Zofia Radikova

High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail

Aims/hypothesisA heavily polluted area of Eastern Slovakia was targeted by the PCBRISK cross-sectional survey to search for possible links between environmental pollution and both prediabetes and diabetes.MethodsAssociations of serum levels of five persistent organic pollutants (POPs), namely polychlorinated biphenyls (PCBs), 2,2′-bis(4-chlorophenyl)-1,1-dichloroethylene (p,p′-DDE), 2,2′-bis(4-chlorophenyl)-1,1,1-trichloro-ethane (p,p′-DDT), hexachlorobenzene (HCB) and β-hexachlorocyclohexane (β-HCH), with prediabetes and diabetes were investigated in 2,047 adults. Diabetes and prediabetes were diagnosed by fasting plasma glucose in all participants and by OGTT in 1,220 compliant participants.ResultsOur population was stratified in terms of individual POPs quintiles and associations between environmental pollution, prediabetes and diabetes were investigated. Prevalence of prediabetes and diabetes increased in a dose-dependent manner, with individuals in upper quintiles of individual POPs showing striking increases in prevalence of prediabetes as shown by OR and 95% CI for PCBs (2.74; 1.92–3.90), DDE (1.86; 1.17–2.95), DDT (2.48; 1.77–3.48), HCB (1.86; 1.7–2.95) and β-HCH (1.97; 1.28–3.04). Interestingly, unlike PCBs, DDT and DDE, increased levels of HCB and β-HCH seemed not to be associated with increased prevalence of diabetes. Nevertheless, individuals in the 5th quintile of the variable expressing the cumulative effect of all five POPs (sum of orders) had a more than tripled prevalence of prediabetes and more than six times higher prevalence of diabetes when compared with the 1st referent quintile.Conclusions/interpretationIncreasing serum concentrations of individual POPs considerably increased prevalence of prediabetes and diabetes in a dose-dependent manner. Interaction of industrial and agricultural pollutants in increasing prevalence of prediabetes or diabetes is likely.

Heart rate variability and catecholamines during hypoglycemia and orthostasis.

The low frequency component of heart rate variability (HRV) is believed to be affected by sympathetic activity, but an evidence for this suggestion remains controversial. This study analyzed association between HRV and plasma catecholamines in response to two distinct conditions activating sympathetic nervous system. Changes in HRV were analysed from ECG recording and plasma norepinephrine and epinephrine levels were measured in response to head-up tilt (60 degrees, 10 min) in 14 healthy volunteers (6 males, mean age 27.2+/-0.8) and in response to insulin-induced hypoglycemia (0.1 IU per kg, i.v. bolus) in 11 healthy volunteers (5 males, mean age 26.6+/-0.9 yr). Normalized low frequency power, low/high frequency ratio, plasma catecholamines increased, whereas normalized high frequency power decreased in response to head-up tilt or hypoglycemia. When analyzed individual time points of orthostatic test, plasma epinephrine correlated positively with low/high frequency ratio and negatively with normalized high frequency at the 3rd min of the head-up tilt. When all data at different time points were pooled significant correlations were found between catecholamines and normalized low frequency power and low/high frequency ratio. In insulin-induced hypoglycemia test plasma epinephrine correlated negatively with normalized high frequency power at the 30th minute. When all data measured at different time points were pooled no significant correlation was found between plasma catecholamines and HRV parameters. In conclusion, the present study shows an increase in low frequency component of HRV in response to orthostasis or hypoglycemia with significant, however inconsistent association to changes in plasma catecholamines.

Comparison of salivary cortisol and calculated free plasma cortisol during low-dose ACTH test in healthy subjects

OBJECTIVES To compare free plasma cortisol (FPC) with salivary and calculated cortisol. DESIGN AND METHODS FPC, salivary cortisol, free cortisol index (FCI), albumin-derived free cortisol index (FCIalb), Coolens and Dorins cortisol were assayed during repeated low-dose ACTH test in healthy women. RESULTS FPC significantly correlated with its surrogates, the most with FCIalb and salivary cortisol. FPC and salivary cortisol showed the highest method agreement. CONCLUSIONS FCIalb and salivary cortisol are preferred surrogates of FPC.

An endocrinologist's view on relative adrenocortical insufficiency in rheumatoid arthritis

The concept of relative adrenal insufficiency (RAI) has been originally introduced to describe a situation in which critically ill patients, without any prior risk or evidence for adrenal insufficiency, have total serum cortisol levels inadequate for the severity of patients’ illness. The concept provided a framework for other disease states, in which higher than normal adrenal function could be expected, such as in chronic inflammation. An intense research in RAI field highlighted some new methodological aspects that significantly improved assessment of adrenal function in chronic illness. Measurement of salivary cortisol may provide additional information on locally available cortisol in target tissues. Low levels of dehydroepiandrosterone (DHEAS) for given age and gender were confirmed as a simple and reliable indicator of decreased adrenal function, even in subjects with normal baseline cortisol or normal corticotropin‐stimulated cortisol response. Combined lower DHEAS and lower baseline cortisol levels could be an example of hypocompetence of adrenocortical function, yet clinically not apparent.

Sympathetic Nervous System Response to Orthostatic Stress in Female Patients with Rheumatoid Arthritis

Sympathoneural and adrenomedullary impairments have been suggested in patients with rheumatoid arthritis (RA). In the present study, sympathoneural and adrenomedullary responses to orthostasis were evaluated in eight female RA patients and in eight matched healthy controls. The testing consisted of sequence of stabilization period in supine position, legs‐up position, orthostasis, and supine position. In each body position, blood samples were drawn and ECG was recorded. Plasma levels of epinephrine (EPI), norepinephrine (NE) and neuropeptide Y (NPY) were measured and sympathoneural activity was evaluated by analysis of heart rate variability (HRV). Higher baseline NE levels were found in RA patients (P= 0.034), without any difference in response to orthostasis between the study groups. Levels of EPI tended to be lower in RA patients in base line (P= 0.053) and in response to orthostasis (P= 0.079). The RA and control groups did not differ in NPY levels or in HRV parameters considered to reflect sympathetic activity. A subtle tendency to decreased adrenomedullary reactivity but no evidence for abnormal sympathetic responses to orthostasis was found in RA females.

An endocrinologist's view on relative adrenocortical insufficiency in rheumatoid arthritis: Annals of the New York Academy of Sciences

The concept of relative adrenal insufficiency (RAI) has been originally introduced to describe a situation in which critically ill patients, without any prior risk or evidence for adrenal insufficiency, have total serum cortisol levels inadequate for the severity of patients’ illness. The concept provided a framework for other disease states, in which higher than normal adrenal function could be expected, such as in chronic inflammation. An intense research in RAI field highlighted some new methodological aspects that significantly improved assessment of adrenal function in chronic illness. Measurement of salivary cortisol may provide additional information on locally available cortisol in target tissues. Low levels of dehydroepiandrosterone (DHEAS) for given age and gender were confirmed as a simple and reliable indicator of decreased adrenal function, even in subjects with normal baseline cortisol or normal corticotropin‐stimulated cortisol response. Combined lower DHEAS and lower baseline cortisol levels could be an example of hypocompetence of adrenocortical function, yet clinically not apparent.

Growth hormone response to different consecutive stress stimuli in healthy men: Is there any difference?

The contribution of growth hormone (GH), released during acute and repeated stressful situations, to the development of stress-related disorders is often neglected. We have hypothesized that the modulation of the GH response to sequential stress exposure in humans depends mainly on the nature of the stressor. To test this hypothesis, we compared GH responses to different stressful situations, namely aerobic exercise, hypoglycemia and hyperthermia, which were applied in two sequential sessions separated by 80–150 min. In addition, administration of the dopaminergic drug apomorphine was used as a pharmacological stimulus. GH responses to submaximal exercise (bicycle ergometer, increasing work loads of 1.5, 2.0 and 2.5 W/kg, total duration 20 min) and hyperthermia in a sauna (80°C, 30 min) were prevented when preceded by the same stress stimulus. Hypoglycemia induced by insulin (0.1 IU/kg intravenously) resulted in a significant GH response also during the second of the two consecutive insulin tests, though the response was reduced. Administration of apomorphine (0.75 mg subcutaneously) or insulin prevented the increase in GH release in response to a sequential bolus of apomorphine, while hypoglycemia induced a significant elevation in GH levels even if applied after a previous treatment with apomorphine. In conclusion, the feedback inhibition of the GH response to a sequential stress stimulus depends on the stimulus used. Unlike in the case of exercise and hyperthermia, mechanisms involved in the stress response to hypoglycemia appear to overcome the usual feedback mechanisms and to re-induce the GH response when applied after another stimulus.

The role of norepinephrine and insulin resistance in an early stage of hypertension.

The interrelationship between activity of sympathetic nervous system and metabolic risk factors in youth with hypertension (HT) has been poorly studied. The aim of our present study was to assess the interrelationship between metabolic risk factors, such as insulin resistance, concentration of plasminogen activator inhibitor (PAI)‐1, and catecholamines in an early stage of HT onset. An oral glucose tolerance test was performed in 17 young males with early‐diagnosed nontreated HT grade 1 and 16 gender‐, age‐, and BMI‐matched normotensive controls. Concentrations of glucose, insulin, epinephrine, norepinephrine, PAI‐1, and plasma renin activity (PRA) were determined in venous plasma. Insulin sensitivity indices (ISIs) proposed by Cederholm, Matsuda, and Gutt were calculated. HT had higher baseline levels of norepinephrine, insulin (P= 0.02), and PAI‐1 (P= 0.04). ISIs were lower in HT subjects (P < 0.001). Baseline concentrations of epinephrine were negatively associated with HDL cholesterol (r=−0.415, P= 0.02), ISI Matsuda (r=−0.361, P= 0.04), ISI Cederholm (r=−0.354, P= 0.04), and ISI Gutt (r=−0.429, P= 0.01), and positively with PRA (r= 0.609, P < 0.0001). Positive association was found between baseline concentrations of norepinephrine and PAI‐1 (r= 0.418, P= 0.02). The sympathetic overactivity, which occurs in the early stage of HT may contribute to reduced insulin sensitivity even in young patients and intensify the undesirable development of metabolic cardiovascular risk factors and progress of the disease.

MNU-induced carcinogenesis of rat mammary gland: Effect of thyroid hormone on expression of retinoic acid receptors in tumours of mammary gland

The rat model of N-methyl-N-nitrosourea (MNU)-induced mammary carcinomas is well-established animal model for breast cancer. This study was carried out to investigate whether hypothyroid (thyroidectomy or PTU treatment) or hyperthyroid status of female rats would affect MNU-induced mammary carcinogenesis with specific focus on both retinoid and rexinoid receptor expression in mammary tumours. Application of PTU before and during MNU-induced mammary gland carcinogenesis yielded in a marked decrease of the number and volume of tumours per animal, however, there was no effect of hypothyroid state in thyroidectomized rats as well as hyperthyroid state concerning the number and volume of tumours. Mammary tumours of in euthyroid group of MNU animals showed that there was no tumour, in which all of subtypes of retinoid and rexinoid receptors were expressed. A different pattern of expression of retinoid or rexinoid receptors was found either in MNU-induced mammary carcinomas in both hypothyroid and hyperthyroid rats.

Increased production of IL-6 and IL-17 in lipopolysaccharide-stimulated peripheral mononuclears from patients with rheumatoid arthritis.

TLR4-mediated inflammatory responses are important for innate immune functions, thus their alterations may participate in the pathogenesis of rheumatoid arthritis (RA). Cortisol is one of the most potent immunomodulatory hormones involved in control of inflammation. In this study, we analyzed TLR4-mediated responses and cortisol effects on the process in peripheral blood mononuclear cells (PBMC) from RA patients. Lipopolysaccharide-stimulated PBMC from 23 female patients and 15 healthy controls were cultured in the presence or absence of cortisol (1 μM) for 24 h. A panel of 17 inflammatory cytokines was analyzed in the cell culture supernatants. Higher (p < 0.05) concentrations of IL-6, IL-17 and MCP-1 were found in lipopolysaccharide-stimulated PBMC from RA patients compared to controls. After normalization of stimulated cytokine secretion to unstimulated cells, a significantly higher (p < 0.05) IL-6 and G-CSF production was found in RA PBMC. Cortisol induced stronger (p < 0.05) suppression of lipopolysaccharide-stimulated secretion of IL-1β, IL-6, IL-17 and G-CSF in RA group compared to controls. The observed higher production of the key inflammatory cytokines by RA PBMC to lipopolysaccharide stimulation supports involvement of TLR4-mediated processes in RA pathogenesis. The higher sensitivity of LPS-stimulated RA PBMC to immunosuppressive effects of cortisol may reflect adaptive processes to chronic inflammation.