Does autonomic neuropathy play a role in erythropoietin regulation in non-proteinuric Type 2 diabetic patients?

AIMS: Erythropoietin (EPO)-deficient anaemia has been described in Type 1 diabetic patients with both severe autonomic neuropathy (AN) and proteinuria. This study was aimed at distinguishing between the effects of AN and nephropathy on haemoglobin and EPO levels in Type 2 diabetic patients at an early stage of diabetic nephropathy. METHODS: In 64 Type 2 diabetic patients (age 52 +/- 10 years, duration 10 +/- 9 years) without overt nephropathy and other causes of anaemia or EPO deficit, we assessed cardiovascular tests of AN, 24-h blood pressure (BP) monitoring, urinary albumin excretion rate (UAE), a full blood count, and serum EPO. RESULTS: Although the Type 2 diabetic patients with AN did not show differences in haemoglobin and EPO when compared with patients without AN, the presence of haemoglobin < 13 g/dl was associated with the presence of AN (chi(2)= 3.9, P < 0.05) and of postural hypotension (chi(2)= 7.8, P < 0.05). In a multiple regression analysis including as independent variables gender, body mass index, duration of diabetes, smoking, creatinine, 24-h UAE, 24-h diastolic BP, ferritin, erythrocyte sedimentation rate, and autonomic score, we found that the only variables independently related to haematocrit were autonomic score, ferritin and erythrocyte sedimentation rate. Finally, the physiological inverse relationship between EPO and haemoglobin present in a control group of 42 non-diabetic non-anaemic subjects was completely lost in Type 2 diabetic patients. The slopes of the regression lines between EPO and haemoglobin of the control subjects and the Type 2 diabetic patients were significantly different (t = 14.4, P < 0.0001). CONCLUSIONS: This study documents an early abnormality of EPO regulation in Type 2 diabetes before clinical nephropathy and points to a contributory role of AN in EPO dysregulation.

Osteoporosis and anorexia nervosa: relative role of endocrine alterations and malnutrition.

BACKGROUND AND AIM: Anorexia nervosa (AN) is a psychiatric disorder characterised by self-induced starvation or a very reduced caloric intake, and frequently by severe life-threatening protein calory malnutrition. Its physiological consequences include amenorrhea, estrogen deficiency and osteoporosis. Osteoporosis may develop as a consequence of a lack of estrogens, low calcium or vitamin D intake, hypercortisolemia or the duration of the illness. The aim of this study was to identify the best endocrinological and nutritional indicators of bone density. SUBJECTS AND METHODS: The study involved 49 young females with AN and malnutrition and 24 age-matched normal controls in whom AN had been excluded on the basis of a clinical evaluation using DSM IV criteria. We studied bone density in early osteopenia, a condition in which the potential risk of fractures is certainly high and traditionally related to a variety of endocrinological and nutritional factors. RESULTS: Bone density was significantly lower in the AN than the control group in all of the examined bone districts: bone mineral density (BMD) spine 0.89 +/- 0.19 vs 1.27 +/- 0.2 (p<0.0001), BMD neck 0.75 +/- 0.14 vs 1.08 +/- 0.17 (p<0.001), BMD Ward 0.74 +/- 0.17 vs 1.12 +/- 0.11 (p<0.0001). Non-significant differences were found in the patients who had undergone previous estrogen medication. Body mass index (BMI) correlated with bone density, but caloric and calcium intake were not significant predictors. IGF-1, a known nutritionally dependent trophic bone factor, was significantly reduced in our patients but did not correlate with BMD. Like other authors, we found a close correlation between lean body mass and BMD in neck and spine. Physical exercise, urinary free cortisol osteocalcin and type I collagen-telopeptide (NTX) did not significantly correlate with the degree of osteopenia. CONCLUSIONS: Our data suggest the importance of nutritional factors (particularly lean body mass and BMI) in determining bone mass, and the relatively limited importance of endocrinological factors with the exception of the duration of amenorrhea as an indirect indicator of endocrinological status.

Pattern of abnormal tangential forces in the diabetic neuropathic foot.

OBJECTIVES: The role of tangential stress in neuropathic foot ulceration is yet unknown. The aim of this study was to investigate the tangential forces developed during gait by the whole foot and by selected subareas of it, namely the heel, the metatarsals and the hallux. METHODS: 61 diabetic patients have been evaluated: 27 without neuropathy, 19 with neuropathy and 15 with previous neuropathic ulcer. The patients were compared with 21 healthy volunteers. A piezo-dynamometric platform was used to measure the three components of the ground reaction force under the total foot and the selected subareas. RESULTS: A significant reduction was observed for the forward peak and the backward peak of the anteroposterior ground reaction force component measured under the whole foot. Patients with previous neuropathic ulcer showed a significant increase of the mediolateral stress under the metatarsals. CONCLUSIONS: Tangential stress is altered in diabetic neuropathic patients; the increased mediolateral component suggests that tangential stress could have a role in the high risk of recurrence observed in patients with previous ulceration. RELEVANCE: To assess the effectiveness of a non-invasive methodology for the estimation and the monitoring of significant alterations of the tangential stress with the increase of neuropathy.

Urinary mevalonate excretion rate in type 2 diabetes: role of metabolic control.

An increased cholesterogenesis has been described in obese dyslipidemic type 2 diabetic patients and in a small number of patients with poor glucose control. So far, it is not clear if increased cholesterogenesis in type 2 diabetes is related to the degree of glycemic control or depends on the commonly associated dyslipidemia or both. Therefore, the aim of the present study was to investigate the relationships among cholesterogenesis and degree of metabolic control in a group of non-obese normolipidemic type 2 diabetic patients. Fifty four (25 men and 29 postmenopausal women) non-obese type 2 diabetic patients with cholesterol and triglyceride plasma levels, respectively, below 6.40 and 2.85 mmol/l and 20 normal subjects matched for age and sex were studied. Endogenous cholesterol synthesis was evaluated by the determination of 24-h urinary mevalonate excretion (MVA). In the diabetic group the mean glycated hemoglobin was 8.47+/-2.2% (range 4.6-14.6%), the mean total cholesterol, triglycerides, HDL and LDL cholesterol were, respectively, 4.86+/-0.7, 1.64+/-0.5, 1.19+/-0.3 and 2.87+/-0.7 mmol/l. The mean 24-h MVA urine excretion rates were 1.41+/-0.3 micromol/24 h in control subjects and 1.66+/-0.7 micromol/24 h in diabetics (P=0.05). In diabetics, urinary mevalonate excretion was significantly correlated with glycated hemoglobin concentrations (HbA(1c)) (r=0.65; P=0.0001) and body mass index (BMI) (r=0.33; P=0.009). In the multivariate analysis both HbA(1c) and BMI were independent predictors of urinary mevalonate. These data demonstrate that lower the degree of blood glucose control, higher is the whole body cholesterol production even in the absence of overt dyslipidemia. In conclusion, the relationship between mevalonate excretion rate and glycated hemoglobin gives further weight to the importance of intensive blood-glucose control in diabetic disease and adds a new element to the list of potentially atherogenic factors strictly related to hyperglycemia in type 2 diabetic patients.

Carotid intima-media thickness in patients with Type 2 diabetes and hypercholesterolemia.

Both patients with Type 2 diabetes mellitus (T2DM) and with hypercholesterolemia have a more extensive and accelerated atherosclerosis with higher common carotid artery intima-media thickness (CIMT) values than the general population. The aim of this study was to compare the CIMT in polygenic hypercholesterolemia (HP; n=41: 30 females and 11 males, aged 52+/-15 yr) and in T2DM (n=43: 22 females and 21 males, aged 59+/-11 yr), with a duration of disease less than 5 yr and no evidence of coronary heart disease. A control group (C) of 40 sex- and age-matched healthy subjects was studied. We evaluated the CIMT on the far wall of the distal segment of the common carotid arteries on sites free of plaque. The mean of the CIMT measurements (Tmean; 9 on each side) and the maximal CIMT measured (Tmax) were used as the representative values for each subject. Tmax values were 0.96+/-0.2 mm and 0.82+/-0.2 mm in T2DM and HP, respectively, which were significantly higher than C (0.74+/-0.1 mm). Corresponding values of Tmean were 0.8+/-0.1 mm and 0.71+/-0.2 mm, both significantly higher than C (0.68+/-0.1 mm). In HP, both Tmax and Tmean values were positively correlated to age (p=0.0001 and p=0.0001, respectively), body mass index (BMI; p=0.05 and p=0.05, respectively), presence of hypertension (p=0.003 and p=0.0008, respectively) and fibrinogen (p=0.0009 and p=0.001, respectively); Tmean was also correlated to apolipoprotein B (ApoB; p=0.03). The multiple "stepwise" regression analysis revealed fibrinogen and age as the only significant determinants of Tmax and Tmean. In T2DM Tmax and Tmean were positively correlated to age only (p=0.04 and p=0.01, respectively). In conclusion, T2DM patients have a more accelerated atherosclerosis than subjects with HP. This is evident after a short duration of disease, probably for a longer latency period of disease and the presence of multiple risk factors.

Factors determining the 24-h blood pressure profile in normotensive patients with type 1 and type 2 diabetes.

Some controversy still exists about factors involved in the abnormal circadian pattern of blood pressure (BP) in diabetes, while prognostic value of non-dipping condition is being increasingly recognised. This study was aimed at evaluating the relative influence of autonomic neuropathy (AN) and albumin excretion on 24-h BP profile in type 1 and type 2 diabetes. We measured AN cardiovascular tests, 24-h ambulatory BP, and urinary albumin excretion rate (UAE) in 47 type 1 and 34 type 2 normotensive non-proteinuric diabetic patients. In type 1 diabetic patients day-night differences (Delta) in systolic and diastolic BP were lower in those with AN than in those without (3 +/- 9 vs 10 +/- 6%, P < 0.01, and 8 +/- 9 vs 16 +/- 6%, P < 0.001), and in univariate regression analysis they were inversely related to both autonomic score, index of degree of AN (r = -0.61, P < 0.001 and r = -0.65, P < 0.001), and to 24-h UAE (r = -0.39, P < 0.01 and r = -0.46, P < 0.001). In type 1 diabetic patients AN was also associated with lower nocturnal decrease in UAE (patients with AN vs without AN: -37 +/- 214 vs 49 +/- 37%, P < 0.05), and with a stronger relationship between simultaneous 24-h UAE and 24-h BP (for systolic BP patients with AN vs without AN: r = 0.62, P < 0.01 vs r = 0.28, NS). In type 2 diabetic patients Delta systolic BP was reduced in patients with AN compared to those without (4 +/- 7 vs 10 +/- 4%, P < 0.01), and it was related only to autonomic score (r = -0.42, P < 0.01). Using a stepwise regression analysis, in type 1 diabetic patients autonomic score was the variable of primary importance for Delta BP, while in type 2 diabetic patients it was the unique determinant not only of Delta systolic BP but also of 24-h systolic BP. In conclusion, AN is the pivotal factor of blunted nocturnal fall in BP in both type 1 and type 2 diabetic patients. In type 1 diabetic patients AN is associated with attenuated circadian pattern of albuminuria and with a steeper relationship between albuminuria and BP, in type 2 diabetic patients AN is the only factor related to elevated 24-h BP levels. Longitudinal studies are needed to establish the potential role of autonomic dysfunction as a progression promoter for nephropathy and hypertension in type 1 and type 2 diabetes respectively.

Hyperinsulinaemia in offspring of Type 2 diabetic patients: impaired response of carbohydrate metabolism, but preserved cardiovascular response.

AIMS: To investigate the effects of endogenous insulin on haemodynamics in nine offspring of Type 2 diabetic patients (P), compared with 18 subjects without family history of diabetes (C), all with normal glucose tolerance. METHODS: All subjects underwent a 180-min oral glucose tolerance test with continuous blood pressure and ECG recording. Low-to-high frequency ratio (LF/HF), an index of the sympatho-vagal balance, was calculated by heart rate spectral analysis. RESULTS: At baseline, LF/HF correlated with fasting plasma insulin (r = 0.44, P < 0.03) and with insulin/glucose ratio (r = 0.46, P < 0.03). Plasma insulin, basally similar in the two groups, was significantly increased in P (342 +/- 34.2) when compared to C (177.6 +/- 25.2 pmol/l), P < 0.005 from time 30min onward. Blood glucose, also similar at baseline, remained not significantly different in P (5.74 +/- 0.25) vs. C (5.08 +/- 0.27 mmol/l), throughout the study. Diastolic blood pressure significantly decreased in P, but not in C during the first hour of the study. Finally, LF/HF ratio significantly increased in P (2.5 +/- 0.4 vs. C, 1.7 +/- 0.2) during the first hour. CONCLUSIONS: In conclusion, the offspring of Type 2 diabetic patients with normal glucose tolerance display an increased insulin secretion; however, they are not resistant to the haemodynamic effects of insulin, as suggested by the reduction of diastolic blood pressure. This, in turn, may determine a chronic sympathetic activation, which could be involved in the pathogenesis of Type 2 diabetes mellitus.

Inelastic leg compression is more effective to reduce deep venous refluxes than elastic bandages.

BACKGROUND: Deep venous refluxes play an important triggering role for the development of venous leg ulcers. Compression therapy is able to reduce these refluxes depending on pressure and the kind of material being used. OBJECTIVE: To compare the efficacy of compression bandages of varying pressure and material (elastic, long-stretch versus inelastic, short-stretch bandages, four-layer bandages). METHODS: Venous volume (VV) and venous filling index (VFI) as a quantitative parameter of venous reflux were measured using an airplethysmograph (APG) in a total of 21 patients presenting with venous leg ulcers and deep venous refluxes. Bandage pressure was measured in every experiment. The influence of elastic and inelastic bandages with increasing pressure and the changes in these parameters using different bandages with the same pressure were investigated. RESULTS: The initial median value of VFI without compression was 8.45 ml/sec. VV and VFI were significantly reduced by increasing external pressure, more strongly with inelastic than with elastic material. With a pressure of 25 mmHg inelastic bandages diminished VFI to a median of 3.25 ml/sec while the elastic material did not even approach this value with a pressure of 40 mmHg (4.25 ml/sec). Applying bandages of different material with the same pressure of 30 mmHg, the most intense reduction of VV and VFI was obtained by inelastic and by four-layer bandages. The effect on venous reflux was statistically significantly superior with inelastic compared to elastic material. CONCLUSION: Using the same bandage pressure, inelastic material is more effective at reducing deep venous refluxes than elastic bandages in patients with venous ulcers. Four-layer bandages show similar efficacy to inelastic bandages.

[Current status of diagnosis of lymphedema--a comprehensive Austrian survey of hospitals and patients]. / Ist-Zustand der Diagnose des Lymphödems--gesamtösterreichische Umfrage an Krankenanstalten und bei Patienten.

By means of two questionnaires sent out to all Austrian hospitals and to lymphedema patients data about diagnostic tools have been collected. The geographic distribution as well as the number of different diagnostic tools were highlighted.

Erythema migrans and serodiagnosis by enzyme immunoassay and immunoblot with three borrelia species.

There is wide divergence of opinion between physicians regarding the use of serological measures for the diagnosis and treatment of erythema migrans, the hallmark of Lyme borreliosis. We studied the outcome of an enzyme immunoassay and immunoblot (Western blot) used on the sera of patients who had suffered tick bite and erythema migrans, and had been subsequently treated with various antibiotics. Ninety-nine consecutive patients presenting with erythema migrans after tick bite were prospectively recruited at the outpatient department of two Vienna City hospitals and at the consultation office for Lyme borreliosis of the Institute of Hygiene. University Vienna. Blood samples were taken before antibiotic treatment and 3 and 6 months thereafter. Blood samples from 100 blood donors served as controls. Antibodies against Borrelia burgdorferi sensu lato were determined by enzyme immunoassay (IgG and IgM EIA) and by IgG immunoblot. The latter was performed with isolates of B. alzelii (H2) B. burgdorferi sensu stricto (Le) and B. garinii (W) from Austrian patients. The 4 interpretation criteria for immunoblot results were: A (3 bands out of 8), B (2 bands out of 9), C and D (1 band out of 6). In all patients, the erythema resolved within the treatment period. No complications secondary to the borrelia infection were registered. After treatment there was no significant change in titre, nor was there a difference in the immunoblot pattern between the first, second and third serum samples. Serum antibodies to B. burgdorferi were positive by EIA in 22.9% (IgG) and 2.5% (IgM). Immunoblot results offered by borrelia species and by the interpretation criteria, ranging between 8.3% (criterion A, strain Le) and 44.2% (criterion D, strain H2). By EIA, control samples were IgG and IgM positive in 5% and 1%, respectively. Positive immunoblot results with strain H2 were found in 9%, 13%, 18%, and 20% by the criteria A through D respectively. After antibiotic treatment of erythema migrans the immunological response appears to be abrogated. Thus, serological results are not supportive for the diagnosis of erythema migrans, not will they retrospectively prove successful antibiotic treatment of borrelia infection.

Neural conduction in visual pathways in newly-diagnosed IDDM patients.

OBJECTIVES: Visual evoked potentials (VEPs) show abnormal responses in newly-diagnosed insulin-dependent diabetic (IDDM) patients. Electrophysiological methods allow one to dissect and explore different structures contributing to neural conduction in the visual pathways. The aim of our work was to assess whether the VEP abnormalities are due to impaired function of the retinal layers and/or a delayed conduction in the postretinal visual pathways. METHODS: Simultaneous recordings of VEP and pattern-electroretinogram (PERG) were performed at two intervals (at entry of the study and after 3 months) in 14 newly-diagnosed IDDM patients (age: 24.8+/-6.8 years; duration of disease: 3+/-1.5 months), and in 14 age-matched control subjects. RESULTS: In comparison with control subjects, IDDM patients showed: VEP P100 latencies significantly delayed (P < 0.01), a significant impairment of all PERG parameters (P < 0.01) and retinocortical time (RCT, difference between VEP P100 and PERG P50 latencies) and latency window (LW, difference between VEP N75 and PERG P50 latencies) also significantly increased (P < 0.01). All electrophysiological parameters were not significantly changed when retested after 3 months. No correlations were found between VEP P100 latency, RCT, LW and PERG parameters. CONCLUSIONS: Impaired PERG indicates an involvement of the innermost retinal layers; increased values of RCT and LW represent an index of delayed neural conduction in the postretinal visual pathways. Therefore two sources, one retinal (impaired PERG) and one postretinal (delayed RCT and LW), may independently contribute in to the abnormal responses of VEP observed in newly-diagnosed IDDM patients. Three months of relatively-stable metabolic control have not normalized the VEP and PERG impairment.

Apolipoprotein E genotype and cholesterogenesis in polygenic hypercholesterolemia.

We studied 22 normal-weight patients with polygenic hypercholesterolemia (PH), of which 11 (two males and nine females) had the apolipoprotein (apo) E3/4 genotype and 11 (one male and 10 females) the E3/3 genotype. The two groups were comparable for age, body mass index, total and low-density lipoprotein (LDL) cholesterol levels. The diagnosis of PH was made on the basis of clinical assessment, the criteria being type IIa hypercholesterolemia without tendon xanthomas and/or family history and clinical criteria indicative of familial hypercholesterolemia and/or familial combined hyperlipidemia. To avoid the influence of the habitual individual diet on cholesterogenesis, daily urinary mevalonic acid (MVA) excretion, an index of whole-body cholesterol synthesis, was evaluated in the steady-state condition while patients were on a low-fat, low-cholesterol diet for at least 3 months. Urinary MVA excretion rates were 2.52 +/- 0.8 micromol/24 h in E3/4 patients, significantly higher (P < .001) than in E3/3 patients (1.38 +/- 0.6 micromol/24 h). This is the first evidence of a higher rate of cholesterogenesis in PH patients carrying the epsilon4 allele versus the epsilon3 allele under a standardized lipid-lowering diet. We conclude that the higher rate of cholesterogenesis in PH patients with the epsilon4 allele might partly explain the interindividual differences in response to treatment with cholesterol synthesis inhibitors such as statins.

Diagnosis of cardiovascular autonomic neuropathy in diabetes.

The utility of standard cardiovascular tests for diagnosis of cardiac autonomic neuropathy in diabetes has been well documented. Attention must be paid to standardizing the procedure with regard to time of day, metabolic status, distance from meal and insulin, coffee and smoking avoidance, and patient's collaboration. In the presence of cardiovascular disease or drugs affecting the cardiovascular or autonomic nervous system, some caution is needed in interpreting the results. More recent reflex tests, which evaluate mainly sympathetic or baroreflex activity, despite their ability to detect early autonomic involvement, lack sufficient standardization and still need to be proved as valid alternatives. Of the different methods of measuring heart rate variability, spectral analysis has a greater ability to differentiate vagal and sympathetic modulation of heart rate than do time-domain methods. However, since these latter methods are easier and more widely available, they can be used as a screening approach. Twenty-four-hour evaluation of heart rate variability provides data on the circadian rhythm of sympathovagal activity, which can be affected earlier than and differently from cardiovascular reflex tests. Information obtained could have prognostic implications in terms of cardiovascular morbidity and mortality and offer therapeutic opportunities. However, a wide consensus on many technical aspects of both time-domain and frequency-domain methods is needed. Furthermore, large prospective studies in the diabetic population to assess the prognostic value of 24-h heart rate variability parameters on cardiovascular morbidity and mortality are lacking. Recently, I123 meta-iodobenzylguanidine (MIBG) scintigraphy has documented abnormalities of sympathetic myocardial innervation also in newly diagnosed IDDM. The meaning of this finding, whether it is an expression of functional or structural defects, needs to be clarified. Preliminary data point to a possible pathogenetic meaning of the known association between autonomic neuropathy and other diabetic complications. This area of investigation could provide useful insights into the complex and multifactorial pathogenesis of diabetic complications.

Contribution of central neuropathy to postural instability in IDDM patients with peripheral neuropathy.

OBJECTIVE: To evaluate the contribution of central neuropathy on postural impairment observed in diabetic patients with peripheral neuropathy. RESEARCH DESIGN AND METHODS: Central sensory and motor nervous propagation, nerve conduction velocity, and static posturography were assessed in the following age-matched subjects: 7 IDDM patients with peripheral neuropathy (group DN), 18 IDDM patients without peripheral neuropathy (group D), and 31 control subjects (group C). Somatosensory-evoked potentials (SEPs) during tibial nerve stimulation were recorded, and the spine-to-scalp sensory central conduction time (SCCT) was evaluated. Motor-evoked potentials (MEPs) were recorded from leg muscles during magnetic transcranial brain stimulation, and the scalp-to-spine motor central conduction time (MCCT) was evaluated. The following posturographic parameters were calculated from the statokinesigram: trace length, trace surface, velocity of body sway with its standard deviation, and VFY (a parameter derived from the velocity variance and the anteroposterior mean position of the body). RESULTS: SCCT was significantly higher in the DN group than in the C and D groups (P < 0.001). MCCT was similar in all groups. Posturographic parameters were all significantly impaired in the DN group (P < 0.01). While posturographic parameters showed a direct relationship with some parameters of peripheral nerve conduction, no correlations were observed with SEP and MEP central conduction time. These results were also confirmed by logistic regression, which indicates peripheral neuropathy as the only implicating factor in postural instability (odds ratio 0.22, 95% CI 0.07-0.75) after data reduction by means of factor analysis. CONCLUSIONS: Although diabetic patients with peripheral neuropathy show a delay in central sensory conduction, postural instability may be fully explained by the presence of peripheral neuropathy.

Electrophysiological assessment of visual function in IDDM patients.

Various electrophysiological tests have been employed to reveal functional abnormalities at different levels of the visual system in insulin-dependent diabetic (IDDM) patients. The aim of our work was to assess, with a comprehensive neurophysiological protocol evaluating the retinal, macular and visual pathways functions, whether and when such electrophysiological abnormalities do appear in IDDM patients free of any fluorangiographic sign of retinopathy with various disease duration. Flash-electroretinogram (ERG), oscillatory potentials (OPs), pattern-electroretinogram (PERG), and visual evoked potentials (VEPs) in basal condition and after photostress were assessed in 12 control subjects (C) and 42 aged-matched IDDM patients without clinical retinopathy (DR-) divided, on the basis of the disease duration, into 4 groups (1-5, 6-10, 11-15, 16-20 years). In addition another age-matched group of IDDM patients with a background retinopathy (DR+; n = 12; duration of disease 18 +/- 49 years) was evaluated. In all IDDM DR-patients PERG and VEP were significantly impaired. In addition, groups 11-15 and 16-20 years displayed impaired OPs. All electrophysiological parameters were further impaired in DR+ patients. In conclusion, retinal, macular and visual pathways functions are differently impaired in IDDM (DR-) patients with different disease duration. Electrophysiological impairment starts in the nervous conduction of the visual pathways with an early involvement, goes on in the innermost retinal layers and in the macula and ends in the middle and outer retinal layers.

Plasma mevalonate concentrations in uremic patients.

Mevalonic acid (mevalonate or MVA), is an obligate precursor in the biosynthetic pathway of cholesterol. It is partially metabolized by the kidneys and its plasma concentrations are an index of endogenous cholesterol synthesis. The aim of the present study was to evaluate plasma MVA concentrations in uremic patients with different degrees of chronic renal failure (CRF; group A), and the effects of a single hemodialysis treatment on plasma MVA in a group of patients with end-stage renal disease (ESRD; group B). CRF patients exhibited a higher mean basal mevalonate concentration (13.3 +/- 6.5 ng/ml) than control subjects (4.68 +/- 1.32 ng/ml; P < 0.001). A statistically significant direct correlation was evident in CRF patients between mevalonate and creatinine plasma levels (r = 0.86; P < 0.001). A single hemodialysis treatment was associated with a significant reduction of plasma mevalonate concentrations four hours after the hemodialysis session (-57%; P < 0.001) and an increase up to the basal values 24 hours after the end of the treatment. In conclusion, our results demonstrated: (i) higher plasma MVA concentrations in patients with decreased renal function; (ii) a direct relationship between plasma MVA levels and the degree of kidney failure as expressed by creatinine plasma concentrations; and (iii) a clear cut reduction of elevated plasma MVA levels after a single hemodialysis treatment.

Autonomic neuropathy: clinical and instrumental findings.

The development of sensitive techniques evaluating functions under autonomic control has allowed the early detection of widespread abnormalities in diabetes mellitus. However, despite a high frequency of functional abnormalities, an overt clinical syndrome develops slowly and is quite rare. Characteristic clinical features, more recent methods for evaluating autonomic function, diagnostic procedures, and main instrumental findings in a diabetic population are reported. Emphasis is given to more promising techniques evaluating autonomic control of the cardiovascular system, such as myocardial scintigraphy and assessment of 24-h blood pressure and heart rate variability. The clinical meaning of the number of functional abnormalities observed in diabetic patients is considered. While the role of autonomic neuropathy in the pathogenesis of gastrointestinal motor disorders, hypoglycaemia unawareness or diabetic impotence needs to be revised, the importance of autonomic-related sweating and blood flow abnormalities in the pathogenesis of diabetic foot lesions is now better documented. Moreover, growing evidence of the importance of autonomic control of cardiovascular system, together with cardiovascular dysfunction linked to diabetic autonomic neuropathy, supports the hypothesis of a possible role of autonomic neuropathy in the increased cardiovascular morbidity and mortality observed in diabetic patients.

Autonomic neuropathy and cardiovascular risk factors in insulin-dependent and non insulin-dependent diabetes.

In 97 IDDM and 64 NIDDM patients aged under 65 years, we evaluated the relationship between autonomic neuropathy (AN) and retinopathy, nephropathy, glycemic control and cardiovascular risk factors. Diabetes duration and HbA1 were significantly higher and body mass index was significantly lower in IDDM patients with AN compared to those without. In NIDDM only age was significantly higher in neuropathic patients. AN was associated with retinopathy in both IDDM (chi2 = 10, P < 0.03) and NIDDM patients (chi2 = 14, P < 0.007), while only in IDDM albumin excretion was significantly higher in patients with AN. Blood pressure (BP) was significantly higher in both IDDM and NIDDM patients with AN compared to those without. There were no differences in smoking and serum lipids between patients with and those without AN. We performed a multiple regression analysis using autonomic score, index of cardiovascular tests impairment, as the dependent variable and age, diabetes duration, body mass index, HbA1, albumin excretion, cholesterolemia, triglyceridemia, systolic BP, and retinopathy as independent variables. With this model in IDDM autonomic score was only related to body mass index (r = -0.29, P < 0.05), to HbA1 (r = 0.46, P < 0.001), and to systolic BP (r = 0.24, P < 0.05), while in NIDDM it was only related to systolic BP (r = 0.54, P < 0.001). In conclusion, AN was related to age in NIDDM, and to diabetes duration and glycemic control in IDDM. AN was associated with retinopathy, with nephropathy (only in IDDM), and with BP levels, but not with dyslipidemia, smoking, or obesity. Excess mortality rate observed in diabetic AN cannot be referred to an association with cardiovascular risk factors.