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)

GTP, in physiologic concentration, enhances the binding of cAMP to a protein in the hepatic cytosol that may be the regulatory subunit of protein kinase II. Ingestion of carbohydrate suppresses hepatic gluconeogenesis and glycogenolysis, two processes that are stimulated by cAMP. In this study, we have examined the possibility that carbohydrate inhibits these processes partly by decreasing the sensitivity of the GTP-responsive cAMP-binding protein to the effect of GTP. We found that 100 muM GTP was much less effective in enhancing cAMP binding in the hepatic cytosol of rats given 15% glucose for 2 days than in the cytosol of fasted rats [21 +/- 3% (mean +/- SE) increase vs. 67 +/- 6%, P less than .01]. Corresponding results were noted in diethylaminoethyl (DEAE)-cellulose extracts of the hepatic cytosol of these rats. GTP stimulation of cAMP binding was also diminished in the hepatic cytosol of diabetic rats treated for 7 days with insulin compared with that of untreated diabetic rats (29 +/- 10 vs. 81 +/- 11% increase, P less than .01), but this could have been due to increased food intake in the treated rats. We conclude that GTP stimulation of hepatic cAMP binding is decreased in the carbohydrate-fed state and that this effect may be mediated by the increase in plasma insulin induced by carbohydrate. Our observations suggest that some of the cellular effects of cAMP may be regulated by modulation of the stimulatory effect of GTP on the GTP-responsive cAMP-binding protein.
Diabetes 1987 Jan
PMID:Effects of fasting, feeding, and insulin on enhancing effect of GTP on cAMP binding in rat hepatic cytosol. 302 42

Figure 8 summarizes some of the processes that may impact on the secretion of insulin by regulating Ca2+ handling by the beta-cell endoplasmic reticulum. A role for calmodulin in controlling the rate of Ca2+ efflux is indicated by both the ability of the calmodulin antagonist, W7 to stimulate Ca2+ efflux and by the ability of exogenous calmodulin to antagonize Ca2+ efflux in response to inositol trisphosphate (IP3). The impact of calmodulin on this system may be to serve as link in the feedback control of cellular Ca2+. In addition to IP3, a second messenger that may link signal transduction to the release of Ca2+ is the guanine nucleotide, GTP. GTP stimulates the efflux of Ca2+ from the endoplasmic reticulum through a mechanism distinct from IP3. It will be important to determine whether extracellular glucose concentration, or other modifiers of secretion, acutely regulate the GTP concentrations in the beta-cell and to assess if this function may be altered with a decrease in beta-cell function. A variety of evidence indicates that metabolism of glucose by the beta-cell somehow plays a major role in the cellular control of insulin secretion (Hedeskov, 1980). An important link in this process may be the direct effects of glucose 6-phosphate on the handling of Ca2+ by the endoplasmic reticulum. Glucose 6-phosphate is able to increase the active uptake of Ca2+ by these membranes and also to specifically inhibit Ca2+ efflux produced by the IP3. Concentrations of glucose 6-phosphate needed to achieve these effects are likely achieved under physiological conditions (Aschroft et al., 1970). It is also easy to imagine that in diabetes when the islets are chronically exposed to high glucose that, as a result of the content of the high Km glucokinase in the islet (Meglasson and Matschinsky, 1986), higher concentrations of glucose 6-phosphate may be achieved. Under these conditions glucose 6-phosphate may contribute to the islet-cell pathology by interfering with the acute control of Ca2+ handling by the endoplasmic reticulum.
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PMID:Regulation of calcium uptake/efflux from the islet-cell endoplasmic reticulum with regard to the secretion of insulin. 304 40

Phosphorus is the sixth most abundant element in the body after oxygen, hydrogen, carbon, nitrogen, and calcium. It comprises about 1% of the total body weight of humans. Eighty-five percent of it is stored in the bone in the form of hydroxyapatite crystal; 14% is in the soft tissues in the form of energy-storing bonds with nucleotides (ATP, GTP), nucleic acids in chromosomes and ribosomes, 2,3-DPG in the red blood cells, and phospholipids in the cells' membranes. Less than 1% is in the extracellular fluids. Phosphate balance is maintained by multiple systems. The gut is responsible for the absorption of two thirds of the 4-30 mg/kg/day of phosphate intake. Absorption sites are all along the gut; in humans the most active site is the jejunum. The kidney filters 90% of the plasma phosphate and reabsorbs it in the tubuli. In states of hypophosphatemia the kidney can reabsorb the filtered phosphates very efficiently, reducing the amount excreted in the urine virtually to zero. The healthy kidney can excrete high loads of phosphate and rid the body of phosphate overload. Through the vitamin D-PTH axis the endocrine system regulates the phosphate balance by influencing the kidney, gut, and bone. Other hormones, including thyroid, insulin, glucagon, glucocorticosteroid, and thyrocalcitonin, play a lesser role in regulation of phosphate metabolism. Because of the complex control of phosphate homeostasis, various clinical conditions may lead to hypophosphatemia. These include nutritional repletion, gastrointestinal malabsorption, use of phosphate binders, starvation, diabetes mellitus, and increased urinary losses due to tubular dysfunction. The clinical picture of phosphate depletion is manifested in different organs and is due mainly to the fall in intracellular levels of ATP and decreased availability of oxygen to the tissues, secondary to 2,3-DPG depletion. The various manifestations of phosphate depletion are listed in Table 2. The treatment of hypophosphatemia consists of administering enteral or parenteral phosphate salts. An important aspect of dealing with the potentially serious effects of phosphate depletion is to prevent the depletion from happening in the first place. Hyperphosphatemia can occur in renal failure, hemolysis, tumor lysis syndrome, and rhabdomyolysis. The treatment of hyperphosphatemia usually consists of fluid administration (in the absence of kidney failure). In chronic hyperphosphatemia, phosphate binders such as aluminum and magnesium salts can reduce the phosphate load. The use of these phosphate binders is limited by their potential side effects.
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PMID:Consequences of phosphate imbalance. 306 Jan 61

The purpose of this investigation was to elucidate the factors that regulate the pattern of gene expression in purine and pyrimidine metabolism in normal liver and hepatoma. For this purpose, the action of a hormone, insulin, and the development of resistance to a chemotherapeutic agent, tiazofurin, were studied. This investigation brought detailed evidence showing that in the rat insulin exerted a profound effect on liver purine and pyrimidine metabolism by regulating the concentrations of nucleotides through controlling the activities of strategic enzymes involved in their biosynthesis. When rats were made diabetic by alloxan treatment, in the average liver cell concentrations of ATP, GTP, UTP and CTP decreased to 66, 62, 54 and 63%, respectively, of those of normal liver. Administration of insulin for 2 days returned the hepatic nucleotide concentrations to normal range; further insulin treatment for an additional 5 days raised the concentrations of ATP, GTP, UTP and CTP to 197, 352, 412 and 792% of values observed in the liver of diabetic rats. In diabetic rats the hepatic activities of OMP decarboxylase, orotate phosphoribosyltransferase, uridine phosphorylase, uridine-cytidine kinase and uracil phosphoribosyltransferase decreased to 44, 48, 70, 36 and 41% of the activities of normal liver. Insulin treatment for 2 days returned activities to normal range. Continued insulin treatment for an additional 5 days increased the enzymic activities to 3.9- to 5.3-fold of those of the liver of the diabetic rats. The regulation by insulin treatment of the activities of enzymes of de novo and salvage synthesis of UMP should explain, in part at least, the decline and increase of the uridylate pool in diabetes and after insulin treatment. In the diabetic rat hepatic CTP synthetase, the rate-limiting enzyme of CTP biosynthesis, decreased to 53% and insulin administration for 2 days restored activity to normal range. Insulin treatment for an additional 5 days increased the synthetase activity to 4-fold of the values of the diabetic liver. Thus, the behavior of liver CTP synthetase activity is tightly linked with that of the CTP pool. In the diabetic rat liver, the activity of IMP dehydrogenase, the rate-limiting enzyme of GTP biosynthesis, decreased to 24% of that of the normal liver. Insulin administration for 2 days returned the activity to normal range, yielding a 4.5-fold increase in the activity from the diabetic to the insulin-treated state.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of purine and pyrimidine metabolism by insulin and by resistance to tiazofurin. 390 7

A multifunctional protein kinase, purified from rat liver as ATP-citrate lyase kinase, has been identified as a glycogen synthase kinase. This kinase catalyzed incorporation of up to 1.5 mol of 32PO4/mol of synthase subunit associated with a decrease in the glycogen synthase activity ratio from 0.85 to a value of 0.15. Approximately 65-70% of the 32PO4 was incorporated into site 3 and 30-35% into site 2 as determined by reverse phase high performance liquid chromatography. Release of 32PO4 from the phosphopeptides during automated Edman degradation confirmed the site 3 and 2 assignment. Thermal stability studies established that the phosphorylations of sites 3 and 2 were catalyzed by the same kinase. This multifunctional kinase was distinguished from glycogen synthase kinase-3 on the basis of nucleotide (ATP versus GTP) and protein substrate (glycogen synthase, ATP-citrate lyase, and acetyl-CoA carboxylase) specificities. Since the phosphate contents in glycogen synthase of sites 3 and 2 are altered in diabetes and by insulin administration, the possible involvement of the multifunctional kinase was explored. Glycogen synthase purified from diabetic rabbits was phosphorylated in vitro by this multifunctional kinase at only 10% of the rate compared to synthase purified from control rabbits. Treatment of the diabetics with insulin restored the synthase to a form that was readily phosphorylated in vitro.
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PMID:Phosphorylation of sites 3 and 2 in rabbit skeletal muscle glycogen synthase by a multifunctional protein kinase (ATP-citrate lyase kinase). 393 Apr 92

Adenylate cyclase activity was investigated in myocardial sarcolemma, aorta particulate fractions, and liver plasma membranes from control and 5-day streptozotocin-induced diabetic rats. The basal adenylate cyclase activity was increased in heart sarcolemma from diabetic rats, whereas the extent of stimulation by glucagon, dopamine, isoproterenol, epinephrine, sodium fluoride and forskolin was decreased markedly. The decreased responsiveness was associated with a decrease in Vmax but not in the activation constant. In contrast, GTP stimulated adenylate cyclase in control and diabetic myocardial sarcolemma to the same extent. In addition, the basal adenylate cyclase activity was not altered significantly in aorta particulate fraction of liver plasma membranes from diabetic rats, but the stimulation of adenylate cyclase by catecholamines and forskolin (in the case of aorta) and by adenosine, glucagon, NaF and forskolin (in the case of liver) was diminished markedly. These data suggest that, in streptozotocin-induced diabetes, the responsiveness of adenylate cyclase to various hormones and agents (fluoride and forskolin) which act through receptor-independent mechanisms is decreased.
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PMID:Streptozotocin-induced diabetes and hormone sensitivity of adenylate cyclase in rat myocardial sarcolemma, aorta and liver. 403 39

Experimental diabetes induces increased content of RNA and UTP in the renal cortex. Studies were designed to assess the bioavailability of 5-phosphoribosyl-1-pyrophosphate (PRPP) in the diabetic renal cortex because PRPP is an important determinant of the de novo synthesis of nucleotides. The tissue bioavailability of PRPP determines the effects of orotate or adenine administration on UTP, ATP, and GTP content and on the incorporation of labeled precursors into UTP and ATP. Diabetic and control rats with chronic intravenous cannulas were infused over 2.5-24 h with orotate or adenine. Orotate administration induced greater decreases in ATP and GTP and in labeled adenine incorporation into ATP concomitant with smaller increases in UTP in controls than in diabetic animals. Adenine administration induced a greater decrease of labeled orotate incorporation into UTP and a smaller increase in ATP in controls than in diabetic animals. Prolonging the adenine infusion resulted in disappearance of these differences. The results are compatible with greater initial bioavailability of PRPP in the diabetic renal cortex than in controls but with a rate of maximal PRPP generation that is the same in both tissues.
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PMID:Phosphoribosylpyrophosphate bioavailability in diabetic rat renal cortex in vivo. 615 74

We have investigated alterations in beta-adrenergic receptors and adenylate cyclase activity in myocardial membranes from normal and alloxan-treated diabetic rats. Saturation curves of [3H]dihydroalprenolol binding yielded a Bmax of 96.3 +/- 3.9 fmol/mg protein in normal membranes and 47.6 +/- 3.9 fmol/mg protein in diabetic membranes. Decreased receptor number in membranes from diabetic animals was not accompanied by alteration in receptor affinity for either antagonists or agonists to the beta-receptor. We were unable to detect any alteration in adenylate cyclase activity in similar ventricular membranes. Adenylate cyclase activity in the basal state or in the presence of sodium fluoride, guanyl-5'-yl imidodiphosphate, or isoproterenol, with or without GTP, was not altered by the alloxan-induced diabetic state. Stimulation of adenylate cyclase activity by forskolin, the novel diterpene activator, also was not altered by diabetes. The results suggest that while diabetes reduced beta-receptor number, this is not reflected in any other component of the adenylate cyclase complex.
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PMID:Alloxan-induced diabetes reduces beta-adrenergic receptor number without affecting adenylate cyclase in rat ventricular membranes. 619 Nov 47

Secretin stimulation of adenylate cyclase activity in heart membranes was selectively altered in streptozotocin-diabetic adult male rats suffering from moderately severe diabetes, 40 days after i.v. streptozotocin administration (40 mg/kg body weight). The efficacy of secretin was reduced by 55% whilst its potency was unaffected. By contrast, the stimulation of adenylate cyclase by NaF, GTP, Gpp(NH)p, D,L-isoproterenol, and glucagon remained normal. The present data, together with the markedly reduced secretin response of cardiac adenylate cyclase in genetically obese (fa/fa) Zucker rats might indicate that hypoinsulinemia and insulin resistance both reduce the number of secretin receptors coupled to the adenylate cyclase system, an alteration whose contribution to diabetic cardiomyopathy remains to be determined.
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PMID:Selective alteration of secretin-stimulated cardiac adenylate cyclase activity in streptozotocin-diabetic rats. 622 63

The myocardial beta-receptor adenylate cyclase system was investigated in short-term streptozotocin-diabetic rats. Earlier reports of a decreased sensitivity of the myocardium to isoproterenol (ISO) in these animals were elucidated by measuring the in vivo production of cAMP after ISO. A substantial decrease was seen in diabetic animals compared with controls and starved animals, and thyroxine treatment, known to sensitize the myocardium to catecholamines, did not normalize the response. The desensitization was retained in a membrane fraction in such a way that ISO was unable to increase the cAMP production while stimulation via the nucleotide-binding protein (with NaF or GTP) leads to a normal cAMP response. As the beta-adrenergic receptor number and affinity turned out to be identical in control and diabetic animals, a functional uncoupling of the myocardial beta-receptor from productive adenylate cyclase activation seems thus to exist in experimental diabetes. It is unlikely that it has anything to do with the thyroid status of the animals, but the possibility of a catecholamine-induced densensitization cannot be excluded. The phenomenon is not universal as the beta-receptor-adenylate cyclase system is normal in isolated spleen lymphocytes. Whether the described phenomenon obtained in an animal study has any relevance for the increased incidence of heart failure in human diabetes mellitus is not known at present.
Diabetes 1983 Dec
PMID:The adrenergic beta-receptor adenylate cyclase system in heart and lymphocytes from streptozotocin-diabetic rats. In vivo and in vitro evidence for a desensitized myocardial beta-receptor. 631 97


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