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)

Alterations in the flow of blood to and from the penis are thought to be the most frequent causes of male erectile dysfunction and, therefore, the present review focuses on the penile vasculature. In the flaccid state, tonic noradrenaline release from the sympathetic nerves contracts penile arterial and corporal smooth muscle through activation of postjunctional alpha(1)-adrenoceptors, both by increasing intracellular calcium and by enhancing the sensitivity of the contractile apparatus for calcium. In addition, noradrenaline inhibits vasodilatatory neurotransmitter release by prejunctional alpha(2)-adrenoceptors. The exact role of the sympathetic neurotransmitters, neuropeptide Y and adenosine 5'-triphosphate, in erection is largely unknown. Penile vasodilatation during erection is mediated by nitric oxide (NO) through activation of guanylyl cyclase in the smooth muscle layer, followed by increases in cyclic guanosine monophosphate lowering of intracellular calcium and desensitisation of the contractile apparatus for calcium. Acetylcholine, vasoactive intestinal peptide as well as peptides in sensory nerves probably also play a role in penile vasodilation. Increased flow through the penile arteries stimulates the endothelium leading to release of NO, prostanoids and a non-NO non-prostanoid factor, and as such enhances the vasodilatation, while the role of endothelium-derived contractile factors in penile vasoconstriction is not clear. Erectile dysfunction shares arterial risk factors with ischaemic heart disease, and diabetes, age, and hypercholesterolaemia are associated with impairment of both neurogenic and endothelium-dependent vasodilator mechanisms in corpus cavernosum. Only few studies have investigated the impact of these risk factors on the penile vasculature, although recent evidence suggests that arterial insufficiency precedes changes in corpus cavernosum leading to erectile dysfunction.
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PMID:Penile arteries and erection. 1218 19

The incidence of erectile dysfunction (ED), defined as the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance, increases with age and with risk factors for vascular disease, including smoking, diabetes and hypertension. Penile erection results from an arousal-induced synthesis of nitric oxide (NO) in nonadrenergic-noncholinergic nerves (NANC), endothelial cells and cavernosal smooth muscle cells (SMCs). Vasodilation and relaxation of cavernosal SMCs engorges the corpora cavernosa with blood at arterial pressure. The subcellular mechanism by which tumescence occurs involves NO-induced activation of soluble guanylate cyclase, increased cyclic guanosine monophosphate (cGMP) levels and activation of cGMP-dependent protein kinase (PKG). PKG phosphorylates numerous ion channels and pumps, each promoting a reduction in cytosolic calcium. In particular, PKG activates high-conductance Ca2+(-)sensitive K+ (BKCa) channels, which hyperpolarize the arterial and cavernosal SMC membranes, causing relaxation. This mechanism appears to be compromised with age and with vascular disease, leading to ED. Thus, increasing cavernosal nitric oxide synthase (NOS) expression, cGMP levels and/or BKCa channel expression is an effective therapy for experimental ED. Future therapies may involve augmenting K+ channel expression by gene transfer or increasing channel function through the use of Type 5 phosphodiesterase (Type 5 PDE) inhibitors or phosphatase inhibitors.
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PMID:Potassium channels and erectile dysfunction. 1237 24

Sildenafil citrate is the first oral phosphodiesterase type 5 inhibitor approved for the treatment of erectile dysfunction. The wide use of sildenafil by patients with erectile dysfunction and cardiovascular disease has resulted in a considerable number of independent studies investigating the cardiovascular safety and functional role of the phosphodiesterase type 5-cyclic guanosine monophosphate-nitric oxide pathway in the cardiovascular system. Endothelial dysfunction, defined as a reduction in the bioavailability of nitric oxide, is associated with many of the common risk factors for cardiovascular disease and erectile dysfunction. Sildenafil has been demonstrated to improve the vasomotor aspect of endothelial dysfunction in patients with heart failure and diabetes. Hemodynamic studies suggest that sildenafil is a modest vasodilator with the potential to increase coronary blood flow and coronary flow reserve. In patients with ischemic heart disease, sildenafil is associated with reductions in mean arterial and pulmonary pressure with little effect on heart rate, cardiac output, and systemic or pulmonary vascular resistance. The absence of an effect on cardiac output supports the lack of an inotropic effect of sildenafil. This is consistent with the finding that sildenafil has no effect on cyclic adenosine monophosphate levels in the vasculature. Finally, exciting reports have emerged from clinical experience with the use of phosphodiesterase type 5 inhibitors in patients with pulmonary hypertension.
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PMID:Coronary and systemic hemodynamic effects of sildenafil citrate: from basic science to clinical studies in patients with cardiovascular disease. 1241 49

Glucagon-like peptide-1 (GLP-1) acts through its G-protein-coupled receptor to enhance glucose-stimulated insulin secretion from pancreatic beta-cells. This is believed to result from modulation of at least two ion channels: ATP-sensitive K(+) (K(ATP)) channels and voltage-dependent Ca(2+) channels. Here, we report that GLP-1 receptor signaling also regulates the activity of beta-cell voltage-dependent K(+) (K(V)) channels, themselves potent glucose-dependent regulators of insulin secretion. GLP-1 receptor activation with exendin 4 (10(-8) mol/l) in rat beta-cells antagonized K(V) currents by 43.3 +/- 6.3%, whereas the GLP-1 receptor antagonist exendin 9-39 had no effect. The effect of GLP-1 receptor activation on K(V) currents could be replicated (current reduction of 55.7 +/- 6.0%) by G-protein activation with GMP-PNP (10 nmol/l). The cAMP pathway antagonist Rp-cAMPS (100 micro mol/l) prevented current inhibition by exendin 4, implicating cAMP signaling in GLP-1 receptor modulation of beta-cell K(V) currents. Finally, exendin 4 (10(-8) mol/l) increased the amplitude (130 +/- 5.7%) and duration (285 +/- 15.9%) of the beta-cell depolarization response to current injection, independent of any effect on K(ATP) or Ca(2+) channels. The present results demonstrate that GLP-1 receptor signaling can antagonize beta-cell repolarization by reducing voltage-dependent K(+) currents, an effect likely to contribute to GLP-1's glucose-dependent insulinotropic effect.
Diabetes 2002 Dec
PMID:Glucagon-like peptide-1 receptor activation antagonizes voltage-dependent repolarizing K(+) currents in beta-cells: a possible glucose-dependent insulinotropic mechanism. 1247 88

The role of low testosterone levels in erectile dysfunction (ED) remains unclear. Both organic and psychogenic factors contribute to ED, with vasculogenic causes being the most common etiology. Approximately 10-20% of patients with ED are diagnosed with hormonal abnormalities. At the physiologic level, two second messenger systems are involved in mediating erections, one involving cyclic adenosine monophosphate (cAMP) and the other involving cyclic guanosine monophosphate (cGMP). PDE5 inhibitors such as sildenafil promote the cGMP pathway, while alprostadil affects the cAMP pathway. Evidence is strong that, in animal systems, testosterone has direct effects on erectile tissue. However, although testosterone clearly has an impact on libido in humans, its effect on penile function is less clear. Evaluation of ED includes medical, sexual, and psychosocial history assessments, as well as laboratory tests to check for diabetes and hormonal abnormalities. Initial interventions should involve correction of potentially reversible causes of ED, such as hypogonadism. First-line therapy for other patients is typically oral PDE5 inhibitors, such as sildenafil, tadalafil, or vardenafil. For patients who fail treatment with PDE5 inhibitors, local therapies such as intracavernous alprostadil are highly successful. Recent data also support the success of combination therapy with sildenafil and testosterone. This opens the possibility of other combinations of testosterone and other treatments of ED. The ability to exploit multiple pathways in the physiologic processes leading to erection may help improve therapy for ED.
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PMID:Hypogonadism and erectile dysfunction: the role for testosterone therapy. 1293 45

Erectile dysfunction (ED) often is caused by endothelial dysfunction and may be a sign that a patient has vascular disease elsewhere in the body. Risk factors for coronary artery disease such as lipid abnormalities, smoking, diabetes, and hypertension also are risk factors for ED. Oral therapy for ED, such as sildenafil, inhibits phosphodiesterase-5 (PDE-5) and the breakdown of cyclic guanosine monophosphate. PDE-5 inhibitors have been shown to be safe and effective for the therapy for ED, but remain contraindicated in patients receiving organic nitrates. These agents are mild vasodilators and are being investigated for their treatment potential for patients with pulmonary hypertension, heart failure, and endothelial dysfunction.
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PMID:Erectile dysfunction in the cardiac patient. 1462

Aradigm Corporation has developed an inhaled form of insulin using its proprietary AERx drug delivery system. The system uses liquid insulin that is converted into an aerosol containing very small particles (1-3 micro in diameter), and an electronic device suitable for either the rapid transfer of molecules of insulin into the bloodstream or localised delivery within the lung. The AERx insulin Diabetes Management System (iDMS), AERx iDMS, instructs the user on breathing technique to achieve the best results. Aradigm Corporation and Novo Nordisk have signed an agreement to jointly develop a pulmonary delivery system for insulin [AERx iDMS, NN 1998]. Under the terms of the agreement, Novo Nordisk has exclusive rights for worldwide marketing of any products resulting from the development programme. Aradigm Corporation will initially manufacture the product covered by the agreement, and in return will receive a share of the overall gross profits from Novo Nordisk's sales. Novo Nordisk will cover all development costs incurred by Aradigm Corporation while both parties will co-fund final development of the AERx device. Both companies will explore the possibilities of the AERx platform to deliver other compounds for the regulation of blood glucose levels. Additionally, the agreement gives Novo Nordisk an option to develop the technology for delivery of agents outside the diabetes area. In April 2001, Aradigm Corporation received a milestone payment from Novo Nordisk related to the completion of certain clinical and product development stages of the AERx drug delivery system. Profil, a CRO in Germany, is cooperating with Aradigm and Novo Nordisk in the development of inhaled insulin. Aradigm and Novo Nordisk initiated a pivotal phase III study with inhaled insulin formulation in September 2002. This 24-month, 300-patient trial is evaluating inhaled insulin in comparison with insulin aspart. Both medications will be given three times daily before meals in addition to basal insulin administered once or twice daily. In 2003, the US FDA adopted new GMP guidelines requiring sterile production of inhalation products and their devices. Novo Nordisk, therefore, will need to repeat phase III studies following device optimisation. These studies may begin at the end of 2004 and will include efficacy studies for 6-12 months and safety studies for up to 2 years (Lehman Brothers, Equity research, 7 August 2003). A phase IIb, 12-week clinical trial in 107 patients with type 2 diabetes was completed in the US. This trial was designed to compare the safety and efficacy of pulmonary insulin delivered via AERx iDMS, with intensified treatment with subcutaneous insulin administered at mealtimes. The results of the study positively compared pulmonary insulin with intensified subcutaneous insulin. Aradigm Corporation has a total of 85 patents pertaining to its proprietary AERx drug delivery system. Among those granted patents, 18 patents cover pulmonary insulin formulation including the method of patient breathing technique during pulmonary delivery of insulin. This patent guides patients on how to breathe in certain defined ways to achieve an effective amount and reproducibility of blood levels of insulin.
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PMID:Insulin inhalation: NN 1998. 1472 93

14-3-3-interacting proteins were isolated from extracts of proliferating HeLa cells using 14-3-3 affinity chromatography, eluting with a phosphopeptide that competes with targets for 14-3-3 binding. The isolated proteins did not bind to 14-3-3 proteins (14-3-3s) after dephosphorylation with protein phosphatase 2A (PP2A), indicating that binding to 14-3-3s requires their phosphorylation. The binding proteins identified by tryptic mass fingerprinting and Western blotting include many enzymes involved in generating precursors such as purines (AMP, GMP and ATP), FAD, NADPH, cysteine and S-adenosylmethionine, which are needed for cell growth, regulators of cell proliferation, including enzymes of DNA replication, proteins of anti-oxidative metabolism, regulators of actin dynamics and cellular trafficking, and proteins whose deregulation has been implicated in cancers, diabetes, Parkinsonism and other neurological diseases. Several proteins bound to 14-3-3-Sepharose in extracts of proliferating cells, but not in non-proliferating, serum-starved cells, including a novel microtubule-interacting protein ELP95 (EMAP-like protein of 95 kDa) and a small HVA22/Yop1p-related protein. In contrast, the interactions of 14-3-3s with the N-methyl-D-aspartate receptor 2A subunit and NuMA (nuclear mitotic apparatus protein) were not regulated by serum. Overall, our findings suggest that 14-3-3s may be central to integrating the regulation of biosynthetic metabolism, cell proliferation, survival, and other processes in human cells.
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PMID:14-3-3-affinity purification of over 200 human phosphoproteins reveals new links to regulation of cellular metabolism, proliferation and trafficking. 1506 4

The mechanism of action of the phosphodiesterase type 5 (PDE5) inhibitors (i.e., sildenafil, tadalafil, and vardenafil) involves inhibition of the PDE5 isoenzyme located in penile vascular smooth muscle cells. Sexual stimulation triggers the release of nitric oxide (NO), stimulating the release of guanylyl cyclase, leading to an increase in intracellular cyclic guanosine monophosphate (cGMP) concentrations, a decrease in intracellular calcium, and ultimately relaxation of the vascular smooth muscle in the corpus cavernosum and penile erection. The PDE5 inhibitors have no effect on the penis in the absence of sexual stimulation. Although the various PDE5 inhibitors differ with respect to selectivity and pharmacokinetic profiles, efficacy and safety of these agents are comparable in broad populations of men with erectile dysfunction (ED), including those with diabetes or those taking multiple antihypertensive agents. The most frequently reported adverse events of the PDE5 inhibitors are related to their mild vasodilatory effects and include headache, flushing, dyspepsia, and nasal congestion or rhinitis. Side effects are generally reversible and tend to diminish during continued treatment. Differences in pharmacokinetic properties among the PDE5 inhibitors include the fact that sildenafil and vardenafil have a shorter duration of action (approximately 4 h) compared with the longer period of responsiveness observed with tadalafil (up to 36 h). In addition, in the presence of high-fat food, absorption of sildenafil and vardenafil may be delayed; however, the rate and extent of tadalafil absorption are unaffected by high-fat food.
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PMID:Phosphodiesterase type 5 inhibitor differentiation based on selectivity, pharmacokinetic, and efficacy profiles. 1511 91

The assessment of the postprandial state in diabetes mellitus has gained importance due to postprandial hyperglycemia being considered as an independent risk factor for cardiovascular disease. Hyperglycemia may contribute to vascular dysfunction through the alteration of the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway. The authors assessed the NO/cGMP pathway in the fasting and postprandial state in 20 type 1 diabetic patients (age: 34.1 +/- 2.6 years, body mass index (BMI): 24.1 +/- 1.3 kg/m (2), duration of diabetes: 16 +/- 2.2 years, HbA (1C): 8.3 +/- 0.4 %, [x +/- SEM], 10 without, 10 with late complications) and 20 matched control subjects (age: 39.7 +/- 1.9 years, BMI: 25.3 +/- 1.1 kg/m (2)). In the fasting state NO end product (nitrite/nitrate) levels did not differ between the diabetic and control group, cGMP levels were found to be significantly lower in the diabetic group (2.5 +/- 0.2 vs. 4.6 +/- 0.6 nmol/l, p = 0.01). A higher level of lipid peroxidation end products (TBARS) was found in diabetic subjects (6.7 +/- 0.4 vs. 5.0 +/- 0.3 micro mol/l, p = 0.004). The diabetic subgroup without late complications had significantly higher nitrite/nitrate levels compared to the patients with complications (57.8 +/- 6.6 vs. 30.4 +/- 4.3 micro mol/l, p = 0.006), their TBARS and cGMP levels were similar. The control subjects responded to the test meal with an increase in the cGMP levels (4.6 +/- 0.6 to 5.5 +/- 0.6 nmol/l, p = 0.02), while in the diabetic group no change was detected. Postprandial nitrite/nitrate levels decreased in both groups, they were significantly lower in the diabetic group. There was no difference between postprandial nitrite/nitrate, cGMP, or glucose levels in the diabetic subgroups. Postprandial glucose levels showed a significant negative correlation with cGMP levels in the diabetic group (r = - 0.50, p = 0.02). The results suggest that in subjects with type 1 diabetes mellitus NO might have an impaired ability to induce cGMP production in the fasting state prior to the development of late specific complications or microalbuminuria under hyperglycemic conditions. Postprandial hyperglycemia is suggested to interfere with endothelial NO action, as shown by the decreased nitrite/nitrate and unchanged cGMP plasma levels in the diabetic group. The impairment of the NO/cGMP pathway both in the fasting and postprandial state that was shown in patients without diabetic complications may be an early sign of hyperglycemia induced vascular damage in type 1 diabetes mellitus.
Exp Clin Endocrinol Diabetes 2004 May
PMID:Impairment of the NO/cGMP pathway in the fasting and postprandial state in type 1 diabetes mellitus. 1514 72


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