Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obesity and hypertension are increasing medical problems in adolescents. Serotonin transporter (5-HTT) is involved in mood and eating disturbances. Encoded by the gene SLC6A4, the promoter shows functional insertion/deletion alleles: long (L) and short (S). Because individuals who are carriers for the short version are known to be at risk for higher levels of anxiety, we hypothesized that this variant may be associated with overweight. Data and blood samples were collected from 172 adolescents out of a cross-sectional, population-based study of 934 high school students. To replicate the findings, we also included 119 outpatients from the Nutrition and Diabetes Section of the Children's County Hospital. We found that the S allele was associated with overweight (BMI > 85th percentile), being a risk factor for overweight independently of sex, age, and hypertension [odds ratio (OR): 1.85; 95% confidence interval (CI): 1.13, 3.05; p < 0.02]. Additionally, in the outpatient study, compared with the homozygous LL subjects, S allele carriers showed a higher BMI z-score (1.47 +/- 1.09 vs. 0.51 +/- 1.4; p < 0.002) and were more frequent in overweight children. In conclusion, the S allele of the SLC6A4 promoter variant is associated with overweight being an independent genetic risk factor for obesity.
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PMID:Short allele of serotonin transporter gene promoter is a risk factor for obesity in adolescents. 1729 98

It is well established that diabetes widely affects the functioning of the central nervous system. However, no in vivo study assessed the serotonin (5-HT)-releasing system in the prefrontal cortex (PFC) and amygdala--the crucial regions regulating emotion. We investigated the effects of streptozotocin (STZ)-induced diabetes on the levels of extracellular 5-HT in the PFC and amygdala by using an in vivo microdialysis technique in mice. In addition, the effects of psychological stress on 5-HT secretion were also examined. The basal and the selective 5-HT reuptake inhibitor citalopram (1 microM)-accumulated 5-HT levels remained unchanged in both the PFC and amygdala of diabetic mice. The elevated open platform stress-elicited 5-HT secretion was significantly decreased in the PFC of diabetic mice, and this blunted response was normalized by sub-chronic pretreatment with insulin (5 U/kg, s.c., twice daily). Diabetes had no significant effect on the KCl (100 mM)-stimulated 5-HT release in the PFC. In the amygdala, diabetes had no effect on the stress-elicited 5-HT secretion. Diabetic mice exhibited prolonged freezing as compared to the non-diabetic mice in the elevated open-platform test. In addition, insulin-treated diabetic mice showed the significant shorter duration of freezing than that in diabetic mice. In conclusion, our present findings indicate that diabetes attenuates the serotonergic response to stressful stimuli in a site-specific fashion. In addition, we suggest the possibility that the dysfunction of stress-elicited 5-HT release, but not basal 5-HT release, causes the increased expression of fear-related behavior in diabetic mice.
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PMID:Diabetes attenuates psychological stress-elicited 5-HT secretion in the prefrontal cortex but not in the amygdala of mice. 1732 57

Olanzapine is a second-generation atypical antipsychotic drug (AAPD). Major side effects of olanzapine are weight gain and development of diabetes mellitus, which are risk factors of cardiovascular diseases. The possible causes of metabolic adverse effects are known as poor satiety and increased food intake due to blockade of receptors such as 5-HT(2C) in CNS. In this study, we examine the effect of olanzapine on peripheral adipogenesis using cultured 3T3-L1 cell model. Olanzapine increased triacylglyceride (TG) accumulation during 3T3-L1 preadipocyte differentiation to mature adipocyte phenotype. TG accumulation was accompanied by overexpression of fatty acid synthase and adiponectin that are the downstream genes of sterol regulatory element binding protein-1 (SREBP-1), one of the key transcription factors in lipid homeostasis. We further consisted that mostly SREBP-1 and at a lesser extent peroxisome proliferator-activated receptor gamma (PPAR-gamma), but not CCAAT/enhancer binding protein-alpha (C/EBP-alpha), were overexpressed and activated in 3T3-L1 adipocytes exposed to olanzapine. Furthermore, we showed that olanzapine enhanced the activity of SRE-1-containing LDLR promoter in transfected 3T3-L1 adipocytes and HepG2 cells. Taken together, olanzapine may cause body weight gain not only through influencing CNS receptors, but also affecting the peripheral adipogenesis regulated by SREBP-1.
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PMID:Olanzapine induces SREBP-1-related adipogenesis in 3T3-L1 cells. 1765 82

Several epidemiological and clinical studies have indicated that the prevalence of psychiatric disorders is higher in diabetic patients than in the general population. In the present studies, we examined the behavioral changes in streptozotocin-induced diabetic rats, and investigated the effects of physical and psychological stress on the hippocampal BDNF levels and on the serotonin 2A (5-HT(2A)) receptor-mediated wet-dog shake responses. The streptozotocin (60 mg/kg, i.p.)-induced diabetes had no significant effects on the immobility time in the forced swim test or on locomotor activity in the open-field test. Moreover, there was no significant difference in the wet-dog shake responses induced by DOI, a 5-HT(2A) receptor agonist, between nondiabetic and diabetic rats. Five-day exposure to physical (electric footshock) and psychological (non-footshock) stress had no significant effect on the hippocampal BDNF level in diabetic or nondiabetic rats. The 2 types of stress had no significant effect on the DOI-induced wet-dog shake responses in nondiabetic rats. In diabetic rats, the repeated exposure to physical stress markedly increased the DOI-induced wet-dog shake responses, but the repeated exposure to psychological stress had no effect. These results suggest that exposure to physical stress augmented the susceptibility to the wet-dog shake responses to 5-HT(2A) receptor stimulation in streptozotocin-induced diabetic rats.
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PMID:Effects of physical and psychological stress on 5-HT2A receptor-mediated wet-dog shake responses in streptozotocin-induced diabetic rats. 1772 9

The aim of this study is to evaluate antidiabetic, antioxidant and vasoprotective effects of Posidonia oceanica extract (POE) in alloxan diabetic rats. Posidonia oceanica (L) Delile (Posidoniaceae), is a widely allocated phanerogam in Mediterranean and Aegean Sea. Up to date, no published data relevant to use of the plant in traditional medicine are available. However, decoction of the leaves has been quoted to be used as a remedy for diabetes mellitus and hypertension by villagers living by the sea coast of Western Anatolia. Oral administration of extract for 15 days (50, 150, and 250 mg/kg b.wt.) resulted in a dose-dependent decrease in blood glucose. Relaxant responses to acetylcholine (ACh) in diabetic thoracic aorta were restored by POE treatment (50, 150, and 250 mg/kg b.wt.). POE also attenuated the augmented phenylephrine (PE) and serotonin (5-HT) contractions. At concentration levels of 150 and 250 mg/kg b.wt., POE exerted a protective effect on the significantly decreased levels of antioxidants namely, glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase and nitric oxide (NO). POE (50mg/kg b.wt.) produced no effect on alloxan-induced alterations in the antioxidant status while possessing glucose lowering and vasoprotective activities. Furthermore, liver and kidney function markers, leucocyte counts, body weight and liver glycogen content remained unchanged at dose level of 50mg/kg b.wt., when compared with diabetic control group. These results suggest that antidiabetic and vasoprotective effects of POE may be unrelated to its antioxidant properties.
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PMID:Evaluation of antidiabetic, antioxidant and vasoprotective effects of Posidonia oceanica extract. 1797 78

Hyperglycemia is a well-known factor in reducing nocturnal pineal melatonin production. However, the mechanism underlying diabetes-induced insufficiency of pineal melatonin has remained uncertain. This study was undertaken to examine the structure, innervation and functional activity of the pineal gland in streptozotocin (STZ)-induced diabetes in rats by immunohistochemistry, Western blotting and image analysis. The number of the pinealocytes and the volume of pineal were also estimated using stereologic quantification including the optical fractionator and Cavalieri's method. It has also shown a progressive reduction of the total area of the pineal gland and the nuclear size of pinealocytes beginning at 4 weeks of induced diabetes. Surprisingly, the immunoreactive intensities and protein amounts of serotonin (5-HT) and protein gene product (PGP) 9.5 in the pineal gland were progressively increased from 4 weeks of diabetes. Meanwhile, nerve fibers immunoreactive for PGP 9.5 had disappeared. Diabetes-induced neuropathy was observed in nerve fibers containing tyrosine hydroxylase (TH). The affected nerve fibers appeared swollen and smooth in outline but they showed a distribution pattern, packing density and protein levels comparable to those of the age-matched control animals. Ultrastructural observations have revealed diabetes-induced deformity of Schwann cells and basal lamina, accumulation of synaptic vesicles and deprivation of the dense-core vesicles in the axon terminals and varicosities. The increase in immunoreactivities in 5-HT and PGP 9.5 and shrinkage of pineal gland in the diabetic rats suggest an inefficient enzyme activity of the pinealocytes. This coupled with the occurrence of anomalous TH nerve fibers, may lead to an ineffective sympathetic innervation of the pinealocytes resulting in reduced melatonin production in STZ-induced diabetes.
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PMID:Expression of protein gene product 9.5, tyrosine hydroxylase and serotonin in the pineal gland of rats with streptozotocin-induced diabetes. 1815 92

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis induces hyperglycemia and serotonin (5-HT)2A receptor supersensitivity. In the present study, to investigate the effect of hyperglycemia on the function of 5-HT2A receptors, we compared the 5-HT2A receptor-mediated wet-dog shake responses in rats treated with adrenocorticotropic hormone (ACTH), dexamethasone and streptozotocin. ACTH (100 ug/rat per day, s.c.), dexamethasone (1 mg/kg per day, s.c.) and streptozotocin (60 mg/kg, i.p.) produced significant hyperglycemia at 14 days after the start of these treatments, and the hyperglycemia was most pronounced in the streptozotocin-treated rats. The wet-dog shake responses induced by (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2A receptor agonist, were significantly enhanced at 14 days after repeated treatment with ACTH and dexamethasone. However, streptozotocin-induced diabetes had no effect on the wet-dog shake responses. The results of the present study suggest that hyperglycemia is not strongly associated with the enhanced susceptibility of 5-HT2A receptors under the condition of hyperactivity of the HPA axis.
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PMID:The Influence of hyperactivity of the hypothalamic-pituitary-adrenal axis and hyperglycemia on the 5-HT2A receptor-mediated wet-dog shake responses in rats. 1818 75

Early malnutrition has been associated with a high risk of developing obesity, diabetes and cardiovascular diseases in adulthood. In animals, poor perinatal nutrition produces hyperphagia and persistent increased levels of serotonin (5-HT) in the brain. Inasmuch as 5-HT is directly related to the negative regulation of food intake, here we have investigated whether the anorexic effects of 5-HT are altered by protein malnutrition. Pregnant Sprague-Dawley rats were fed ad libitum either a control (20% protein) or a low-protein (8% protein) diet throughout pregnancy and lactation. At weaning, pups received a standard diet and at 35 days their feeding behaviour was evaluated after the administration of DL-fenfluramine (DL-FEN), an anorexic compound that blocks the reuptake of 5-HT and stimulates its release. Male offspring born to protein-restricted dams exhibited significantly decreased body weight and hyperphagia compared with controls. DL-FEN dose-dependently reduced the 1 h chow intake at the onset of the dark cycle in both control and undernourished rats. However, the hypophagic effects of DL-FEN were significantly attenuated in animals submitted perinatally to protein restriction. The stimulatory action of DL-FEN on c-fos immunoreactivity within the paraventricular nucleus of the hypothalamus was also decreased in low-protein-fed rats. Further pharmacological analysis with selective 5-HT(1B) and 5-HT(2C) receptor agonist showed that the reduced anorexic effects of 5-HT in malnourished animals were coupled to a desensitization of 5-HT(1B) receptors. These observations indicate that the hyperphagia associated with metabolic programming is at least partially related to a reduced regulatory function of 5-HT on food intake.
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PMID:Perinatal protein restriction reduces the inhibitory action of serotonin on food intake. 1833 42

Food restriction and hypoinsulinemia can affect the synthesis, turnover, and receptor function of serotonin (5-HT) in brain. This study explored the effects of food restriction and streptozotocin treatment on behavioral effects related to 5-HT1A (+)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) and 5-HT2A [(+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)] receptor activation. Lower lip retraction and flat body posture (8-OH-DPAT) and head twitching (DOI) were measured in rats during free feeding, food restriction, after treatment with streptozotocin, and finally after insulin replacement. 8-OH-DPAT induced lower lip retraction and flat body posture whereas DOI induced head twitching. One week of food restriction (10 g/day) decreased 8-OH-DPAT-induced lower lip retraction, 8-OH-DPAT-induced flat body posture, and DOI-induced head twitching. Subsequently, 1 week of free access to food restored sensitivity to 8-OH-DPAT and DOI-induced behavioral effects. Finally, 1 week after streptozotocin, 8-OH-DPAT-induced flat body posture and DOI-induced head twitching were markedly reduced whereas 8-OH-DPAT-induced lower lip retraction was unchanged. One week of insulin replacement restored sensitivity to 8-OH-DPAT and DOI-induced behavioral effects. These results show that modest food restriction or experimentally induced diabetes can profoundly affect sensitivity to drugs acting at 5-HT1A or 5-HT2A receptors; these results could be relevant to understanding the comorbidity of depression and diabetes.
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PMID:Food restriction and streptozotocin treatment decrease 5-HT1A and 5-HT2A receptor-mediated behavioral effects in rats. 1862 76

The present studies investigated behavioral and neurochemical aspects of the noradrenergic and serotonergic nervous systems in streptozotocin-induced diabetic mice. We previously reported that intrathecal (i.t.) injection of norepinephrine significantly potentiated antinociception in diabetic mice compared to that in non-diabetic mice, and that antinociception due to norepinephrine injection was completely abolished by pretreatment with yohimbine, an alpha2-adrenoceptor antagonist. The present studies demonstrated that i.t. injection of clonidine also showed more-potent antinociceptive activity in diabetic mice than in non-diabetic mice, but that i.t. methoxamine injection did not affect diabetic or non-diabetic mice. The antinociceptive potency due to i.t. injection of 5-HT was significantly lower in diabetic than in non-diabetic mice. In a neurochemical study, we found that the density of [3H]-rauwolscine binding sites in spinal alpha2-adrenoceptors was significantly higher in diabetic than in non-diabetic mice, but that the binding affinity was unchanged. Spinal norepinephrine turnover was determined by measuring the decline in tissue norepinephrine concentration at 3 h after injection of the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine. The spinal norepinephrine concentration decreased to 43.7% from the baseline in non-diabetic mice, while it was 21.0% in diabetic mice. These results suggest that, based on the decrease of norepinephrine release in the spinal cord, up-regulation of spinal alpha2-adrenoceptors caused the increase of antinociception due to i.t. injection of an alpha2-adrenoceptor agonist in streptozotocin-induced diabetic mice, and it seemed that the stimulation of alpha2-adrenoceptors potentiated the antinociceptive effect. Thus, the spinal noradrenergic systems play an important moderating role in diabetes-induced neuropathic pain.
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PMID:Role of alpha2-adrenoceptors in enhancement of antinociceptive effect in diabetic mice. 1862 15


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