6,455 research outputs found
The role of serotonergic genes and environmental stress on the development of depressive symptoms and neuroticism
No full textBACKGROUND:
Depression is considered to be the result of a complicated synergy between genetic and environmental factors. Several genes of the serotonergic neurotransmission have been related to depression phenotypes, however results are inconsistent, possibly due to the oversight of the role of environmental stress.
METHODS:
We examined gene-environment (GxE) interactions with serotonergic genes on depressive symptoms and neuroticism in a homogeneous population-based sample of 415 females. We chose several genetic variants within candidate genes (SLC6A4, TPH2, HTR1A) that have been previously found to provide some evidence of association with depression outcomes.
RESULTS:
Single marker analyses showed a significant GxE interaction with several TPH2 variants, including rs4570625, on depressive symptoms. Significant GxE interactions were also observed with TPH2 haplotypes. No reliable associations were observed with SLC6A4 and HTR1A genes. We did not find any robust evidence of a direct impact of serotonergic genes on depressive symptoms or neuroticism.
LIMITATIONS:
Due to the high number of analyses conducted, results must be interpreted with caution.
CONCLUSIONS:
The present study indicates an association between TPH2 and depressive symptoms that is conditional on prior experience of stressful life events. Further evidence is provided about the role of the environment in genetic vulnerability to depressio
The 3111T/C polymorphism interacts with stressful life events to influence patterns of sleep in females.
No full textGenetic variations in clock-relevant genes have been investigated in relation to sleep abnormalities, both in healthy populations and in mood-disorder patients with inconsistent results. Environmental influences may moderate associations between genes and phenotype. The authors examined the CLOCK 3111T/C polymorphism and several variants within the PER3 gene and their possible interaction with stressful life events in a group of female volunteers (n = 415). Gene-environment (G × E) interactions and gene main effects were investigated on depressive symptoms using the Beck Depression Inventory and on change of sleep patterns (Item 16). Results showed a G × E interaction on alteration of sleeping pattern: the 3111C homozygous genotype reported greater disruption in sleep pattern after the experience of stressful life events. Within the PER3 gene, one G × E interaction was observed with rs228642 on sleep change. These findings show that the 3111T/C polymorphism is not associated with depressive symptoms, but only with symptoms of sleep change in the case of prior stressful life experiences. The combination of a sensitive genotype (3111C/C) and environmental stress increases vulnerability to circadian rhythm disruption in females
Potential role of membrane-bound COMT gene polymorphisms in female depression vulnerability.
No full textBACKGROUND:
Several polymorphic variants within the catechol-O-methyltransferase (COMT) gene locus have been associated with a number of diverse psychiatric phenotypes including affective disorders. COMT enzyme participates in metabolic pathways involving brain catecholamines, as well as steroid hormones such as estrogens. Given the suggested mood enhancing role of estrogens and the higher prevalence of depression in women, we set out to investigate the potential impact of functional COMT genetic variants on depression and anxiety symptoms in a homogeneous female community sample.
METHODS:
We genotyped three common polymorphisms within the COMT gene in a rural female population isolate (n=391) interviewed for the presence of lifetime major depression episodes and generalized anxiety disorder. Furthermore, well validated self-rated questionnaires were administered evaluating state depressive symptoms and neuroticism personality trait. Single-marker and haplotype association analyses were performed.
RESULTS:
Two highly correlated markers located in the membrane-bound (MB) COMT promoter region (rs2020917, rs737865) were significantly associated with both self-rated and clinician-rated depressive symptomatology. We did not detect any robust association with generalized anxiety disorder or neuroticism. Exploratory haplotype analysis examining the two promoter markers in combination with the extensively studied val158met polymorphism (rs4680) did not provide any further support for the contribution of this variant in depressive mood.
LIMITATIONS:
The relative small sample size should be considered a limitation of this study.
CONCLUSIONS:
Our results provide promising evidence that MB-COMT specific genetic variation may represent an as yet unrecognized genetic factor that influences predisposition to depression amongst females
Reduced sensitivity of fa/fa Zucker rats to adrenomedullin
No full textRat adrenomedullin is a peptide vasodepressor that may be of importance in the pathogenesis of hypertensive disease. Because of the known link between obesity and hypertension, we hypothesized that decreased responsiveness to adrenomedullin might be seen in an obese rodent model. In this study, the in vivo vasodilator actions of exogenous adrenomedullin were compared in anesthetized lean (n = 7) and obese (fa/fa) Zucker rats (n = 8). Adrenomedullin dose dependently lowered mean arterial pressure in both phenotypes, but the half-maximal dose (ID50) was 2-fold higher in fa/fa rats (1.7 +/- 0.22 vs. 0.83 +/- 0.06 nmol/kg). Moreover, the duration of effect was markedly reduced in the fa/fa rats, to 1-2 min from about 5 min in the lean animals. There was no evidence for an increased rate of degradation of adrenomedullin in the fa/fa rats. Although the rats used in this study were not hypertensive, adrenomedullin had reduced sensitivity and duration of action. The evidence suggests possible defects at the target receptor or altered metabolism of adrenomedullin in obesity.LR: 20061115; PUBM: Print; JID: 0372712; 0 (Peptides); 0 (Vasodilator Agents); 148498-78-6 (Adrenomedullin); ppublishSource type: Electronic(1
Identification of biochemical defects in pancreatic islets of fa/fa rats: a developmental study
No full textAdult obese (fa/fa) Zucker rats hypersecrete insulin in response to glucose and other secretagogues. Functional changes in islet alpha 2-adrenoceptors (8) and glycolytic regulation (9) have been reported. In this study, the development of these biochemical lesions in islets isolated from suckling (3 week old) and weanling (5 week old) lean and fa/fa rats was investigated and compared to results in adult animals. Glucose (15 mM)-induced insulin secretion was inhibited by mannoheptulose (MH) in lean (n = 8) but not fa/fa (n = 10) adult rats, indicating loss of sensitivity of glucokinase to competitive inhibition. Sensitivity to MH was somewhat reduced in the islets of 3- and 5-week-old fa/fa (n = 7 and 12) compared to lean (n = 15 and 9) rats, requiring 30-100 fold higher concentrations to achieve significant inhibition. At 3 weeks of age fa/fa rats did not differ from lean controls in either islet insulin content or body weight, but both parameters were increased in fa/fa rats by 5 weeks. The presence of altered alpha 2-adrenoceptor function in fa/fa rats could not be confirmed in this study. Unlike the previous report, prazosin did not antagonize alpha 2-agonist mediated inhibition of insulin secretion. The presence of defective regulation of the glycolytic pathway by mannoheptulose in suckling and weanling rats may contribute to development of hyperinsulinemia in fa/fa rats.LR: 20061115; PUBM: Print; JID: 9305691; 0 (Receptors, Adrenergic, alpha); 11061-68-0 (Insulin); 50-99-7 (Glucose); 654-29-5 (Mannoheptulose); EC 2.7.1.2 (Glucokinase); ppublishSource type: Electronic(1
Effect of adrenalectomy on the development of a pancreatic islet lesion in fa/fa rats
No full textAdrenalectomy prevents development of obesity and hyperinsulinaemia in obese (fa/fa) Zucker rats, thereby implicating the hypothalamo- pituitary-adrenal axis in the pathogenesis of obesity. In this study glucose-induced insulin secretion and glucokinase activity were investigated in isolated islets from adrenalectomized and control obese and lean female rats. Islets from control fa/fa rats were more sensitive to glucose with a half-maximal effective concentration (EC50) of 6.1 +/- 2.0 mmol. 1(-1) compared with 10.6 +/- 2.7 mmol. 1(-1) for adrenalectomized fa/fa rat islets. Adrenalectomy did not alter the islet sensitivity to glucose in the lean rats (EC50 of 9.4 +/- 1.5 mmol.1(-1) and 9.3 +/- 2.0 mmol. 1(-1) for adrenalectomized and control lean rats respectively). Mannoheptulose did not inhibit insulin secretion from control obese rats; however at concentrations of 1.0 mmol. 1(-1) or more it significantly inhibited glucose-induced insulin secretion in adrenalectomized obese and lean, and control lean rat islets (P < 0.05). In adrenalectomized fa/fa islets the glucokinase Km was increased twofold compared with the control fa/fa rats (9.5 +/- 1.5 mmol. 1(-1) vs 5.0 +/- 1.5 mmol. 1(-1), respectively), but there was no significant change in glucokinase Km in the lean rat islets after adrenalectomy. Mannoheptulose (10 mmol.1(-1) caused a significant reduction in glucose phosphorylation in disrupted islets of adrenalectomized fa/fa and lean, and of control lean rats, but not of control fa/fa rats. These data demonstrate that development of abnormal regulation of glycolysis in pancreatic islet beta cells of fa/fa rats, as indicated by the insulin response to manno-heptulose and glucokinase activity, is dependent on an intact hypothalamo-pituitary-adrenal axis.LR: 20061115; PUBM: Print; JID: 0006777; 0 (Blood Glucose); 11061-68-0 (Insulin); 50-22-6 (Corticosterone); 50-99-7 (Glucose); 654-29-5 (Mannoheptulose); EC 2.7.1.1 (Hexokinase); EC 2.7.1.2 (Glucokinase); ppublishSource type: Electronic(1
Ultrastructural and secretory heterogeneity of fa/fa (Zucker) rat islets
No full textMany previous studies of obese rodents documented biochemical changes in pancreatic islets that contribute to hyperinsulinemia in vivo. Those studies used heterogeneous populations of islets, although the size of islets from obese rats ranges from 500 microm. Here, functional and morphological changes in size-sorted ( 250 microm diameter) islets from obese Zucker (fa/fa) rats were correlated. Ultrastructural examination revealed that > 250 microm cultured islets had an increased number of immature secretory granules in the beta cells. The number of degranulated beta cells in > 250 and 250 microm, 250 microm islets compared with small islets. Studies of individual beta cells by reverse hemolytic plaque assay revealed 3-fold more cells from > 250 microm islets were stimulated by 1.4 mmol.l(-1) glucose than cells from < 125 microm islets. We conclude that functional defects in mixed size populations of islets from fa/fa rats are mainly due to alterations in the large islets, whereas smaller islets have relatively normal function. Exposure to high glucose exacerbates morphological and functional differences of large islets, which could have important implications in the transition to noninsulin-dependent diabetes when beta cell insulin production is unable to compensate for hyperglycemia.LR: 20061115; PUBM: Print; JID: 7500844; 11061-68-0 (Insulin); 50-99-7 (Glucose); 654-29-5 (Mannoheptulose); 7782-44-7 (Oxygen); ppublishSource type: Electronic(1
Evidence for defective glucose sensing by islets of fa/fa obese Zucker rats
No full textThe hypothesis that a defect in glucose sensing by islets of fa/fa Zucker rats contributes to hyperinsulinemia in these animals was tested. Islets from lean and fa/fa rats were isolated by collagenase digestion and step-density gradient purification and then cultured overnight in Dulbecco's modified Eagle's medium containing 12.5 mM glucose. Obese rat islets were more sensitive to hypoglycemic glucose levels with half-maximal effective concentration (EC50) of 5.6 mM compared with an EC50 of 8.2 mM for lean rat islets. In contrast, responsiveness of both phenotypes to alpha-ketoisocaproate and quinine was similar. Mannoheptulose did not inhibit insulin secretion from fa/fa islets, although inhibitors of later events in the stimulus-secretion coupling pathway were normally inhibited by iodoacetate and diazoxide. Finally, starvation in vivo and culture of islets in low glucose concentrations (5 mM) in vitro both decreased glucose-stimulated insulin secretion from lean but not fa/fa rat islets. We conclude that fa/fa rat islets have an exaggerated insulin response to hypoglycemic stimuli, possibly as a result of a defect in B-cell glucokinase function.LR: 20061115; PUBM: Print; JID: 0372712; 0 (Amino Acids); 0 (Blood Glucose); 0 (Iodoacetates); 11061-68-0 (Insulin); 130-95-0 (Quinine); 364-98-7 (Diazoxide); 50-99-7 (Glucose); 56-65-5 (Adenosine Triphosphate); 64-69-7 (Iodoacetic Acid); 654-29-5 (Mannoheptulose); EC 2.7.1.2 (Glucokinase); ppublishSource type: Electronic(1
Functional characterization of alpha-adrenoceptors on pancreatic islets of fa/fa Zucker rats
No full textRecently, a defect in pertussis toxin-independent actions of epinephrine on pancreatic B-cells of fa/fa Zucker rats was reported (Cawthorn and Chan (1991) Mol. Cell. Endocrinol. 75, 197-204). We now report studies of islet alpha 2-adrenoceptor function of fa/fa rats. Insulin and cAMP production by islets of obese rats were both inhibited by the alpha 2-adrenoceptor agonist clonidine. Calculated pD2 values for clonidine were 9.57 +/- 0.59 and 9.43 +/- 0.33 for lean and fa/fa rat islets, respectively. Yohimbine reversed clonidine effects equipotently in lean and obese rat islets (pA2 values of 7.48 +/- 0.57 vs 7.43 +/- 0.58). Unexpectedly, the alpha 1-antagonist prazosin stimulated insulin secretion from islets of obese but not lean rats. Functional characteristics of the alpha-adrenoceptors on fa/fa islets are thus similar to those recently designated alpha 2B. Altered expression of alpha-adrenoceptors on pancreatic islets of fa/fa rats may contribute to changes in the pertussis toxin-independent pathway of epinephrine action previously observed.LR: 20061115; PUBM: Print; JID: 7500844; 0 (Receptors, Adrenergic, alpha); 11061-68-0 (Insulin); 146-48-5 (Yohimbine); 19216-56-9 (Prazosin); 4205-90-7 (Clonidine); 50-99-7 (Glucose); 51-43-4 (Epinephrine); 60-92-4 (Cyclic AMP); 66428-89-5 (Forskolin); ppublishSource type: Electronic(1
Glucose refractoriness of beta-cells from fed fa/fa rats is ameliorated by nonesterified fatty acids
No full textThe aim of this study was to characterize the glucose responsiveness of individual beta-cells from fa/fa rats under ad libitum feeding conditions. Enlarged intact islets from fed fa/fa rats had a compressed insulin response curve to glucose compared with smaller islets. Size-sorted islets from obese rats yielded beta-cells whose glucose responsiveness was assessed by reverse hemolytic plaque assay to determine whether glucose refractoriness was caused by a decreased number of responsive cells or output per cell. In addition, the effects of palmitic acid on glucose-stimulated insulin secretion were assessed because of evidence that nonesterified fatty acids have acute beneficial effects. Two- to threefold more beta-cells from >250 microm diameter (large) islets than 10-fold increase in recruitment of active cells from small islets, compared with only a 2.6-fold increase in large islets. This refractoriness was partially reversed by preincubation of the cells in low glucose for 2 h. In addition, secretion per cell of the large islet beta-cell population was significantly reduced compared with lean beta-cells, so that the overall response capacity of large but not small islet beta-cells was significantly reduced at high glucose. Therefore, continued near-normal function of the beta-cells from small islets of fa/fa rats seems crucial for glucose responsiveness. Incubation of beta-cells from large islets with palmitic acid normalized the secretory capacity to glucose mainly by increasing recruitment and secondarily by increasing secretion per cell. In conclusion, these studies demonstrate refractoriness to glucose of beta-cells from large islets of fa/fa rats under ad libitum feeding conditions. When acutely exposed to nonesterified fatty acids, islets from fa/fa rats have a potentiated insulin response despite chronic elevation of plasma lipids in vivo.LR: 20061115; PUBM: Print; JID: 0372712; 0 (Fatty Acids, Nonesterified); 0 (Lipids); 11061-68-0 (Insulin); 50-99-7 (Glucose); 57-10-3 (Palmitic Acid); ppublishSource type: Electronic(1
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