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)

The (3H) cyclic AMP accumulation was measured in incubations of pancreatic islets from one-day, six-day, and thirty-five-day-old rats exposed to a low (0.6 mg./ml.) or a high (3.0 mg./ml.) glucose concentration with or without the addition of 0.1 mM. of the phosphodiesterase inhibitor 3-isobutyl- 1 -methylxanthine (IBMX). In the thirty-five-day-old rats, (3H) cyclic AMP accumulation was significantly enhanced after sixty minutes' incubation in a high glucose concentration and further increased by IBMX. These changes were paralleled by a stimulated insulin release, measured simultaneously. By contrast, in the one-day-old rats, no effect of glucose with or without IBMX was seen on (3H) cyclic AMP, while the minor insulin release due to high glucose alone was markedly potentiated by IBMX. Even in the presence of this agent the insulin response to glucose was, however, clearly inferior to that seen in the thirty-five-day-old animals. The stimulatory patterns of glucose-induced insulin release in the six-day-old animals was intermediate between the other two age groups. At this age, stimulation of (3H) cyclic AMP due to glucose was observed only in the presence of IBMX. Measurement of (3H) cyclic AMP after three minutes' incubation confirmed these different stimulatory patterns of glucose in the age groups studied. It is suggested that the inefficiency of glucose to stimulate the adenyl cyclase-cyclic AMP system of the beta cell from fetal and neonatal animals may be one important factor determining the insensitivity to the insulin-releasing action of glucose that exists at this stage of development.
Diabetes 1975 Aug
PMID:Decreased cyclic AMP and insulin response to glucose in isolated islets of neonatal rats. 16 74

The effects of insulin and adrenaline on cyclic AMP (cAMP) levels in diaphragms of normal, streptozotocin-diabetic and insulin-treated diabetic rats were studied. Adrenaline caused a biphasic rise in cAMP with peak values of cAMP within the first few minutes. Diaphragms of diabetic rats showed an increased responsiveness to adrenaline. Injection of insulin to diabetic rats normalized the rise in cAMP after addition of adrenaline. There was no difference in basal levels of cAMP between diaphragms of normal, diabetic or insulin-treated diabetic rats. Insulin in vitro did not affect basal cAMP-levels or the release of cAMP from the tissue but significantly decreased adrenaline-induced peak levels of cAMP. This effect of insulin was abolished by theophylline. The results of the present study suggest that experimental diabetes is associated with changes of the adenylate cyclase and/or phosphodiesterase enzyme activities in skeletal muscle resulting in an increased responsiveness to adrenaline. Since insulin in vitro depressed the adrenaline-induced elevation of cAMP the increased responsiveness in diaphragms of diabetic rats might be attributed to the specific lack of insulin.
 ...
PMID:Effect of insulin and adrenaline on cyclic AMP in the diaphragm of normal and diabetic rats. 19 69

In rat adipose tissue, insulin (100 muU./ml.) increases the activity of cyclic AMP (but not cyclic GMP) phosphodiesterase (PDE). Radioisotopic assay, autoradiography, and histochemical stains demonstrated that cyclic nucleotide PDE activity is associated with multiple bands of protein separable by polyacrylamide gel electrophoresis. The insulin activation of cyclic AMP PDE, however, was limited to a single band corresponding to the "low" Km enzyme specific for cyclic AMP; insulin had no effect on the "high" Km enzyme or on PDE bands with activity directed toward cyclic GMP. These data support the concept that insulin may modulate the activity of at least one of the cyclic AMP phosphodiesterases.
Diabetes 1977 Oct
PMID:Cyclic nucleotide phosphodiesterase. Insulin activation detected in adipose tissue by gel electrophoresis. 19 22

The character of the insulin effect on the activity of phosphodiesterase (PDE) cAMP of various subcellular localization was studied in the liver of normal and diabetic rats. As a result of kinetic investigations for PDE cAMP preparations of the plasma membranes there were obtained kinetic characteristics of two PDE forms, differing by their affinity to the substrate. For the both PDE cAMP forms stimulation of the activity with insulin was indicated. In examining the insulin effect on the activity of PDE cAMP of the liver of rats with streptozotocin-induced diabetes there was revealed a significant effect of the hormone on the kinetics of the enzyme with a high affinity to cAMP only.
 ...
PMID:[Regulation of the activity of 3', 5'-cyclic AMP phosphodiesterase by pancreatic hormones]. 22 45

Transgenic mice with elevated levels of beta-cell calmodulin develop severe diabetes even though pancreatic beta-cells contain reserve levels of insulin. Electron microscopic examination of transgenic pancreas confirmed the presence of abundant insulin secretory granules and failed to reveal obvious morphological abnormalities. These observations suggested that excess calmodulin may specifically impair the secretory process. To directly assess the effect of excess calmodulin on beta-cell function we have isolated pancreatic islets from transgenic animals. Transgenic islets from 6- to 8-day-old mice used 40% less glucose than normal islets and contained 58% of the normal insulin content, 90% of the normal glucagon content, and 5-fold higher levels of calmodulin than islets from control mice of the same age. Parallel perifusions of normal and transgenic islets confirmed that excess calmodulin inhibited glucose-stimulated insulin secretion; first phase secretion was reduced by 60%, and second phase secretion was essentially absent. Static assays were performed to assess the response to other secretagogues. All fuel secretagogues tested were ineffective in stimulating insulin secretion from transgenic islets. Secretion in response to depolarizing levels of potassium was also severely impaired. The phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine increased transgenic secretion, but not to the level obtained in normal islets. Of the compounds examined, only phorbol 12-myristate 13-acetate and carbachol, two substances thought to act in beta-cells by stimulation of protein kinase-C, produced equivalent secretion in normal and transgenic islets. Phorbol 12-myristate 13-acetate also appeared to restore second phase secretion in transgenic islets. These results indicate that the initial period of calmodulin-induced diabetes is due to a secretory defect. This defect appears to be distal to membrane depolarization and is selective for the second phase of insulin secretion.
 ...
PMID:Elevated beta-cell calmodulin produces a unique insulin secretory defect in transgenic mice. 137 47

Effects of cilostazol (OPC-13013, CAS 73963-72-1), a selective inhibitor of platelet cAMP-phosphodiesterase, on peripheral vascular disease in diabetes mellitus were studied. Cilostazol in a dose of 200 to 300 mg/d was administered to 5 diabetic patients with arteriosclerosis obliterans. Skin temperature of the finger and the toe, which reflects blood flow to the tissue, was selected as an objective index of cilostazol effects and measured by infra-red thermography at a constant temperature of 26 degrees C. Before administration, digital skin temperatures were low in 9 limbs of 5 patients. 200 mg/d of cilostazol significantly (p less than 0.001) increased the digital skin temperatures of 8 limbs, the increase (mean +/- SD) ranging from 29.9 +/- 1.4 degrees C to 33.2 degrees C +/- 1.2 degrees C for the average skin temperatures and from 28.7 +/- 2.1 degrees C to 33.1 +/- 1.5 degrees C for the lowest ones. An increase in the dose to 300 mg/d resulted in further elevation of skin temperatures of the digits. Cilostazol constantly elicited an increase in blood flow to the digits within the range of its therapeutic dose. This effect was observed about 1 month after initiation of administration and persisted while administration was continued. The measurement of digital skin temperatures by infrared thermography provided a noninvasive means to individualize the dosage of cilostazol and to monitor the cilostazol effect and patient complicance during long-term administration. It is concluded that cilostazol exerts a potent and steady vasodilatory effect on peripheral circulation in patients with diabetes mellitus.
 ...
PMID:Effects of the anti-platelet agent cilostazol on peripheral vascular disease in patients with diabetes mellitus. 149 93

Enoximone, a new phosphodiesterase-inhibitor with positive inotropic and vasodilating activities is available for intravenous use in patients with severe heart failure. A review of the current knowledge regarding the adverse effects of this substance reveals that they are characterized by cardiovascular, central nervous, and gastrointestinal side effects. Adverse effects occurred in 20% of patients and were mostly due to the pharmacological properties of enoximone. Cardiovascular side effects (10%) were the most frequent; ventricular and supraventricular arrhythmias were most common. Two to three percent of the patients experienced hypotension due to the vasodilator activity of enoximone. Headache, insomnia, and anxiety were the most frequent adverse effects on the central nervous system. Three percent of the patients treated experienced vomiting, nausea, abdominal pain, and diarrhea. An increase of liver enzymes and serum glucose could be observed, mostly in patients with previous liver disease or diabetes. Pharmacokinetic drug interactions are not known; possible pharmacodynamic interactions result from the pharmacological properties of the drugs. Intravenous therapy with enoximone causes a few serious side effects that can only be controlled by careful observation of the patients treated.
 ...
PMID:[Tolerance of enoximone in patients with heart failure]. 183 4

Diabetes mellitus is associated with high levels of adenosine 3',5'-cyclic monophosphate in tissue and plasma. Diabetes inhibits and insulin stimulates and restores low Km adenosine 3',5'-cyclic monophosphate phosphodiesterase activity. We recently reported that phorbol ester, a tumor promoting agent known to act through protein kinase C also stimulates phosphodiesterase. Here, we address the issue of whether or not the activation of phosphodiesterase by insulin and phorbol ester is different in streptozotocin diabetic adipose tissue. Rat adipose tissue was incubated with insulin, phorbol ester or other known components or effectors of the protein kinase C pathway, i.e. 1,2 dioleoyl-glycerol, 1- oleoyl, 2- acetylglycerol, Ca(++)-Ionophore A 23187, and nifedipine. After incubation, preparation and assay of adenosine 3',5'-cyclic monophosphate phosphodiesterase was made. As in previous data streptozotocin-diabetes inhibits basal phosphodiesterase by about 50% (P less than .02); insulin and phorbol ester each stimulate phosphodiesterase, in streptozotocin-diabetes less than normal (P less than .025); nifedipine inhibits phorbol stimulated phosphodiesterase in streptozotocin-diabetes but not normal (P less than .001); and nifedipine inhibits insulin stimulated phosphodiesterase in normal (84%) and diabetic (97%) (P less than .005). In normal and diabetic tissue, diacyl glycerol and oleoyl-acyl glycerol stimulate phosphodiesterase, are augmented by ionophore and inhibited by nifedipine. In addition 32P incorporation studies and measurements of tyrosine kinase activity are presented which support these differences between normal and diabetic. In summary then, these data suggest common pathways of activation for low Km adenosine 3',5'-cyclic monophosphate phosphodiesterase by insulin and phorbol ester; imply a relationship between two second messenger systems, phosphoinositides and adenosine 3',5'-cyclic monophosphate; and demonstrate a difference in activation of phosphodiesterase between normal and diabetic adipose tissue.
 ...
PMID:Activation of cyclic AMP phosphodiesterase by phorbol and protein kinase C pathway: differences in normal and diabetic tissue. 196 4

In past studies, we have demonstrated that in streptozotocin-induced diabetic or spontaneously diabetic (BB) animal models, low Km cAMP phosphodiesterase and calmodulin are decreased while a low MW inhibitor of calmodulin is increased. To extend these studies, we have determined the rate of [35S]-methionine incorporation into calmodulin in isolated fat cells from these diabetic animals, i.e. streptozotocin-induced diabetic and the BB rats, spontaneous diabetic rat, non-diabetic rat, and control. We found markedly decreased rates of synthesis of calmodulin in the fully diabetic BB rat. In order to investigate the mechanism of the reduced calmodulin biosynthesis, we probed poly A+ mRNA from control and diabetic rat livers with a calmodulin specific anti-sense oligonucleotide probe and found that the fully diabetic animals, streptozotocin-induced diabetic and genetically diabetic BB, contained markedly reduced levels of calmodulin transcripts. Thus, both calmodulin protein and its putative mRNA are decreased in diabetic rat liver. We believe that in uncontrolled diabetes, the observed elevation in the levels of cyclic AMP in plasma and tissue results in part from decreased activity of phosphodiesterase. The insulin-sensitive phosphodiesterase appears to be regulated by calmodulin. We hypothesize that cyclic AMP phosphodiesterase inactivation in diabetes results in part from insulin insufficiency and to a less well-defined genetic lesion leading to calmodulin down-regulation.
 ...
PMID:Expression of calmodulin gene is down-regulated in diabetic BB rats. 197 47

The mechanism of stimulation of insulin release from isolated rat islets by 0.3 mM SaRI 59-801 (DL-alpha-dimethylaminomethyl-2-[ 3-ethyl-5-methyl-4-isoxazoyl]-1H-indole-3-methanol) was investigated, considering cAMP concentration and Ca2+ uptake. Ten millimolar theophylline or 1 mM 1-methyl-3-isobutylxanthine, which inhibit cAMP phosphodiesterase, each greatly increased the stimulation of insulin release by 59-801. Forskolin (0.1 mM), an activator of adenylate cyclase, or 1 mM dibutyryl cAMP also potentiated 59-801, suggesting that 59-801 does not elevate islet cAMP but is potentiated by other compounds that do. Measurement of cAMP in islets by radioimmunoassay confirmed that it was not significantly elevated by 59-801 but was increased sevenfold by forskolin or 1-methyl-3-isobutylxanthine. SaRI 59-801 was not effective in the absence of Ca2+ and presence of 1 mM EGTA. Agents that block entry of Ca2+ into beta-cells, verapamil, nifedipine, or CoCl2, inhibited the release of insulin in response to 59-801. Studies of 45Ca2+ uptake by isolated islets revealed an increased uptake in the presence of 59-801 and blockage of this effect by 50 microM verapamil. Thus, the stimulation of insulin secretion by 59-801 appears to involve a stimulation of Ca2+ uptake rather than an increase of cAMP concentration. The mechanism of stimulation of Ca2+ uptake by 59-801 requires further investigation.
Diabetes 1985 Jul
PMID:Stimulation of insulin secretion from isolated rat islets by SaRI 59-801. Relation to cAMP concentration and Ca2+ uptake. 240 49


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