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Biomedical subjects

T Battelino

Publications and source records attributed to T Battelino.

At least 19 recordsLinked to original sources
PubMed2006

Goiter prevalence and urinary iodine concentration in Slovenian adolescents.

CONTEXT: Slovenian school-age children are, as are more than half of European school-age children, still considered to be iodine deficient. In 1999, supplementation of salt was increased from 10 to 25 mg of KI/kg of salt. OBJECTIVE: The objective of our study was to determine the success of this intervention. DESIGN AND PATIENTS: Twelve hundred sixty-four girls (mean age +/- SD: 15.7 +/- 0.6 years) and 1200 boys (15.8 +/- 0.8 years) representing 10% of all 15-year-old Slovenian adolescents were studied. Thyroid size was estimated by clinical examination in all subjects and by ultrasound when enlarged thyroid was suspected. Thyroid volume was also determined by ultrasound in 108 random iodine-sufficient adolescents. In addition, urinary iodine concentration was determined in all subjects. RESULTS: Enlarged thyroid was determined by clinical examination and ultrasound in 0.9% of all subjects. In randomly selected iodine-sufficient subjects, enlarged thyroid was determined in 4.6%. Median urinary iodine concentration for the population was 140 microg/L. In all regions it was greater than or equal to 100 microg/L. Values less than 50 microg/L were determined in 2.5% of all subjects. CONCLUSIONS: Slovenian adolescents are iodine sufficient and the prevalence of goiter is low, indicating that increased KI supplementation of salt in 1999 was successful.

Adolescent↗
PubMed2005

Mutational spectrum of steroid 21-hydroxylase and the genotype-phenotype association in Middle European patients with congenital adrenal hyperplasia.

OBJECTIVE: To analyze the mutational spectrum of steroid 21-hydroxylase (CYP21) and the genotype- phenotype correlation in patients with congenital adrenal hyperplasia (CAH) registered in the Middle European Society for Pediatric Endocrinology CAH database, and to design a reliable and rational approach for CYP21 mutation detection in Middle European populations. DESIGN AND METHODS: Molecular analysis of the CYP21 gene was performed in 432 CAH patients and 298 family members. Low-resolution genotyping was performed to detect the eight most common point mutations. High-resolution genotyping, including Southern blotting and sequencing was performed to detect CYP21 gene deletions, conversions, point mutations or other sequence changes. RESULTS: CYP21 gene deletion and In2 and Ile172Asn mutation accounted for 72.7% of the affected alleles in the whole study group. A good genotype-phenotype correlation was observed, with the exception of Ile172Asn and Pro30Leu mutations. In 37% of patients low resolution genotyping could not identify the causative mutation or distinguish homozygosity from hemizygosity. Using high-resolution genotyping, the causative mutations could be identified in 341 out of 348 analyzed patients. A novel mutation Gln315Stop was found in one simple virilising CAH (SV-CAH) patient from Austria. In the remaining seven patients polymorphisms were identified as the leading sequence alteration. The presence of elevated basal and ACTH-stimulated 17-hydroxyprogesterone, premature pubarche, advanced bone age and clitoral hypertrophy directly implicated Asn493Ser polymorphism in the manifestation of nonclassical- (NC) and even SV-CAH. CONCLUSIONS: By genotyping for the most common point mutations, CYP21 gene deletion/conversion and the 8 bp deletion in exon 3, it should be possible to identify the mutation in 94-99% of the diseased alleles in any investigated Middle European population. In patients with a mild form of the disease and no detectable mutation CYP21 gene polymorphisms should be considered as a plausible disease-causing mutation.

Adrenal Hyperplasia, Congenital↗
PubMed2004

Motor activity during asymptomatic nocturnal hypoglycemia in adolescents with type 1 diabetes mellitus.

Nocturnal hypoglycemia is reported in 13%-56% of adolescents with type 1 diabetes mellitus. It may be asymptomatic in more than 50% of patients. No noninvasive method for detecting asymptomatic nocturnal hypoglycemia (ANH) has so far proven successful. The aim of the present study was to evaluate quantitative changes of motor activity by actigraphy during episodes of ANH in adolescents with type 1 diabetes mellitus. A total of 18 patients aged 10-16 years with a history of ANH were investigated. Blood was sampled at half-hourly intervals between 22.30 and 06.00 hours with a micropump, and an actigraph was fastened to the right wrist. Blood glucose concentrations were measured and compared to motor activity. Nocturnal hypoglycemia was recorded in 10 patients (55%), with blood glucose during periods of hypoglycemia of 3.00+0.17 mmol/l (range, 1.2-3.4 mmol/l), and duration of hypoglycemia of 1.95+1.34 hours (range, 0.5-5.0 hours). All periods of hypoglycemia were clinically asymptomatic. Regression analysis revealed a statistically significant linear correlation ( p=0.03) between blood glucose concentration and the respective 30-min activity counts. Activity counts in patients with nocturnal hypoglycemia were significantly (ANOVA, p<0.02) higher than in patients with normoglycemia. We conclude that low blood glucose was significantly correlated with an increase in motor activity as detected by actigraphy. This implies the possibility of noninvasive screening of asymptomatic nocturnal hypoglycemia.

Adolescent↗
PubMed2003

Mutations in galactose-1-phosphate uridyltransferase gene in patients with idiopathic presenile cataract.

Impaired activity of the enzyme galactose-1-phosphate uridyltransferase (GALT) has been proposed as a risk factor for idiopathic presenile cataract. A study was undertaken to determine the prevalence of the three most common mutations in the GALT gene (Q188R, K285N and N314D, including its variant Duarte-2) in a group of Slovenian patients with idiopathic presenile cataract. GALT activity was determined in the erythrocytes of 30 cataract patients. DNA was isolated from their blood and analysed for Q188R, K285N and N314D mutations and IVS5-24G>A intronic variation by means of polymerase chain reaction and digestion with restriction enzymes. The average GALT activity of the cataract group was 19.5+/-4.9 U/g Hb, which is lower than the normal range (p = 0.034). Frequencies of Q188R, K285N, N314D and Duarte-2 alleles in the cataract group were 0.00%, 5.0%, 11.7% and 3.3%, respectively. Only the frequency of the K285N mutation was significantly higher in the patient group than in the control group (p = 0.0244). Our results support the reported association of decreased GALT activity with idiopathic presenile cataract. Molecular analysis indicates that, in the Slovenian population, this association is linked to the K285N mutation, which is neonatally benign in heterozygotes.

Adult↗
PubMed2003

The HLA-DRB, -DQB polymorphism and anti-insulin antibody response in Slovenian patients with type 1 diabetes.

A combination of specific HLA class II antigens and the presence of type 1 diabetes (T1D)-related antibodies has a high positive predictive value for T1D but low sensitivity. The aim of the present study was to determine the frequencies of HLA-DRB-DQB deduced haplotypes associated with susceptibility and protection in Slovenian patients with established T1D, to evaluate the relationship between the HLA-DRB1-QBP-DQB1 haplotypes and the presence of insulin autoantibodies (IAA) and glutamic acid decarboxylase antibodies (GADA), and to access the possible impact of polymorphic QBP promoters on this relationship. A cohort of 135 patients with T1D (age 17.5 +/- 7.0 years, duration of T1D 9.14 +/- 6.3 years) was investigated. HLA-DRB1 and DQB1 alleles were typed using the polymerase chain reaction (PCR)-reverse line blot method. QBP promoter region alleles were determined using PCR-sequence-specific oligonucleotide hybridization (SSO) and PCR-sequence-specific primers (SSP). IAA and GADA antibodies were determined by enzyme-linked immunosorbent assay (ELISA). The chi-square test with Yates' correction was used for statistical analysis. Deduced haplotypes DRB1*0301-DQB1*0201 (P = 0.0001, OR = 3.4), DRB1*0401-DQB1*0302 (P = 0.0001, OR = 29.8), and DRB1*0402-DQB1*0302 (P = 0.008, OR = 4.7) were significantly more common, and DRB1*1501-DQB1*0602 (P = 0.0001, OR = 0.03) significantly less common in the investigated cohort than in a Slovenian control group. The highest risk and the strongest protective HLA-DR-DQ haplotypes found in Slovenian patients with T1D did not differ from those found in other Caucasian populations. While the DRB1*0301-QBP2.1-DQB1*0201 haplotype, where QBP2.1 did not help to further distinguish DQB1*0201-possessing haplotypes in IAA-positive and IAA-negative patients, was strongly associated with the presence of IAA, the DRB1*0101-QBP5.12-DQB1*0501 haplotype, although not protective compared to the control population, was associated with an absence of IAA in the investigated cohort. It is suggested that there may be a combined influence of the QBP5.12 promoter and the DQB1*0501 functional molecule on reduced IAA production.

Adolescent↗
PubMed2003

Mutational spectrum of congenital adrenal hyperplasia in Slovenian patients: a novel Ala15Thr mutation and Pro30Leu within a larger gene conversion associated with a severe form of the disease.

OBJECTIVE: To analyse the mutational spectrum, the associated haplotypes and the genotype-phenotype correlation, and to design a reliable and rational approach for CYP21 mutation detection in Slovenian congenital adrenal hyperplasia (CAH) patients. DESIGN: Molecular analysis of the CYP21 gene was performed in 36 CAH patients and 79 family members. METHODS: Southern blotting, sequence-specific PCR amplification (PCR-SSP), sequence-specific oligonucleotide hybridisation (PCR-SSO) and sequencing were used to detect CYP21 gene deletions, conversions and point mutations. RESULTS: CYP21 gene deletion was the most frequent mutation (36.4%). Large gene conversions detectable only by Southern blotting represented 12.1%, and gene conversions involving the promoter region represented 7.6% of the mutated alleles. The most frequent point mutations were: intron 2 splice mutation 16.7%, Ile172Asn mutation 7.6%, Gln318Stop 7.5% and Pro30Leu 12.2% of alleles. A correlation between the genotype and the clinical phenotype similar to those described for large populations was observed. The finding of Pro30Leu mutation linked to a gene conversion could explain the simple virilising (SV) phenotype in compound heterozygotes for the Pro30Leu and a severe mutation. In two siblings with a salt wasting form of CAH (SW-CAH), a novel mutation Ala15Thr was found on the allele characterised by Pro30Leu mutation and gene conversion involving the promoter region. CONCLUSIONS: Our genotyping approach allowed reliable diagnosis of CAH in the Slovenian population. The high frequency of CYP21 gene aberrations on Pro30Leu positive alleles justified systematic searching for a gene conversion in the promoter region using the PCR-SSP reaction.

Adrenal Hyperplasia, Congenital↗
PubMed2002

Similar incidence of type 1 diabetes in two ethnically different populations (Italy and Slovenia) is sustained by similar HLA susceptible/protective haplotype frequencies.

The incidence of type 1 diabetes (T1DM) seems to depend in part on the population frequencies of susceptible and protective HLA haplotypes. The present study aimed to (i): characterize the genetic susceptibility to T1DM in the Slovenian population, (ii) test the general hypothesis that T1DM incidence is related to the frequencies of susceptible/protective haplotypes, (iii) compare allele, haplotype and genotype frequencies in Slovenians and Italians that represent two white populations with a similar incidence of T1DM (7.9/100,000/year and 8.1/100,000/year, respectively). The haplotype found most frequently among Slovenian T1DM patients was DRB1*0301-DQA1*0501-DQB1*0201 (53%). The DR4-DQA1*0301-DQB1*0302 haplotypes conferring susceptibility to T1DM were those bearing DRB1*0401 (OR = 12), DRB1*0404 (OR = 4.7) and DRB1*0402 (OR = 4.5). Negative associations with the disease were found for the following haplotypes: DRB1*1501-DQA1*0102-DQB1*0602, DRB1*1301-DQA1*0102-DQB1*0603, DRB1*1101/1104-DQA1*0501-DQB1*0301, and DRB1*1401-DQA1*0101-DQB1*0503. Our findings indicate that the low frequencies of susceptible genotypes, in particular, DR3-DQA1*0501-DQB1*0201/DR4-DQA1*0301-DQB1*0302, together with a high frequency of protective haplotypes, could in part explain the low incidence of T1DM in the Slovenian population. The combined frequencies of susceptible genotypes were similar in the two populations (Slovenia = 19.2%, Italy = 17.6%), and the 95% confidence limits of the OR values for each genotype in the two populations overlapped, indicating no significant differences between the values. We conclude that the similar incidences of T1DM in Italian and Slovenian populations are in part a reflection of similar frequencies of HLA susceptible/protective haplotypes.

Adult↗
PubMed2002

Congenital adrenal hyperplasia: lessons from a multinational study.

A study group of paediatric endocrinologists was established in Austria, Czech Republic, Hungary, Slovenia and Slovakia in order to investigate various aspects in children with congenital adrenal hyperplasia (CAH). Five hundred and ninety-eight patients with CAH who were diagnosed between 1969 and 1998 were included in order to analyze the following questions. Epidemiological data: There were significantly fewer males (43%) than females (57%), and the percentage of males did not increase during the observation period. Salt wasters (SW) totalled 64.7%, whereas 35.3% had simple virilizing (SV) CAH. Diagnosis was established significantly later in boys than in girls (median of 26 vs. 13 days for SW, p < 0.0001; 1,817 vs. 1,010 days for SV, p < 0.03). Mortality in the general population was significantly lower than in CAH siblings (1.8% vs. 7.0%, p < 0.0001) or in SW children (2.2% vs. 11.3%, p < 0.0001). According to our calculation with the present clinical diagnostic criteria in Central Europe, from 40 expected CAH patients/year, 2-2.5 SW, and one female and four male SV patients will not be diagnosed. Auxological data: Growth data from 341 patients were analyzed retrospectively. Percentiles were constructed in a longitudinal/cross-sectional study and pubertal growth was described in a longitudinal analysis. Growth of SW patients was impaired in early childhood (0-3 years), but followed a normal course until puberty. In contrast, SV children had a normal growth pattern during early childhood, but were above the standard thereafter. The pubertal growth spurt was of normal magnitude in boys and girls, but started too early. Final height was reduced compared with both standard and target heights. There was no correlation between final height and age of starting treatment or the year of birth. Bone age was accelerated in both CAH types, but more so in SV patients. Molecular genetics: Three hundred and fifty-six patients were investigated for 11-14 of the most frequent mutations by direct allele-specific polymerase chain reaction (PCR) and/or PCR followed by sequence-specific oligonucleotide, single strand chain polymorphism and restriction fragment length polymorphism. In the group as a whole, we most frequently found the Intron 2 splice mutation (30.8%) or a deletion/conversion (28.5%). The Intron 2 mutation was most frequent in the Hungarian population, whereas deletions/conversions were found more frequently in Slovenians. The other mutations had a similar distribution to those seen in other populations. Genotype-phenotype correlation confirms previous reports.

Adolescent↗
PubMed2001

Novel AIRE mutations and P450 cytochrome autoantibodies in Central and Eastern European patients with APECED.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare recessive disorder that results in several autoimmune diseases due to the mutations in the AIRE (autoimmune regulator) gene. APECED patients develop several autoimmune endocrine disorders and are characterized by the high titer autoantibodies to organ-specific antigens such as the steroidogenic P450 cytochromes. So far, 38 mutations have been identified in the AIRE gene. We report here the genetic and autoantibody analysis of 27 APECED patients of Eastern and Central European origins and one Egyptian patient. From 54 analyzed APECED chromosomes, eight mutations were detected, four of which (T16M, W78R, IVS1_IVS4, 30-53dup23bp) are novel. The most prevalent reason for APECED in these populations was the occurrence of R257X (36 chromosomes) that has been described earlier as a common and recurrent mutation in several other populations. The analysis of humoral immunity to steroidogenic P450 cytochromes by the immunoblotting of E. coli expressed antigens in the 18 APECED patients showed that 67%, 44%, and 61% of the Eastern and Central European APECED patients had autoantibodies to P450c17, P450c21, and P450scc, respectively.

Autoantibodies↗
PubMed2001

Incidence of childhood-onset Type I diabetes in Slovenia and the Tuzia region (Bosnia and Herzegovina) in the period 1990-1998.

AIMS/HYPOTHESIS: The incidence rate of childhood-onset Type I (insulin-dependent) diabetes mellitus in Slovenian children during the period 1990-1998 was studied and compared to that of children from the Tuzla region (Bosnia and Herzegovina). The secular trend for a 25-year period in Slovenia was also investigated. METHODS: The incidence data were obtained from the national Slovenian Type I diabetes register and from the local Type I diabetes register held in Tuzla. The ascertainment was based on the capture-recapture method and was estimated to be 100%. RESULTS: The age-standardized incidence of Type I diabetes mellitus for the age group 0-14 years for Slovenia was 8.54 per 100,000 (95 %-C.I. 7.5-9.5) person-years for both sexes. The incidence for boys was 8.03 per 100,000 (95 %-C.I. 6.7-9.4) and 9.12 per 100,000 (95% -C.I. 7.6-10.6) for girls. The age-standardized incidence in the Tuzla region was much lower: 3.03 per 100,000 (95 %-C.I. 2.0-4.1) for the whole group, 3.44 per 100 000 (95 %-C.I. 1.8-5.0) for boys and 3.21 per 100,000 (95 %-C.I. 1.6-4.7) for girls. A very low incidence of 0.8 per 100,000 in the youngest age group (0-4 years) was observed in the Tuzla region. The linear trend of the Type I diabetes incidence rate in Slovenia has been steadily increasing by 3.6% per year for the last 25 years. The incidence rate in the period 1974-1985 was significantly lower than that in the period 1986-1998 (p < 0.00026). CONCLUSIONS/INTERPRETATION: Although the incidence rate in Slovenia slightly increased during the period 1990-1998, the incidence rate in the Tuzla region remained at the pre-war level.

Age Factors↗
PubMed2001

Growth patterns and final height in congenital adrenal hyperplasia due to classical 21-hydroxylase deficiency. Results of a multicenter study.

BACKGROUND: Longitudinal growth and bone age (BA) development are the most important clinical parameters for monitoring adequate glucocorticoid replacement in children with congenital adrenal hyperplasia (CAH). AIM OF THE STUDY: To analyze the growth pattern of patients treated for CAH of the salt wasting (SW) and simple virilizing (SV) clinical forms; to evaluate final height as compared to reference data and individual target height; to evaluate the course of BA development. PATIENTS AND METHODS: A large database of 598 patients with CAH was created in 5 Central European countries and growth data of 341 treated patients with 21-hydroxylase deficiency were analyzed retrospectively. The patients were of Caucasian origin. Centiles were constructed in a cross-sectional manner and an additional longitudinal analysis was performed in order to evaluate the pubertal growth spurt by applying particular statistical methods (Preece-Baines model). RESULTS: The growth of SW CAH patients was impaired in infancy and early childhood (0-3 years of age), but followed normal patterns in childhood until puberty. In contrast, children with SV CAH had normal patterns of growth in infancy and early childhood and were considerably taller than healthy references during childhood. In the longitudinal study, peak height velocity in both boys and girls was normal, but it occurred at an earlier age than in the standard population. The final height of patients with CAH was reduced in comparison to both the reference and the individual target height. No correlations were found between final height and age at the start of the therapy in SV patients or between final height and year of birth. BA was advanced in both types of CAH, but more accelerated in SV patients. CONCLUSION: Characteristic growth patterns for treated SV and SW CAH children were identified, with a normal pubertal growth spurt and reduced final height being observed.

Adolescent↗
PubMed2001

TNFalpha decreases gluconeogenesis in hepatocytes isolated from 10-day-old rats.

Gluconeogenesis decreases during septic shock, but its mechanism is not well known. Tumor necrosis factor alpha (TNF-alpha), which is a key cytokine in septic shock, can increase GLUT1 gene expression and glucose uptake in muscles and fatty tissues. TNF-alpha does not alter the metabolism of hepatocytes in which GLUT2 is the predominant glucose transporter. However, GLUT1 is the predominant glucose transporter in hepatocytes of 10-d-old rats. Thus, we hypothesized that TNF-alpha might increase glucose uptake and glycolysis in those cells, and decrease gluconeogenesis. In the present study, hepatocytes isolated from 10-d-old rats were incubated with TNF-alpha at the concentrations of 0, 0.98, 9.8, 98, and 980 ng/mL to evaluate TNF-alpha effects on gluconeogenesis and glucose uptake. TNF-alpha increased glucose uptake (41.1 +/- 8 to 114 +/- 21.4 micromol/10(6) cells at the concentration of 980 ng/mL of TNF-alpha) in a dose-dependent manner, and decreased gluconeogenesis (98.2 +/- 8.2 to 1.1 +/- 3.2 micromol/10(6) cells at the concentration of 980 ng/mL of TNF-alpha) in a dose-dependent manner. The decrease of glucokinase mRNA and GLUT1 mRNA abundance correlated with glucose uptake (r = 0.988 and 0.997, respectively), and the decrease of phosphoenolpyruvate carboxykinase mRNA abundance correlated with the decrease of gluconeogenesis (r = 0.972). The decrease of gluconeogenesis by TNF-alpha correlated with the increase of glucose uptake (r = -0.988). We concluded that TNF-alpha reciprocally suppressed gluconeogenesis in hepatocytes isolated from 10-d-old rats.

Aging↗
PubMed2001

Lessons from 30 years of clinical diagnosis and treatment of congenital adrenal hyperplasia in five middle European countries.

Despite the fact that congenital adrenal hyperplasia (CAH) is one of the most common inborn endocrine disorders, some patients are not identified, or may even die, in an acute salt-losing crisis. In a retrospective study covering the last 30 yr, we examined the time elapsing before diagnosis of CAH patients, in 5 Middle European countries, and the mortality rate in diagnosed patients and their siblings during childhood; we also attempted to estimate how many patients are not diagnosed clinically each year. Basic and follow-up clinical data and the family histories of 484 patients with classical forms of CAH diagnosed between 1969 and 1998 were collected and recorded in 5 Middle European countries. The sex-ratio, time elapsing before diagnosis, and mortality among siblings and patients were calculated, and the number of undiagnosed patients was estimated. We found significantly fewer genetic males (43.0%) than females (57.0%) among 484 classic CAH patients, and the percentage of diagnosed boys did not increase with time; 64.7% of them suffered from the salt-wasting (SW) form, and 35.3% from the simple virilizing (SV) form, of the disease. The diagnosis of CAH was established significantly later in males than in females in both forms [SW: 26 vs. 13 days (median), P < 0.0001; SV: 5.0 vs. 2.8 yr, P = 0.03]. Infant mortality in the general population was significantly lower than in either siblings (1.8% vs. 7.0%; P < 0.0001) or in SW (2.29% vs. 11.3%; P < 0.0001). According to our calculations, by our current praxis of clinical ascertainment, 2-2.5 SW and up to 5 SV stay undiagnosed, out of 40 expected CAH patients per year in the countries investigated. Both clinical detection and treatment of CAH patients, at least in males, were insufficient in the five Middle European countries examined during the last 30 yr. Neonatal mass screening and/or greater awareness of the medical community are discussed as ways of improving the efficacy of CAH management. Our experience may be applicable to other countries with similar health care systems.

Adrenal Hyperplasia, Congenital↗
PubMed2001

Seasonality of birth in children (0-14 years) with type 1 diabetes mellitus in Slovenia.

The aim of this study was to find out whether there is seasonality of month of birth of children with diabetes in Slovenia and if so whether it differs from that of the general population. A cohort of 849 children and adolescents (0-14 years) with type 1 diabetes mellitus born between 1956 and 1998 were included in the study. Monthly and seasonal patterns of birth of the patients with diabetes were compared with the pattern of normal live births (n = 1,345,921) and the pattern of disease onset. Statistical analysis was made using Student's t-test to compare the means between the four seasons of the year, and single cosinor analysis for a period of 12 months. The children and adolescents with diabetes had a statistically significant different seasonality of month of birth compared to that of the general population, and an opposite pattern from the seasonality of month of onset of disease. The observations made are in accordance with observations made recently in other countries and support the hypothesis that a virus infection transmitted by the mother to the fetus during the annual viral epidemic induces the autoimmune process in the pancreatic beta-cells in genetically susceptible individuals who will subsequently develop clinical diabetes during childhood.

Adolescent↗
PubMed2000

Insulin tolerance during endotoxic shock in 10-day-old rats.

PURPOSE: The purpose was to investigate insulin tolerance during endotoxic shock in 10-day-old rats. MATERIALS AND METHODS: [(14)C]Deoxy-glucose (2DG) with or without insulin (1 unit/kg) was injected to 10-day-old and 6-week-old rats 3 h after an injection of endotoxin (lipopolysaccharide: LPS). Plasma concentrations of glucose and 2DG were serially measured for 45 min. Gluconeogenesis was measured in hepatocytes isolated from control and endotoxic 10-day-old rats to evaluate effects of insulin on gluconeogenesis. RESULTS: In endotoxic 10-day-old rats, plasma glucose concentration at 45 min was 48 +/- 3% (P < 0.05) of value at 0 min, and when insulin was injected with 2DG, it was 29 +/- 4% (P < 0.05) after insulin injection. Plasma 2DG disappearance was enhanced by insulin injection in the control (t(1/2) = 17.9 vs 20.5 min, P < 0.05), but not in the endotoxic rats (t(1/2) = 17.9 vs 18.4 min), indicating the presence of insulin tolerance in septic rats. Insulin decreased gluconeogenesis (P < 0.05) in hepatocytes from both control and endotoxic 10-day-old rats. In endotoxic 6-week-old rats, plasma glucose concentration was decreased to 46 +/- 10% at 45 min and further decreased to 38 +/- 4% (P < 0.05) by insulin injection. Plasma 2DG disappearance was enhanced by insulin injection in the control (t(1/2) = 11.8 vs 17.4 min, P < 0.05) and in the septic rats (t(1/2) = 14.8 vs 12.2 min). However, the enhancement of plasma 2DG disappearance by insulin was less (P < 0.05) in the septic rats than in the control, confirming reports of other investigators which showed insulin tolerance in septic shock. CONCLUSION: Although hepatocytes from endotoxic rats retained insulin sensitivity, insulin tolerance which was evaluated by 2DG disappearance occurred during septic shock in newborn rats.

Animals↗
PubMed2000

TGF-beta activates genes identified by differential mRNA display in pancreatic rudiments.

The effect of TGF-beta on gene activation in embryonic pancreatic rudiments was investigated using differential mRNA display. Several cDNA bands were augmented and some were suppressed in the presence of TGF-beta. Differentially expressed cDNAs were re-amplified, sequenced, and sequences compared to the GeneBank database. Glucagone and brain alpha-tropomyosin cDNAs were identified from the group of augmented cDNAs, and B-carboxypeptidase form the group of suppressed cDNAs. PCR experiments were confirmed with Northern blots. Obtained results are in accordance with immunohistochemical findings and render differential mRNA display a useful technique in identifying differentially expressed genes in embryonic pancreatic rudiments. Several unknown differentially expressed cDNA sequences obtained in our experiments remain to be identified.

Animals↗
PubMed1999

Tumor necrosis factor-alpha alters glucose metabolism in suckling rats.

Tumor necrosis factor-alpha (TNF-alpha), an important mediator of endotoxic shock, induces hypoglycemia and shock in adult animals. Indomethacin ameliorates TNF-alpha-induced hypoglycemia in the adult. However, effects of TNF-alpha on glucose metabolism in the newborn have not been well documented. The present study showed that in 10-day-old rats injected with TNF-alpha (4.5 x 10(7) U/kg, intraperitoneally) the plasma glucose concentration increased from 4.1 +/- 0.3 mmol/L to 6.9 +/- 0.5 mmol/L (P < .05) at 2 hours and subsequently decreased to 1.4 +/- 0.5 mmol/L (P < .05) at 6 hours, although plasma lactate concentration increased from 1.1 +/- 0.1 mmol/L to 5.5 +/- 0.3 mmol/L (P < .05) at 6 hours. Plasma insulin concentration remained unchanged throughout the experiment. TNF-alpha increased GLUT 1 messenger RNA (mRNA) abundance in the brain, liver, muscle, and fatty tissue (P < .05). Glucose uptake increased in association with the increase of GLUT1 mRNA abundance. TNF-alpha decreased mRNA abundance of GLUT 2 and phosphoenolpyruvate carboxykinase (PEPCK) in liver, suggesting decreased gluconeogenesis. Indomethacin (1.5 mg/kg 20 minutes before TNF-alpha, intraperitoneally) attenuated the hypoglycemia, the lactacidemia, and the increase of GLUT1 mRNA abundance and glucose uptake. Indomethacin attenuated the decrease of PEPCK mRNA abundance. We concluded that TNF-alpha induced hypoglycemia, increasing GLUT1 mRNA abundance and glucose uptake and decreasing PEPCK mRNA abundance in 10-day-old rats. Indomethacin attenuated the TNF-alpha-induced glucose dyshomeostasis.

Animals↗
PubMed1998

TGF-beta plays a key role in morphogenesis of the pancreatic islets of Langerhans by controlling the activity of the matrix metalloproteinase MMP-2.

Islets of Langerhans are microorgans scattered throughout the pancreas, and are responsible for synthesizing and secreting pancreatic hormones. While progress has recently been made concerning cell differentiation of the islets of Langerhans, the mechanism controlling islet morphogenesis is not known. It is thought that these islets are formed by mature cell association, first differentiating in the primitive pancreatic epithelium, then migrating in the extracellular matrix, and finally associating into islets of Langerhans. This mechanism suggests that the extracellular matrix has to be degraded for proper islet morphogenesis. We demonstrated in the present study that during rat pancreatic development, matrix metalloproteinase 2 (MMP-2) is activated in vivo between E17 and E19 when islet morphogenesis occurs. We next demonstrated that when E12.5 pancreatic epithelia develop in vitro, MMP-2 is activated in an in vitro model that recapitulates endocrine pancreas development (Miralles, F., P. Czernichow, and R. Scharfmann. 1998. Development. 125: 1017-1024). On the other hand, islet morphogenesis was impaired when MMP-2 activity was inhibited. We next demonstrated that exogenous TGF-beta1 positively controls both islet morphogenesis and MMP-2 activity. Finally, we demonstrated that both islet morphogenesis and MMP-2 activation were abolished in the presence of a pan-specific TGF-beta neutralizing antibody. Taken together, these observations demonstrate that in vitro, TGF-beta is a key activator of pancreatic MMP-2, and that MMP-2 activity is necessary for islet morphogenesis.

Animals↗