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)

The effects of 5-hydroxytryptophan on plasma concentrations of glucose and immunoreactive insulin were examined in conscious mice. Blood samples were obtained after anaesthetizing the mice lightly with ether at the desired time. Large doses of L-5-hydroxytryptophan (5HTP) (200-400 mg/kg IV) produced a dose-dependent hypoglycaemic response in fasted mice (e.g. control 5.7 +/- 0.2 mmol/l, 5HTP 400 mg/kg 2.6 +/- 0.3 mmol/l). This response was preceded by a significant elevation in the plasma immunoreactive insulin concentration (e.g. control 6 +/- 2 mU/l; 5HTP 400 mg/kg 53 +/- 7 mU/l). Induction of diabetes with alloxan (80 mg/kg IV 72 h previously) prevented the hypoglycaemic effect of 5HTP. Alloxan diabetes abolished the hyperinsulinaemic response to 100 mg/kg of 5HTP and reduced by 66% the response to 400 mg/kg of 5HTP. In alloxan diabetic mice 5HTP produced a marked hyperglycaemic response (control 17.9 +/- 2.0 mmol/l; 5HTP 100 mg/kg 36.1 +/- 2.3 mmol/l). In normal mice pre-treated with nialamide, a monoamine oxidase inhibitor, much lower doses of 5 HTP (5-10 mg/kg) were required to produce hypoglycaemia. There was no detectable elevation in the plasma insulin concentration accompanying the hypoglycaemic response to smaller doses of 5HTP in nialamide treated mice. The hyperinsulinaemic and hypoglycaemic actions of 5HTP in normal mice were prevented completely by pretreatment with benserazide, an inhibitor of aromatic amino acid decarboxylase. 5-hydroxytryptamine did not modify the plasma glucose concentration in either normal or nialamide-treated animals. It is concluded that the hypoglycaemic response to 5HTP in normal mice is mediated at least partly through an elevation in the plasma insulin concentration, although it is likely that additional mechanisms are involved.
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PMID:Further studies on the effects of 5-hydroxytryptophan on plasma glucose and insulin in the mouse. 700 Jun 1

Plasma glucose concentration was measured at 3-h intervals in streptozotocin-induced diabetic rats placed on various insulin replacement regimens using three different kinds of insulin. High insulin dosages produced at least periodic hypoglycemia, even though there were no overt signs of insulin overdose. Low- and single-dose regimens produced periods of hyperglycemia. Both high and low doses of protamine zinc insulin normalized diabetes-induced reductions in 5-hydroxyindole-3-acetic acid [5-HIAA; the principal metabolite of 5-hydroxytryptamine (5-HT)] and 5-HT turnover (5-HIAA/5-HT), despite the failure of the low-dose regimen to normalize plasma glucose. Diabetic rats evidenced continued hyperphagia and hyperdipsia during insulin treatment, and insulin treatment also induced hyperphagia and excessive weight gain in nondiabetic rats. Insulin treatment only partially normalized diabetes-induced adrenal hypertrophy. Adrenal hypertrophy is an indication of a continued stresslike physiological state in diabetes even during insulin therapy. This state may be involved in the enhanced risk in diabetic humans for development of anxiety disorders and clinical depression.
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PMID:Metabolic and neurochemical profiles in insulin-treated diabetic rats. 750 9

1. We have previously reported maximum responses to 5-hydroxytryptamine (5-HT) are diminished in endothelium-intact and -denuded aortae from rats with streptozotocin-induced diabetes of 2-weeks duration. 2. In the present study, the thromboxane A2/prostaglandin H2 (TP) receptor antagonist GR32191B (1 microM) significantly reduced maximum responses to 5-HT in endothelium-intact aortae from both control and diabetic rats. In the presence of GR32191B, maximum responses to 5-HT, in endothelium-intact aortae from diabetic rats, were still significantly reduced compared to those obtained in aortae from controls. 3. GR32191B (1 microM) had no significant effect on maximum responses to 5-HT in endothelium-denuded aortae from either control or diabetic rats. 4. Interaction between 5-HT (0.1 microM-0.1 mM) and threshold concentrations of endothelin-1 (ET-1) or the thromboxane (Tx)A2-mimetic, U46619, were examined in endothelium-intact and -denuded aortae from control and 2-week streptozotocin-diabetic rats. 5. Maximum responses to 5-HT in the presence of a threshold concentration of ET-1 (3 nM), in endothelium-intact aortae from diabetic rats, were not significantly different from those of control rats. 6. Maximum responses to 5-HT in the combined presence of ET-1 (3 nM) and GR32191B (1 microM), in endothelium-intact aortae from diabetic rats, were significantly reduced compared to those obtained in aortae from controls. 7. Maximum responses to 5-HT in the presence of ET-1 (3 nM) in endothelium-denuded aortae from diabetic rats were significantly reduced compared to those from controls. 8. Maximum responses to 5-HT in the presence of a threshold concentration of U46619 (20 or 30 nM),in endothelium-intact aortae from diabetic rats, were not significantly different from responses of controls.9. Maximum responses to 5-HT in the presence of a threshold (5-20 nM) concentration of U46619, in endothelium-denuded aortae from diabetic rats, were not significantly different from responses of controls.10 The results of the present study indicate that endothelial-derived TxA2 contributes to the contractile response to 5-HT in aortae from control and diabetic rats. Endothelial-derived TxA2 also appears to play a role in the potentiation of 5-HT responses by ET-1 in aortae from diabetic rats.
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PMID:Potentiation by endothelin-1 of 5-hydroxytryptamine responses in aortae from streptozotocin-diabetic rats: a role for thromboxane A2. 762 Jul 14

The aim of this study was to determine how the contractile responses to 5-hydroxytryptamine (5-HT) are altered in aortas from rats with streptozotocin-induced diabetes and to explore the possible mechanisms of the altered vascular reactivity to 5-HT in diabetes. In the presence of extracellular Ca2+ (2.5 mM), the contractile responses to stimulation of 5-HT2 receptors with 5-HT were greater in aortas from diabetic rats as compared with those from age-matched controls. Similarly, phorbol-12,13-dibutyrate (PDBu) (> or = 30 nM) induced significantly greater contractions in diabetic aortas. The enhanced contractile responses of diabetic aortas to 5-HT and PDBu were abolished in the presence of 1 microM nifedipine. Pretreatment with 20 nM staurosporine caused a complete inhibition of the contractile responses to 5-HT in both control and diabetic aortas. In contrast to those to 5-HT and PDBu, the contractile responses to high K+ (40 mM) were markedly diminished in diabetic aortas. The nifedipine-sensitive uptake of 45Ca2+ induced by 5-HT was significantly greater in diabetic aortas than in controls, whereas that induced by high K+ was significantly less in diabetics. The phasic contractions produced by 5-HT in Ca(2+)-free medium were significantly attenuated in diabetic aortas, but those produced by norepinephrine were unchanged. Accumulation of [3H]inositol monophosphate (IP1) in aortic strips prelabeled with myo-[3H]inositol was increased to a similar extent by 5-HT and norepinephrine in control rats, but the 5-HT-induced increase in [3H]IP1 accumulation was significantly less than the norepinephrine-induced one in diabetics. These findings indicate that the extracellular Ca(2+)-dependent contractions mediated by 5-HT2 receptors are enhanced in aortas from diabetic rats, and this is presumably related to a greater influx of Ca2+ through transmembrane Ca2+ channels as a consequence of increased protein kinase C activated processes. On the other hand, the contraction induced by release of Ca2+ from intracellular stores in response to 5-HT is diminished in these tissues, possibly due to the impaired phosphoinositide response.
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PMID:Enhanced 5-HT2 receptor mediated contractions in diabetic rat aorta: participation of Ca2+ channels associated with protein kinase C activity. 765 79

A long-term study to identify age-dependent alterations in vascular reactivity in obese Zucker rats, a model for non-insulin-dependent diabetes mellitus, was carried out. On aortic rings of 12-week-old obese Zucker rats, but not in older animals (36 and 52 weeks), the following different effects in comparison to the lean rat control group were observed: (i) a significantly enhanced maximal relaxation to acetylcholine and A23187, which was abolished by the nitric oxide-synthase inhibitor L-nitro-arginine methyl ester (L-NAME); relaxation of aortic rings to the endothelium-independent vasodilator nitroglycerin was similar; (ii) more pronounced maximal 5-hydroxytryptamine-induced-contractions in the presence of L-NAME, and (iii) a more pronounced reduction in phenylephrine-induced contractions by verapamil. These results are suggestive of an altered calcium metabolism in the first weeks of development in the obese rat strain, which is probably responsible for the hypotension seen in this early time period.
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PMID:Age-related changes in vascular reactivity in genetically diabetic rats. 779 11

1. Venous resistance contributes very little to total peripheral resistance; more than half of the total blood volume, however, is contained in the extrathoracic veins. Owing to marked differences between venous and arterial anatomy and physiology, studies on veins and arteries usually require different methodological approaches. Whereas for arteries the most relevant parameters are resistance, pressure and flow, for veins volume and compliance are most important. For studies of general aspects of the peripheral circulatory system, venous occlusion plethysmography is probably the most useful method. The determination of both the rate of rise in limb volume and the total volume rise after inflating a proximally applied occlusion cuff to a subdiastolic pressure permits the concomitant estimation of both arterial flow and venous compliance. 2. Studies of direct pharmacological or physiological effects on veins, interactions of various pharmacological or physiological stimuli, or pathophysiological changes in venous responsiveness have been facilitated by the development of investigational techniques relying on direct measurements of the compliance of single human veins in vivo. One of these, relying on the use of a linear variable differential transformer (LVDT) for determining changes in the compliance of superficial veins at a standardized congestion pressure, has been found very suitable for the practical application in both patients and healthy subjects. 3. Physiological studies were carried out on the effect of age, exercise, temperature, and the menstrual cycle on venous compliance and venous responsiveness to various stimuli. In addition, interindividual variability in venous responsiveness in monozygotic and dizygotic twins and in unrelated subjects was investigated, and studies on the function of the endothelium were carried out in man in vivo. 4. Pathophysiological studies using this technique were reported from patients with hypertension, orthostatic hypotension, myocardial infarction, varicosis, cystic fibrosis, asthma, diabetes, systemic sclerosis, and cluster headache. 5. Clinical pharmacological studies represent a most important field for the use of this method. Studies were carried out on the effects of a large number of constrictor and dilator agents, and also on drug interactions on human veins in vivo. Venoconstriction was observed after local administration of alpha-adrenoceptor and 5-HT-receptor agonists, ergot derivatives, angiotensinogen, angiotensin I and II, and several prostaglandins. 6. Owing to the low venous tone present under effects can usually be quantified only on veins e.g. noradrenaline or 5-hydroxytryptamine. Under these conditions dilatation was observed after the administration of beta-adrenoceptor agonists, cholinergic (muscarinic) agonists, nitrates, calcium antagonists, bradykinin, substance P and several prostaglandins.
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PMID:Clinical pharmacology, physiology and pathophysiology of superficial veins--1. 782 19

Insulin administration can cause or worsen experimental and human diabetic neuropathy ("insulin neuritis"). In this study, we tested the hypothesis that insulin administration impairs tissue oxygenation. We infused insulin under nonhypoglycemic conditions and evaluated its effect on endoneurial oxygen tension, nerve blood flow, and the oxyhemoglobin dissociation curve of peripheral nerve in normal and diabetic rats. Intravenous insulin infusion resulted in a dose-dependent reduction in endoneurial oxygen tension in normal nerves (from 26% at 0.04 U/kg insulin to 55% at 32 U/kg). The nerves of rats with streptozotocin-induced diabetes were resistant, but with control of hyperglycemia this susceptibility to the endoneurial hypoxic effect of insulin returned. The reduction in endoneurial oxygen tension regressed with glycosylated hemoglobin (Y = 53.8-2.7X, where Y = %reduction in endoneurial oxygen tension and X = HbA1; r = 0.87; P = < 0.001). Diabetes or insulin administration resulted in only minimal and physiologically insignificant alterations in the oxygen dissociation curve and 2,3-diphosphoglycerate of sciatic nerve. Instead, insulin administration resulted in a reduction in nerve nutritive blood flow and an increase in arteriovenous shunt flow. When the latter was eliminated by the closure of arteriovenous shunts (infusion of 5-hydroxytryptamine), endoneurial oxygen reverted to normal. These findings indicate a deleterious vasoactive effect of insulin and may explain the development of insulin neuritis.
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PMID:Hypoxic effect of exogenous insulin on normal and diabetic peripheral nerve. 802 30

Kinetic studies were conducted on the contractile response elicited by phenylephrine (PE) and 5-hydroxytryptamine (5-HT) activation of the alpha 1-adrenergic- and 5-HT2 receptor subtypes, respectively, in aortic rings isolated from streptozotocin (STZ)-diabetic and age-matched control rats. The maximal PE- and 5-HT-induced contractile responses were separated into distinct phasic and tonic components, and the tonic portion of the response was assessed by evaluation of the calculated maximal rate constant for onset of contraction (kobsmax; min-1). Statistical analysis revealed that the mean kobsmax values for PE alone (10 microM), 5-HT alone (10 microM) and mixtures of PE and 5-HT (10 microM each) were significantly greater in diabetic animals than in age-matched control animals. These increases in kobsmax resulted in significant diabetes-related increases in the rate and relative magnitude of response generation during the initial minutes of contraction. Such observations emphasize the importance of kinetic studies, and given the central role played by the aorta in cardiovascular homeostasis, suggest that altered aortic contractility may play a role in some aspects of diabetic vascular disease. Moreover, if these kinetic alterations reflect a more generalized feature of diabetic vasculature (e.g., resistance vessels), then it is conceivable that such changes may further exacerbate diabetic vasculopathy.
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PMID:Augmentation in the kinetic characteristics of phenylephrine- and 5-hydroxytryptamine-induced contractions in the isolated rat aorta following eight weeks of STZ-diabetes. 807 77

1. The responsiveness of isolated aortic rings from 1, 4 and 12 week streptozotocin-induced diabetic rats to noradrenaline (NA) and 5-hydroxytryptamine (5-HT) were compared with those of non-diabetic controls under standard organ bath procedure. 2. There were significant increases in the maximum contractile responses to both agents after 1 and 4 weeks but not after 12 weeks of diabetes mellitus. 3. The variable responses show that duration-dependent functional changes occur in the course of streptozotocin diabetes in rats.
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PMID:Duration-dependent variability in the responses of diabetic rat aorta to noradrenaline and 5-hydroxytryptamine. 848 2

Increased oxidative stress has been suggested to contribute to disturbances in the regulation of coronary flow and the increased cardiac risk in diabetes mellitus. Using the isolated perfused heart of streptozotocin-diabetic rats our study shows that basal and maximal coronary flow (tested by infusion of sodium nitroprusside) are not altered in diabetes, but that 5-hydroxytryptamine (5-HT) stimulated endothelium-dependent increase in coronary flow becomes progressively impaired. This defect of the endothelium-dependent vasodilatation was prevented by perfusion of the hearts with superoxide dismutase and pretreatment of the diabetic rats with tocopherol-acetate. Morphological studies also revealed that pretreatment with tocopherol-acetate was cardioprotective, and largely prevented severe alterations of myocardial structure typically observed after a diabetes duration of 3 months; deterioration and fragmentation of myofilament bundles were seen less, and the numbers of areas of focal necrosis and of contraction bands were clearly reduced. In contrast to untreated diabetic hearts the autonomic nerve fibers detected by catecholamine fluorescence were running in parallel in hearts of tocopherol-treated diabetic rats, and the amount of catecholamines was not different from that of healthy control rats. Trichrome staining and immunohistochemical staining of collagen I and III showed a dramatic increase in number and the size of deposits of collagen fibers at precapillary locations in the diabetic hearts which were significantly reduced by anti-oxidative treatment. These findings demonstrate that oxidative stress may not only play a major role in the impairment of endothelium-dependent regulation of coronary flow, but also in the development of perivascular fibrosis and severe changes of the autonomic nerves and contractile system in myocardium.
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PMID:Endothelial relaxation is disturbed by oxidative stress in the diabetic rat heart: influence of tocopherol as antioxidant. 869 Jan 67


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