Beta-Cell Golgi Stress Response to Lipotoxicity and Glucolipotoxicity: A Preliminary Study of a Potential Mechanism of Beta-Cell Failure in Posttransplant Diabetes and Intraportal Islet Transplant.

OBJECTIVES: Lipotoxicity and glucolipotoxicity are among the mostimportanttriggers of beta-cell failure in patients with type 2 and posttransplant diabetes. Because the Golgi apparatus is a vital organelle in secretory cells like beta cells, its behavior under stress conditions determines the cell's functional capacity. MATERIALS AND METHODS: To mimic lipotoxicity and glucolipotoxicity as metabolic stresses for beta-cell failure, rat insulinoma INS-1E cells were treated with palmitic acid, glucose, or both. Cells were cultured in the presence of 5.0, 16.7, or 33 mM glucose with or without 0.5 mM palmitic acid for 8, 16, 24, and 48 hours. Incubation in the presence of any of the 3 concentrations of glucose with 0.5 mM palmitic acid provided glucolipotoxicity. In addition to the endoplasmic reticulum stress marker (Hspa5), we evaluated changes in Golgi function under experimental metabolic stresses. In doing this, we measured expression levels of the genes coding Golgi structural proteins (Acbd3,Golga2, and Arf1), Golgi glycosylation enzymes sialyltransferaz10 and sialyltransferase 1 (St3gal1), and Golgi stress mediators (Creb3 and Arf4). RESULTS: Golgi responded to lipotoxicity and glucolipotoxicity by increasing the expression of St3gal1 (P = .05 in both conditions) and Creb3 (P = .022 and P = .01, respectively). The Arf4 gene transcript also increased in glucolipotoxic media (P = .03). Glucotoxicity alone did not induce a change in the transcript levels of Creb3 and Arf4. Lipotoxicity and glucolipotoxicity induced Creb3 and Arf4 expression, which are important Golgi stress response mediators leading to apoptosis. CONCLUSIONS: This preliminary study showed that the Golgi stress response is important in lipotoxic and glucolipotoxic conditions in terms of beta-cell failure. Solving the mystery of intracellular molecular mechanisms leading to beta-cell dysfunction is crucial to understanding the pathophysiology of posttransplant diabetes and most probably the failure of intraportal islet transplants in the long term.

Uncoupling protein gene UCP1-3826A/G, UCP2 Ins/Del and UCP3-55C/T polymorphisms in obese Turkish children.

BACKGROUND: Mitochondrial uncoupling proteins (UCP) 1, 2 and 3 are members of the anion carrier protein family located in the inner mitochondrial membrane. There are various controversial reports on UCP genotypes and obesity in adults and children. This study aims to investigate the link between mostly studied UCP polymorphisms (UCP1-3826A/G, UCP2 Insertion/Deletion (Ins/Del) polymorphism of exon 8, and UCP3-55C/T Polymorphisms) and obesity in Turkish children. Furthermore, the relationships of UCP polymorphisms are also analyzed within the scope of metabolic parameters of obese children. METHODS: Molecular screening of the UCP1, UCP2, and UCP3 gene polymorphisms was carried out in 189 children aged 6 to 18 years, 102 of who had exogenous obesity (54 girls) and 87 of whom were healthy controls (48 girls). In the obese group, fasting lipids, glucose and insulin levels were measured. In 60 obese children, an oral glucose tolerance test (OGTT) was performed with 0, 30, 60, 90 and 120 minutes of sampling for plasma glucose and insulin levels. RESULTS: The frequency of UCP polymorphisms was similar in obese and non-obese children. In obese children, fasting lipids, glucose and insulin levels were not different among the UCP 1, 2 and 3 genotypes. While no relationship was found between the UCP 1 and 3 genotypes and glucose/insulin levels during OGTT, carriers of the Insertion allele with UCP2 Ins/Del polymorphism had significantly higher 30-minute insulin levels (p=0.018). CONCLUSIONS: Polymorphisms of the UCP1-3826A/G, UCP2 Ins/Del, and UCP3-55C/T are not associated with obesity and related pathologies in Turkish children. However, the presence of the Ins allele of the UCP2 gene has been found to have an unfavorable influence on early insulin excursion after glucose loading.

Congenital Hypothyroidism and Bone Remodeling Cycle.

OBJECTIVE: The present study aimed to evaluate the biochemical markers of bone turnover in children with congenital hypothyroidism during the course of treatment as compared to healthy children selected as controls. METHODS: The study included 31 children with congenital hypothyroidism and 29 healthy children. In both groups, we evaluated serum procollagen type-1 N-terminal propeptide (PINP) and tartrate-resistant acid phosphatase type 5b isoform (TRACP 5b) levels as bone turnover markers. RESULTS: In both groups, thyroid hormone levels were within normal limits. The levels of vitamin D were significantly higher in the cases with congenital hypothyroidism. Although PINP levels were not found to be different, TRACP 5b levels which are related to osteoclastic activities were significantly higher in the control group. CONCLUSION: We did not detect an increase in bone resorption in patients with congenital hypothyroidism, despite long-term treatment with LT4. Our results suggest that with effective vitamin D treatment and thyroxin replacement, congenital hypothyroidism is not a deleterious factor for bone turnover.

Changes in body composition and growth pattern after adenotonsillectomy in prepubertal children.

OBJECTIVE: Adenotonsillar hypertrophy and chronic tonsillitis are associated with growth interruption during childhood, while adenotonsillectomy has been associated with growth improvement and increased body mass index (BMI). However, no reported study has investigated the effect of adenotonsillectomy on the proportion of body muscle and fat mass. The aim of this prospective study was to evaluate the effect of adenoidectomy and adenotonsillectomy on body muscle and fat composition in prepubertal children. METHODS: Thirty prepubertal children (22 boys, 8 girls; 3-9 years of age) were followed up for 6 months after adenoidectomy or adenotonsillectomy. Twenty-eight age-matched healthy children (12 boys, 16 girls) were followed for the same period, as controls. Data on dietary habits and physical activity were obtained from parent-completed questionnaires at baseline and 6 months. Height and weight z-scores, the amount and percentage of body fat and muscle mass, BMI z-scores, relative BMI and basal metabolic rate were evaluated before and 6 months after surgery with bioelectrical impedance analysis. RESULTS: After 6 months, body muscle mass and basal metabolic rate scores were significantly higher than at baseline in both groups (P<0.05). The rate of increase was not different between the groups. In the study group, the relative BMI scores improved significantly (P<0.05). Increases in body fat mass, body fat percentage, height z-scores, weight z-scores and BMI z-scores were not significantly different between the groups at 6 months (P>0.05). The number of overweight and obese children did not change significantly in either group (P<0.05). CONCLUSIONS: Adenotonsillectomy led to improvement in relative BMI and promoted healthy weight gain without increased body fat percentage in prepubertal children.

AMH levels at central precocious puberty and premature thelarche: is it a parameter?

BACKGROUND: The possible difference of antimüllerian hormone (AMH) levels at central precocious puberty (CPP) and premature thelarche (PT) has not been properly evaluated. OBJECTIVE/HYPOTHESIS: By evaluating AMH levels in girls with diagnosed CPP and PT, we aim to show the change of AMH levels at the pubertal onset. SUBJECTS: Sixty-five girls who have breast development before the age of 8 years and 25 healthy girls were enrolled in the study. METHODS: The subjects were divided into two groups as CPP and PT, according to results of GnRH test. AMH levels were determined in the two groups. RESULTS: The mean AMH levels of the CPP group were significantly lower than those in the PT group (13.57±9.85 pmol/L and 58.42±12.78 pmol/L, respectively, p=0.022). CONCLUSION: These results suggest that the AMH levels decrease in the duration of the hypothalamus-pituitary-ovarian axis activation. We thought that AMH might/may be a marker for distinguishing between CPP and PT.

ß-3AR W64R Polymorphism and 30-Minute Post-Challenge Plasma Glucose Levels in Obese Children.

OBJECTIVE: In this study, we aimed to investigate the association of W64R polymorphism of the ß3-adrenergic receptor gene (ß-3AR) with childhood obesity and related pathologies. METHODS: ß-3AR gene W64R genotyping was carried out in 251 children aged 6-18 years. Of these subjects, 130 were obese (62 boys) and 121 were normal-weight (53 boys). In the obese group, fasting lipids, glucose and insulin levels were measured. Oral glucose tolerance test (OGTT) was performed in 75 of the obese patients. RESULTS: The frequency of W64R genotype was similar in obese and non-obese children. In obese children, relative body mass index, waist-to-hip ratio, serum lipid, glucose and insulin levels, as well as homeostasis model assessment of insulin resistance (HOMA-IR) scores were not different between Arg allele carriers (W64R and R64R) and noncarriers (W64W). In 75 obese children, OGTT results showed that Arg allele carriers had significantly higher 30-minute glucose levels (p=0.027). CONCLUSION: W64R polymorphism of the ß-3AR gene is not associated with obesity and waist-to-hip ratio in Turkish children. Although there were no relationships between the genotypes and lipid, glucose/insulin levels or HOMA-IR, the presence of W64R variant seemed to have an unfavorable influence on early glucose excursion after glucose loading.

Neonatal thyrotoxicosis with severe supraventricular tachycardia: case report and review of the literature.

Neonatal thyrotoxicosis is a rare condition caused by the transplacental passage of thyroid stimulating immunoglobulins from mothers with Graves' disease. We report a case of neonatal thyrotoxicosis with concurrent supraventricular tachycardia (SVT). The female infant, who was born by section due to breech delivery and meconium in the amniotic fluid at 36 weeks of gestation, presented with tachycardia on day 7. Her heart rate was between 260 and 300 beats/min, and an electrocardiogram revealed ongoing SVT. Sotalol was effective after two cardioversions in maintaining sinus rhythm. Thyroid function studies revealed hyperthyroidism in the infant, and her mother was found to have Graves' disease. Since symptoms and signs can vary, especially in preterm infants with neonatal hyperthyroidism, we want to emphasize the importance of prenatal care and follow-ups of Graves' disease associated pregnancies and management of newborns after birth.

Neuroblastoma accompanied by hyperaldosteronism.

BACKGROUND: Tumors known derived from kidneys which take place in secondary hyperaldosteronism etiology are juxtaglomerular cell tumor and Wilms' tumor. Neuroblastoma presenting with hyperaldosteronism is rare. CASE: A 15-month-old girl who had been having diarrhea and fever for 2 weeks presented with a 3 day history of bilious vomiting, metabolic acidosis and severe hypokalemia. She was referred to our hospital with the pre-diagnosis of unknown manifest hypertension etiology, diarrhea, and paralytic ileus after having therapy-resistant hypokalemia and severe resistant acidosis. On her examination after being admitted to our clinic, she was weak, unwell and lethargic with a blood pressure of 140/93 mmHg. Due to the hypertension and severe hypokalemia, the patient was considered to be hyperaldosteronism. Serum aldosterone level, plasma renin activity and cortisol level were elevated. Radiologic findings were compatible with neuroblastoma. The patient underwent an abdominal surgery and the mass excision. The histopathological examination was proved neuroblastoma. CONCLUSION: Hyperaldosteronism can be presented by unexpected atypical forms as in our patient.

Congenital hyperinsulinism in a newborn with a novel homozygous mutation (p.Q392H) in the ABCC8 gene.

Congenital hyperinsulinism is the most frequent cause of persistent hypoglycemia in infancy. We present the case of a preterm, large-for-gestation-age infant with congenital hyperinsulinism who was found to have a novel p.Q392H homozygous mutation in the ABCC8 gene. The patient had severe brain damage, despite early diagnosis and appropriate management. The new mutations may provide an understanding of the prognosis and treatment of the disease. In addition, the data will help the family make informed decisions about future pregnancies.

Abdominal aorta intima media thickness in obese children.

The aim of this study is to investigate whether abdominal aorta intima media thickness (aIMT), increases in obese children and to determine risk factors. Ninety-six children aged 5-16 (51 obese and 45 non-obese) were enrolled in this prospective and cross-sectional study. Age, gender, and relative body mass index (BMI) were recorded. Their serum lipids, thyrotropin, fasting glucose and insulin levels were analyzed. The homeostasis model assessment (HOMA-IR) score was calculated for insulin resistance. Anthropometric and biochemical data were assessed along with aIMT. Findings in obese children were compared with those of non-obese control subjects. The aIMT was significantly greater in obese children. Similar trends were observed in both prepubertal children and adolescents. In obese children, the mean aIMT (mm) was 0.021 (years of age) +0.519. In non-obese children, the mean aIMT (mm) was 0.017 (years of age) +0.381. Our data suggests a relationship between glucose metabolism and aIMT in obese children. BMI was an independent risk factor for increasing aIMT. In conclusion, when compared with non-obese controls, obese children demonstrated significantly increased aIMT. Higher BMI, insulin, HOMA-IR and increased systolic blood pressure seem to be the main factors contributing to increased aIMT and risk for developing vascular disease. Childhood obesity contributes to the development of an increased aIMT.

Cushing syndrome related to leukemic infiltration of the central nervous system: a case report and a possible role of LIF.

BACKGROUND: Adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome (CS) in the presence of leukemic central nervous system infiltration is very rare. CASE: A 3.8-year-old girl who had been treated for B-cell acute lymphoblastic leukemia (ALL) for 1.5 years was admitted to our hospital with excessive weight gain and depression for the last 2 months. Prior to her admission, she was on maintenance with the ALL-BFM95 study protocol for 10 months that does not contain corticosteroids. On physical examination, central obesity and moon face appearance were determined. Laboratory tests revealed high morning ACTH, cortisol level, and 24-h urinary free cortisol level. Morning cortisol level was 33.94 nmol/L after a 2-day (4 × 0.5 mg) dexamethasone suppression test. A lumbar puncture revealed leukemic cells in the cerebrospinal fluid. No pituitary adenoma was detected on magnetic resonance imaging. We diagnosed the patient with ACTH-dependent CS related to leukemic infiltration of the central nervous system. CONCLUSION: Central nervous system infiltration should be considered in leukemic patients who have developed CS. We believe increased leukemia inhibitory factor levels may be a factor for CS in our patient with ALL.

OGTT results in obese adolescents with normal HOMA-IR values.

OBJECTIVE: To investigate insulin resistance (IR) with OGTT in obese adolescents who have normal fasting insulin and homeostasis model assessment for insulin resistance (HOMA-IR). SUBJECTS: A total of 97 obese adolescents who had values of HOMA-IR <3.16 and insulin levels <18 µU/mL (125 pmol/L) were included in the study. METHODS: Oral glucose tolerance test (OGTT) was performed on all cases. Subjects were divided into two groups: subjects with and without IR using an insulin peak of ≥150 µU/mL (1041.8 pmol/L) and/or ≥75 µU/mL (520.9 pmol/L) 120 min after glucose charge and the sum of insulin levels >2083.5 pmol/L (300 µU/mL) in OGTT. IR risk factors were defined as family history of diabetes mellitus, acanthosis nigricans (AN), and hepatic steatosis. RESULTS: IR was detected in 61 (62.9%) patients. The IR group had significantly more frequent AN (p=0.0001). As the number of risk factors increased, the frequency of IR also increased (p=0.01). CONCLUSION: We advise to perform OGTT in obese adolescents with normal HOMA-IR, if they have risk factors for IR.

Hyperprolactinemia as a rare cause of hypertension in chronic renal failure.

Chronic renal failure (CRF) is associated with a high risk for hypertension. An individualized treatment should be initiated after the diagnosis of hypertension and underlying etiology. Many metabolic and endocrinal abnormalities are encountered in CRF. We present an 11-year-old boy with CRF developing galactorrhea and hyperprolactinemia associated with α-methyldopa, defective dopaminergic control, and resistance to multi-antihypertensive therapy. Cabergoline, a dopamine receptor agonist, was effectively used in the treatment of hypertension. It is important to remember that sometimes treatment of an illness becomes the cause of this illness.

The effect of corrective surgery on serum IGF-1, IGFBP-3 levels and growth in children with congenital heart disease.

The aim of this study is to evaluate growth and insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) levels in infants with congenital heart disease (CHD) pre- and postoperatively over a period of a year. Anthropometric values and serum levels of IGF-1 and IGFBP-3 of 40 infants with CHD (20 cyanotic and 20 acyanotic) were compared with 32 healthy controls. Acyanotic infants and infants with pulmonary hypertension (PH) presented significantly more growth failure. Preoperatively, serum IGF-1 and IGFBP-3 levels were lower in the acyanotic group than the cyanotic and the control groups (p = 0.22; p < 0.01). The upward trend in IGF-1 and IGFBP-3 levels in this year-long study demonstrated that the values in the third month and the first year were higher than the preoperative values (p < 0.05). The parallel increase of weight gain and IGF-1, IGFBP-3 levels were the best evidence that these parameters are good nutritional indicators. Timing the corrective surgery before chronic malnutrition or PH develops is an important issue to maintain a normal growth for children with CHD.

Transforming growth factor-beta1 (509 C/T, 915 G/C, 869 T/C) polymorphisms are not related to obesity in Turkish children.

Increasing expression of transforming growth factor-beta 1 (TGF-beta1) from fatty tissue affects the serum level and hence may stimulate expression of the other cytokines. The studies concerning the relation between TGF-beta1 polymorphisms and obesity have been performed in adults, and diverse results have been reported. In this study, we aimed to investigate the association of TGF-beta1 509 C/T, 915 G/C, 869 T/C polymorphisms in childhood obesity and related pathologies. Two hundred and seventy-one children and adolescents were included in the study. One hundred and twenty-one of these cases were in the Obese Group and 150 were in the Control Group. In the Obesity Group, we searched the carbohydrate and lipid metabolism disorders such as insulin resistance, dyslipidemia and hepatosteatosis. The results of this study revealed the lack of an association between TGF-beta1 509 C/T, 915 G/C and 869 T/C polymorphisms and obesity. There were no relations between the polymorphism genotypes and obesity-related metabolic disturbances.

Diagnosis of a trend towards obesity in preschool children: a longitudinal study.

The study was planned to determine identifiable starting points of a trend towards obesity and the influence of variables in preschool children aged 0 to 6 years. In this longitudinal follow-up study, 102 children were enrolled. Anthropometric measurements such as weight-height centiles (specific for gender and age group), weight-height growth velocities, and body mass indices were taken annually and compared within each group from birth to 6 years. Family history and lifestyle variables were also recorded and compared. Our study has shown that gender does not affect the trend towards obesity. In obese children, the earliest sign of a trend was the rapid increase of weight and weight gain velocity after 6 months. There were upward trends in the BMI values indicating obesity at 1 year of age in boys and at 6 months of age in girls. The height was higher in obese children than in non-obese ones after 4 years of age. Paternal obesity and having an obese sibling were significant risk factors for obesity. In conclusion, 6 months are considered to be the most critical periods for evaluating the development of obesity in childhood. The efforts for preventing obesity should be initiated at 6 months of age.

A case of Hirschsprung disease: does thyroid hormone have any effect?

Hirschsprung disease, the colonization defect of neural crest cells through the colon, is one of the reasons for functional obstruction in neonates. Furthermore, hypothyroidism has been known to be one of the causes of bowel hypomotility and pseudoobstruction. These two diseases are generally considered in the differential diagnosis. Although defective thyroid function has been found to be responsible for inappropriate neuronal migration in the brain, the effect of thyroid hormone on neural crest cell migration to the bowel has not yet been evaluated. Here, we report a case with Hirschsprung disease and congenital hypothyroidism, which may point to the need for future studies evaluating the interaction of colonic neural crest cell colonization and thyroid hormone.

PAI-1 gene 4G/5G polymorphism, cytokine levels and their relations with metabolic parameters in obese children.

Obesity is associated with the changes of plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-alpha (TNFalpha) and transforming growth factor beta (TGFbeta) levels. However, the precise effect of the 4G allele on obesity is still contradictory. Here, we aimed to elucidate the role of the 4G/5G polymorphism of the PAI-1 gene on the PAI-1 level and determine the associations between cytokines, glucose and lipid metabolism parameters in obese children. Thirty-nine obese children (mean age 11.4 +/- 3.3 years) and 38 age-matched healthy control group (mean age 10.3 +/- 3.5 years) were included in the study. In all cases, serum levels of glucose, lipid and insulin were measured, homeostasis model assessment of insulin resistance (HOMA-IR) was calculated, and 4G/5G polymorphism of PAI-1 gene, plasma PAI-1 level and serum TNFalpha and TGFbeta levels were studied. The mean relative body mass index (BMI) and HOMA-IR score, VLDL, TG, insulin, PAI-1, TNFalpha levels were higher, and HDL and TGFbeta levels were lower in the obese group. The frequency of the 4G/4G genotype was considerably higher in obese children than in controls. Also, a positive correlation was found between PAI-1 and TNFalpha levels, and relative BMI, HOMA-IR score, insulin, TG, HDL levels. TGFbeta was inversely correlated only with relative BMI. There was no correlation among three cytokines. In conclusion, childhood obesity contributes to higher PAI-1 and TNFalpha and lower TGFbeta levels. Especially PAI-1 and TNFalpha accompany insulin resistance and dyslipidemia.