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 effect of oral administration of sodium orthovanadate for 5 wk on hepatic glycogen metabolism was studied in control and streptozocin-induced diabetic rats. Diabetes caused hyperglycemia (5-fold increase), hypoinsulinemia (85% decrease), and hyperglucagonemia (4-fold increase). There were also marked decreases in liver glycogen and activities of glycogen-metabolizing enzymes in liver. Although vanadate administration in control animals showed no significant effect on the various parameters measured except for a 70% decrease in plasma insulin, this treatment in diabetic rats restored these parameters to near control values. In diabetic rats, glycogen synthase a and the activity ratio (activity of glycogen synthase a divided by activity of total glycogen synthase) decreased to 30% of control levels and were restored to approximately 70-80% of control values after vanadate administration. A similar pattern was observed for the activity of synthase phosphatase. The activities of glycogenolytic enzymes, i.e., phosphorylase (activity of phosphorylase a and activity of total phosphorylase), phosphorylase kinase, and protein kinase (in presence or absence of cAMP), were significantly decreased by 40-70% in diabetic rats. These enzyme activities were recovered to 70-100% of control values after vanadate treatment. Phosphorylase phosphatase was not altered by diabetes, but the vanadate treatment of both groups, i.e., control and diabetic rats, showed a 25% increase in its activity (P less than 0.01). In conclusion, these results show insulinlike in vivo action of vanadate on various parameters related to hepatic glycogen metabolism.
Diabetes 1990 Jul
PMID:Insulinlike effects of vanadate on hepatic glycogen metabolism in nondiabetic and streptozocin-induced diabetic rats. 211 14

Picotamide is the most interesting compound of 4-OH isophthalic acid. It is effective in vitro and in vivo. Picotamide induces inhibition of platelet aggregation: it is a thromboxane synthetase inhibitor and a thromboxane receptor antagonist. Picotamide causes cyclic endoperoxide accumulation and diverts their metabolism toward PgI2 synthesis in endothelial cells. PGI2 stimulates the adenylate cyclase with cAMP synthesis which makes platelets less sensitive to aggregatory stimulation. Picotamide induces enhancement of fibrinolytic activity, with significant reduction in the level of circulating plasminogen but in the same time it does not affect antithrombin III and FDP levels. In the present study picotamide or placebo were administered in a double blind trial at 600 mg daily for six months to 51 patients effected by diabetic macro and/or microangiopathy. The patients were 38 men and 13 women, the age was between 20 and 80 years (mean age 62.34). Twenty-seven patients were affected by type I diabetes and 24 by type II diabetes. Twenty-three of these patients presented macro-angiopathic lesions, 9 only microangiopathic lesions and 13 both. Twenty-five patients received picotamide and the other 25 an identical placebo for six months. One patient manifested myocardial infarction during the wash-out period and failed to enter the study. The following determinations were carried out: at T0 clinical examination, Doppler ultrasonography, Winsor Index, laboratory parameters; after 90 days (T90) clinical examination and Winsor Index and after 180 days (T180) were repeated photoplethysmography and clinical parameters too. Patients were not only evaluated for the vascular disease of lower extremities, but also for the other complications of diabetes, as retinopathy, nephropathy, cardiac and cerebrovascular disease.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[Picotamide: prevention and therapy of diabetic vasculopathies. A double-blind clinical study]. 214 11

The anatomic distribution of fat is related to the risk for obesity-associated morbidity. Among individuals with equal degrees of relative adiposity, those with an upper-body preponderance of fat distribution (android) have higher rates of diabetes, stroke, ischemic heart disease, and early death than those with preferential deposition of adipose tissue in lower portions of the body (hips, thighs, buttocks; gynecoid. There are well-documented anatomic site-related differences in the relative activities of the adrenergic receptors (beta 1----lipolysis; alpha 2----antilipolysis) that control lipolysis. We assessed modifications of the status of alpha 2- and beta 1-adrenergic receptor and subreceptor function in small fragments of adipose tissue obtained by needle biopsy from the gluteal and abdominal subcutaneous regions of five android, seven gynecoid, and six uniformly obese women during a period of weight maintenance (4 weeks) (T1), and after 15% weight loss on an 840 kcal/d diet (T2). Measurements of body shape and adipocyte size were made and related to changes in the metabolism of these adipocytes. The waist-to-hip ratio (WHR) was used to define these three types of regional distribution of fat in these obese subjects: android = WHR greater than 0.86; gynecoid = WHR less than or equal to 0.76; uniform = WHR greater than 0.76 less than or equal to 0.86. WHR was not significantly altered by weight loss in any of the three groups. Although significant effects of time and/or anatomic site on in vitro responses to isoproterenol, norepinephrine, clonidine, forskolin, and dibutyryl cAMP were found, these did not correlate with intra-individual changes in anthropometry or adipocyte size.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Regional changes in adrenergic receptor status during hypocaloric intake do not predict changes in adipocyte size or body shape. 215 70

Hormonal regulation of hepatic gluconeogenic pathway flux is brought about by phosphorylation/dephosphorylation and control of gene expression of several key regulatory enzymes. Regulation by cAMP-dependent phosphorylation occurs at the level of pyruvate kinase and 6-phosphofructo-2-kinase (6PF-1-K)/fructose-2,6-bisphosphatase (Fru-2,6-P2ase). The latter is a unique bifunctional enzyme that catalyzes both the synthesis and degradation of fructose-2,6-bisphosphate (Fru-2,6-P2), which is an activator of 6PF-1-K and an inhibitor of Fru-1,6-P2ase. The bifunctional enzyme is a homodimer whose activities are regulated by cAMP-dependent protein kinase-catalyzed phosphorylation at a single NH2-terminal seryl residue/subunit, which results in activation of the Fru-2,6-P2ase and inhibition of the PF-1-K reactions. Hormone-mediated changes in the phosphorylation state of the bifunctional enzyme are responsible for acute regulation of Fru-2,6-P2 levels. 6PF-2-K/Fru-2,6-P2ase thus provides a switching mechanism between glycolysis and gluconeogenesis in mammalian liver. Pyruvate kinase is regulated by both phosphorylation and allosteric effectors. Fru-1,6-P2, an allosteric activator, also inhibits cAMP-dependent enzyme phosphorylation, and its steady-state concentration is indirectly determined by the level of Fru-2,6-P2. Therefore, acute regulation of both pyruvate kinase and the bifunctional enzyme provide coordinated control at both the pyruvate/phosphoenolpyruvate and Fru-6-P/Fru-1,6-P2 substrate cycles. The Fru-2,6-P2 system is also subject to complex multihormonal long-term control through regulation of 6 PF-2-K/Fru-2,6-P2ase gene expression. Glucocorticoids are the major factor in turning on this gene in liver, but insulin is also a positive effector. cAMP prevents the effects of glucocorticoids and insulin. Although Fru-2,6-P2 plays a key role in the regulation of carbon flux in the gluconeogenic pathway, the regulation of this flux depends on several factors and regulation of other key enzymes whose importance varies depending on the dietary and hormonal status of the animal. Molecular cloning of the cDNA encoding PF-2-K/Fru-2,6-P2ase has elucidated its structure and permitted analysis of its evolutionary origin as well as its tissue distribution and control of its gene expression. The rat liver and skeletal muscle isoforms arose by alternative splicing of a single gene. The muscle form differs from the liver form only at the NH2-terminal and does not have a cAMP-dependent protein kinase phosphorylation site. The hepatic enzyme subunit consists of 470 amino acids.(ABSTRACT TRUNCATED AT 400 WORDS)
Diabetes Care 1990 Jun
PMID:Fructose-2,6-bisphosphate in control of hepatic gluconeogenesis. From metabolites to molecular genetics. 216 55

Aberrant expression of the islet amyloid polypeptide (IAPP) gene might be involved in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM). Here, we report that IAPP promoter-luciferase constructs revealed tissue-specific activity. This activity was not mediated by cAMP. Sequential 5' deletions of the IAPP promoter caused a progressive derepression of the IAPP gene promoter in IAPP-producing cells. Comparison of the nucleotide sequence of the IAPP promoter with that of the insulin promoter (both active in pancreatic beta-cells) reveals two sequence elements of putative importance: an insulin enhancer-like sequence and an element which corresponds to a protected domain in rat insulin I gene promoter footprint experiments.
 ...
PMID:IAPP/amylin gene transcriptional control region: evidence for negative regulation. 217 4

Metabolic acidosis (6 days NH4Cl) causes a fourfold increase in the relative abundance of mRNA encoding phosphoenolpyruvate carboxykinase in rat kidney. Streptozotocin-diabetes (6 days) also results in an increased abundance of the mRNA but this increase can be prevented if the acidosis associated with bicarbonate is corrected by treatment with bicarbonate. The results confirm that renal phosphoenolpyruvate carboxykinase is regulated primarily by changes in acid-base status and that this control is at a pretranslational step. Isolated kidney tubules in short-term incubation have been used to identify which agents regulate levels of phosphoenolpyruvate carboxykinase mRNA. The relative abundance of the mRNA was increased by glucocorticoids and hormones which act via cAMP, or by cAMP analogues directly, but was not affected by hormones acting via Ca2+. Neither incubation at pH 7.1 nor the presence of serum from acidotic rats had any effect on the level of phosphoenolpyruvate carboxykinase mRNA. It is concluded that acidosis, glucocorticoids, and cAMP independently regulate expression of renal phosphoenolpyruvate carboxykinase.
 ...
PMID:Hormonal and acid-base regulation of phosphoenolpyruvate carboxykinase mRNA levels in rat kidney. 217 84

Glucokinase is expressed in both the liver and the pancreatic beta-cell and plays a key role in the metabolism of glucose by both tissues. Expression of this enzyme is differentially regulated; hepatic glucokinase is stimulated by insulin and repressed by cAMP, whereas beta-cell glucokinase activity is increased by glucose. Recently, the glucokinase gene has been characterized and was found to contain two different transcription control regions. One region regulates transcription of the gene in the liver, whereas the other region, which lies at least 12 kilobases further upstream, controls transcription in the pancreatic beta-cell. The finding of two different transcription control regions in a single glucokinase gene provides a genetic basis for the tissue-specific differential regulation of glucokinase and will serve as the basis for further studies to identify and characterize the different regulatory elements and factors in the liver and beta-cell, which are presumably involved. Comparison of different glucokinase cDNAs isolated from hepatic, insulinoma, and islet cDNA libraries indicates that at least three glucokinase isoforms are generated by differential RNA processing of the glucokinase gene transcripts. Whether any of these glucokinase isoforms are functionally unique remains to be determined.
Diabetes 1990 May
PMID:Glucokinase gene structure. Functional implications of molecular genetic studies. 218 4

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

The presence of an enzyme that hydrolyzes ATP to AMP and PPi was demonstrated in a 27,000 X g particulate and supernatant fraction of mouse pancreatic islets. The enzyme was stimulated by addition of Ca2+, Zn2+, and Co2+. Addition of calmodulin or trifluoperazine had no effect. In the presence of Ca2+ and Zn2+, the Michaelis constant (Km) for ATP was approximately 0.1 mM and the maximum velocity (Vmax) was close to 90 nmol X min-1 X mg protein-1. After preincubation of the islets for 30 min with 16.7 mM glucose or 5 mM glucose with 1 mM 3-isobutyl-1-methylxanthine (IBMX), a three- to fourfold increase in enzyme activity was seen. Direct addition of IBMX or cAMP to the enzyme assay also had a small stimulatory effect. Preincubation with the insulin secretagogues leucine and alpha-ketoisocaproic acid did not affect the enzyme activity. The possible function of the enzyme in pancreatic islets is discussed in relation to hypotheses given for the function of similar enzyme(s) in other tissues.
Diabetes 1986 Oct
PMID:Presence of ATP-pyrophosphohydrolase in mouse pancreatic islets. 242 87

With an SV40-transformed hamster beta-cell line (HIT cells) as a model system, we tested the hypothesis that a rise in cAMP levels potentiates insulin release by an effect on the cytosolic free-Ca2+ concentration ([Ca2+]i). Intracellular cAMP levels were measured by radioimmunoassay, and [Ca2+]i was monitored with the fluorescent Ca2+ indicator quin 2. Insulin secretion was followed in static incubations or perifusion of the cells. In perifusion, both high glucose and depolarization of the beta-cell with 40 mM K+ trigger a monophasic pattern of insulin release without altering the HIT cell cAMP content. Addition of either the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) or the adenylate cyclase activator forskolin dramatically increased the cellular cAMP content, potentiated the burst phase of insulin release, and coupled the immediate phase of insulin secretion to a sustained secretory response. However, increases in cellular cAMP content were not associated with a change in [Ca2+]i. Thus, the potentiation of insulin secretion by a rise in cAMP in the HIT cell is not mediated by a release of stored Ca2+. Either a glucose-generated signal or a rise in [Ca2+]i triggered by high K+ can synergize with a rise in cAMP to couple the burst or immediate release of insulin evoked by either secretagogue to the sustained release of insulin.
Diabetes 1987 Apr
PMID:Increase in cAMP levels in beta-cell line potentiates insulin secretion without altering cytosolic free-calcium concentration. 243 78


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