Biomedical subjects

I Klimes

Publications and source records attributed to I Klimes.

At least 37 records · Page 2Linked to original sources

PubMed2001

Further studies of blood levels of some tumor markers in the area polluted by polychlorinated biphenyls and control population.

The levels of beta2-microglobulin (beta2-m), alpha-fetoprotein (AFP) and thyroglobulin (TG) were measured in the serum of 245 employees of chemical factory formerly producing polychlorinated biphenyls (PCB) consisting of 54 males (age range 24-65 years, median 45) and 191 females (age range 20-69 years, median 45). The control population consisted of 636 adults from control areas of northwest and east Slovakia. The frequency of beta2-microglobulin levels lower than 1.6 microg/ml in 242 employees of chemical factory was 76.8% (186/242) which was three times higher (P<0.001) than 24.4% (155/635) in 636 controls. Still more remarkable difference was obtained when using the cut/off level of 1.2 microg/ml, the frequency of such values in the employees being 45.4% (110/242) vs. 4.4% (28/635) in the controls. In contrast, no difference in alpha-fetoprotein levels was observed between the employees and the controls, the respective frequency of these < 5.0 ng/ml being 87.6% (212/242) vs. 86.2% (389/451) and these < 10.0 ng/ml being 100.0% (242/242) vs. 97.8% (441/451). Similarly, the frequency of normal thyroglobulin levels < 50.0 ng/ml) did not differ, being 95.6% (174/182) in the employees and 87.9% (87/99) in the controls. Most of a total of 20 cases with thyroglobulin level > 50.0 ng/ml showed sonographicaly enlarged and multinodular thyroid with focal or diffuse hypoechogenicity, three of them showed solitary nodule with a diameter > 10 mm. Although the decreased levels of beta2-microglobulin might be somehow related to the modulation of immune system, more plausible explanation appears to be the possible impairment of renal tubules by PCB similar to that caused by heavy metals resulting in increased urinary excretion of beta2-microglobulin and decrease of its blood level.

Adult↗

PubMed2001

Delta-6 desaturase activity and gene expression, tissue fatty acid profile and glucose turnover rate in hereditary hypertriglyceridemic rats.

OBJECTIVE: We have shown previously that the impaired insulin action in hereditary hypertriglyceridemic (hHTg) rat is accompanied by a specific fatty acid (FA) profile in the insulin target tissues, possibly due to a desaturation defect. Thus, the aim of this study was to measure the enzymatic activity and gene expression of delta-6 desaturase in liver of hHTg rats and the tissue FA composition in relation to insulin action. METHODS: Glucose, triglycerides and insulin in plasma were measured using commercially available enzymatic sets. The hepatic delta-6 desaturase activity in hHTg rats was determined radiometrically in a microsomal fraction using the 1-14C-linoleic acid as substrate. delta-6 Desaturase gene expression was measured by the Northern blot technique using a specific cDNA probe. Tissue FA profile was determined by gas chromatography in the total lipid fraction extracted to chloroform. The glucose turnover rate was measured in conscious freely moving animals with the aid of euglycemic hyperinsulinic clamp method. RESULTS: Tissue triglycerides showed a high accumulation in skeletal muscle of hHTg rats. In the liver of these animals, a defect in delta-6 desaturase enzymatic activity was found, while the gene expression for delta-6 desaturase was not changed. Such decreased delta-6 desaturase activity in the liver was linked to a decrease of delta-6 desaturase index as calculated from the liver FA composition. Also the concentration of arachidonic acid (a final metabolite in the biosynthesis of polyunsaturated fatty acids of the n-6 series) was significantly decreased in hHTg rat liver. These changes in FA metabolism were accompanied by a decreased glucose infusion rate (a measure of in vivo insulin action) required to maintain euglycemia at hyperinsulinemia in hHTg rats, and correlated with the hepatic delta-6 desaturase activity. CONCLUSIONS: 1. hHTg rats showed a reduced activity of the delta-6 desaturase in liver without any changes in gene expression for this enzyme; 2. such impairment is accompanied by a lower delta-6 desaturase index (18:2n-6/18:3n-6) found in the liver of these animals and by specific FA profiles in the tissues, particularly regarding the amount of long-chain PUFAs and 18:2n-6 metabolites; and (4) these alterations seem to be related to the impaired insulin action of hHTg rats.

Animals↗

PubMed2000

Effects of new hypoglycemic agent A-4166 on lipolysis and lipogenesis in rat adipocytes.

OBJECTIVE: To test the effects of novel oral hypoglycemic agent A-4166 on lipolysis and lipogenesis in adipocytes from normal rats and non-obese, hypertriglyceridemic, insulin resistant and hypertensive rats (HTG) fed basal or high fat diet. METHODS: Adult male Wistar rats and hereditary HTG rats (from our own colony) were used. They were fed either basal or high fat diet for three weeks. On the day of observation the active substance A-4166 was administered intragastrically by gavage 30 minutes before decapitation. Blood was collected for the determination of insulin, glycemia, non esterified fatty acids (NEFA) by using commercial kits. The isolated adipocytes were prepared from epididymal fat pads and lipolysis (by measurement of glycerol release) and lipogenesis (by estimation of labeled glucose incorporation into lipids) were determined. RESULTS: The administration of A-4166 results in increased serum insulin and decreased serum glucose level in all rats irrespective of the diet. A significant diminution of serum NEFA levels was observed in A-4166 administered Wistar and HTG rats fed high fat diet. In both groups of rats fed basal diet the lipolysis was not affected by A-4166. However, a decrease of lipolysis was found after A-4166 in Wistar rats fed high fat diet. The stimulation of lipolysis by norepinephrine was not influenced by A-4166. A lowered basal lipolysis was found in HTG rats fed high fat diet. The stimulation of lipolysis by norepinephrine was diminished in HTG rats as compared to Wistar animals. Administration of A-4166 did not affect the stimulation of lipolysis by norepinephrine in HTG rats. A decrease of stimulatory action of insulin on lipogenesis was found in Wistar rats fed high fat diet and in all groups of HTG rats. The administration of A-4166 did not change the basal lipogenesis and also the effect of insulin on lipogenesis. CONCLUSIONS: Besides the hyperinsulinemic and hypoglycemic effect of A-4166 also an influence on nonesterified fatty acid serum levels was observed in rats fed high fat diet. This can be partially explained by an antilipolytic action of hyperinsulinemia after A-4166. The studies of lipogenesis showed that Wistar rats fed high fat diet and HTG animals are resistant to the stimulatory action of insulin on lipogenesis and that administration of A-4166 did not affect this response to insulin.

Adipocytes↗

PubMed2000

Autoimmune thyroiditis with severe hypothyroidism resistant to the treatment with high peroral doses of thyroxine: case report.

Female patient (42 yr) suffered from autoimmune thyroiditis resulting in severe hypothyroidism. She was treated for several years by district physician with the dose of 150 microg L-thyroxine daily. Since the level of TSH was repeatedly very high and no improvement of clinical signs has been observed, she was referred to the Medical Faculty Hospital. Thyroid ultrasound showed remarkable diffuse hypoechogenicity, thyroid scintigraphy showed enlarged thyroid with low 99mTc uptake, TRH test was normal, thin needle biopsy supported autoimmune thyroiditis. X-ray examination showed normal sella turcica and no changes in the pituitary were observed with computer tomography. In spite of increasing the dose of peroral L-thyroxine to 300 microg/d and later to 500 microg/d the clinical status and TSH level did not improve. The patient was originally suspected from malabsorption of thyroxine. However, the test with a large single peroral dose (1000 microg) of L-thyroxine showed a rapid decrease of TSH level (from 126 to 75 mU/l) and increase of total T4 level (from 18 to 64 nmol/l) within 4 hr. Later the patient has been treated with intravenous L-thyroxine (500 microg every 3-4 days for 4 weeks) which resulted in the decrease of TSH level to 10 mU/l and increase of T4 level to 80-100 nmol/l. After that it was concluded that the problem is a poor compliance of the patient who apparently does not actually take the medication, although she always claimed that she is doing so. Referring to some similar cases described in the literature the case was classified as thyroxine pseudomalabsorption. In spite that this problem has been explained to her and her relatives, she refused to take any medication and is consistently neglecting all invitations to further examinations.

Administration, Oral↗

PubMed2000

[Epidemiological profile of thyroid volume and disorders in Slovakia].

UNLABELLED: After 45 years of successful iodine prophylaxis a total of 6324 subject aged 7 to 70 years from East (72.0%), Central (16.2%) and West Slovakia (11.8%) were examined. The thyroid volume (ThV) by ultrasound was examined in a total of 6045 subjects. Serum level of thyrotropin (TSH) was estimated in 1919 (30.3%) and anti-thyroperoxidase antibodies (anti-TPO) in 2589 (40.9%) subjects. Iodine was estimated in 1983 (31.3%) spot urine samples. The median and 75th percentile of ThV were increasing (respectively) from 3.9 and 5.2 ml (10 yr), 8.2 and 10.2 ml (17 yr), 12.4 and 16.3 ml (31-40 yr) up to 14.1 and 19.9 ml (61-70 yr). The frequency of ultrasound hypoechogenicity as an early sign of autoimmune thyroiditis increased from 3.9% (28/709; 10 yr), 16.3% (66/403; 21-40 yr) and 30.3% (205/665; 41-60 yr) up to 51.0% (48/94; 61-70 yr). Positive anti-TPO level as an other sign of autoimmune thyroiditis was found in 1.6% (11/683; 7-13 yr), 7.3% (47/644; 17-30 yr) and 20.4% (257/1262; 31-70 yr). In the adults 19.0% (268/1409) positive anti-TPO were found. Among 1367 adults 6.2% (N = 85) of TSH levels were higher than 4.0 mU/l and 7.5% (N = 103) were lower than 0.2 mU/l. Among 1504 adults a total of 93 (6.1%) of nodules larger than 10 mm in diameter was found (14 in males and 75 in females). In this study the nature of nodules remained unidentified, since all subjects were referred to additional examinations. Malignant nodules were suspected in 3 females with high serum thyroglobulin level and in one additional female with occasionally found very large nodule. The estimation of urinary iodine showed a majority of values in optimal range (> 100-200 microg/l). CONCLUSIONS: Thyroid volume in about 75% examined subjects of all age groups may be considered as relatively small which is apparently due to 45 years of effective iodine prophylaxis. In spite of that the volume of remaining about 25% thyroids were apparently increased which may be presubambly explained by the effect of mainly genetic, but also environmental factors.

Adolescent↗

PubMed1999

Possible role of genetic factors in thyroid growth rate and in the assessment of upper limit of normal thyroid volume in iodine-replete adolescents.

The objective of this study was to answer the question whether thyroid volume in adolescent siblings of similar age and a life-long sufficient iodine intake is uniform. If different, it would indicate that genetic or environmental factors unrelated to iodine intake can influence thyroid growth. We measured thyroid volume by ultrasound in: (1) 251 sibling pairs (SP) and 19 sibling triads 10 to 18 years of age. The age range of each SP was less than 24 months and of each triad less than 42 months; (2) 28 monozygotic and 13 dizygotic sets of twins 7 to 18 years of age. The sibling pairs were retrospectively divided into 3 groups irrespective of age (thyroid volume as means+/-S.E. mL/m2). Group 1: 159 pairs with low thyroid volume in both siblings; mean thyroid volume of each pair less than 5.00 mL/m2 (3.96+/-0.05, median 4.08, range 2.07-4.98); group 2: 69 pairs with high thyroid volume in both siblings; mean thyroid volume greater than 5.00 mL/m2 (5.85+/-0.12, median 5.57, range 5.03-11.02); group 3: 23 pairs with low thyroid volume in 1 sibling (3.53+/-0.15, median 3.53, range 1.71-4.91) and high thyroid volume in another (7.36+/-0.23, median 7.18, range 5.96-10.30). The majority of triads, monozygotic, and dizygotic twins resembled group 1, a few resembled group 2, and only 3 triads and 1 set of dizygotic twins resembled group 3. Among monozygotic twins, there was no pair with a strikingly discordant thyroid volume and only 1 such pair was found among dizygotic twins. In monozygotic twins, the thyroid volume was almost identical (mean difference 0.34+/-0.06 mL/m2) and significantly less (p < 0.012) than in dizygotic twins (0.9+/-0.25 mL/m2). Among 502 children of 251 sibling pairs the frequency of high thyroid volume (>5.00 mL/m2) was greater in girls (103/279, 36.9%, p < 0.01) than in boys (49/223, 22.0%). The same was true for the frequency of hypoechogenicity (42/279 or 15.0% in girls vs. 12/223 or 5.4% in boys; p < 0.01). The frequency of hypoechogenicity in both sexes of the combined groups 2 and 3 (40/186, 21.5%) was higher (p < 0.001) than in group 1 (14/316, 4.4%). All siblings examined lived in a common household with their parents, eating the same daily meals at home and school. Our results suggest that the observed differences in thyroid volume of siblings were not related to iodine intake, but to other factors, eg, genetic and environmental. It is not clear whether the children with high thyroid volume and increased frequency of hypoechogenicity should be included into the recently recommended range of normal thyroid volume for adolescents.

Adolescent↗

PubMed1999

Cytosolic citrate and malonyl-CoA regulation in rat muscle in vivo.

In liver, insulin and glucose acutely increase the concentration of malonyl-CoA by dephosphorylating and activating acetyl-CoA carboxylase (ACC). In contrast, in incubated rat skeletal muscle, they appear to act by increasing the cytosolic concentration of citrate, an allosteric activator of ACC, as reflected by increases in the whole cell concentrations of citrate and malate [Saha, A. K., D. Vavvas, T. G. Kurowski, A. Apazidis, L. A. Witters, E. Shafrir, and N. B. Ruderman. Am. J. Physiol. 272 (Endocrinol. Metab. 35): E641-E648, 1997]. We report here that sustained increases in plasma insulin and glucose may also increase the concentration of malonyl-CoA in rat skeletal muscle in vivo by this mechanism. Thus 70 and 125% increases in malonyl-CoA induced in skeletal muscle by infusions of glucose for 1 and 4 days, respectively, and a twofold increase in its concentration during a 90-min euglycemic-hyperinsulinemic clamp were all associated with significant increases in the sum of whole cell concentrations of citrate and/or malate. Similar correlations were observed in muscle of the hyperinsulinemic fa/fa rat, in denervated muscle, and in muscle of rats infused with insulin for 5 h. In muscle of 48-h-starved rats 3 and 24 h after refeeding, increases in malonyl-CoA were not accompanied by consistent increases in the concentrations of malate or citrate. However, they were associated with a decrease in the whole cell concentration of long-chain fatty acyl-CoA (LCFA-CoA), an allosteric inhibitor of ACC. The results suggest that increases in the concentration of malonyl-CoA, caused in rat muscle in vivo by sustained increases in plasma insulin and glucose or denervation, may be due to increases in the cytosolic concentration of citrate. In contrast, during refeeding after starvation, the increase in malonyl-CoA in muscle is probably due to another mechanism.

Acetyl-CoA Carboxylase↗

PubMed1999

Defect in long-term activation of phosphatidylinositol 3-kinase by insulin in vivo: studies in insulin-resistant hHTg rats.

OBJECTIVE: To study the regulation of phosphatidylinositol (PI) 3-kinase by insulin in vivo in hereditary hypertriglyceridemic and insulin resistant rat (hHTg). METHODS: Total and insulin receptor substrate-1 (IRS-1) associated PI 3-kinase activities were measured in skeletal muscles and adipose tissue after an intense insulin induced glucose utilization as accomplished by 90 min euglycemic hyperinsulinemic clamp. RESULTS: In quadriceps femoris muscle, no stimulation of total or IRS-1 associated PI 3-kinase activities was found after hyperinsulinemia in both hHTg and control rats. In contrast, in soleus muscle of control rats total PI 3-kinase activity was stimulated by insulin (P<0.001), while any such effect was not found in hHTg rats. IRS-1 associated PI 3-kinase activity in soleus muscle was significantly decreased in hHTg rats when compared to control rats (P<0.001), but was not affected by insulin. In white adipose tissue (WAT), both the total (P<0.05) and IRS-1 associated PI 3-kinase activities (P<0.001) were increased after 90 min hyperinsulinemia in control animals but not in hHTg animals. CONCLUSIONS: Long-term activation of PI 3-kinase activity by insulin in vivo involves IRS-1 in white adipose tissue, but not in skeletal muscle which implies tissue specificity. The impairment in the PI 3-kinase activation by insulin in hHTg rats may participate in insulin resistance of these animals.

Adipose Tissue↗

PubMed1999

Effects of a new hypoglycemic agent A-4166 on glucose metabolism in rat adipocytes and muscle tissues.

The effects of the oral administration of a non-sulfonylurea hypoglycemic agent, the phenylalanine derivative A-4166, on serum insulin and glucose levels and glucose metabolism in isolated rat adipocytes and slices of muscle tissues were studied. An increase in serum insulin and a decrease in glucose levels were observed 30 minutes after A-4166 administration to rats fed basal or high fat diet. No changes in basal glucose transport in isolated fat cells were observed after the administration of A-4166. The effect of in vitro added insulin was, however, stronger in rats fed basal diet and treated with A-4166. An elevation of the membrane glucose transporter GLUT 4 was observed in rats treated with A-4166. An increase of basal lipogenesis, measured by incorporation of radiocarbon labeled glucose into lipids, was noted in adipocytes from rats fed high fat diet. The addition of insulin was followed by stimulation of lipogenesis in rats fed basal diet, however, this hormone had no effect in rats fed high fat diet. The administration of A-4166 did not affect the basal or insulin stimulated lipogenesis. Basal glucose oxidation in the diaphragm was not influenced by high fat diet or by A-4166 treatment. In the soleus muscle, basal glucose oxidation was decreased in rats fed high fat diet, and treatment with A-4166 increased the glucose oxidation up to values observed in the control basal diet fed rats. These results indicate that the administration of A-4166 can affect glucose metabolism in muscle tissue and the sensitivity of adipocytes to insulin.

Adipocytes↗

PubMed1998

The effect of the new oral hypoglycemic agent A-4166 on glucose turnover in the high fat diet-induced and/or in the hereditary insulin resistance of rats.

A-4166, a phenylalanine derivative, is a hypoglycemic agent, which has been shown to improve blood glucose levels mainly due to the rapid and short term stimulation of insulin release. Nevertheless, a possible extrapancreatic action of A-4166 has not yet been investigated. Therefore, insulin action (euglycemic hyperinsulinemic 6.4 mU.kg-1.min-1 clamp plus 3H-2-deoxyglucose tracer administration) was studied after 3 weeks on either standard (BD) or high fat (HF) diet in normal control (C) or in hereditary insulin resistant (hHTg) rats which were given a single dose of A-4166 (10 mg per kg BW, i.v.) 60 min after clamp commencement. HF feeding reduced the glucose infusion rate (GIR) required to maintain euglycemia to about 50% of C (p < 0.001). In hHTg rats, HF did not further pronounce the pre-existing decrease of GIR of hHTg animals fed BD. A-4166 changed GIR neither in C, nor in the hHTg group. The estimated glucose disposal (Rd) (C-BD: 32.3 +/- 1.9 vs C-HF: 25.5 +/- 1.9 mg.kg-1.min-1, p < 0.001) and glucose metabolic index (Rg') in skeletal muscles (Q. femoris: C-BD: 25.6 +/- 1.5 vs C-HF: 12.3 +/- 1.1 mmol.100 g-1.min-1, p < 0.001) were reduced by HF in control rats but were not restored by a concomitant bolus of A-4166. Nevertheless, in hHTg rats fed the HF diet a single dose of A-4166 brought back their Rd (hHTg-HF: 23.5 +/- 1.3 vs hHTg-HF plus A-4166: 31.0 +/- 3.5 p < 0.03) and Rg' (Soleus muscle: hHTg-HF: 29.2 +/- 3.2 vs hHTg-HF plus A-4166: 41.3 +/- 4.0) to values of the control group on BD. In summary, a) a single bolus administration of A-4166 to the control or to the insulin resistant hHTg rats, fed either the BD or HF diets, did not abolish the reduction of GIR required to maintain euglycemia during hyperinsulinemic clamps; b) nevertheless, A-4166 caused a significant increase of the estimated plasma glucose disposal (Rd) and skeletal muscle glucose metabolic index (Rg') of hHTG rats fed the HF diet; c) we suggest that A-4166 may have an extrapancreatic action but this needs to be proven using a long-term administration plan of A-4166.

Animals↗

PubMed1998

Search for Extrapancreatic Effects of New Oral Hypoglycemic Agent A-4166: 1. Oral Glucose Tolerance Tests in Normal and Hereditary Insulin Resistant Rats.

OBJECTIVE: To test the effect of new oral hypoglycemic compound A-4166 on insulin secretion during oral glucose challenge in normal and hereditary non-obese, hypertriglyceridemic, insulin resistant and hypertensive rats fed either a normal or high fat diet. METHODS: The rats used were 15 weeks old males of Wistar Charles River strain (controls) and Wistar-derived hereditary hypertriglyceridemic (hHTg) rats of our own colony. They were fed either basal (12 cal% of fat) or high fat diet (70 cal% fat). After 3 weeks of feeding the above diets, the oral glucose tolerance tests (2 g/kg) were carried out in unrestrained conscious rats kept in special metabolic cages after overnight fasting and ten minutes after the administration of A-4166 (100 mg/kg) or placebo by the stomach tube. Plasma glucose, triglycerides, free fatty acids and insulin levels were measured by routine analytical methods. RESULTS: High fat diet feeding resulted in an increase in fasting plasma insulin in both rat strains, while fasting plasma glucose in high fat diet fed animals remained unchanged as compared to those fed basal diet. No differences in the fasting FFA levels were found. The glucose area under curve (AUC) did not differ between the two strains used and high fat diet resulted in a higher glucose AUC in both strains. The administration of A-4166 improved the glucose tolerance in all animals, namely in those fed the basal diet. Insulin AUC showed very similar pattern in both rat strains proving the stimulatory effect of A-4166 on insulin secretion during an oral glucose challenge. High fat feeding resulted in an impairment of insulin action, but the administration of A-4166 restored the antilipolysis in both strains to the normal range. CONCLUSIONS: The previously reported hypoglycemic action of A-4166 resulting from the increased insulin secretion was confirmed. Moreover, some beneficial action of A-4166 on antilipolysis in vivo was demonstrated.

Journal Article↗

PubMed1997