Epilepsy is the most common neurological disorder of young humans. Each year 150,000 children in the United States experience their first seizure. Antiepileptic drugs (AEDs), used to treat seizures in children, infants, and pregnant women, cause cognitive impairment, microcephaly, and birth defects. The cause of unwanted effects of therapy with AEDs is unknown. Here we reveal that phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, and valproate cause apoptotic neurodegeneration in the developing rat brain at plasma concentrations relevant for seizure control in humans. Neuronal death is associated with reduced expression of neurotrophins and decreased concentrations of survival-promoting proteins in the brain. ␤-Estradiol, which stimulates pathways that are activated by neurotrophins, ameliorates AED-induced apoptotic neurodegeneration. Our findings present one possible mechanism to explain cognitive impairment and reduced brain mass associated with prenatal or postnatal exposure of humans to antiepileptic therapy.survival ͉ epilepsy ͉ rat ͉ neurotrophins

OBJECTIVE -Adiponectin encoded by the ADIPOQ gene modulates insulin sensitivity and glucose homeostasis. The aim of the current study was to investigate whether ADIPOQ gene variants in the promoter region predict adiponectin levels and type 2 diabetes progression. RESEARCH DESIGN AND METHODS-A total of 550 subjects with increased risk of type 2 diabetes were investigated; they underwent a 75-g oral glucose tolerance test, repeated after 3 years. Adiponectin levels were analyzed, and two ADIPOQ promoter variant single nucleotide polymorphisms, Ϫ11391GϾA and Ϫ11377CϾG, were genotyped.RESULTS -Tertiles of the adjusted adiponectin levels were associated with single nucleotide polymorphism Ϫ11391GϾA and Ϫ11377CϾG haplotypes (P Ͻ 0.0001). Carriers of the intermediate/high-level haplotype combination showed a bisected diabetes risk at the 3-year follow-up and were characterized by a "regression" of glucose tolerance. Evolution of disease status correlates with preexisting low adiponectin levels at inclusion rather than with variation in adiponectin levels.CONCLUSIONS -We present data that gene variants in the ADIPOQ promoter region are associated with variations in adiponectin levels and thus with future type 2 diabetes and disease progression. Diabetes Care 29:1645-1650, 2006I n conjunction with environmental and behavioral factors, genetic susceptibility is an integral part in the pathogenesis of type 2 diabetes (1). There is evidence that adipose tissue not only functions as an energy reservoir but also produces and secretes several cytokines that modulate energy metabolism and glucose homeostasis (2-5).The ADIPOQ gene encoding adiponectin has been mapped to chromosome 3q27 (6) and is expressed in adult adipocyte tissue (7). Both reduced expression of adiponectin and lower serum adiponectin levels were detected in patients with obesity, type 2 diabetes, and coronary artery disease (8,9). Moreover, treatment of diabetic mice with adiponectin was shown to induce a marked improvement in insulin sensitivity (10).Clinical studies showed that an altered serum adiponectin level is an independent risk factor for progression to type 2 diabetes (11,12). Screening for mutation within the adiponectin gene in the French, AfricanAmerican, and Swedish populations (13-15) revealed an association of haplotypes Ϫ11391GϾA and Ϫ11377CϾG single nucleotide polymorphisms (SNPs) comprising promoter and coding variants of the adiponectin gene with insulin resistance and type 2 diabetes (13,14,16 -18) as well as adiponectin levels (16,19). These data provide evidence that genetic variation within the ADIPOQ gene may be part of the genetic determinants of risk of type 2 diabetes and insulin resistance (13,18) via modulation of adiponectin levels (16,17,20).By using a prospective cohort study, our objective in this investigation was to test the hypothesis that adiponectin promoter variants predict adiponectin levels and that adiponectin promoter variants and/or adiponectin serum levels predict type 2 diabetes progression. Because of the prev...

Adiponectin, which is encoded by the ADIPOQ gene, has been shown to modulate insulin sensitivity and glucose homeostasis. Plasma adiponectin levels are decreased in type 2 diabetes and obesity. Genetic variations within the ADIPOQ gene are associated with decreased adiponectin hormone levels. To analyze specific single-nucleotide polymorphisms (SNPs) and their association with T2D, 365 German subjects with T2D and 323 control subjects were screened. Three common SNPs - +45T>G in exon 2, and 2 promoter variants SNPs -11391G>A and -11377C>G - were analyzed. We found that the variant allele of SNP -11391G>A was significantly more frequent in the diabetic patient group than in the control group (p=0.003). Carrying the haplotype of SNP -11391A and SNP -11377C was associated with a 1.50-fold (p=0.03) increase in diabetes risk. The combination of the A-C haplotype and the G-C haplotype was associated with significantly elevated diabetes risk (OR=2.82 (95% CI: 1.35-5.91), p=0.006) after correction for BMI and age. Our observations suggest that diploid combinations of haplotype in the adiponectin gene promoter region contribute to the genetic risk of T2D in individuals from a German Caucasian population.