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 effects of dietary modification, starvation, stress and diabetes on the activity of phosphatidate phosphohydrolase are discussed. Evidence is presented that this enzyme is involved in controlling the rate of triacylglycerol synthesis in the liver. Drugs such as fenfluramine and benfluorex are able to inhibit phosphatidate phosphohydrolase by interacting with the substrate. This decreases the rate of triacylglycerol synthesis and redirects the route of glycerolipid metabolism. Benfluroex also partly prevents the ethanol-induced increase in triacylglycerol synthesis and in phosphohydrolase activity. The implications of these findings are discussed with respect to the mode of action of fenfluramine and benfluorex and to the control of triacylglycerol synthesis.
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PMID:Some aspects of the physiological and pharmacological control of the synthesis of triacylglycerols and phospholipids. 21 94

1. Male rats were injected daily for 5 days with 0.15m-NaCl, corticotropin, cortisol or l-thyroxine and the rates of glycerolipid synthesis were measured in the livers after intraportal injection of [(14)C]palmitate and [(3)H]glycerol. 2. Injection of all three hormones decreased the rates of body-weight gain. 3. Cortisol treatment increased the weight of the liver relative to body weight. 4. Thyroxine treatment increased the relative rate of triacylglycerol synthesis from [(3)H]glycerol and decreased the relative accumulation of (3)H and (14)C in diacylglycerol. It did not significantly alter the accumulation of these isotopes in phosphatidate nor the activity of the soluble phosphatidate phosphohydrolase in the total liver. However, this activity increased by 1.5-fold when expressed relative to the soluble protein of the liver. The increased triacylglycerol synthesis appears to be related to a general increase in the turnover of fatty acids in the liver. 5. Treatment with cortisol and corticotropin increased the relative rate of triacylglycerol synthesis from [(3)H]glycerol, decreased the accumulation of (3)H in phosphatidate and increased the flux of both isotopes from phosphatidate to diacylglycerol. This appeared to be caused by the increased activity of the soluble phosphatidate phosphohydrolase that was observed in the livers of the cortisol-treated rats. 6. It is proposed that cortisol could be directly or indirectly involved in increasing the activity of hepatic phosphatidate phosphohydrolase in starvation, diabetes, laparotomy, subtotal hepatectomy, liver damage, ethanol feeding and in obesity. This enzyme adaptation could contribute to the potential of the liver to increase its synthesis and accumulation of triacylglycerols or to secrete very-low-density lipoproteins.
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PMID:The effects of cortisol, corticotropin and thyroxine on the synthesis of glycerolipids and on the phosphatidate phosphohydrolase activity in rat liver. 21 53

The influence of diabetes and starvation on uracil nucleotide metabolism in muscle was studied. It was found that the uridine triphosphate (UTP) content of heart and diaphragm muscle was decreased in fasted and streptozotocin-diabetic rats and that insulin treatment of diabetic animals restored the UTP concentration to normal levels. The ATP content of heart tissue was not altered under these conditions. It was also demonstrated that hemidiaphragms from streptozotocin-diabetic rats synthesized less UTP from uridine in vitro than hemidiaphragms from normal animals. Uridine kinase activity of extracts of cardiac and skeletal muscle from fasted and diabetic rats was lower than the activity found in extracts from control animals. It was concluded that uracil nucleotide synthesis by the salvage pathway is decreased in experimental diabetes and fasting.
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PMID:Effect of diabetes and fasting on the uridine triphosphate content and uridine kinase activity of rat cardiac and skeletal muscle. 22 81

In animal tissues the pyruvate dehydrogenase complex is regulated by product inhibition and by a phosphorylation-dephosphorylation cycle catalysed by a kinase and a phosphatase. Physiologic and molecular aspects of this regulation are reviewed, and the results of recent studies are described. Insulin deficiency in the rat (diabetes or starvation) is shown to inhibit the conversion of inactive (phospho-) complex into active (dephospho-) complex by the phosphatase by an effect on the substrate for the phosphatase (phosphorylated complex). This change is stable and persists during isolation, incubation, and extraction of mitochondria or purification of phosphorylated complex. The subunit ratios in the purified pig heart pyruvate dehydrogenase complex and the stoichiometry of phosphorylations have been determined by radioamidination and incorporation of 32P. The ratios of decarboxylase tetramer (alpha 2, beta 2) : dihydrolipoyl acetyltransferase monomer : dihydrolipoly dehydrogenase monomer were 1:1:0.5. Inactivation of the complex was accomplished by incorporation of a single phosphate into one alpha subunit of the decarboxylase tetramer. Two further phosphates are then incorporated and these additional phosphorylations inhibit reactivation of the complex by the phosphate. It is suggested that multisite phosphorylations may inhibit reactivation of the complex by the phosphatase in diabetes and in starvation.
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PMID:Regulation of pyruvate dehydrogenase by insulin action. 23 84

The enhanced protein degradation associated with diabetes and starvation is fundamentally different from normal protein catabolism. In normal eukaryotic cells large molecular weight proteins tend to be degraded more rapidly than small proteins, acidic proteins tend to be degraded more rapidly than neutral or basic proteins, and glycoproteins tend to be degraded more rapidly than nonglycoproteins. All three of these general correlations are absent or markedly reduced in liver and muscle of diabetic and starved rats. In contrast, the correlations between proteins size and half-life, between protein net charge and half-life, and between protein carbohydrate content and half-life are not affected in brain of diabetic or starved animals. These results suggest that diabetes and starvation alter the general characteristics of intracellular protein degradation in target tissues of insulin. Degradation of serum proteins is also affected in diabetes and starvation. In normal animals a general correlation exists between isoelectric points of serum proteins and their degradative rates. This relationship is abolished in diabetes and starvation, as it is among liver and muscle proteins. The implications of our findings are discussed with regard to possible mechanisms of the enhanced protein breakdown.
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PMID:General characteristics of protein degradation in diabetes and starvation. 27 54

The activity of microsomal drug-metabolizing enzymes is altered by several pathological or abnormal physiological states, such as changes in nutritional status, liver, heart or kidney diseases, hormonal disturbances, pregnancy, tumour-bearing state, adjuvant arthritis, changes in reticuloendothelial system and environmental factors (stress, irradiation, heavy metals). The activities of other metabolic pathways, such as glucuronidation, sulphate conjugation, acetylation and alcohol oxidation are generally affected to lesser extents. Rats are most commonly used in drug metabolism studies, and it is important to know that the activity of most of the microsomal drug-metabolizing enzymes is higher in males than in females through androgen action which is readily impaire drug-metabolizing enzymes in male rats are thus manifested by two mechanisms; one is by impairment of androgen action and the other is by depression of the basic enzymic activity. Therefore, those effects of pathological states, observed only in male rats but not in females, are generally not seen in other species of animals, including man. The effects of starvation, hyperthyroidism, adrenal insufficiency, diabetes and morphine administration are cases where changes in metabolism are due solely to impairment of androgen action. In other pathological cases, those drug-metabolizing enzymes showing sex differences are depressed more markedly in male rats than those showing no clear sex difference. The author therefore recommends the use of female rats in the evaluation of the effects of pathological states on hepatic microsomal drug-metabolizing enzymes. Generally, changes in activity of the hepatic enzymes reflect closely the changes in the rates of drug metabolism in vivo. However, the protein-binding of drugs, hepatic blood flow and renal function are also known to affect the rate of drug metabolism and excretion in vivo, and therefore changes of these factors in pathological states should also be taken into consideration.
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PMID:Drug metabolism under pathological and abnormal physiological states in animals and man. 32 97

In animals the pyruvate dehydrogenase reaction is mainly responsible for the irreversible loss of glucose carbon by oxidation. Regulation of this reaction is shown to be a major determinant of glucose conservation in starvation and diabetes. Estimates of conservation in man in starvation and diabetes are reviewed. The pyruvate dehydrogenase complex is inhibited by products of its reactions; it is also regulated by a phosphorylation-dephosphorylation cycle catalysed by a kinase intrinsic to the complex and by a more loosely associated phosphatase. Inactivation is largely accomplished by phosphorylation of the tetrameric decarboxylase component (alpha2beta2) to alpha2Pbeta2. Complete phosphorylation produces the (alpha2P3)beta2 form. Both forms are completely reactivated by phosphatase action but the initial rate of reactivation of a complex containing alpha2Pbeta2 is approximately three times that of (alpha2P3)beta2. The proportion of active (dephosphorylated) complex is decreased in rat tissues by starvation and diabetes and in perfused rat heart by oxidation of fatty acids and ketone bodies. In adipose tissue in vitro, insulin increases the proportion of active complex and lipolytic hormones may decrease this proportion. It is suggested that rates of oxidation of lipid fuels may be a major determinant of the activity of pyruvate dehydrogenase in tissues in relation to the actions of insulin and lipolytic hormones and the effects of diabetes and starvation. Phosphorylation and inactivation of the complex are enhanced by high mitochondrial ratios of [acetyl-CoA]/[CoA], [ATP]/[ADP], [NADH]/[NAD+] and low concentrations of pyruvate, Mg2+ and Ca2+, and vice versa.
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PMID:Regulation of pyruvate oxidation and the conservation of glucose. 37 69

1. Regulation of gluconeogenic substrate supply and modulation of the gluconeogenic pathway in the liver are both important in the control of gluconeogenesis by glucocorticoids. 2. Adrenal deficiency decreases the release of gluconeogenic and other amino acids from skeletal muscle during starvation. The effect is reversed by glucocorticoid replacement. The changes in amino acid release are accompanied by similar alterations in tissue amino acid levels and are not explained by alterations in net protein breakdown. Glucocorticoids do not alter protein catabolism and cause a small inhibition of protein synthesis. The biochemical alterations underlying the changes in amino acid metabolism induced by these steroids remain to be elucidated. Glucocorticoids may also regulate the supply of gluconeogenic substrates through permissive effects on the lipolytic action of catecholamines and other hormones in adipose tissue and on the glycogenolytic action of catecholamines on skeletal muscle. 3. Glucocorticoids are required for the increases in gluconeogenesis in starvation and diabetes. Part of their action is exerted directly on the liver and appears to involve modulation of P-enlopyruvate carboxykinase levels. Glucocorticoids increase the synthesis of this enzyme apparently through effects at the level of transcription. 4. Glucocorticoids exert permissive effects on the stimulation of gluconeogenesis in the liver by glucagon and epinephrine. The steroids are not required for cAMP generation or protein kinase activation by these hormones, but appear to act by maintaining the responsiveness of certain enzymes to the effects of the cAMP and alpha-adrenergic systems. It is proposed that this involves the maintenance of a normal intracellular ionic environment.
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PMID:Regulation of gluconeogenesis by glucocorticoids. 38 91

The increased protein degradation associated with diabetes appears to be different in many respects from protein catabolism in normal, well-nourished cells. In all normal eukaryotic cells examined, degradation of cytosolic proteins exhibits several striking features. Large proteins tend to be degraded more rapidly than small proteins, acidic proteins tend to be degraded more rapidly than neutral or basic proteins, and glycoproteins are degraded more rapidly than non-glycoproteins. Furthermore, a general correlation exists between protein half-life in vivo and susceptibility to proteolytic attack in vitro. In streptozotocin-diabetic rats the relationships between degradative rate and protein size, net charge, and carbohydrate content are absent or markedly reduced among cytosolic proteins of the liver. However, the correlation between protein half-life and susceptibility to proteinase in vitro is unaltered. Therefore, the enhanced protein degradation in diabetes shows little or no selectivity towards large, acidic, glycoproteins but does show specificity for proteins than tend to be sensitive to proteinases. Similar studies using other tissues from diabetic rats are reported and general characteristics of the enhanced liver protein catabolism in starvation and hyperthyroidism are briefly discussed. The biochemical reasons for the increased protein catabolism in diabetes are unclear although several possible explanations are presented. The enhanced breakdown is probably not due to cellular proteins becoming more proteinase sensitive in diabetes since experiments with a variety of endoproteinases including pronase, chymotrypsin, pepsin, and lysosomal cathepsins have failed to demonstrate more rapid digestion of liver proteins from diabetic animals.
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PMID:Protein degradation in metabolic and nutritional disorders. 39 94

Blood glucose levels were studied prospectively in 40 patients undergoing elective major craniotomy. A significant (p less than 0.01) hyperglycaemic response was noted after scalp infiltration with adrenaline and incision (0.5 mmol/l) and with continued surgery (0.9 mmol/l). Patients aged 50 years and under showed a significantly greater rise with adrenaline and incision than older patients (0.8 compared with 0.4 mmol/l p less than 0.01). Preoperative high dose steroid therapy did not modify the response. Blood glucose changes were unrelated to sex, obesity, a family history of diabetes, the duration of starvation, intraoperative body temperature, anaesthetic technique, induced hypotension or blood loss.
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PMID:Blood glucose changes during neurosurgery. 43 41


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