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

Treatment by a beta 1-beta 2-adrenoceptor antagonist has been much used during pathological pregnancies. These agents can reduce the oxygen consumption of the myocardium, increase the coronary blood flow towards ischemic heart areas and improve return of venous blood flow towards the heart. The aim of this study was to determine the mechanism of action of this agent and to investigate whether a total beta-adrenoceptor antagonist could reduce the fetoplacental disorders elicited in streptozotocin-diabetic pregnant rats. Diabetes was engendered on day 7.5 of pregnancy, and the animals were studied on day 21. Untreated nondiabetic rats or nondiabetic rats treated with propranolol, a total beta-adrenoceptor blocker (2 mg kg-1/ day, i.p.), had a healthy placenta without vascular disturbances, with normal arterial blood velocity in the uterine artery, placenta, umbilical cord and fetal aorta, and showed eutrophic fetuses (3.9 +/- 0.0 g, mean +/- SEM). Untreated diabetic rats had severe placental lesions, with a reduction of arterial blood velocity in the uterine artery (p < 0.01), placenta (p < 0.01) and umbilical artery (p < 0.05), and exhibited fetal hypotrophy (2.3 +/- 0.1 g, mean +/- SEM, p < 0.001) compared with nondiabetic untreated rats. Treatment of diabetic rats with propranolol (2 mg kg-1/day, i.p.) enhanced fetal weight (3.66 +/- 0.2 g) and slightly increased fetal insulin secretion, restored arterial blood velocity to control values in the uterine artery and fetal aorta and reduced placental lesions. In conclusion, our results suggest that the beneficial effects of propranolol were at least in part related to an improvement of uteroplacental hemodynamics; it induced a better redistribution of the blood towards the placenta and the fetal systemic circulation. Propranolol treatment could protect cell membranes against free oxygen radicals and lipid peroxidation, involved in the pathogenesis of ischemic injury in diabetes.
 ...
PMID:Beneficial effect induced by a beta-adrenoceptor blocker on fetal growth in streptozotocin-diabetic rats. 909 96

The beta 3 subtype of adrenaline and noradrenaline receptors has now been extensively characterized at the structural and functional levels. Ligand binding and adenylyl cyclase activation studies helped define a beta-adrenergic profile that is quite distinct from that of the beta 1- and beta 2-adrenergic receptors, but strongly reminiscent of most of the "atypical" responses reported in earlier pharmacologic studies. Human, other large mammal, and rodent receptors share most of the characteristic beta 3 properties, although obvious species-specific differences have been identified. Recently, the incidence of a naturally occurring variant of the human beta 3-adrenergic receptor was shown to be correlated with hereditary obesity in Pima Indians and in Japanese individuals, and in Western obese patients with increased dynamic capacity to add on weight and develop non-insulin-dependent diabetes mellitus (NIDDM). A mild weight increase was also shown to develop in female, but not male, mice in which the beta 3 receptor gene was disrupted. Taken together, these results now provide a consistent picture of an important role of the beta 3-adrenoceptor in the regulation of lipid metabolism and as an obvious target for drugs to treat some forms of obesity.
 ...
PMID:Structure and function of the beta 3-adrenergic receptor. 913 Dec 60

The anti-obesity and anti-diabetic effects of a highly specific beta 3-adrenoceptor agonist, CL316,243 (CL; beta 1: beta 2: beta 3 = 0:1:100,000), were investigated in Otsuka Long-Evans Tokushima Fatty (fatty) and Long-Evans Tokushima Otsuka (control) rats. Daily injection of CL (0.1 mg/kg, s.c.) to these rats (10 weeks old) for 14 weeks caused a significant reduction in body weight (fatty, 27%; control, 15%), associated with a marked decrease in fat pad weight (inguinal: fatty, 60%; control, 36%; retroperitoneal: fatty, 75%; control, 77%) without affecting food intake. The levels of uncoupling protein mRNA and protein levels of uncoupling protein (UCP), as well as guanosine 5'-diphosphate-binding (a reliable index of thermogenesis) in brown adipose tissue, were lower in the fatty than in the control rats. However, after CL treatment, these parameters in brown adipose tissue increased significantly 2- to 3-fold in both groups. Furthermore, uncoupling protein was induced in white adipose tissue as well as in brown adipose tissue. The fatty rats showed hyperglycemia and hyperinsulinemia during the glucose tolerance test, but CL ameliorated these parameters. These findings suggest that decreased thermogenesis in brown adipose tissue may be one of the causes of obesity in the fatty rats and that administration of CL prevents obesity by decreasing white fat mass, by activating brown adipose tissue thermogenesis, and by inducing uncoupling protein in white adipose tissue. Furthermore, CL treatment may inhibit diabetes mellitus by ameliorating obesity and by activating glucose transporter 4 in white adipose tissue and brown adipose tissue.
 ...
PMID:Anti-obesity and anti-diabetic effects of CL316,243, a highly specific beta 3-adrenoceptor agonist, in Otsuka Long-Evans Tokushima Fatty rats: induction of uncoupling protein and activation of glucose transporter 4 in white fat. 915 Jun 93

Diabetic cardiomyopathy has been associated with a decrease in Na,K-ATPase activity and expression, as well as alterations in membrane lipid composition. The aim of this study was twofold: 1) to document in rats the effect of streptozotocin-induced diabetes on myocardial Na,K-ATPase and fatty acids, and 2) to evaluate the potential effect of a dietary supplementation with fish oil (n-3 fatty acids) on the streptozotocin-induced changes. Assays were performed in purified cardiac plasma membranes to determine Na,K-ATPase activity, expression of the different alpha- and beta-subunits of Na,K-ATPase, and the fatty acid content of total phospholipids. Relative abundance of the mRNAs encoding the alpha 1, alpha 2 and beta 1 isoforms was studied by Northern blot analysis. Results demonstrated that diabetes significantly decreased activities of alpha 1 and alpha 2 isoforms and mRNA levels of alpha 2 and beta 1 isoforms, and, at the protein level, increased alpha 1-isoforms and decreased both alpha 2- and beta 1-isoforms. Changes in fatty acid content of the membrane were consistent with inhibition of desaturase. Fish-oil supplementation produced an increase in membrane incorporation of eicosapentaenoic acid. It also increased the level of beta 1-isoforms and restored the activity of the alpha 2-isoenzyme without significant changes in the level of alpha 1- and alpha 2-isoforms. Northern blot analysis showed no effect of fish oil supplementation. Experimental diabetes and prevention by the fish oil rich (n-3 fatty acids) diet induced specific effects on the activity and expression of alpha and beta Na,K-ATPase subunit isoforms. These studies suggest that fish oil therapy may be effective in preventing some of the adverse consequences of diabetes.
 ...
PMID:Alteration of Na,K-ATPase isoenzymes in diabetic cardiomyopathy: effect of dietary supplementation with fish oil (n-3 fatty acids) in rats. 916 16

The effects of aging and diabetes on the distribution of beta-adrenoceptor subtypes in the gut were investigated in the BB rat. [125I]Cyanopindolol binding to 10-micron sections was evaluated using film autoradiography. Cyanopindolol binding to beta-, beta 1-, and beta 2-adrenoceptors was displaced by 1 microM propranolol, 50 nM ICI-89-406, and 100 nM ICI-118-551, respectively. beta-Adrenoceptor binding was highest in the circular muscle of proximal colon and lowest in the pylorus of 4- to 5-month-old rats. Aging (8- to 10-month-old vs. 4- to 5-month-old rats) was associated with increased beta-adrenoceptor binding in the pylorus and reduced binding in the proximal colon. Diabetes had a time-dependent effect on the level of beta-adrenoceptor binding. It was increased in the antral and pyloric stomach but longer periods of diabetes caused a reduction in beta-adrenoceptor binding in the pylorus. Those in the intestine were reduced time-dependently and involved beta 1- or beta 2-adrenoceptors or both.
 ...
PMID:Distribution of beta-adrenoceptor subtypes in gastrointestinal tract of nondiabetic and diabetic BB rats. A longitudinal study. 920 Oct 75

The literature on the influence of diabetes on cardiac beta-adrenoceptors is still a matter of controversy. Hence, in the present study, the responsiveness of spontaneously beating right atria from streptozotocin (STZ)-diabetic rats to beta-adrenoceptor agonists were compared with those from non-diabetic controls. The responsiveness of right atria from 8-week diabetic rats to the chronotropic effects of isoprenaline, noradrenaline and fenoterol was found to be unchanged. As the disease progressed, on the other hand, the diabetic atria were found to have decreased responsiveness to the chronotropic effects of noradrenaline. The pD2 value and maximum chronotropic effect of noradrenaline were decreased in 14-week diabetic right atria when compared with those from age-matched controls. A significant decrease in the maximum chronotropic response to isoprenaline with no change in pD2 value was also observed in 14-week diabetes. These results suggest that beta 1--but not beta 2-adrenoceptor mediated chronotropic responses were reduced in the right atria due to the increase in the duration of diabetes. On the other hand, the inotropic responses to beta-adrenoceptor agonists were also assessed on diabetic and nondiabetic human atrial tissue. There were no significant differences in the inotropic responses to each agonists in either of the diabetic and nondiabetic human atrial tissues. The full agonist potency order was isoprenaline > or = fenoterol > noradrenaline.
Diabetes Res Clin Pract 1998 May
PMID:The effects of diabetes on beta-adrenoceptor mediated responsiveness of human and rat atria. 968 Dec 76

When used as first-line treatment, any monotherapy selected from one of the main classes of agents for the management of slight to moderate arterial hypertension cannot be expected to have a success rate exceeding 60%. However, this level of efficacy approaches 80% if two classes of antihypertensive drugs with complementary modes of action are combined--a notable example being the combination of a beta-blocker, atenolol 50 mg, and a calcium antagonist, sustained-release nifedipine 20 mg. This fixed combination provides efficacy and tolerability in the treatment of arterial hypertension. Atenolol has beta-adrenolytic properties similar to those of propranolol, the most commonly named comparator drug. Atenolol is a selective beta 1-adrenergic antagonist with negative chronotropic, bathmotropic, dromotropic and inotropic actions. Because of its selectivity, it induces only moderate vasoconstriction. Its cardioselective nature diminishes the risk of bronchospasm, an event commonly induced by this type of drug. Atenolol reduces renin secretion from the renin-angiotensin system and consequently decreases the production of angiotensin II and plasma aldosterone. The renal effects of atenolol are an increase in both diuresis and natriuresis, with a reduction in the renal plasma flow. beta-Adrenergic antagonists in general modify carbohydrate metabolism and may mask the precursor signs of hypoglycaemia. They have a negligible effect upon lipid metabolism and practically no effect on total or high density lipoprotein cholesterol levels. Nifedipine belongs to the class of dihydropyridines. It acts by blocking the influx of calcium ions through the slow channels. Although a potent vasodilating agent, nifedipine does not induce tachycardia or water-sodium retention. The negative inotropic effect observed in vitro has not been reported in humans; the coronary dilatation produced by nifedipine is indisputable, both in unstable angina and exertional or exercise-induced angina. However, its cardioprotective effect remains questionable outside the context of recent-onset atheromatous plaques. Nifedipine increases renal blood flow and is practically devoid of diabetes-inducing factors. The fixed combination of atenolol 50 mg and sustained release nifedipine 20 mg offers a particularly interesting complementary action, the beta-blocker reducing the dihydropyridine-induced activation of the sympathetic nervous system and the latter reducing the vasoconstriction induced by the beta-blocker. Compared with each agent used alone, the pharmacokinetic profiles of atenolol and nifedipine remain unmodified by their administration in the fixed combination.
 ...
PMID:[Pharmacologic importance of the combination atenolol/nifedipine in hypertensive patients]. 981 39

Selection of beta-adrenergic blockers for formulary addition can be a difficult task, especially with the increasing availability of new beta-blockers, as well as the numerous differences in pharmacodynamic and pharmacokinetic properties of currently available agents. Nevertheless, appropriate evaluation of the important characteristics of beta-blockers should allow selection of the most cost-effective agents for formulary addition. Most importantly, differences in efficacy, product formulation and cost should be carefully considered when making formulary decisions. Notably, evidence from clinical trials indicates differences in efficacy among beta-blockers for post-myocardial infarction prophylaxis, situational anxiety, essential tremor, thyrotoxicosis, migraine prophylaxis and prevention of bleeding associated with oesophageal varices. For many clinical situations, it is also important to select an effective agent that is available in both an oral and intravenous formulation, especially for cardioprotection after acute myocardial infarction and for use in supraventricular arrhythmias. In addition, availability of sustained release products and generic formulations should be considered for their potential to increase compliance and decrease cost, respectively. Comparative drug costs, as well as costs associated with decreased compliance, should also be carefully evaluated. Differences in beta-receptor selectivity, duration of action and presence of intrinsic sympathomimetic activity (ISA) are also important considerations in the selection of beta-blockers for formulary consideration. Although degree of selectivity is relative, beta 1-selective agents may be less likely to induce bronchospasm in patients with chronic obstructive pulmonary disease (COPD) and may be less likely to affect glucose homeostasis in patients with diabetes mellitus. Duration of action of a beta-blocker is an important consideration for evaluation of efficacy throughout the recommended dosage interval. In addition, beta-blockers with a long duration of action can often be administered once or twice daily, potentially leading to increased compliance and thereby improved effectiveness and economic efficiency. The presence of ISA is an important consideration because certain beta-blockers with ISA may be less effective than those without ISA for certain indications. Factors considered to be less important when making formulary decisions of choice of beta-blockers include the route of elimination, lipophilicity and presence of membrane stabilising activity.
 ...
PMID:Formulary considerations in selection of beta-blockers. 1015 Jan 54

Beta 3-adrenoceptor (beta 3-AR) agonists were found to have remarkable anti-obesity and anti-diabetic effects in rodents shortly after their discovery in the early 1980s. Despite these promising qualities, several pharmaceutical problems and theoretical concerns have slowed the development of these products as therapeutic agents in humans during the last 15 years. To date, the pharmaceutical industry has not been successful in developing a beta 3-AR agonist for use in the treatment of human obesity and type 2 diabetes. Pharmaceutical problems in this area concern important differences between rodent and human beta 3-AR and the difficulty in finding a compound with sufficient bioavailability that is a highly selective and full agonist at the human receptor. Some of these problems seem to have been solved with the cloning of the human beta 3-AR, which has made it possible to develop novel compounds directly and specifically against the human receptor. However, several theoretical concerns still remain. These include the major question as to whether the number of biologically active beta 3-ARs in adult humans is sufficient to produce relevant metabolic effects and, if so, whether their long-term stimulation is safe and free of unwarranted side effects. In addition, the mechanisms of action of beta 3-AR agonists remain poorly understood. Recent studies using CL 316,243, a highly selective beta 3-adrenergic compound, have provided new insights into the potential mechanisms of action of these drugs in rodents as well as the first evidence that treatment with a highly selective beta 3-AR agonist exerts relevant metabolic effects in humans. It appears that chronic beta 3-adrenergic stimulation in white adipose tissue increases the expression of newly discovered mitochondrial uncoupling proteins (UCP 2 and 3) and a "reawakening" of dormant brown adipocytes. In addition, beta 3-ARs may be present in skeletal muscle where ectopic expression of UCP-1 has been reported. If these findings are confirmed, tissues other than brown fat may play an important role in mediating beta 3-adrenergic effects on thermogenesis and substrate oxidation. In humans, treatment with CL 316,243 for 8 weeks, in spite of limited bioavailability, induced marked plasma concentration-dependent increases in insulin sensitivity, lipolysis, and fat oxidation in lean volunteers, without causing beta 1-, or beta 2-mediated side effects. These results clearly indicate that favourable metabolic effects can be achieved by selective beta 3-AR stimulation in humans. The compounds of the next generation currently emerging from preclinical development are full agonists at the human beta 3-AR. These agents have demonstrated promising results in non-human primates. It will be interesting to see whether their efficacy in clinical trials is superior to that achieved with previous (rodent) beta 3-AR agonists and, if so, whether their effects will eventually translate into weight loss and improved metabolic control that could facilitate their use as effective drugs for the treatment of obesity and Type 2 diabetes in humans.
Diabetes Metab 1999 Mar
PMID:Development of beta 3-adrenoceptor agonists for the treatment of obesity and diabetes--an update. 1033 19

Heart failure is one of the commonest debilitating conditions of industrialized society, with mortality and morbidity comparable with that of the common neoplastic diseases. The role of beta-blockers in heart failure has been the subject of debate for many years. The results of recent prospective, placebo-controlled studies of the addition of beta-blockers to standard therapy in patients with chronic heart failure have confirmed a significant beneficial effect on ventricular function, clinical status, morbidity and mortality. The importance of these trials suggests that beta-adrenergic blocker therapy can save one life out of every 35 patients treated with mild-to-moderate heart failure. These major trials have used one of four beta-blockers (metoprolol, bisoprolol, carvedilol, or bucindolol) in varying study designs with different patient populations. Beta-blockers improve function of the failing left ventricle, prevent or reverse progressive left ventricular dilation, chamber sphericity, and hypertrophy, and consequently have a positive impact on cardiac remodeling. Beta-blockers also reduce heart rate and left ventricular wall stress, leading to reduced myocardial oxygen consumption, a clear benefit to the failing heart. Moreover, beta-blockers can improve the intrinsic contractile function of cardiomyocytes and have been shown to improve myocardial energetics in heart failure, possibly through desirable changes in substrate utilization. Many important clinical questions still remain unanswered. These questions include whether beta-blockers are of benefit in patients with severe NYHA functional class (IIIB-IV), in patients with asymptomatic left ventricular dysfunction, in the extreme elderly, in patients with diabetes mellitus and renal impairment. Furthermore, it is not clear whether beta-blockade by itself is the real mechanism of clinical benefit. Although certain effects of beta-blockers may be considered class effects, it is not yet clear whether there are differences between beta 1-selective antagonists and nonselective agents. Major studies are currently being undertaken to address the above questions.
 ...
PMID:[Critical analysis of beta blockers in heart failure: certainty and incompleteness]. 1099 6


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>