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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BBZDR/Wor rat is a new model of type II diabetes with spontaneous obesity and clinical characteristics close to human diabetes. In this study the time-course of cerebroarterial dysfunction was characterized. Posterior cerebral arteries from BBZDR/Wor rats and their age-matched lean controls were pressurized to 70 mm Hg in an arteriograph. Effects of intraluminal pressure and different pharmacological agents on myogenic tone were evaluated. Pressure-myogenic tone curves in diabetic arteries were similar to that in non-diabetic arteries at pre-diabetic age, showed leftward shift at 4 weeks and were significantly different with higher myogenic tone at 5 and 8 months of diabetes. Age-dependent decrease in myogenic tone was observed in non-diabetic arteries. Dilation to histamine was similar to that in non-diabetic arteries at pre-diabetic and at 4 weeks but significantly reduced at 5 and 8 months of diabetes. Bradykinin-mediated dilation was significantly reduced in early and chronic diabetes, whereas (+/-)-S-nitroso-N-acetylpenicillamine (SNAP)-mediated dilation was decreased modestly at 8 months of diabetes. Sensitivity and constriction to 5-hydroxytryptamine were increased in early and chronic diabetes. Responses to bradykinin and 5-hydroxytryptamine were decreased and increased, respectively. Myogenic tone was significantly less sensitive to (lower pIC(50)) U-73122 than normal arteries at 4 weeks and 8 months of diabetes suggesting an increased activation of phospholipase C (PLC). This study shows that pressure-mediated autoregulation of cerebral arteries in type II diabetes operates at higher resistance. Endothelium-dependent dilation was decreased with chronic diabetes with increased sensitivity to constrictor agonist. Endothelium-independent dilation was modestly affected. Arterial hyper-reactivity to pressure and constrictor agonist were likely due to increased PLC activation.
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PMID:Myogenic tone and reactivity of cerebral arteries in type II diabetic BBZDR/Wor rat. 1803 20

The G protein-coupled serotonin 5-hydroxytryptamine (5-HT)(2A) receptor is primarily recognized for its role in brain neurotransmission, where it mediates a wide variety of functions, including certain aspects of cognition. However, there is significant expression of this receptor in peripheral tissues, where its importance is largely unknown. We have now discovered that activation of 5-HT(2A) receptors in primary aortic smooth muscle cells provides a previously unknown and extremely potent inhibition of tumor necrosis factor (TNF)-alpha-mediated inflammation. 5-HT(2A) receptor stimulation with the agonist (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(R)-DOI] rapidly inhibits a variety of TNF-alpha-mediated proinflammatory markers, including intracellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), and interleukin (IL)-6 gene expression, nitric-oxide synthase activity, and nuclear translocation of nuclear factor kappaB, with IC(50) values of only 10 to 20 pM. It is significant that proinflammatory markers can also be inhibited by (R)-DOI hours after treatment with TNF-alpha. With the exception of a few natural toxins, no current drugs or small molecule therapeutics demonstrate a comparable potency for any physiological effect. TNF-alpha-mediated inflammatory pathways have been strongly implicated in a number of diseases, including atherosclerosis, rheumatoid arthritis, psoriasis, type II diabetes, depression, schizophrenia, and Alzheimer's disease. Our results indicate that activation of 5-HT(2A) receptors represents a novel, and extraordinarily potent, potential therapeutic avenue for the treatment of disorders involving TNF-alpha-mediated inflammation. Note that because (R)-DOI can significantly inhibit the effects of TNF-alpha many hours after the administration of TNF-alpha, potential therapies could be aimed not only at preventing inflammation but also treating inflammatory injury that has already occurred or is ongoing.
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PMID:Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency. 1870 86

Diabetic ketoacidosis and hyperglycaemic hyperosmolar syndrome are rare, but potentially fatal complications of antipsychotic-associated hyperglycaemia. The mechanisms for this remain unclear, but are probably multifactorial. The suggested reasons include drug-induced weight gain and adiposity, development of the metabolic syndrome, antagonism of serotonin (5-hydroxytryptamine) receptors, drug-induced leptin resistance, dyslipidaemia mediated pancreatic beta-cell damage and hepatocyte transcription factor dysregulation. Patients with schizophrenia are known to be at a higher genetic risk of developing diabetes mellitus and cardiovascular disease. This review emphasizes a rare case of hyperosmolar hyperglycaemic syndrome in a young man with schizophrenia and discusses proposed mechanisms for the development of antipsychotic-associated diabetes mellitus.
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PMID:Atypical antipsychotic-induced diabetes mellitus: an update on epidemiology and postulated mechanisms. 1871 5

Recent studies reveal that serotonin (5-hydroxytryptamine, 5-HT) might play a role in the aetiology of gestational diabetes mellitus (GDM). The involvement of the serotonin transporter (SERT) and 5-HT(2A) receptor (5-HT(2A)R) in diabetes has also been suggested. However, placental SERT and 5-HT(2A)R have never been studied in GDM-complicated pregnancies. The aim of this study was to investigate the effect of GDM on the expression of both placental SERT and 5-HT(2A)R. First, immunohistochemical analysis demonstrated the presence of SERT and 5-HT(2A)R proteins in the villous trophoblast and the fetal capillary endothelium of normal term placental tissue. Protein and mRNA expression of SERT and 5-HT(2A)R in the villous cytotrophoblastic and syncytiotrophoblastic cells was further confirmed in primary culture. A significantly (P < 0.05) decreased expression of SERT mRNA (56.3%) and protein (79.7%), and 5-HT(2A)R mRNA (79.1%) and protein (29.1%) was observed in placental tissues from GDM compared with non-GDM pregnancies. These data suggest that SERT and 5-HT(2A)R might be implicated in the aetiology of GDM. Moreover, the presence of SERT and 5-HT(2A)R in villous trophoblastic cells argues in favour of an important role of serotonin in human placental function.
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PMID:Expression of placental serotonin transporter and 5-HT 2A receptor in normal and gestational diabetes mellitus pregnancies. 1971 56

Obesity is a major public health problem. For many obese patients, diet and exercise are an inadequate treatment and bariatric surgery may be too extreme of a treatment. As with many other chronic diseases, pharmacologic treatment may be an attractive option for selected obese patients. Antiobesity drugs may potentially work through one of three mechanisms: (1) appetite suppression, (2) interference with absorption of nutrients, and (3) increased metabolism of nutrients. The three most widely prescribed drugs approved to treat obesity are phentermine, sibutramine, and orlistat. Drugs approved for treating obesity usually result in an additional weight loss of approximately 2-5 kg in addition to placebo. For pharmacologic therapy in obesity to be widely utilized, greater effectiveness and safety will be needed. Four types of single-agent drugs are in late stage development, including (1) selective central cannabinoid-1 receptor blockers, (2) selective central 5-hydroxytryptamine 2C serotonin receptor agonists, (3) an intestinal lipase blocker, and (4) central-acting incretin mimetic drugs. Four combination agent compounds in late stage development include (1) Contrave, which combines long-acting versions of naltrexone and bupropion; (2) Empatic, which combines long-acting bupropion and long-acting zonisamide; (3) Qnexa, which combines phentermine with controlled release topiramate; and (4) an injectable combination of leptin and pramlintide. Peptide YY and melanin-concentrating hormone receptor-1 antagonists are centrally acting agents in early stage development. It is expected that several new drug products for obesity will become available over the next few years. Their role in managing this disease remains to be determined.
J Diabetes Sci Technol 2008 Sep
PMID:Drugs in the pipeline for the obesity market. 1988 78

Neurotransmitters such as serotonin (5-hydroxytryptamine, 5-HT) work closely with leptin and insulin to fine-tune the metabolic and neuroendocrine responses to dietary intake. Losing the sensitivity to excess food intake can lead to obesity, diabetes, and a multitude of behavioral disorders. It is largely unclear how different serotonin receptor subtypes respond to and integrate metabolic signals and which genetic variations in these receptor genes lead to individual differences in susceptibility to metabolic disorders. In an obese cohort of families of Northern European descent (n = 2,209), the serotonin type 5A receptor gene, HTR5A, was identified as a prominent factor affecting plasma levels of triglycerides (TG), supported by our data from both genome-wide linkage and targeted association analyses using 28 publicly available and 12 newly discovered single nucleotide polymorphisms (SNPs), of which 3 were strongly associated with plasma TG levels (P < 0.00125). Bayesian quantitative trait nucleotide (BQTN) analysis identified a putative causal promoter SNP (rs3734967) with substantial posterior probability (P = 0.59). Functional analysis of rs3734967 by electrophoretic mobility shift assay (EMSA) showed distinct binding patterns of the two alleles of this SNP with nuclear proteins from glioma cell lines. In conclusion, sequence variants in HTR5A are strongly associated with high plasma levels of TG in a Northern European population, suggesting a novel role of the serotonin receptor system in humans. This suggests a potential brain-specific regulation of plasma TG levels, possibly by alteration of the expression of HTR5A.
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PMID:Serotonin (5-HT) receptor 5A sequence variants affect human plasma triglyceride levels. 2038 41

We analysed the type and/or subtype of 5-hydroxytryptamine (5-HT) receptors involved in the inhibitory mechanisms of 5-HT on the pressor responses induced by stimulation of sympathetic vasopressor outflow in long-term diabetic pithed rats. Diabetes was induced in male Wistar rats by a single subcutaneous injection of alloxan. Eight weeks later, rats were anaesthetized, pre-treated with atropine, and pithed. The effect of 5-HT on the pressor responses elicited by stimulation of the sympathetic outflow was analysed in eight-week alloxan-induced diabetic pithed rats. 5-HT (20 microg/kg/min) reduced the pressor action obtained by electrical stimulation of the sympathetic outflow. However, there was no effect on exogenous noradrenaline-induced pressor responses. 5-CT (5 microg/kg/min), 8-OH-DPAT (5 microg/kg/min), and alpha-methyl-5-HT (5 microg/kg/min), selective 5-HT(1), 5-HT(1A) and 5-HT(2) receptor agonists, respectively, reproduced the 5-HT inhibitory action. Nevertheless, infusion of 5 microg/kg/min of 1-phenylbiguanide, CGS-12066B, L-694,247, BW273C86 or MK212 (5-HT(3), 5-HT(1B), 5-HT(1D), 5-HT(2B) and 5-HT(2C) receptor agonists, respectively) had no effect on the pressor responses elicited by stimulation of the sympathetic outflow. Methiothepin (100 microg/kg) and a cocktail of WAY-100,635 (100 microg/kg) and spiperone (125 microg/kg) blocked the 5-HT inhibitory effect on the pressor action obtained by sympathetic stimulation. Moreover, WAY-100, 635 abolished the 8-OH-DPAT inhibitory effect and spiperone blocked alpha-methyl-5-HT action. In conclusion, this study revealed that long-term experimental diabetes induces changes in the receptor type/subtype involved in the 5-HT inhibitory action on the sympathetic pressor responses produced by electrical stimulation. This is mainly mediated by pre-junctional 5-HT(1A) and 5-HT(2A) receptors.
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PMID:Pharmacological profile of 5-hydroxytryptamine-induced inhibition on the pressor effect elicited by sympathetic stimulation in long-term diabetic pithed rats. 2054 48

Obesity and metabolic syndrome increase the risk of coronary heart disease and lead to a proinflammatory state of the vascular wall. Endothelial dysfunction is associated with up-regulation of cyclooxygenase-2 (COX-2) and enhanced synthesis of constrictor prostaglandins in systemic arteries in diabetes. The present study assessed whether changes in the arachidonic acid (AA) metabolism via COX-1 and COX-2 may affect endothelial function of coronary arteries in obesity. Intramyocardial arteries from obese Zucker rats (OZR) and from lean Zucker rats (LZR) were mounted in microvascular myographs to assess vascular function and COX expression was determined by both immunohistochemistry and Western blot. AA elicited relaxations of similar magnitude in arteries from LZR and OZR which were abolished by endothelial cell removal. Selective inhibition of COX-1 enhanced the AA relaxant responses and inhibited the 5-hydroxytryptamine (5-HT)-induced vasoconstriction in arteries from both LZR and OZR. Antagonism of the TXA(2)/PGH(2) (TP) receptor mimicked the effects of COX-1 blockade in arteries from LZR but not OZR. Selective inhibition of COX-2 markedly reduced the vasodilatation induced by AA in OZR, but not in LZR, without altering 5-HT or ACh responses. COX-1 was widely distributed throughout the endothelial layer of coronary arteries from both LZR and OZR, while COX-2 protein, which was predominantly expressed in the endothelium, was significantly increased in arteries from OZR. Whereas AA is mainly metabolised to vasoconstrictor prostanoids via COX-1 in coronary arteries from healthy animals, endothelial COX-2 is up-regulated to produce vasodilator prostaglandins thus protecting coronary arteries in insulin resistant obese rats.
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PMID:Enhanced cyclooxygenase 2-mediated vasorelaxation in coronary arteries from insulin-resistant obese Zucker rats. 2095 3

Although sarpogrelate, a 5-HT(2A) receptor antagonist, has been reported to exert beneficial effects in diabetes, the mechanisms of its action are not understood. In this study, diabetes was induced in rats by an injection of streptozotocin (65 mg/kg) and the animals were assessed 7 weeks later. Decreased serum insulin as well as increased serum glucose, cholesterol, and triglyceride levels in diabetic animals were associated with increased blood pressure and heart/body weight ratio. Impaired cardiac performance in diabetic animals was evident by decreased heart rate, left ventricular developed pressure, rate of pressure development, and rate of pressure decay. Treatment of diabetic animals with sarpogrelate (5 mg/kg) or insulin (10 units/kg) daily for 6 weeks attenuated the observed changes in serum insulin, glucose, and lipid levels as well as blood pressure and cardiac function by varying degrees. Protein content for membrane glucose transporters (GLUT-1 and GLUT-4) was depressed in diabetic heart; the observed alteration in GLUT-4 was partially prevented by both sarpogrelate and insulin, whereas that in GLUT-1 was attenuated by sarpogrelate only. Incubation of myoblast cells with sarpogrelate and insulin stimulated glucose uptake; these effects were additive. 5-hydroxytryptamine was found to inhibit glucose-induced insulin release from the pancreas; this effect was prevented by sarpogrelate. These results suggest that sarpogrelate may improve cardiac function in chronic diabetes by promoting the expression of membrane glucose transporters as well as by releasing insulin from the pancreas.
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PMID:Mechanism of sarpogrelate action in improving cardiac function in diabetes. 2118 29

We analyzed the modulation of serotonin on the bradycardia induced in vivo by vagal electrical stimulation in alloxan-induced long-term diabetic rats. Bolus intravenous administration of serotonin had a dual effect on the bradycardia induced either by vagal stimulation or exogenous Ach, increasing it at low doses and decreasing it at high doses of 5-hydroxytryptamine (5-HT), effect reproduced by 5-carboxamidotryptamine maleate (5-CT), a 5-HT(1/7) agonist. The enhancement of the bradycardia at low doses of 5-CT was reproduced by 5-HT(1A) agonist 8-hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT) and abolished by WAY-100,635, 5-HT(1A) antagonist. Pretreatment with 5-HT(1) antagonist methiothepin blocked the stimulatory and inhibitory effect of 5-CT, whereas pimozide, 5-HT(7) antagonist, only abolished 5-CT inhibitory action. In conclusion, long-term diabetes elicits changes in the subtype of the 5-HT receptor involved in modulation of vagally induced bradycardia. Activation of the 5-HT(1A) receptors induces enhancement, whereas attenuation is due to 5-HT(7) receptor activation. This 5-HT dual effect occurs at pre- and postjunctional levels.
Exp Diabetes Res 2010
PMID:Peripheral 5-HT1A and 5-HT7 serotonergic receptors modulate parasympathetic neurotransmission in long-term diabetic rats. 2140 18


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