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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Measurements have been made of the activities of the enzymes of the de novo and salvage pathways of pyrimidine synthesis (carbamoyl phosphate synthetase II (glutamine) (EC 6.3.5.5); dihydroorotate dehydrogenase (EC 1.3.99.11); the overall activity of Complex II (orotate phosphoribosyl pyrophosphate transferase (EC 2.4.2.10) and orotidine 5-phosphate decarboxylase (EC 4.1.1.23); uracil phosphoribosyltransferase (EC 2.4.2.9)) in the mammary gland of rats at different stages of the lactation cycle and the effects of diabetes on the activity of these enzymes in lactation have been studied. From a consideration of the changes in enzyme activities and the changes in the tissue concentration of phosphoribosyl pyrophosphate, an activator of the de novo pathway and substrate for both the de novo and salvage routes, it is concluded that the de novo pathway is the major route of pyrimidine synthesis in mammary tissue. Diabetes decreases the activity of the enzymes of the de novo pathway; the effects are particularly marked for Complex II. The present results on pyrimidine synthesis are compared to the pattern for purine synthesis previously published.
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PMID:Pyrimidine nucleotide synthesis in the rat mammary gland: changes in the lactation cycle and effects of diabetes. 147 92

Early renal hypertrophy of diabetes is associated with increases in the tissue content of RNA, DNA, and sugar nucleotides involved in the formation of carbohydrate-containing macromolecules. We have previously reported an increase in the activity of enzymes of the de novo and salvage pathways of purine synthesis in early diabetes; the present communication explores the changes in the pathways of pyrimidine synthesis. Measurements have been made of key enzymes of the de novo and salvage pathways at 3, 5, and 14 days after induction of diabetes with streptozotocin (STZ), phosphoribosyl pyrophosphate (PPRibP), and some purine and pyrimidine bases. Carbamoyl-phosphate synthetase II, the rate-limiting enzyme of the de novo route, did not increase in the first 5 days after STZ treatment, the period of most rapid renal growth; a significant rise was seen at 14 days (+38%). Dihydroorotate dehydrogenase, a mitochondrial enzyme, showed the most marked rise (+147%) at 14 days. The conversion of orotate to UMP, catalyzed by the enzymes of complex II, was increased at 3 days (+42%), a rise sustained to 14 days. The salvage route enzyme, uracil phosphoribosyltransferase (UPRTase), showed a pattern of change similar to complex II. The effect of the decreased concentration of PPRibP on the activities of CPSII, for which it is an allosteric activator, and on activities of OPRTase and UPRTase, for which it is an essential substrate, is discussed with respect to the relative Ka and Km values for PPRibP and the possibility of metabolite channeling.
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PMID:Pyrimidine nucleotide synthesis in the rat kidney in early diabetes. 172 7

The biosynthesis of uridine 5'-triphosphate (UTP), uridine 5'-diphosphohexoses, and 5'-diphosphohexosamines (UDP-sugars) was studied in isolated rat glomeruli 48 h after streptozotocin-induced diabetes. Compared with control, diabetic glomeruli demonstrated an increase in the following: exogenous orotate utilization, orotate incorporation into UTP and UDP-sugars, UTP accretion rate, and UDP-sugar pool size. Since these phenomena were not associated with enhanced biosynthesis of orotate de novo, the increased glomerular UDP-sugar bioavailability in diabetes is due to enhanced utilization of exogenous orotate. Plasma concentrations of orotate and uridine were measured in control, sham operated, and unilaterally nephrectomized rats receiving 5, 20, or 60% protein diets. The concentration of pyrimidine precursors correlated directly with protein intake, with doubling at the 60% dietary protein level. In conclusion, glomerular uracil ribonucleotide biosynthesis may be modulated by the quantity of dietary protein. Because UDP-sugars are necessary for basement membrane material formation, an increase in their bioavailability may be part of the metabolic change responsible for diabetic glomerulosclerosis. Diets with high protein content could augment this metabolic alteration.
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PMID:Glomerular uracil nucleotide synthesis: effects of diabetes and protein intake. 245 73

Evidence is provided that insulin controls the amount and synthetic rate of liver carbamoyl-phosphate synthase II (EC 6.3.5.5) (synthase II) in rat. In 3- and 6-day starvation, with low plasma insulin, synthase II specific activity decreased to 47 and 30%, respectively, of normal; on re-feeding and with concurrent insulin injections, liver synthase II activity increased to 2.5 and 3 times that of starved rats respectively. Treatment with anti-insulin serum during re-feeding prevented the rise in synthase II activity. In diabetic rats, synthase II activity decreased to 28% of normal and was increased by insulin treatment for 2 and 7 days to 4.8- and 5.6-fold of the activity in diabetic liver; this rise in activity was blocked by actinomycin. Immunotitration demonstrated that alterations in synthase II activity were due to changes in the enzyme amount. In starvation, the relative synthesis rate of synthase II decreased to 44%, with an increase in catabolic rate to 122%; re-feeding returned these to control values. In diabetes the synthase II synthesis rate decreased to 52% and the degradative rate was accelerated to 180%; insulin treatment induced synthesis and returned degradation to the control range. Thus the integrative action of insulin in liver pyrimidine metabolism entails regulation of the amount and turnover of synthase II.
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PMID:Regulation by insulin of liver carbamoyl-phosphate synthase II (glutamine-hydrolysing). 331 Oct 28

Studies by our and other laboratories have demonstrated that cholesterol synthesis is increased in the small intestine of insulinopenic diabetic animals. In normal animals, many factors have been shown to regulate cholesterol synthesis in the small intestine, including changes in plasma cholesterol levels. The purpose of this study was to determine the effect of lowering plasma cholesterol levels on small intestine cholesterol synthesis in streptozocin-induced diabetic rats. In diabetic rats, 4-aminopyrazolo[3,4-d]pyrimidine (4-APP)-induced hypocholesterolemia (plasma cholesterol levels less than 20 mg/dl) resulted in a 2.5-fold increase in small intestine cholesterol synthesis, which was most marked in the distal small intestine, decreasing proximally. In the distal small intestine the incorporation of 3H2O into cholesterol was 0.28 +/- 0.04 mumol.h-1.g-1 in diabetic rats versus 1.60 +/- 0.38 in diabetic rats administered 4-APP (P less than .01). This stimulation of cholesterol synthesis occurred in the upper villus, middle villus, and crypt cells isolated from the middle intestine of the 4-APP-treated diabetic animals. In agreement with these observations, "functional hypocholesterolemia" due to Triton WR-1339 administration also stimulated cholesterol synthesis 2.5-fold in the small intestine of normal and diabetic animals. In the distal small intestine, cholesterol synthesis was 0.43 +/- 0.10 mumol.h-1.g-1 in the diabetic rats versus 1.08 +/- 0.21 in diabetic rats treated with Triton WR-1339 (P less than .05). In both the 4-APP and Triton WR-1339 experiments, the response of the diabetic rats was similar to that observed in normal rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1987 Nov
PMID:Effect of hypocholesterolemia on cholesterol synthesis in small intestine of diabetic rats. 366 15

The use of insulin by diabetics has largely removed the threat of death from ketotic coma but cardiovascular dysfunction remains a major cause of death in patients with diabetes. Recent research has indicated a generalized membrane defect, which may cause abnormalities of calcium metabolism in nerves, cardiac and smooth muscle as well as endothelial cells and thus may lead respectively to the development of neuropathy, primary cardiomyopathy, microangiopathy and atherosclerosis in the diabetic population. Each of these pathogenic processes, which are associated with insulin deficiency, alone or in combination with others, may result in cardiac dysfunction in chronic diabetes. Activation of the sympathetic nervous system and abnormalities in catecholamine metabolism have been identified in diabetes; their involvement in the genesis of cardiac pump failure as well as large and small vessel disease is likely. The membrane defects as indicated by changes in both plasma membrane and glycocalyx in diabetic cardiomyopathy appear to be complex and may involve alterations in the metabolism of lipids and pyrimidine nucleotides. It seems that intracellular calcium overload is intimately involved in the development of diabetic cardiomyopathy; however, a concentrated research effort is required to understand the primary biochemical lesion in the pathogenesis of cardiac dysfunction in diabetes. In the meantime, a heightened awareness on the part of clinicians concerning the susceptibility of diabetic patients to cardiovascular problems may help in reducing mortality and morbidity in the diabetic population.
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PMID:Pathogenesis of cardiac dysfunction in diabetes mellitus. 385 Jul 73

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

Activities of pyruvate kinase, lactate and malate dehydrogenases as well as concentration of oxaloacetate, lactic and pyruvic acids and of glycerol-I-phosphate were altered in liver tissues of rats with alloxane diabetes. Alteration in activity of LDH and MDH isoenzymes appears to be responsible for regulation of the content of pyrimidine nucleotides oxidized and reduced forms, which limit the glucose oxidation.
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PMID:[Changes in liver enzyme activity in alloxan diabetes rats]. 708 Apr 80

These experiments were undertaken to assess the role of sorbitol dehydrogenase in mediating sorbitol pathway-linked neural and vascular dysfunction in rats with streptozocin-induced diabetes. 2-methyl-4-[N,N-dimethylsulfamoyl-piperazino]-pyrimidine (S-0773), a putative inhibitor of sorbitol dehydrogenase, was given in the drinking water to control and diabetic rats. After 5 weeks of diabetes, glycosylated hemoglobin levels were increased twofold and were unaffected by S-0773. Sorbitol levels in diabetic rats were increased 11- to 14-fold in ocular tissues and sciatic nerve; S-0773 increased sorbitol levels another 4-fold or more in these same tissues but had much smaller effects in other tissues. Diabetes-associated increases in fructose levels and lactate:pyruvate ratios in retina and in sciatic nerve were markedly attenuated by S-0773. S-0773 also attenuated, but did not completely normalize, impaired caudal nerve conduction and vascular dysfunction in ocular tissues, sciatic nerve, and aorta in diabetic rats. These observations, together with other evidence, suggest that sorbitol pathway-linked vascular dysfunction (in ocular tissues, peripheral nerve, and aorta) and electrophysiological dysfunction (in peripheral nerve) induced by diabetes are more closely linked to increased oxidation of sorbitol to fructose than to putative osmotic effects of elevated sorbitol levels or redox and metabolic imbalances associated with reduction of glucose to sorbitol by aldose reductase.
Diabetes 1995 Feb
PMID:Inhibition of sorbitol dehydrogenase. Effects on vascular and neural dysfunction in streptozocin-induced diabetic rats. 785 46

We assessed the effect of dipyridamole, RA-642 and mopidamol, on lenticular opacities in a model of experimental diabetic cataracts in rats. All three pyrimido-pyrimidine derivatives caused a statistically significant reduction of opacification in crystalline lens as compared with untreated diabetic animals. The production of superoxide anions (phenazine methosulphate [PMS]-induced nitroblue tetrazolium [NBT] reduction) showed a decrease of 81.6%, 78.9% and 1.8% in lens tissue homogenates from rats treated with dipyridamole, RA-642 and mopidamol, respectively. Dipyridamole and RA-642 produced a statistically significant inhibition (50% and 64.8%, respectively) of lipid peroxidation (ferrous sulphate and ascorbic acid [FeAs]-induced malondialdehyde [MDA] production) as compared with the group of untreated diabetic rats. Mopidamol did not exert any inhibitory effect on lipid peroxidation. There was a statistically significant correlation between opacification of lens and PMS-induced NBT reduction and FeAs-induced MDA production. We conclude that the protective effect of dipyridamole and RA-642 from free radical damage to crystalline lens in the model of experimental diabetes used in this study, is the result of the antioxidant action of these compounds. The effect exerted by mopidamol, however, suggest a possible complementary effect of the pyrimido-pyrimidine derivatives through interaction with other mechanisms (e.g., the sorbitol pathway) implicated in the development of cataracts.
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PMID:The pyrimido-pyrimidine derivatives, dipyridamole and RA-642, reduce opacification of crystalline lens in diabetic rats. 787 Jun 94


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