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 (PDE) 3B is a key enzyme in the mediation of the antilipolytic action of insulin in adipocytes, and activation of this molecule results in a reduced output of free fatty acids (FFAs). An elevation of serum FFAs is known to cause insulin resistance in skeletal muscle and liver, which could be the primary cause of type 2 diabetes. To elucidate whether PDE3B is involved in this disease, we examined the PDE3B gene expression in epididymal fat tissues of obese insulin-resistant diabetic KKAy mice. We also examined the effect of an insulin-sensitizing drug, pioglitazone, on this gene expression. In adipose tissue of KKAy mice, PDE3B mRNA and its corresponding protein were reduced to 48 and 43% of those in C57BL/6J control mice. Basal and insulin-stimulated membrane-bound PDE activities were also decreased to 50 and 36% of those in the controls, respectively. Pioglitazone increased both PDE3B mRNA and protein levels by 1.8-fold of those in untreated KKAy mice. Basal and insulin-induced membrane-bound PDE activities were also increased by 1.6- and 2.0-fold, respectively. Pioglitazone reduced the elevated levels of serum insulin, glucose, FFAs, and triglyceride in KKAy mice. Thus, the reduced PDE3B gene expression in adipose tissues could be the primary event in the development of insulin resistance in KKAy mice, which was improved by pioglitazone possibly because of the restoration of the reduced PDE3B gene expression.
Diabetes 1999 Sep
PMID:Improvement in insulin resistance and the restoration of reduced phosphodiesterase 3B gene expression by pioglitazone in adipose tissue of obese diabetic KKAy mice. 1048 Jun 15

Phosphodiesterase (PDE) 3B, when activated by insulin, causes a decrease in intracellular cAMP concentration. The activation of this enzyme results in the reduced output of free fatty acids (FFA) from adipocytes, and an increased lipogenesis in liver. We have recently shown that PDE3B gene expression is reduced in adipose tissues of KKAy mice. We intend to further elucidate the regulation of PDE3B in liver as well as adipose tissues in relation to the insulin resistant state. We examined PDE3B gene expression in liver and adipose tissues of obese, insulin-resistant diabetic db/db mice and also checked the effect of an insulin-sensitizing drug, troglitazone, on this gene expression. In the liver of db/db mice, PDE3B mRNA, its corresponding protein, and the associated catalytic activity were all increased by 2.1, 1.9 and 1.6-fold, respectively, over those in db/+ control mice. Histological examination revealed substantial triglyceride storage in the liver of db/db mice. Conversely, in the adipose tissue of db/db mice, PDE3B mRNA, protein, and its associated activity were all decreased by 0.38, 0.33 and 0.36-fold, respectively. Troglitazone, which has no effect on PDE3B in liver, increased the expression of this gene in adipocytes. This increase is associated with a reduction in the elevated levels of serum insulin, glucose, FFA and triglycerides. The reduced PDE3B gene expression in adipose tissues, which results in the elevation of serum FFA, could be the primary event in the development of insulin resistance in db/db mice. The enhanced PDE3B gene expression may correlate with changes in triglyceride storage in the liver of these mice.
Diabetes Res Clin Pract 2001 Dec
PMID:Phosphodiesterase 3B gene expression is enhanced in the liver but reduced in the adipose tissue of obese insulin resistant db/db mouse. 1168 69

Phosphodiesterase (PDE) 3B, a major isoform of PDE in adipocytes, mediates the antilipolytic action of insulin. PDE3B gene expression is generally reduced in adipocytes of either monogenic or polygenic rodent models of obese, insulin-resistance. An increased fat cell size, a common feature of obesity, could account for this reduction. Insulin receptor substrate-1 (IRS-1) (-/-) mice are lean with a reduced fat cell size and have insulin resistance due to a primary defect of insulin signaling. To determine whether the regulation of PDE3B gene expression is correlated with fat cell size, we examined this gene expression in adipose tissues of IRS-1 (-/-) mice. In IRS-1 (-/-) mice, PDE3B mRNA and protein levels were increased 1.24- and 1.35-fold those in C57BL/6J control mice, respectively. Independently, the fold induction of PDE activity by insulin (insulin-induced/basal) was 1.7-fold in control mice, but was reduced to 1.35-fold in IRS-1 (-/-) mice. Thus, PDE3B gene expression may be inversely correlated with a fat cell size, whereas insulin-induced PDE3B activation is mediated through IRS-1.
Diabetes Res Clin Pract 2002 Nov
PMID:Differential regulation of gene expression and insulin-induced activation of phosphodiesterase 3B in adipocytes of lean insulin-resistant IRS-1 (-/-) mice. 1221 48

Phosphodiesterase (PDE)-3B, a major PDE isoform in adipocytes, plays a pivotal role in the antilipolytic action of insulin. Insulin-induced phosphorylation and activation of PDE3B is phosphatidylinositol 3-kinase (PI3-K) and Akt dependent, but the precise mechanism of PDE3B activation is not fully understood. We have identified 14-3-3 beta, a critical scaffolding molecule in signal transduction, as a protein that interacts with PDE3B using the yeast two-hybrid system. The interaction between PDE3B and 14-3-3 beta was then confirmed in vitro. The glutathione S-transferase (GST)-tagged 14-3-3 beta interacts with endogenous PDE3B of rat adipocytes, and this interaction is enhanced when adipocytes are treated with insulin. Coimmunoprecipitation experiments reveal that endogenous PDE3B also associates with endogenous 14-3-3 beta in rat adipocytes, and this interaction is enhanced by insulin. Two different PI3-K inhibitors, wortmannin and Ly294002, block this induction, suggesting that PI3-K is required. Synthetic 15 amino acid peptides of rat PDE3B containing phosphorylated Ser-279 or -302 inhibit this interaction, indicating that the insulin-regulated phosphorylation of these serine residues is involved. Because insulin receptor substrate-1 also associates with 14-3-3, the dimeric 14-3-3 beta could function as a scaffolding protein in the activation of PDE3B by insulin.
Diabetes 2002 Dec
PMID:Identification of the insulin-regulated interaction of phosphodiesterase 3B with 14-3-3 beta protein. 1245 87

Phosphodiesterase (PDE) inhibitors represent an important advance in the treatment of erectile dysfunction (ED). In spite of widespread use and generally good efficacy, as a class they remain ineffective in 15-57% of men. Specific cohorts of patients with severe vascular or neurogenic basis to their ED, such as diabetic men or those who have undergone radical pelvic surgery, demonstrate lower response rates with PDE inhibition treatment. We believe that circulating levels of nitric oxide (NO) may be enhanced through delivery of adequate concentrations of free oxygen radical scavenger molecules such as vitamin E. Higher levels of NO, theoretically, should produce increased penile blood flow with the potential for a synergistic effect when combined with a PDE5 inhibitor. With this hypothesis in mind, 20 adult male Sprague-Dawley streptozotocin-induced (60 mg/kg i.p.) diabetic rats were divided into four therapeutic groups (n=5). Group I--control animals received peanut oil, group II--vitamin E 20 IU/day, group III--sildenafil 5 mg/kg/day and group IV--vitamin E 20 IU/day plus sildenafil 5 mg/kg/day, by oral gavage daily for 3 weeks. Erectile function was assessed as a rise in intracavernous pressure following cavernous nerve electrostimulation. Penile tissue was harvested to determine the changes in tissue morphology including neuronal nitric oxide synthase, smooth muscle alpha-actin and endothelial cell integrity. PDE5 protein content and activity were measured. Significant increases in intracavernous pressure were measured in the animals receiving combined vitamin E plus sildenafil treatment. Immunohistochemical staining showed increases of neuronal nitric oxide synthase, endothelial cell and smooth muscle cell staining. Western blot analysis did not show significant differences of PDE5 protein between the groups. However, higher PDE5 activity was measured in the sildenafil group and lower activity of PDE5 was recorded in the cohort receiving vitamin E with sildenafil. Vitamin E enhanced the therapeutic effect of the PDE5 inhibitor in a meaningful way in this animal model of diabetes. This study indicates a potential means of salvaging erectile function among patients who are refractory to sildenafil.
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PMID:Effect of PDE5 inhibition combined with free oxygen radical scavenger therapy on erectile function in a diabetic animal model. 1456 36

Erectile dysfunction (ED) is commonly associated with risk factors for cardiovascular disease, including diabetes. The prevalence of ED in diabetic patients is high--about 75% of diabetic men 60 yr of age or older had ED in one study. Endothelial dysfunction, accelerated atherosclerosis, and diabetic neuropathy likely contribute to ED in diabetics. As silent ischemia is common in the diabetic patient, and diabetes is now often thought of as a coronary heart disease risk equivalent, diabetic men seeking therapy for ED may be considered candidates for exercise stress testing. Phosphodiesterase 5 (PDE5) inhibitors improve erectile function in diabetic men with ED; however, efficacy rates may be somewhat lower than in nondiabetic men. Studies to date have suggested that PDE5 inhibitors per se do not cause an increase in myocardial infarction rates in men being treated for ED.
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PMID:Assessment of cardiovascular risk in patients with erectile dysfunction: focus on the diabetic patient. 1514 90

Phosphodiesterase 5 (PDE5) inhibitors prevent the normal hydrolysis of cGMP. As the resulting cGMP accumulation facilitates penile smooth muscle relaxation, PDE5 inhibitors can partially reverse deficiencies in the nitric oxide (NO)/cGMP pathway to treat erectile dysfunction (ED). However, approximately 30-40% of men with ED do not respond to drug therapy. Patients with severe neurologic damage, diabetes mellitus, or severe vascular disease may be resistant to PDE5 inhibitors. Decreased expression or activity of neuronal or endothelial NO synthase (NOS), impaired NO release, or NO destruction will preclude sufficient cGMP formation to permit PDE5 inhibitor efficacy. This article discusses the possible reasons for unresponsiveness and strategies to overcome it. Therapeutic approaches proposed to increase available NO in penile tissue include facilitating NO release by using alpha-2 antagonists, enhancing NO synthesis by providing more substrate for the reaction, and using antioxidants to inhibit NO breakdown by reactive oxygen species.
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PMID:Therapeutic strategies for optimizing PDE-5 inhibitor therapy in patients with erectile dysfunction considered difficult or challenging to treat. 1522 36

Diabetes is a frequent aetiology of erectile dysfunction. The prevalence of erectile dysfunction in diabetics is three times higher than in the general population. Erectile dysfunction in diabetics is multifactorial. Phosphodiesterase type 5 inhibitors represent the treatment of first intention.
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PMID:[Erectile dysfunction]. 1603 18

Phosphodiesterase 5 inhibitors are recommended as first-line treatment of erectile dysfunction in many guidelines, because of their convenience, higher efficacy, and less side-effects. Since its first launch in 1998, sildenafil has been currently the best investigated phosphodiesterase 5 inhibitor with respect to long-term trails and quantity. Clinical trials showed the efficacy of sildenafil compared with placebo in many of the groups of patients who have ED, including those with cardiovascular disease, diabetes mellitus, depression, radical prostatectomy and dialysis. Typically the adverse effects reported in patients from clinical trials of sildenafil have been mild to moderate, and commonly include flushing and dyspepsia and transient visual disturbances. This article summarized recent reports on efficacy and safety of phosphodiesters 5 inhibitors in the treatment of erectile dysfunction.
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PMID:[Efficacy and safety of phosphodiesterase 5 inhibitors in the treatment of erectile dysfunction]. 1613 88

Erectile dysfunction (ED) is a common medical condition linked both to aging and to many medical conditions such as diabetes mellitus and cardiovascular disease. Although a common condition, treatment for ED has in the past been conducted by a few specialists, mostly urologists and sex therapists. The revolutionary introduction of oral therapy, and the massive amount of research into sexual dysfunction that followed, has led to paradigm shift in the treatment of ED. This is no longer something done by a few for a few; it involves all disciplines of medicine and more patients are being treated by a greater number of physicians. Several medications administered by different routes are available for treating ED but oral pharmacotherapy represents the first-line option. Phosphodiesterase (PDE) type 5 inhibitors are the most widely prescribed oral agents and they have a satisfactory efficacy-safety profile in patients of all categories. An alternative for men who do not respond to PDE5 inhibitors is intracavernosal injection therapy with alprostadil, a prostaglandin analogue. Other alternatives include sublingual apomorphine and intraurethral alprostadil. Both agents have a less satisfactory efficacy profile than PDE5 inhibitors and a low compliance rate. The aim of ED treatment is to restore an erection satisfactory for the sexual needs of the patient. Thus, the patient-reported outcome is the gold standard in efficacy evaluation. There are now three PDE inhibitors available, all with satisfactory efficacy-safety profiles, but with different pharmacokinetic properties. The availability of three different agents has initiated studies aiming to evaluate them regarding patient preference. However, the results are rather conflicting with some studies suggesting that tadalafil has the best patient preference, while others fail to demonstrate a clinically significant difference between the three agents. However, there is a tendency for younger men to choose tadalafil because it gives them a broader window of opportunity, while older men tend to prefer vardenafil or sildenafil. These data could be used when making a decision on which PDE5 inhibitor to prescribe, although another option is to let the patient try all three available agents and make his own choice.
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PMID:Treatment for erectile dysfunction based on patient-reported outcomes: to every man the PDE5 inhibitor that he finds superior. 1626 93


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