Lack of association of CTLA-4 + 49 A/G polymorphism with predisposition to type 1 diabetes in a cohort of Egyptian families

Type 1 diabetes is one of the most common chronic childhood illnesses. Interplay between genetic susceptibility and environmental factors is thought to provide the fundamental element for the disease. Apart from the Major Histocompatibility locus which is the main contributor to risk susceptibility, more than 40 loci are recognized. One among these is the CTLA-4, however data from the literature are controversial. The aim of our study was to investigate the role of CTLA4 49 A/G as a risk susceptibility factor for the development of type 1 diabetes in a cohort of Egyptian families. This is a case control study including 88 Egyptian families with one or more index cases [< 18 years]. The control group comprised 369 healthy unrelated subjects with no family history of diabetes or autoimmune disease. Using PCR-RFLP methodology, CTLA4 49 A/G was analyzed in 738 samples representing 88 families [88 patients, 125 siblings and 156 parents] and 369 control. The age of onset was 6 days-12.5 years with a mean of 5.3 +/- 3.6 and a median of 5 years. The mode of presentation was classic symptoms in 51 and diabetic ketoacidosis in 37 cases. Twenty-two cases had a history of viral infection or exanthematous disease and four had associated autoimmune diseases. No significant differences were encountered between the different groups with regard to CTLA4 +49 A/G genotype or allele frequencies. Neither was there a relation between the various genotypes and age of onset or the mode of presentation. CTLA4 49 A/G polymorphism was not recognized as a risk susceptibility factor in our cohort. This may be attributed to the low co-incidence of autoimmune diseases. Up to our best knowledge, this is the first study involving families. We recommend that all studies performed on risk susceptibility to type 1 diabetes should include proper investigation for other autoimmune diseases to exclude their confounding effect on data analysis

Paraoxonase gene polymorphism and serum paraoxonase activity: relationship with type I diabetes and nephropathy

Human serum paraoxonase-I [PON1] is physically associated with high density lippprotein [HDL] and has been implicated in the prevention of LDL lipid peroxidation. PON1 gene displays several polymorphisms that influence both its level of expression and its catalytic activity. The goal of this study was to examine the association between paraoxonase-1 [PON1] activity and gene polymorphism and the micro-vascular complications in children and adolescence suffering from type 1 DM [TIDM]. Case-control study. One study centre at a University hospital. Thirty eight patients, with type 1 diabetes [n=38], 13 patients presenting with diabetic nephropathy [mean age 18.76 +/- 5.59 years. 8 males and 5 females] and 25 without diabetic nephropathy [mean age 14.48 +/- 3.69 years. 14 males and 11 females] and 16 healthy controls [mean age 12.38 +/- 8.25 years, 10 males and 6 females]. The allele variants of PON1 gene polymorphisms in the PON1 coding region Q192R and L55M have been identified by polymerase chain reaction followed by restriction fragment length polymorphism analysis. Serum PON1 enzyme activity was measured spectrophotometrically. Serum PON1 activity was significantly decreased in complicated diabetics when compared to both non-complicated patients and the control persons [103.33 +/- 35.46 nmol/ml/min, 462.57 +/- 200.69 nmol/ml/min and 1132 +/- 317.61 nmol/ml/min respectively]. As regards PON1 Q192R polymorphism, the R allele was more frequent in complicated diabetics versus both non-complicated diabetics and controls [p=0.0113 and p=0.001 respectively]. PON1 192QR genotype is a risk factor for developing type 1 diabetes OR=7.8; 95% CI [1.12-65.7] with p=0.043. PON1 192QR genotype and 192R allele are risk factors for developing micro-vascular complications with OR =6.40 and 4.00; 95% CI [1.44.28.29] and [1.15-13.87] with p=0.01 and 0.023 respectively. In PON1 L55M polymorphism, non significant differences in the genotype or allele frequency were found between T TIDM, both complicated and non-complicated diabetics and control persons. The association of PON1 Q192R polymorphisms, lower PON1 activity and poorer diabetic control found in patients with diabetic nephropathy further support an idea of genetic factors contributing to development of vascular complications in diabetes

Lipoprotein oxidizability and antioxidant activity in type 1 diabetics: relation to duration, glycemic control and hyperketonemia, and the effect of vitamin E supplementation

Among many hypotheses, oxidizability of lipoproteins has been implicated in the hyperlipidemia and the development of atherosclerosis and cardiovascular disease in diabetics as well as in the general population. Children with type 1 diabetes are particularly at high risk of early development of atherosclerosis. Studies evaluating LDL oxidizability in type 1 diabetics reported conflicting results and the benefit of anti-oxidants supplementation is still debatable. The present study included 70 [29 males, 41 females] children and adolescents with type 1 diabetes, attending the Diabetic Endocrine Metabolic pediatric Unit at Children's Hospital of Cairo University, who were investigated and compared to a control group of 36 [18 males, 18 females] healthy children and adolescents regarding lipid profile, susceptibility of LDL to in vitro oxidation as well as antioxidant activity. Special emphasis was done on the relation of increased lipid peroxidation to diabetes duration, glycemic control and hyperketonemia. The benefit of Vitamin E supplementation [400IU/day] was tested in 46/70 type 1 diabetics regarding lipid peroxidation, lipid profile and glycosylation. Results revealed significantly higher mean levels of fasting blood glucose, glycated hemoglobin, acetoacetate, beta-hydroxybuterate, total cholesterol, triglycerides. LDL and phospholipids in diabetics compared to controls. Diabetics also showed significantly increased oxidative stress [LDL oxidizability and serum malondialdehyde] as well as significantly lower antioxidant profile [reduced glutathione, serum vitamin E and vitamin E/cholesterol]. While hyperlipidemia increased significantly with diabetes duration, the increased LDL oxidizability and decreased antioxidant activity did not show significant difference with the diabetes duration, and LDL oxidizbility didn't show correlation with diabetes duration or glycated hemoglobin level. On the other hand, diabetics with subclinical hyperketonemia, showed significantly increased oxidative stress [LDL oxidizability and serum malondialdehyde] compared to the normoketonemic, and LDL oxidizability correlated significantly with acetoactate levels in diabetics. Vitamin E supplementation [400IU/for 3 moths] achieved a significant decrease in glycosylation with improvement of HbA[1] in 30/46 diabetics, a significant improvement of lipid profile, as well as a significant reduction in LDL oxidizability, and serum malondialdehyde, with a significant increase in reduced glutathione and vitamin E levels. There was also a significant increase in vitamin E/cholesterol and HDL/cholesterol indicating cardiovascular protection. Type 1 diabetics are at risk of hyperlipidemia with increased LDL oxidizability and reduced antioxidant activity. LDL oxidizability and antioxidant activity were not related to the duration of diabetes or the level of glycated hemoglobin, but were a significantly related to increased serum actetoacete levels. Hyperketonemic type 1 diabetics appear to be at higher risk of increased LDL oxidizability and reduced antioxidant activity. Vitamin E supplementation in a dose of 400IU given daily for 3 months was beneficial with improvement of glycated hemoglobin and lipid profile, reduced oxidative stress, and increased antioxidant activity

Optimization glucocorticoid therapy in female infants with 21 hydroxylase deficiency

Females with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency usually present to medical care early in life for the ambiguous genitalia and/or salt wasting symptoms with dehydration. Several studies have demonstrated loss of height potency during the first year of life that has considerable consequences on final adult height. Whether this decreased height potential is caused by inadequate suppression of adrenal androgens, excess steroid treatment or the salt wasting state itself is a matter of debate. Besides the challenge of achieving optimum growth velocity, there is the concern about behavioral masculinization and atypical gender identity caused by exposure to high androgens early in life. The objective of the present study is to evaluate management of 21 females with congenital adrenal hyperplasia due to 21-hydroxylase deficiency during the period of infancy. The present study included 21 females presenting to the Diabetic Endocrine and Metabolic Pediatric Unit [DEMPU] for genital ambiguity and/or salt wasting symptoms and diagnosed as 21-hydroxylase deficiency congenital adrenal hyperplasia [21-OHD CAH]. Diagnosis based on clinical, electrolytes, hormonal assay and karyotype was 21-OHD [10 of the salt wasting [SW] type in 12 cases and the non-salt wasting [NSW] type in 9 cases. Initial dose of hydrocortisone acetate was 15 mg/sqm/d in the NSW type, and 30 mg/sqm/d in the SW type. Fludrocortisone acetate [0.05-0.1 mg/d] was given to the 12 cases with SW type along with salt in diet. Follow up was done 3-monthly for 1 year after diagnosis and initiation of treatment with clinical assessment for salt wasting symptoms and signs of dehydration, pigmentation, serum Na and K, 17-OHP, A, and PRA. Length was measured every 3 months and growth velocity was calculated for the first year of treatment. Adjustment of hydrocortisone dose was done so that adrenal androgens [17 OHP and A] were kept < 10 ng/dl; also PRA was kept within normal [

Lipoprotein oxidizability and antioxidant activity in type 1 diabetics: relation to duration, glycemic control and hyperketonemia, and the effect of vitamin E supplementation

Among many hypotheses, oxidizability of lipoproteins has been implicated in the hyperlipidemia and the development of atherosclerosis and cardiovascular disease in diabetics as well as in the general population. Children with type 1 diabetes are particularly at high risk of early development of atherosclerosis. Studies evaluating LDL oxidizability in type 1 diabetics reported conflicting results and the benefit of antioxidants supplementation is still debatable. The present study included 70 [29 males, 41 females] children and adolescents with type 1 diabetes, attending the diabetic endocrine metabolic pediatric unit at children's hospital of Cairo University, who were investigated and compared to a control group of 36 [18 males, 18 females] healthy children and adolescents regarding lipid profile, susceptibility of LDL to in vitro oxidation as well as antioxidant activity. Special emphasis was done on the relation of increased lipid peroxidation to diabetes duration, glycemic control and hyperketonemia. The benefit of vitamin E supplementation [400 IU/day] was tested in 46/70 type 1 diabetics regarding lipid peroxidation, lipid profile and glycosylation. Results revealed significantly higher mean levels of fasting blood glucose, glycated hemoglobin, acetoacetate, beta-hydroxybuterate, total cholesterol, triglycerides. LDL and phospholipids in diabetics compared to controls. Diabetics also showed significantly increased oxidative stress [LDL oxidizability and serum malondialdehyde] as well as significantly lower antioxidant profile [reduced glutathione, serum vitamin E and vitamin E/cholesterol]. While hyperlipidemia increased significantly with diabetes duration, the increased LDL oxidizability and decreased antioxidant activity did not show significant difference with the diabetes duration, and LDL oxidizability didn't show correlation with diabetes duration or glycated hemoglobin level. On the other hand, diabetics with subclinical hyperketonemia, showed significantly increased oxidative stress [LDL oxidizability and serum malondialdehyde] compared to the normoketonemic, and LDL oxidizability correlated significantly with acetoacetate levels in diabetics. Vitamin E supplementation [400 IU/for 3 months] achieved a significant decrease in glycosylation with improvement of HbA[1], in 30/46 diabetics, a significant improvement of lipid profile, as well as a significant reduction in LDL oxidizability, and serum malondialdehyde, with a significant increase in reduced glutathione and vitamin E levels. There was also a significant increase in vitamin E/cholesterol and HDL/cholesterol indicating cardiovascular protection. Type 1 diabetics are at risk of hyperlipidemia with increased LDL oxidizability and reduced antioxidant activity. LDL oxidizability and antioxidant activity were not related to the duration of diabetes or the level of glycated hemoglobin, but were significantly related to increased serum acetoacetate levels. Hyperketonemic type 1 diabetics appear to be at higher risk of increased LDL oxidizability and reduced antioxidant activity. Vitamin E supplementation in a dose of 400 IU given daily for 3 months was beneficial with improvement of glycated hemoglobin and lipid profile, reduced oxidative stress, and increased antioxidant activity

Changes in insulin like growth factor-1 [IGF-1] and insulin like growth factor binding protein 3 [IGFBP-3] in relation to age and pubertal development in children

The present study was carried out to determine the changes in the values of both insulin like growth factor-1 [IGF-1] and insulin like growth factor binding protein 3 [IGFBP-3] in healthy children and adolescents in different ages and in both sexes. The results of the present study revealed that IGF-1 and IGFBP-3 concentrations increased slowly with age with a steep increase near the age of puberty. No difference was observed for IGF-1 and IGFBP-3 levels between males and females in the studied age groups. A significant increase in both IGF-1 and IGFBP-3 was noted with an advancement in the pubertal stage. A significant positive correlation was noted between age and both IGF-1 and IGFBP-3 as well as between both analytes and body mass index [BMI]. A significant correlation was encountered between IGF-1 and IGFBP-3 suggesting a common regulatory mechanism