA) as a reflection of lipid peroxidation. In addition, comparisons were made to a nondiabetic reference group. RESULTS: Baseline alpha-tocopherol levels did not differ from those in nondiabetic subjects. alpha-Tocopherol decreased significantly, from 33.5+/-12.1 mumol/l before treatment to 28.11+/-6.85 mumol/l (-16%) after 1 month of insulin therapy (p<0.04) to 26.6+/-7.03 mumol/l (-20%) after 3 months of insulin therapy (p<0.02). This trend did not change after adjusting for variations in cholesterol levels. After 6 months, alpha-tocopherol was no longer decreased compared to baseline levels (29.6+/-7.4 mumol/l). MDA concentrations at baseline were significantly higher in the diabetic patients (3.79+/-2.91 mumol/l) than in the nondiabetic subjects (1.57+/-0.21 mumol/l, p=0.006). MDA concentrations decreased significantly following the start of insulin treatment. CONCLUSIONS: Patients with new-onset, insulin-dependent diabetes mellitus have alpha-tocopherol levels that are similar to those in normal subjects. Insulin treatment and/or improved metabolic control cause a significant decrease in alpha-tocopherol levels during the first months.

[The adrenocortical carcinoma, a tumour of wide clinical diversity]. / Het bijnierschorscarcinoom, een tumor met een grote klinische verscheidenheid.

Over the course of a few years, an obese 52-year-old woman with a 23-year history of hypertension developed a number of abdominal complaints including gall stones. Her blood pressure became increasingly difficult to control and she developed diabetes mellitus and suffered palpitations and headaches. It became noticeable that she had a moon face. Laboratory tests revealed hypercortisolism. CT-scan showed a large inhomogeneous mass of nine centimetres in her left adrenal gland, which was subsequently removed surgically. The histopathological diagnosis was consistent with an adenoma. After a number of months the patient developed bone and liver metastases and the diagnosis was amended to carcinoma of the adrenal cortex. She then underwent radiotherapy and chemotherapy treatment. One year after surgery she developed a pancytopenia and died. Adrenocortical carcinomas are rare tumours with an incidence of about 1-2 cases per million of the population. Symptoms are heterogeneous since both functional (hormonal overproduction) and non-functional (mass effect) tumours exist. Surgical resection is the only curative therapy. It may be difficult to distinguish between benign and malignant cortical tumours.

Somatotropic-axis deficiency affects brain substrates of selective attention in childhood-onset growth hormone deficient patients.

Reduced levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are associated with deteriorated cognitive performance in senescence. Little work has been done on the effect of GH and IGF-1 on a crucial aspect of cognition, selective attention. This study investigated the effect of GH/IGF-1 on performance and brain potentials (EEG) during a selective-attention task in patients with low levels of GH and IGF-1 (childhood-onset growth hormone deficiency) compared to healthy controls. Detection of occasional visual target patterns was impaired in patients. This was paralleled by a reduction in an attention-related brain potential, which has been associated previously with anterior cingulate cortex functioning.

Prevalence of delayed gastric emptying in diabetic patients and relationship to dyspeptic symptoms: a prospective study in unselected diabetic patients.

OBJECTIVE: Data on the prevalence of abnormal gastric emptying in diabetic patients are still lacking. The relation between gastric emptying and dyspeptic symptoms assessed during gastric emptying measurement has not yet been investigated. The aim was to investigate the prevalence of delayed gastric emptying in a large cohort of unselected diabetic patients and to investigate the relation between gastric emptying and gastrointestinal sensations experienced in the 2 weeks before and during the test meal, prospectively. RESEARCH DESIGN AND METHODS: Gastric emptying was evaluated in 186 patients (106 with type 1 diabetes, mean duration of diabetes 11.6 +/- 11.3 years) using 100 mg (13)C-enriched octanoic acid added to a solid meal. RESULTS: Gastric emptying was significantly slower in the diabetic subjects than in the healthy volunteers (T(50): 99.5 +/- 35.4 vs. 76.8 +/- 21.4 min, P < 0.003; Ret(120 min): 30.6 +/- 17.2 vs. 20.4 +/- 9.7%, P < 0.006). Delayed gastric emptying was observed in 51 (28%) diabetic subjects. The sensations experienced in the 2 weeks before the test were weakly correlated with the sensation scored during the gastric emptying test. Sensations assessed during the gastric emptying test did predict gastric emptying to some extent (r = 0.46, P < 0.0001), whereas sensations experienced in the previous 2 weeks did not. CONCLUSIONS: This prospective study shows that delayed gastric emptying can be observed in 28% of unselected patients with diabetes. Upper gastrointestinal sensations scored during the gastric emptying tests do predict the rate of gastric emptying to some extent and sensation experienced during daily life does not.

Small intestinal glucose absorption and duodenal motility in type 1 diabetes mellitus.

OBJECTIVE: Small intestinal glucose absorption is increased in animal models of diabetes mellitus, but little data are available in humans. Small intestinal motility is reported to be frequently abnormal in patients with diabetes and could potentially affect glucose absorption. Our aim was to evaluate small intestinal glucose absorption and duodenal motor responses to intraduodenal nutrients, in patients with type 1 diabetes and controls. METHODS: Eight type 1 patients (two with autonomic neuropathy) and nine controls were studied during euglycemia. A manometric catheter was positioned across the pylorus, and nutrient infused intraduodenally (90 kcal over 30 min), followed by a bolus of 3-O-methylglucose (3-OMG). Blood was sampled to measure glucose and 3-OMG concentrations. RESULTS: During nutrient infusion, the number of duodenal waves did not differ between patients and controls. After the infusion, patients with diabetes had more propagated duodenal wave sequences (p < 0.05). The area under the plasma 3-OMG curve did not differ between the groups but correlated with both the blood glucose concentration at the time of 3-OMG administration (r = 0.64, p < 0.005) and the number of duodenal waves (r = 0.52, p < 0.05) and antegrade propagated duodenal sequences (r = 0.51, p < 0.05) preceding the 3-OMG bolus. CONCLUSIONS: During euglycemia, duodenal motor responses to small intestinal nutrient are comparable in patients with relatively uncomplicated type 1 diabetes and healthy subjects, but duodenal motility after nutrient infusion is increased in patients. Small intestinal glucose absorption is similar in patients and controls, but may be dependent on the blood glucose concentration and duodenal motor activity.

Glutathione and alpha-lipoate in diabetic rats: nerve function, blood flow and oxidative state.

BACKGROUND: Increased oxidative stress is considered to be a causal factor in the development of diabetic complications, among which peripheral neuropathy. The pathophysiology of nerve dysfunction in diabetes has been explained both by reduced endoneurial microcirculation and alterations in endoneurial metabolism. It is unclear whether antioxidants primarily improve nerve blood flow or normalise systemic or endoneurial oxidative metabolism. Therefore, we evaluated the effects of the antioxidants glutathione and alpha-lipoic acid on both nerve microcirculation and the antioxidative capacity and lipid peroxidation in experimentally diabetic rats. MATERIALS AND METHODS: Streptozotocin-diabetic rats were treated with different doses of alpha-lipoic acid, reduced glutathione or placebo, and were compared with nondiabetic controls. We measured systemic and endoneurial antioxidants, malondialdehyde and whole blood hydrogen peroxide. Furthermore, we evaluated sciatic and tibial motor and sensory nerve conduction velocity, caudal nerve conduction velocity, and assessed sciatic nerve blood flow and vascular resistance by Laser-Doppler flowmetry. RESULTS: We observed a rise in erythrocyte glutathione by 27 % (P < 0.05), and a trend towards decreased plasma malondialdehyde in alpha-lipoic acid, but not in glutathione-treated animals in comparison with the placebo group. Simultaneously, sciatic nerve blood flow and vascular resistance were improved by daily alpha-lipoic acid administration by 38% (P < 0.05). Peripheral nerve conduction velocity and endoneurial glutathione were not significantly influenced by antioxidant treatment. CONCLUSIONS: Only minor beneficial effects of alpha-lipoic acid on nerve blood flow and oxidative state occur at the given doses; these effects were insufficient to improve nerve conduction deficits.

Growth hormone, insulin-like growth factor I and cognitive function in adults.

This review focuses on the possible contribution of the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis to cognitive function. Binding sites for GH and IGF-I are found in various areas of the brain. Their distribution suggests that GH and IGF-I contribute to the function of the hippocampus, a brain structure important for the maintenance of cognitive functions such as learning and memory. Evidence for cognitive deficits in GH-deficient individuals has been found in various studies, some of which have shown that these deficits can be reversed by GH substitution therapy. In addition to examining conditions of GH deficiency, this article reviews studies evaluating the correlation between the cognitive deficits associated with ageing and age-related decreases in GH or IGF-I secretion. Based on the available data, one might hypothesize that relative GH or IGF-I deficiency could contribute to the deterioration of cognitive functions observed in the elderly.

[Diabetic peripheral neuropathy: international guidelines for prevention, diagnosis, and treatment]. / Diabetische perifere neuropathie: internationale richtlijnen voor preventie, diagnostiek en behandeling.

Recently, international guidelines for the diagnosis and management of diabetic polyneuropathy were issued. The aim of this initiative was to develop simple and practical guidelines for general practitioners and hospital physicians in day-to-day practice. Regular assessment of peripheral nerve function can be performed in diabetic patients using simple diagnostic tools. In such a way, patients will become more aware of the risks associated with diabetic neuropathy. Early detection of neuropathy and other risk factors for the development of foot ulcers may lead to avoidance of amputations. The guidelines emphasize foot care education of diabetic patients with or without neuropathy and early referral of patients with ulcerations to specialised outpatient foot clinic.

Growth hormone (GH) treatment decreases postprandial remnant-like particle cholesterol concentration and improves endothelial function in adult-onset GH deficiency.

Premature atherosclerosis is a clinical feature in adult-onset GH deficiency. Evidence is accumulating that disturbances in triglyceride metabolism, reflected by abnormalities in circulating remnant lipoproteins, are associated with increased atherogenic potential. In a case-controlled intervention study, we investigated postprandial lipoprotein metabolism using a new remnant lipoprotein method based on immunoseparation principle [RLP-cholesterol (RLP-C)]. In addition, we analyzed retinyl ester (RE) analysis in plasma and in Sf < 1000 fraction. Endothelial function was assessed as flow-mediated dilatation (FMD). Eight patients diagnosed with acquired adult-onset GH deficiency and eight controls matched for gender, age, body mass index, and apolipoprotein (apo) E genotype were enrolled in the study. Oral vitamin A fat loading tests were performed at baseline in both groups and after 6 months of treatment with recombinant human GH (rh-GH) in the adult-onset GH-deficient patients. Adult-onset GH-deficient patients had significantly higher fasting RLP-C, postprandial RLP-C concentrations (plasma RLP-C, 0.29 +/- 0.14 mmol/L; and incremental area under the curve-RLP-C, 2.13 +/- 1.60 mmol*h/L, respectively) than controls (0.19 +/- 0.06 mmol/L and 1.05 +/- 0.72 mmol*h/L (P: < 0.05), respectively). They also had significantly higher postprandial RE in plasma and Sf < 1000 fraction. Treatment with rh-GH significantly reduced postprandial RLP-C concentrations (incremental area under the curve-RPL-C 0.73 +/- 0.34 mmol*h/L; P: < 0.05) but had no effects on the fasting RLP-C concentrations (0.317 +/- 0.09 mmol/L, P: < 0.05), or on the postprandial RE in plasma and in Sf < 1000 fraction. Endothelial function measured as FMD was improved from 5.9 +/- 3.3% to 10.2 +/- 4.0% (P: < 0.05) in patients treated with rh-GH. It is concluded that patients with adult-onset GH deficiency have increased levels of fasting and postprandial RLP-C and an impaired endothelial function as measured as FMD. Treatment with rh-GH resulted in a decrease of postprandial RLP-C concentration, thereby improving the postprandial atherogenic lipoprotein profile and improvement of endothelial function, however, the clearance of large chylomicron particles as reflected by RE remained disturbed.

Reduction of free fatty acids by acipimox enhances the growth hormone (GH) responses to GH-releasing peptide 2 in elderly men.

GH release is increased by reducing circulating free fatty acids (FFAs). Aging is associated with decreased plasma GH concentrations. We evaluated GH releasing capacity in nine healthy elderly men after administration of GH-releasing peptide 2 (GHRP-2), with or without pretreatment with the antilipolytic drug acipimox, and compared the GHRP-2-induced GH release with the response to GHRH. The area under the curve (AUC) of the GH response after GHRP-2 alone was 4.8 times higher compared with GHRH alone (1834 +/- 255 vs. 382 +/- 78 microg/L.60 min, P: < 0.001). Acipimox, which reduced FFAs from 607 micromol/L to 180 micromol/L, increased the GH AUC to 1087 after GHRH and to 2956 microg/L.60 min after GHRP-2 (P: < 0.01). The AUC after acipimox/GHRP-2 were positively correlated with the AUC after GHRP-2 alone (r = 0.93, P: < 0.01); this was also observed between acipimox/GHRH and GHRH alone (r = 0.73, P: = 0.03). Significant negative correlations were observed between basal FFAs and AUC after GHRH or GHRP-2 after combining the data with and without acipimox (r = 0.58, P: = 0.01 and r = 0.48, P: = 0.04, respectively), and between basal FFAs and GH at t = 0 (r = -0.44, P: = 0.001). Interestingly, GHRP-2 administration was followed by a significant early rise in plasma FFAs by 60% (P = 0.01), indicating an acute lipolytic effect. In conclusion, reduction of circulating FFAs strongly enhances GHRP-2-stimulated GH release in elderly men. The data indicate that the decreased GH release associated with aging can be reversed by acipimox and that the pituitary GH secretory capacity in elderly men is still sufficient.

High rat food vitamin E content improves nerve function in streptozotocin-diabetic rats.

Antioxidants can improve nerve dysfunction in hyperglycaemic rats. We evaluated whether the standard supplementation of rat food with vitamin E (normally added for preservation purposes) or high-dose vitamin E treatment improves nerve conduction in maturing streptozotocin-diabetic rats, a model widely used to study diabetic neuropathy. Hyperglycaemic rats received food containing 25 mg/kg (non-supplemented), 70 mg/kg (standard food) or 12 g/kg (high-dose) vitamin E. Non-diabetic controls received non-supplemented food. Sciatic and tibial sensory and motor nerve conduction velocity were decreased in all diabetic animals. In comparison with standard feeding, the non-supplemented diabetic rats showed lower plasma vitamin E levels but no significant change in nerve conduction. High-dose treatment prevented nerve dysfunction by 50%, and led to attenuated endoneurial lipid peroxidation (measured as malondialdehyde). We conclude that high doses of vitamin E, but not standard vitamin E supplementation of rat food partially prevent nerve dysfunction in young adult streptozotocin-diabetic rats.

Mineralocorticoid status and endocrine dysfunction in severe hemochromatosis.

Selective iron deposition in the zona glomerulosa of the adrenal cortex is observed in hemochromatosis. Hypoaldosteronism should be excluded before starting venesection, to avoid long-term volume depletion. We evaluated the aldosterone status in patients with hemochromatosis. As other endocrine organs can be affected by the disease as well, we simultaneously evaluated anterior pituitary, gonadal, thyroid and pancreatic beta-cell activity. Nine patients with hereditary or acquired hemochromatosis and highly increased plasma ferritin levels were investigated. In patients, liver cirrhosis had been confirmed histologically. Five patients complained of sexual dysfunction, and one had impaired glucose tolerance. Plasma aldosterone (PA) and renin activity (PRA) were measured after a period of normal (100 mmol/day) and low (10 mmol/day) sodium intake. A combined anterior pituitary function test and a glucagon stimulation test were undertaken to evaluate other endocrine functions. Both PA and PRA levels were decreased in one patient with liver cirrhosis, who also presented attenuated cortisol, prolactin and gonadotrophin secretion. No patients had signs of primary hypoaldosteronism with hyperreninemia. Hypogonadotropic hypogonadism was observed in 3 males and 1 female. Pituitary ACTH reserve was impaired in 2, GH and prolactin response in 1, and thyroid function in none of the patients. Glucagon-stimulated plasma C-peptide was impaired in one patient. In conclusion, primary aldosterone deficiency was not observed in patients with severe iron overload. Hyporeninemic hypoaldosteronism was found in one patient who also presented other endocrinopathies. Hypogonadotropic hypogonadism is the most frequent endocrine abnormality in hemochromatosis.

Nerve conduction and antioxidant levels in experimentally diabetic rats: effects of streptozotocin dose and diabetes duration.

Oxidative stress supposedly plays a role in the pathogenesis of diabetic neuropathy. We have studied whether a variation in the streptozotocin (STZ) dose or diabetes duration affects the outcome of measurements of oxidative damage in relation to nerve conduction. In experiment 1, we induced diabetes in rats using 40 or 60 mg/kg STZ intravenously and assessed sciatic nerve conduction velocity. After 18 weeks, we measured plasma malondialdehyde (MDA) and red blood cell (RBC) and nerve glutathione levels. We observed a dose-dependent effect of STZ on body weight, and to a lesser extent on nerve conduction, but not on RBC or nerve glutathione and plasma MDA. In experiment 2, we administered a fixed dose of STZ (40 mg/kg) and measured antioxidants and MDA in RBCs, plasma, and sciatic nerve after 2, 4, 8, and 18 weeks in diabetic and control rats. RBC glutathione decreased in diabetic animals initially, but did not differ from control values after week 4. Plasma total glutathione increased until week 8. The ratio of total to oxidized glutathione in the sciatic nerve from diabetic animals paralleled the decrease observed in RBCs, and subsequently increased compared with controls. Nerve catalase increased in diabetic animals. Endoneurial MDA remained unchanged, whereas plasma MDA increased and RBC superoxide dismutase (SOD) decreased in the diabetic group. We conclude that differences in antioxidant levels between STZ-diabetic and control rats depend on the duration of hyperglycemia. Furthermore, dose-related effects of STZ on nerve conduction are not reflected in endoneurial lipid peroxidation or glutathione.

Nerve function and oxidative stress in diabetic and vitamin E-deficient rats.

Nerve dysfunction in diabetes is associated with increased oxidative stress. Vitamin E depletion also leads to enhanced presence of reactive oxygen species (ROS). We compared systemic and endoneurial ROS activity and nerve conduction in vitamin E-depleted control and streptozotocin-diabetic rats (CE- and DE-), and in normally fed control and diabetic animals (CE+ and DE+). Nerve conduction was reduced in both diabetic groups. Vitamin E depletion caused a small further nerve conduction deficit in the diabetic, but not in the control animals. The combination of vitamin E deficiency and streptozotocin-diabetes (group DE-) appeared to be lethal. In the remaining groups, an important rise in sciatic nerve malondialdehyde (MDA) was observed in the vitamin E-depleted control rats. In contrast, plasma MDA levels were elevated in group DE+ only, whereas hydrogen peroxide levels were increased in group CE-. Endoneurial total and oxidized glutathione and catalase were predominantly elevated in group DE+. These data show that nerve lipid peroxidation induced by vitamin E depletion does not lead to reduced nerve conduction or changes in antioxidant concentrations as observed in STZ-diabetes. The marked systemic changes in MDA and antioxidants suggest that nerve dysfunction in experimental hyperglycemia is rather a consequence of systemic than direct nerve damage.

Effects of insulin treatment on endoneurial and systemic oxidative stress in relation to nerve conduction in streptozotocin-diabetic rats.

As increased oxidative stress is probably a pathogenetic factor in the development of diabetic complications, we studied nerve function and endogenous antioxidants in plasma, erythrocytes and sciatic nerve of untreated and insulin-treated streptozotocin-diabetic rats. After 18 weeks, the diabetes-induced sciatic nerve conduction velocity deficits were approximately 65% improved by insulin (P < 0.001). Plasma superoxide dismutase was significantly reduced in diabetes (P < 0.01); smaller decreases in plasma catalase and glutathione levels were observed. These changes were corrected by insulin treatment. In erythrocytes, decreased superoxide dismutase (P < 0.05) and increased total glutathione levels (P < 0.05) were found. All effects of diabetes, including a rise in plasma malonyldialdehyde (P < 0.05), were partially reversed by insulin treatment. In nervous tissue, diabetes caused increased catalase activity, uninfluenced by insulin (P < 0.05). Nerve superoxide dismutase and glutathione did not change. The data suggest that in diabetes, changes in systemic rather than endoneurial oxidative stress lead to nerve dysfunction.

Antihypoxic treatment at an early stage of diabetic neuropathy: an electrophysiological study with sabeluzole.

Thirty-seven non-IDDM patients at an early stage of polyneuropathy, defined as the presence of symptoms for less than two years, as well as an abnormal perception threshold and/or abnormal thermal discrimination threshold, were treated with sabeluzole, a new antihypoxic drug, or placebo for 1 year in a double-blind, placebo-controlled study. They were examined neurophysiologically every 3 months, when motor (tibial, ulnar) nerve and sensory (sural, ulnar) nerve conduction velocities, H-reflex of the soleus muscle, SF-EMG of the anterior tibial muscle, static and dynamic pupillometry were measured. Statistical analysis did not show significant differences in nerve function between the sabeluzole group and the placebo group. There were also no significant changes within each group over the 1-year period. The results of the present study show no beneficial effect of sabeluzole on peripheral nerve function in patients at an early stage of diabetic polyneuropathy.