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)

Phosphodiesterase 3B (PDE3B), is known to play an important role in acute insulin and cAMP-mediated regulation of lipid metabolism, and PDE4 are the main PDE types expressed in adipocytes. Here, we show that members of all PDE4 isoforms are expressed in 3T3-L1 and primary mouse adipocytes. Long-term treatment of 3T3-L1 adipocytes with insulin induced up-regulation of PDE3B and PDE4D in a phosphatidylinositol 3-kinase-dependent manner whereas long-term treatment with beta-adrenergic agonists induced down-regulation of PDE3B and up-regulation of PDE4D. Thus, PDE3B and PDE4D can be added to the list of genes regulated by insulin and cAMP-increasing hormones. Altered expression of PDE3B and PDE4D in response to long-term treatment with insulin and catecholamines may contribute to altered regulation of metabolism in diabetes.
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PMID:Long-term regulation of cyclic nucleotide phosphodiesterase type 3B and 4 in 3T3-L1 adipocytes. 1719 76

Erectile dysfunction (ED) is a common condition with a significant effect on quality of life. The prevalence of ED increases with age and other risk factors (hypertension, diabetes, smoking, coronary heart disease, dyslipidemia and depression). Nitric oxide (NO) activity is adversely affected, in penile and vascular tissue, by these risk factors. Endothelial dysfunction and a reduced generation or bioavailability of NO have emerged as major pathophysiological mechanisms in ED. Hyperlipidemia may impair erectile function by affecting endothelial and smooth muscle cells of the penis. Oxidized low-density lipoprotein is a causative factor for the impaired relaxation response of the corpus cavernosum. Elevated serum cholesterol and reduced high density lipoprotein cholesterol levels are associated with an increased risk of ED. It follows that treating dyslipidemia could have a beneficial effect on ED. Phosphodiesterase type 5 inhibitors are now considered as first line treatment for ED. There is evidence that statins improve responses to these drugs. ED is considered as a warning sign of silent or early vascular disease. The use of statins may be beneficial in these patients.
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PMID:Dyslipidemia as a risk factor for erectile dysfunction. 1762 14

Recent experimental evidence suggests that arterial insufficiency precedes the structural and functional changes in corpora cavernosa (CC) leading to organic erectile dysfunction (ED). The present review gives an overview of the physiological factors involved in the regulation of penile vasculature. Sympathetic nerves maintain flaccidity and tonically released noradrenaline induces vasoconstriction of both arteries and veins through alpha(1)- and alpha(2)-postsynaptic receptors and downregulates its own release and that of nitric oxide (NO) through alpha(2)-presynaptic receptors. The sympathetic cotransmitter neuropeptide Y (NPY) modulates noradrenergic vasoconstriction in penile small arteries by both enhancing and depressing noradrenaline contractions through Y(1)- and Y(2)-postsynaptic and a NO-independent atypical endothelial receptor, respectively. Activation of alpha(1)-adrenoceptors involves both Ca(2+) influx through L-type and receptor-operated Ca(2+) channels (ROC) and Ca(2+) sensitization mechanisms mediated by protein kinase C (PKC), tyrosine kinases (TKs) and Rho kinase (RhoK). In addition, RhoK can regulate Ca(2+) entry in penile arteries upon receptor stimulation. Vasodilatation of penile arteries and large veins during erection is mediated by neurally released NO. The subsequent increased arterial inflow to the cavernosal sinoids and shear stress on the endothelium lining penile arteries activates endothelial NO production through Akt phosphorylation of endothelial NO synthase (eNOS). NO stimulates guanylate cyclase and increased cyclic guanin 3'-monophosphate (cGMP) levels in turn activate protein kinase G (PKG), which enhances K(+) efflux through Ca(2+)-activated (K(Ca)) and voltage-dependent Ca(2+) (K(v)) channels in penile arteries and veins, respectively. PKG-mediated decrease in Ca(2+) sensitivity and its regulation by RhoK remains to be clarified in penile vasculature. Phosphodiesterase type 5 (PDE5) inhibitors are potent vasodilators of penile resistance arteries and increase the content and effects of basally released endothelial NO. Endothelium-dependent relaxations of penile small arteries also include an endothelium-derived hyperpolarizing factor (EDHF)-type response, which is impaired in diabetes and hypertension-associated ED. Locally produced contractile and relaxant prostanoids regulate penile venous and arterial tone, respectively. The latter activates prostaglandin I (IP) and prostaglandin E (EP) receptors coupled to adenylate cyclase and to the increase of cyclic adenosine monophosphate (cAMP) levels, which in turn stimulates K(+) efflux through ATP-sensitive K(+) (K(ATP)) channels. There is a crosstalk between the cGMP and cAMP signaling pathways in penile small arteries. Relevant issues such as the mechanisms underlying the excitation-secretion coupling of the endothelial cells, as well as those involved in cell proliferation and vascular remodeling of the penile vasculature remain to be elucidated. In addition, only few studies have investigated the changes in structure and function of penile arteries in cardiovascular risk situations leading to ED.
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PMID:Physiological regulation of penile arteries and veins. 1763 89

Erectile dysfunction (ED) is a common complication of diabetes mellitus. Phosphodiesterase-5 (PDE5) inhibitors, which inhibit the breakdown of intracellular cyclic guanosine monophosphate (cGMP), are used to treat diabetic ED. Caffeine, a nonselective PDE inhibitor used in our daily diet, is controversial regarding its effect on erectile function. To investigate the effect of caffeine on erectile function in diabetic rat models and explore the mechanism, male Sprague-Dawley rats were injected with streptozotocin to induce diabetes mellitus. The rats with blood glucose levels above 300 mg/dL were selected for the study. The rats were divided into 4 groups: group A (normal control rats), group B (diabetic rats treated with normal saline), group C (diabetic rats treated with caffeine, 10 mg/kg per day), and group D (diabetic rats treated with caffeine, 20 mg/kg per day). After 8 weeks of treatment, intracavernous pressure (ICP) was measured to assess erectile function. The radioimmunoassay was used to evaluate the level of cGMP in the cavernosum. The ICP and the cavernous cGMP decreased significantly in the diabetic rats compared with normal controls. An 8-week administration of caffeine at the given dosages increased the ICP and cavernous cGMP in diabetic rats. Caffeine consumption improved the erectile function of diabetic rats by up-regulating cavernous cGMP.
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PMID:Effect of caffeine on erectile function via up-regulating cavernous cyclic guanosine monophosphate in diabetic rats. 1842 Oct 70

Tumescence occurs as a result of nitric oxide (NO)-mediated smooth muscle relaxation of the erectile tissue leading to engorgement of the corpus cavernosum. The process is initiated by neuronal NO release and maintained by NO released by the local vascular endothelium. Erectile dysfunction (ED) affects 30% to 40% of diabetic men and occurs as a result of endothelial dysfunction and autonomic neuropathy. The close association with endothelial dysfunction means ED is an early marker of cardiovascular risk. Managing ED is easy and must be part of a diabetes care service. Phosphodiesterase type 5 inhibitors are the treatment of choice, but are effective in only 50% to 60% of diabetic men. The reasons for nonresponsiveness remain uncertain and research is needed in this area. There has been much recent interest in the potential relationship between late-onset hypogonadism and diabetes, but there is no evidence of a causal relationship and the evidence in favor of treating borderline hypogonadism in diabetes is limited.
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PMID:Management of erectile dysfunction in diabetes: an update for 2008. 1899 Feb 99

Risk factors for cardiovascular disease and erectile dysfunction (ED) are similar, as might be expected given their shared etiologic and pathophysiologic origins. It is now generally accepted that most cases of ED result from a vascular disturbance of the endothelium. Recent epidemiological studies have documented a strong association between ED and comorbid conditions such as hypertension, diabetes mellitus, and dyslipidemia. Phosphodiesterase type 5 (PDE5) inhibitors are recommended as first-line therapy for erection problems of all etiologies and severities. The efficacy and safety of PDE5 inhibitors in the general ED population is well documented and has been extensively reviewed. To examine the association between ED and vascular disorders in the context of current knowledge regarding PDE5 inhibitors, an electronic search was performed of articles published from January 2002 through April 2008 using the PubMed, EMBASE, and MEDLINE databases. Although preference was given to randomized, blinded, controlled clinical trials, data from retrospective studies were also reviewed when appropriate. This analysis revealed that the clinical evidence linking ED to future cardiovascular events is compelling, presenting physicians with a unique interventional opportunity to address underlying cardiovascular health concerns in men presenting with ED. In most studies, PDE5 inhibitors were shown to effectively and safely improve erectile function regardless of cause, severity, or presence of comorbid conditions, including hypertension, diabetes mellitus, and dyslipidemia.
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PMID:Erectile dysfunction and cardiovascular disease: efficacy and safety of phosphodiesterase type 5 inhibitors in men with both conditions. 1948 78

Prevalence of erectile dysfunction (ED) has a higher incidence in patients treated for diabetes mellitus as it concerns more than 30% of them. ED's physiopathology is complex and multifactorial, involving a combination of classical risk factors (endothelial dysfunction), specific factors (e.g., diabetic neuropathy) and psychological factors. ED is most often forewarning a cardiovascular disease. Therefore, it needs to be detected by the physician who is taking care of the diabetic patient. ED is responsible for a deterioration of the quality of life. Therapeutic management relies, on one hand, on specific measures such as prevention of diabetic complications and, on the other hand, on psychological accompaniment of the patient. Phosphodiesterase-5 inhibitors have become the first-line treatment as they are efficient and safe in most cases. As a second line, intracavernous injections remain a gold-standard treatment but the vacuum can be proposed as well. In case of failure, penile prosthesis can even be considered. The psychological dimension of ED has to be considered as much as organic matters.
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PMID:[Etiology and management of erectile dysfunction in patients with diabetes mellitus]. 1946 54

Erectile dysfunction (ED) has been revolutionized during the last two decades, as several treatment options are available today. Phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil, vardenafil) are currently the first choice treatment option for ED by most physicians and patients due to their high efficacy rates and favourable safety profiles. Despite the fact that more than 50 million ED patients have been treated successfully worldwide with PDE5i several issues remain to be addressed. Patients with severe neurologic damage, diabetes mellitus, or severe vascular disease may be resistant to PDE5i. Inappropriate instructions, lack of follow-up and lack of patient-centered care models have been identified as main reasons for "nonresponse", leading to drop-out rates of even > 50%. Preservation of corporal smooth muscle with chronic administration of PDE5i has been reported and there is a substantial body of evidence for beneficial effects of these drugs on endothelium and cardiovascular function. Finally, improvement of lower urinary symptoms after PDE5i administration has been reported and a possible role on treatment of premature ejaculation has been proposed. Many new PDE5i are candidates to enter the market in the forthcoming years. However, pharmacokinetic differences should be obvious to consider a truly better option for patients. Patients must be aware of all treatment options since no ideal treatment exists and physicians must offer personalized medicine to their patients in the future. The development and adaptation of a patient-centered care model in sexual medicine will increase efficacy and safety of current and future treatments.
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PMID:Phosphodiesterase type 5 inhibitors: unmet needs. 1986 Jun 93

Erectile dysfunction (ED) is the most common sexual problem in men. The incidence increases with age and affects up to one third of men throughout their lives. It causes a substantial negative impact on intimate relationships, quality of life, and self-esteem. History and physical examination are sufficient to make a diagnosis of ED in most cases, because there is no preferred, first-line diagnostic test. Initial diagnostic workup should usually be limited to a fasting serum glucose level and lipid panel, thyroid-stimulating hormone test, and morning total testosterone level. First-line therapy for ED consists of lifestyle changes, modifying drug therapy that may cause ED, and pharmacotherapy with phosphodiesterase type 5 inhibitors. Obesity, sedentary lifestyle, and smoking greatly increase the risk of ED. Phosphodiesterase type 5 inhibitors are the most effective oral drugs for treatment of ED, including ED associated with diabetes mellitus, spinal cord injury, and antidepressants. Intraurethral and intracavernosal alprostadil, vacuum pump devices, and surgically implanted penile prostheses are alternative therapeutic options when phosphodiesterase type 5 inhibitors fail. Testosterone supplementation in men with hypogonadism improves ED and libido, but requires interval monitoring of hemoglobin, serum transaminase, and prostate-specific antigen levels because of an increased risk of prostate adenocarcinoma. Cognitive behavior therapy and therapy aimed at improving relationships may help to improve ED. Screening for cardiovascular risk factors should be considered in men with ED, because symptoms of ED present on average three years earlier than symptoms of coronary artery disease. Men with ED are at increased risk of coronary, cerebrovascular, and peripheral vascular diseases.
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PMID:Management of erectile dysfunction. 2011 89

Nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC) is the receptor that catalyzes the formation of the intracellular messenger cyclic guanosine monophosphate (cGMP). Binding of the physiological activator, NO, to the reduced heme moiety of sGC increases the conversion of guanosine triphosphate (GTP) to cyclic GMP (cGMP) and engages crucial effector systems such as protein kinases, phosphodiesterases, and ion channels. The development of compounds that activate sGC independent of NO release has therapeutic implications. Recent studies have demonstrated the potential use of heme-dependent sGC stimulators (e.g. YC-1, BAY 41-2272, BAY 41-8543, BAY 63-2521, CFM-1571 and A-350619) and heme-independent sGC activators (e.g. BAY 58-2667, HMR-1766, S-3448, A-778935) in the treatment of cardiovascular diseases. Erectile dysfunction (ED) affects millions of men. Phosphodiesterase (PDE)-5 inhibitors, produce an NO-dependent increase in intracellular cGMP concentration, have been a successful approach in the treatment of ED. However, >30% of men with ED do not respond to PDE-5 inhibitor therapy, implying that endogenous NO production may be impaired to such an extent that inhibition of cGMP degradation produces no significant therapeutic advantage. Endogenous NO released from nitrergic nerves in the corpora cavernosa is significantly decreased in various conditions (e.g. diabetes, aging, and hypertension) and have reduced activation of the NO-sGC-cGMP pathway. It is conceivable that sGC stimulators and/or activators may be more effective than PDE5 inhibitors in the treatment of ED in such circumstances by improving NO-sGC-cGMP signaling and erectile function. This novel drug therapy approach for the treatment of ED shows promise.
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PMID:Exploring the potential of NO-independent stimulators and activators of soluble guanylate cyclase for the medical treatment of erectile dysfunction. 2020 88


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