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)

The hepatic branched-chain alpha-ketoacid dehydrogenase complex plays an important role in regulating branched-chain amino acid levels. These compounds are essential for protein synthesis but toxic if present in excess. When dietary protein is deficient, the hepatic enzyme is converted to the inactive, phosphorylated state to conserve branched-chain amino acids for protein synthesis. When dietary protein is excessive, the enzyme is in the active, dephosphorylated state to commit the excess branched-chain amino acids to degradation. Inhibition of protein synthesis by cycloheximide, even when the animal is starving for dietary protein, results in activation of the hepatic branched-chain alpha-ketoacid dehydrogenase complex to prevent accumulation of branched-chain amino acids. Likewise, the increase in branched-chain amino acids caused by body wasting during starvation and uncontrolled diabetes is blunted by activation of the hepatic branched-chain alpha-ketoacid dehydrogenase complex. The activity state of the complex is regulated in the short term by the concentration of branched-chain alpha-ketoacids (inhibitors of branched-chain alpha-ketoacid dehydrogenase kinase) and in the long term by alteration in total branched-chain alpha-ketoacid dehydrogenase kinase activity. cDNAs have been cloned and the primary structure of the mature proteins deduced for the E1 alpha subunit of the human and rat liver branched-chain alpha-ketoacid dehydrogenase complex. The cDNA and protein sequences are highly conserved for the two species. Considerable sequence similarity is also apparent between the E1 alpha subunits of the human branched-chain alpha-ketoacid dehydrogenase complex and the pyruvate dehydrogenase complex. Maple syrup urine disease is caused by an inherited deficiency in the branched-chain alpha-ketoacid dehydrogenase complex. The molecular basis of one maple syrup urine disease family has been determined for the first time. The patient was found to be a compound heterozygote, inheriting an allele encoding an abnormal E1 alpha from the father, and an allele which is not expressed from the mother. The only known animal model for the disease (Polled Hereford cattle) has also been characterized. The mutation in these animals introduces a stop codon in the leader peptide of the E1 alpha subunit, resulting in premature termination of translation. Two thiamine responsive patients have been studied. The deduced amino acid sequences of the mature E1 alpha subunit and its leader sequence were normal, suggesting that the defect in these patients must exist in some other subunit of the complex. 3-Hydroxyisobutyrate dehydrogenase and methylmalonate-semialdehyde dehydrogenase, two enzymes of the valine catabolic pathway, were purified from liver tissue and characterized.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of the branched-chain alpha-ketoacid dehydrogenase and elucidation of a molecular basis for maple syrup urine disease. 240 34

Measurements have been made of the tissue content of phosphoribosyl pyrophosphate (PPRibP) and of a range of metabolic intermediates involved in the energy charge of the cell, the glycolytic and pentose phosphate pathways, and of the activity of the enzymes of the pentose phosphate pathway and of PPRibP synthetase (EC 2.7.6.1) in the livers of normal, diabetic, insulin-treated diabetic and starved rats and in livers of rats previously starved and then re-fed with high-fat or high-carbohydrate diets. Diabetes, starvation and high-fat diet all caused a fall in the hepatic PPRibP content, whereas insulin treatment and high-carbohydrate diet raised the tissue content. A positive correlation was shown between the PPRibP content and ATP, energy charge and the cytosolic [NAD+]/[NADH] quotient. A positive association between the PPRibP content and the flux of glucose through the pentose phosphate pathway and the synthesis of ribose 5-phosphate via the oxidative enzymes of that pathway, including ribose-5-phosphate isomerase (EC 5.3.1.6), was also observed. A negative correlation was found between the ADP, AMP and Pi contents, and no correlation existed between PPRibP content and the enzymes of the non-oxidative branch of the pentose phosphate pathway. There was no correlation between hepatic PPRibP content and the activity of PPRibP synthetase measured in vitro. These results are considered in relation to the control of PPRibP synthetase in the liver in vivo.
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PMID:Hepatic phosphoribosyl pyrophosphate concentration. Regulation by the oxidative pentose phosphate pathway and cellular energy status. 244 9

The effect of maternal diabetes (induced by i.p. injections of 40-50 mg/kg BW Streptozotocin on the day of mating) on TRH in the pancreas of newborn rats was studied. Determination of peptide alpha amidation activity and TRH precursor level on the day of birth revealed decreased biosynthesis of TRH resulting in profoundly (10 times) lower pancreatic TRH and TRH-OH concentrations in pups of diabetic rats. Pancreatic His-Pro-diketopiperazine (His-Pro-DKP) remained unaffected by maternal diabetes. The depression of pancreatic TRH was less profound 24 h later, and even elevated TRH was measured in the pancreas of pups of diabetic mothers on postnatal day 5. Short term postnatal starvation or nursing of intact pups by the diabetic foster mother did not affect pancreatic TRH. It could be postulated that postnatal TRH development in the rat pancreas is retarded by maternal diabetes, while His-Pro-DKP remains unaltered.
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PMID:Thyrotropin releasing hormone in the pancreas of newborn rats from streptozotocin-treated mothers. 249 94

Carnitine palmitoyltransferase (CPT total) activity and synthesis increase in states where the insulin/glucagon ratio is low, such as starvation and diabetes [Brady & Brady (1987) Biochem. J. 246, 641-646]. However, the effect of glucagon and insulin on CPT synthesis is unknown. The present experiments were designed to determine the effect of glucagon, cAMP [8-(chlorophenylthio) cyclic AMP], and insulin + cAMP on CPT transcription and mRNA amounts over time after injection. The CPT protein that was purified, used to generate antibody, and cloned in these studies was the 68 kDa mitochondrial protein described previously [Brady & Brady (1987) Biochem. J. 246, 641-646; Brady, Feng & Brady (1988) J. Nutr. 118, 1128-1136; Brady & Brady (1989) Diabetes 38, in the press]. Saline-injected control rats exhibited a 2-fold increase in hepatic CPT transcription rate and CPT mRNA over the 5 h experiment from 09:00 to 14:00 h. The effect was most probably due to the fasting state of the rats during the day. Glucagon injection caused an 8-fold increase in transcription rate by 90 min and a 4-fold increase in CPT mRNA by 90-120 min. The cAMP effect had reached a peak by the first time point taken (15 min). Transcription rate was increased 4-fold and CPT mRNA was increased 3-fold at this time. The combination of cAMP + insulin injection did not produce any significant increase in transcription rate or CPT mRNA over the saline-injected controls. CPT mRNA and transcription rate showed a clear dose-response to glucagon injection from 0 to 150 micrograms/100 g body wt. Total CPT activity and immunoreactive CPT were not increased during these experiments. The data indicate that glucagon and insulin interact in control of transcription rate and amount of CPT mRNA, but that increases in CPT immunoreactive protein and activity are temporally delayed. This lag probably relates to the half-life of the CPT protein in vivo, which has been estimated as 2-7 days.
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PMID:Regulation of carnitine palmitoyltransferase in vivo by glucagon and insulin. 254 60

The effect of short term (2-wk) diabetes induced by streptozotocin and starvation (1-wk) on antioxidant enzymes and lipid peroxidation in the liver, kidney and heart of rats was investigated. The activity of mitochondrial oxidative markers was increased in diabetic liver and kidney, while the activity in tissues of starved rats tended to be decreased. Immunoreactive manganese superoxide dismutase was increased only in diabetic liver and was unchanged or decreased in the rest of the tissues. Glutathione peroxidase activity was increased in tissues of diabetic but not starved rats. The changes in copper-zinc superoxide dismutase and catalase in diabetic rats were similar to those in starved rats. In both groups, copper-zinc superoxide dismutase was decreased in liver, while catalase activity was decreased in liver and kidney, and increased in heart. The lipid peroxide level was increased in diabetic kidney and in the heart of starved rats, and decreased in the rest of the tissues. Insulin treatment in diabetic rats and refeeding in starved rats restored most of the abnormalities toward normal. These results suggest that accelerated mitochondrial oxidative metabolism not accompanied by induction of manganes superoxide dismutase results in oxidative injury in the hypertrophied kidney at an early stage of diabetes and possibly contributes to the development of nephropathy. Peroxidative myocardial damage in starved rat appears to be mediated by a catabolic process.
Diabetes Res 1989 Oct
PMID:Antioxidant enzyme status and lipid peroxidation in various tissues of diabetic and starved rats. 256 53

Administration of clofibric acid, 2,2'-(decamethylenedithio)diethanol, di(2-ethylhexyl)phthalate or perfluorooctanoic acid to male rates increased markedly microsomal 1-acylglycerophosphocholine (a-acyl-GPC) acyltransferase in a dose-dependent manner in liver. Simultaneous administration of actinomycin D or cycloheximide completely abolished the increase in the enzyme activity. The treatment of rats with clofibric acid did not affect the rate of decay of 1-acyl-GPC acyltransferase. Regardless of a great difference in the chemical structures of the peroxisome proliferators, high correlation was observed between the induced activities of microsomal 1-acyl-GPC acyltransferase and peroxisomal beta-oxidation. Stearoyl-CoA desaturase was induced by peroxisome proliferators in a dose-dependent manner; nevertheless, high correlation was not seen between the induced activities of desaturase and peroxisomal beta-oxidation. Hormonal (adrenalectomy, diabetes, hyperthyroidism and hypothyroidism) and nutritional (starvation, starvation-refeeding, fat-free diet feeding and high-fat diet feeding) alterations hardly affected the activity of 1-acyl-GPC acyltransferase. The present results indicate that microsomal 1-acyl-GPC acyltransferase is a useful parameter responsive to the challenges by peroxisome proliferators and suggest that a similar regulatory mechanism operates for the inductions of microsomal 1-acyl-GPC acyltransferase and peroxisomal beta-oxidation.
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PMID:Co-induction by peroxisome proliferators of microsomal 1-acylglycerophosphocholine acyltransferase with peroxisomal beta-oxidation in rat liver. 257 Jun 10

Induction of microsomal 1-acyl-glycerophosphocholine (GPC) acyltransferase in rat tissues by four peroxisome proliferators, clofibric acid, tiadenol, DEHP and PFOA, was examined. Among the nine tissues examined, kidney, liver and intestinal mucosa responded to the challenges by the peroxisome proliferators to induce the enzyme. The treatment of rats with various dose of clofibric acid, tiadenol, DEHP or PFOA resulted in an induction of kidney microsomal 1-acyl-GPC acyltransferase in a dose-dependent manner. Despite the structural dissimilarity of peroxisome proliferators, the induction of microsomal 1-acyl-GPC acyltransferase was highly correlated with the induction of peroxisomal beta-oxidation. The activity of microsomal 1-acyl-GPC acyltransferase was not affected by changes in hormonal (adrenalectomy, diabetes, hyperthyroidism and hypothyroidism) and nutritional (starvation, starvation-refeeding, fat-free-diet feeding and high-fat-diet feeding) states. The induction of renal microsomal 1-acyl-GPC acyltransferase was seen in mice subsequent to the administration of clofibric acid and tiadenol and in guinea pigs subsequent to the administration of tiadenol. These results may indicate that kidney microsomal 1-acyl-GPC acyltransferase is a highly specific parameter responsive to the challenges by peroxisome proliferators and may suggest that the possibility that the inductions by peroxisome proliferators of microsomal 1-acyl-GPC acyltransferase and peroxisomal beta-oxidation in kidney are co-regulated.
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PMID:Induction of microsomal 1-acylglycerophosphocholine acyltransferase by peroxisome proliferators in rat kidney; co-induction with peroxisomal beta-oxidation. 259 69

The hepatic branched-chain alpha-keto acid dehydrogenase complex plays an important role in regulating branched-chain amino acid levels. These compounds are essential for protein synthesis but are toxic if present in excess. When dietary protein is deficient, the hepatic enzyme is present in the inactive, phosphorylated state to allow conservation of branched-chain amino acids for protein synthesis. When dietary protein is excessive, the enzyme is in the active, dephosphorylated state to commit the excess branched-chain amino acids to degradation. Inhibition of protein synthesis by cycloheximide, even when the animal is starving for protein, results in activation of the hepatic branched-chain alpha-keto acid dehydrogenase complex to prevent accumulation of branched-chain amino acids. Likewise, the increase in branched-chain amino acids caused by body wasting during starvation and uncontrolled diabetes is blunted by activation of the hepatic branched-chain alpha-keto acid dehydrogenase complex. The activity state of the hepatic branched-chain alpha-keto acid dehydrogenase complex is regulated in the short term by the concentration of branched-chain alpha-keto acids (inhibitors of branched-chain alpha-keto acid dehydrogenase kinase) and in the long term by alteration in the total branched chain alpha-keto acid dehydrogenase kinase activity.
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PMID:Nutritional and hormonal regulation of the activity state of hepatic branched-chain alpha-keto acid dehydrogenase complex. 263 49

In order to examine the effects of streptozotocin-induced diabetes, dietary protein, and starvation on protein degradation in skeletal muscle of perfused rat hindquarters, rates of myofibrillar and total protein degradation were estimated from the release of 3-methylhistidine (N tau-methylhistidine, 3-MH) and tyrosine, respectively. In rats fed a 20% protein diet (controls), the fractional degradation rate of myofibrillar protein was approximately 56% of the total muscle protein. In streptozotocin-induced diabetic rats, 3-MH release by perfused muscle increased significantly on d 1 of treatment and sustained a high level thereafter. By contrast, tyrosine release did not change. Feeding a 50% protein diet for 1 wk altered neither 3-MH nor tyrosine release. Protein-free feeding, though, suppressed tyrosine release to 49% of controls, but did not affect 3-MH release. Starvation for 3 d did not affect tyrosine release, but did increase 3-MH release to 203% of controls. These results indicate that in diabetic and starved rats myofibrillar protein is preferentially degraded, while in protein-deficient rats, non-myofibrillar protein degradation is selectively suppressed. From these observations, we conclude that the degradation of myofibrillar and non-myofibrillar proteins in skeletal muscle can be differentially regulated.
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PMID:Differential regulation of the degradation of myofibrillar and total proteins in skeletal muscle of rats: effects of streptozotocin-induced diabetes, dietary protein and starvation. 264 2

The degradation of intracellular protein and other cytoplasmic macromolecules in liver is an ongoing process that regulates cytoplasmic mass and provides amino acids for energy and other metabolic uses early in starvation. Cellular proteins are conveniently divided into two general classes according to readily discernable differences in average rates of turnover. A short-lived class, having a half-life of approximately 10 min, comprises about 0.6% of total protein. Its degradation is not physiologically controlled, and the mechanism is probably nonlysosomal in nature. The second or long-lived group, with an average half-life 250 times greater, constitutes more than 99% of the cell's protein. By contrast, its breakdown is strongly regulated, and the site of catabolism is believed to be the vacuolar-lysosomal system. Cytoplasmic sequestration by lysosomes can be divided into two categories; macro- and microautophagy. The first is induced by amino acid and/or insulin deprivation. Amino acids are considered to be primary regulators, since they can control this process over the full range of induced proteolysis in the absence of hormones. Glucagon, cyclic AMP, and beta-agonists also stimulate macroautophagy in hepatocytes but have opposite effects in myocytes. Micrautophagy differs from the former in that the cytoplasmic "bite" is smaller and the uptake process is not acutely regulated. However, the latter does decrease during starvation in parallel with basal proteolysis, effects that might be linked to the loss of endoplasmic reticulum. The primary control of macroautophagy is accomplished through a small group of direct regulators (Leu, Tyr/Phe, Gln, Pro, Met, His, and Trp) and a specific coregulatory action of alanine. As a group, regulatory amino acids produce direct inhibitory responses in the perfused rat liver that are identical to those of the complete amino acid mixture at 0.5x and 4x (times) normal plasma concentrations. However, they lose effectiveness almost completely within a narrow zone centered at normal levels, a loss that can be abolished by the addition of alanine at its normal plasma concentration (0.5 mM). At this level, alanine does not inhibit directly. Interestingly, this zonal loss is also eliminated by insulin. Glucagon, though, specifically blocks the initial inhibition evoked by 0.5x amino acid mixtures and thus induces maximal rates of protein degradation at normal amino acid concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)
Diabetes Metab Rev 1989 Feb
PMID:Mechanism and regulation of protein degradation in liver. 264 36


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