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 streptozotocin-induced diabetes and the subsequent treatment of diabetic animals with insulin were studied using a dose of streptozotocin that produces highly ketotic animals 48 h after injection. Carnitine palmitoyltransferase of diabetic animals had apparent Ki values for malonyl-CoA that were approximately 10 times greater than control animals, indicating a greatly decreased affinity for malonyl-CoA in the diabetic state. Subsequent treatment of diabetic animals with insulin for 5 days produced non-ketotic animals with normal blood glucose, and the affinity of carnitine palmitoyltransferase for malonyl-CoA was increased to the control level. Treatment of other groups of ketotic diabetic animals with insulin produced substantial changes in the carnitine palmitoyltransferase apparent Ki value for malonyl-CoA within 4 h. These results suggest that insulin modulates the ketotic state, at least in part, by increasing the affinity of carnitine palmitoyltransferase for malonyl-CoA to bring about inhibition of fatty acid oxidation and ketogenesis.
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PMID:Alteration of the apparent Ki of carnitine palmitoyltransferase for malonyl-CoA by the diabetic state and reversal by insulin. 389 56

Intact mitochondria and inverted submitochondrial vesicles were prepared from the liver of fed, starved (48 h) and streptozotocin-diabetic rats in order to characterize carnitine palmitoyltransferase kinetics and malonyl-CoA sensitivity in situ. In intact mitochondria, both starved and diabetic rats exhibited increased Vmax., increased Km for palmitoyl-CoA, and decreased sensitivity to malonyl-CoA inhibition. Inverted submitochondrial vesicles also showed increased Vmax. with starvation and diabetes, with no change in Km for either palmitoyl-CoA or carnitine. Inverted vesicles were uniformly less sensitive to malonyl-CoA regardless of treatment, and diabetes resulted in a further decrease in sensitivity. In part, differences in the response of carnitine palmitoyltransferase to starvation and diabetes may reside in differences in the membrane environment, as observed with Arrhenius plots, and the relation of enzyme activity and membrane fluidity. In all cases, whether rats were fed, starved or diabetic, and whether intact or inverted vesicles were examined, increasing membrane fluidity was associated with increasing activity. Malonyl-CoA was found to produce a decrease in intact mitochondrial membrane fluidity in the fed state, particularly at pH 7.0 or less. No effect was observed in intact mitochondria from starved or diabetic rats, or in inverted vesicles from any of the treatment groups. Through its effect on membrane fluidity, malonyl-CoA could regulate carnitine palmitoyltransferase activity on both surfaces of the inner membrane through an interaction with only the outer surface.
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PMID:Hepatic mitochondrial inner membrane properties and carnitine palmitoyltransferase A and B. Effect of diabetes and starvation. 409 1

Ketone bodies accumulate in the plasma in conditions of fasting and uncontrolled diabetes. The initiating event is a change in the molar ratio of glucagon:insulin. Insulin deficiency triggers the lipolytic process in adipose tissue with the result that free fatty acids pass into the plasma for uptake by liver and other tissues. Glucagon appears to be the primary hormone involved in the induction of fatty acid oxidation and ketogenesis in the liver. It acts by acutely dropping hepatic malonyl-CoA concentrations as a consequence of inhibitory effects exerted in the glycolytic pathway and on acetyl-CoA carboxylase (EC 6.4.1.2). The fall in malonyl-CoA concentration activates carnitine acyltransferase I (EC 2.3.1.21) such that long-chain fatty acids can be transported through the inner mitochondrial membrane to the enzymes of fatty acid oxidation and ketogenesis. The latter are high-capacity systems assuring that fatty acids entering the mitochondria are rapidly oxidized to ketone bodies. Thus, the rate-controlling step for ketogenesis is carnitine acyltransferase I. Administration of food after a fast, or of insulin to the diabetic subject, reduces plasma free fatty acid concentrations, increases the liver concentration of malonyl-CoA, inhibits carnitine acyltransferase I and reverses the ketogenic process.
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PMID:The regulation of ketogenesis. 612 45

1. Pantothenate kinase, which is present in cytosol, was studied in preparations from livers of rats fed normal or clofibrate-enriched diets. Effects of CoA, dephospho-CoA and different acyl-CoA derivatives on this enzyme activity were examined in vitro. 2. With partially purified pantothenate kinase or crude particle-free supernatant from the liver of normal or clofibrate-treated rats, Km for pantothenic acid was 0.016 mmol/l at the pH optimum 6.1. 3. Acetyl-CoA, propionyl-CoA, malonyl-CoA and other short-chain acyl-CoA derivatives were strong inhibitors of pantothenate kinase, with Ki in the range 0.001-0.003 mmol/l. The mechanism of inhibition appeared to be of an uncompetitive type. 4. Free CoA has been held to be the main regulator of pantothenate kinase. We found, however, that free CoASH, dephospho-CoA and long-chain acyl-CoA (with Ki 0.003-0.08 mmol/l) were less efficient inhibitors than acetyl-CoA. 5. With pantothenate kinase from clofibrate-treated animals, all inhibitors were less potent. This was most pronounced when the enzyme was assayed in a crude supernatant fraction, possibly because the inhibitors were degraded and/or protein bound. Such a reduction of normal inhibition may contribute to the increased biosynthesis of CoA previously observed during clofibrate treatment. 6. Fasting or diabetes leads to an increase of long-chain acyl-CoA and total CoA in the liver. The increase of CoA has been explained by increased acylation of CoA, and thereby reduced feed-back inhibition by free CoASH at the pantothenate kinase level. We propose another explanation. In these metabolic states, the cytosolic pool of acetyl-CoA is decreased. Since pantothenate kinase is present only in the cytosol, its activity will be released and the biosynthesis of CoA will increase. 7. Acetyl-CoA is probably a more important physiological regulator of pantothenate kinase activity than is free CoASH.
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PMID:Regulation of the biosynthesis of CoA at the level of pantothenate kinase. 708 27

Studies were conducted to clarify the relationship between the external fatty acid concentration and glucagon in the regulation of hepatic fatty acid metabolism. Hepatocytes from fed rats were incubated with increasing concentrations of oleate (up to 1 mM) in the presence and absence of glucagon and the time sequence of changes in cellular malonyl-CoA levels, fatty acid synthesis, fatty acid oxidation, and ketogenesis were measured. At low concentrations of fatty acid the effect of glucagon was to abolish malonyl-CoA synthesis and lipogenesis and to produce a marked stimulation of fatty acid oxidation and ketogenesis. Similar effects were obtained with high concentrations of fatty acid in the absence of glucagon and, under these conditions, the additional presence of the hormone produced little further response. The results are consistent with the concept that the rate of fatty acid oxidation in liver is dictated largely by the relative concentrations of long-chain acyl-CoA (substrate for carnitine acyltransferase I) and malonyl-CoA (inhibitor of the transferase). They also indicate that the preemptive effect of fatty acids on glucagon-induced changes in fatty acid metabolism stems from their ability to reduce the tissue malonyl-CoA content, probably through long-chain acyl-CoA suppression of acetyl-CoA carboxylase.
Diabetes 1980 Mar
PMID:Effects of exogenous fatty acid concentration on glucagon-induced changes in hepatic fatty acid metabolism. 738 Jan 10

The regulation of hepatic mitochondrial carnitine palmitoyltransferase-I (CPT-I) was studied in rats during starvation and insulin-dependent diabetes and in rat H4IIE cells. The Vmax. for CPT-I in hepatic mitochondrial outer membranes isolated from starved and diabetic rats increased 2- and 3-fold respectively over fed control values with no change in Km values for substrates. Regulation of malonyl-CoA sensitivity of CPT-I in isolated mitochondrial outer membranes was indicated by an 8-fold increase in Ki during starvation and by a 50-fold increase in Ki in the diabetic state. Peroxisomal and microsomal CPT also had decreased sensitivity to inhibition by malonyl-CoA during starvation. CPT-I mRNA abundance was 7.5 times greater in livers of 48-h-starved rats and 14.6 times greater in livers of insulin-dependent diabetic rats compared with livers of fed rats. In H4IIE cells, insulin increased CPT-I sensitivity to inhibition by malonyl-CoA in 4 h, and sensitivity continued to increase up to 24 h after insulin addition. CPT-I mRNA levels in H4IIE cells were decreased by insulin after 4 h and continued to decrease so that at 24 h there was a 10-fold difference. The half-life of CPT-I mRNA was 4 h in the presence of actinomycin D or with actinomycin D plus insulin. These results suggest that insulin regulates CPT-I by inhibiting transcription of the CPT-I gene.
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PMID:Insulin regulates enzyme activity, malonyl-CoA sensitivity and mRNA abundance of hepatic carnitine palmitoyltransferase-I. 757 18

Malonyl-CoA binding and malonyl-CoA inhibition of carnitine palmitoyltransferase-I (CPT-I) were measured in hepatic mitochondria from normal and diabetic rats and in protease-treated mitochondria from fed rats to test the hypothesis that proteolysis represents a mechanism by which diabetes produces changes in the sensitivity of CPT-I to inhibition by malonyl-CoA. As in diabetes, protease treatment increased the apparent Ki values for malonyl-CoA. Palmitoyl-CoA greatly diminished malonyl-CoA specific binding in the mitochondrial system being studied, suggesting strong competition at the malonyl-CoA binding site. Proteolysis decreased capacity for specific binding of malonyl-CoA by 60-80%, but it had no effect on binding affinity. In contrast, the decreased specific binding of malonyl-CoA seen in the diabetic state is accompanied by increased binding affinity. Furthermore, observed Kd values differed from Ki values by a factor of 10 or more, suggesting that measured Kd and Ki may represent different ligand-protein complexes. These data suggest that alterations in inhibition of CPT-I by malonyl-CoA occurring in the diabetic state may involve mechanisms other than simple proteolytic removal of malonyl-CoA binding sites.
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PMID:Diabetes and proteolysis: effects on carnitine palmitoyltransferase-I and malonyl-CoA binding. 763 57

We sought to explore the emerging concept that malonyl-CoA generation, with concomitant suppression of mitochondrial carnitine palmitoyltransferase I (CPT I), represents an important component of glucose-stimulated insulin secretion (GSIS) by the pancreatic beta-cell (Prentki M, Vischer S, Glennon MC, Regazzi R, Deeney JT, Corkey BE: Malonyl-CoA and long-chain acyl-CoA esters as metabolic coupling factors in nutrient-induced insulin secretion. J Biol Chem 267:5802-5810, 1992). Accordingly, pancreases from fed rats were perfused with basal (3 mM) followed by high (20 mM) glucose in the absence or presence of 2 mM hydroxycitrate (HC), an inhibitor of ATP-citrate (CIT) lyase (the penultimate step in the glucose-->malonyl-CoA conversion). HC profoundly inhibited GSIS, whereas CIT had no effect. Inclusion of 0.5 mM palmitate in the perfusate significantly enhanced GSIS and completely offset the negative effect of HC. In isolated islets, HC stimulated [1-14C]palmitate oxidation in the presence of basal glucose and markedly obtunded the inhibitory effect of high glucose. Directional changes in 14C incorporation into phospholipids were opposite to those of 14CO2 production. At a concentration of 0.2 mM, 2-bromostearate, 2-bromopalmitate and etomoxir (all CPT I inhibitors) potentiated GSIS by the pancreas and inhibited palmitate oxidation in islets. However, at 0.05 mM, etomoxir did not influence insulin secretion but still caused significant suppression of fatty acid oxidation. The results provide more direct evidence for a pivotal role of malonyl-CoA suppression of CPT I, with attendant elevation of the cytosolic long-chain acyl-CoA concentration, in GSIS from the normal pancreatic beta-cell.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1994 Jul
PMID:More direct evidence for a malonyl-CoA-carnitine palmitoyltransferase I interaction as a key event in pancreatic beta-cell signaling. 801 51

The effects of diabetes on fatty acid oxidation in platelets was determined in streptozotocin-induced diabetic rats. In platelets isolated from diabetes, the oxygen consumption which reflects mainly the degree of fatty acid oxidation and ADP- and thrombin-induced aggregation were increased as compared to non-diabetic rat platelets. Carnitine palmitoyltransferase I (CPT I), the rate-limiting enzyme for fatty acid oxidation, in platelets obtained from diabetes showed a higher Vmax for palmitoyl-CoA and an increased I50 (concentration giving 50% inhibition of CPT I activity) for malonyl-CoA inhibition. These changes observed in fatty acid oxidation in platelets derived from diabetes returned to the control levels after insulin therapy. When platelets were stimulated with thrombin, platelet CPT I activity increased over time in both diabetic and non-diabetic rats. From these findings, fatty acid oxidation in platelets, as in the liver, is likely to be regulated by insulin and both increased CPT I activity and decreased sensitivity to malonyl-CoA inhibition are attributable to enhanced platelet fatty acid oxidation in diabetic rats.
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PMID:Increased platelet aggregation and fatty acid oxidation in diabetic rats. 835 30

A metabolic model of fuel sensing has been proposed in which malonyl-CoA and long-chain acyl-CoA esters may act as coupling factors in nutrient-induced insulin release (Prentki M, Vischer S, Glennon MC, Regazzi R, Deeney J, Corkey BE: Malonyl-CoA and long chain acyl-CoA esters as metabolic coupling factors in nutrient-induced insulin secretion. J Biol Chem 267:5802-5810, 1992). To gain further insight into the control of malonyl-CoA content in islet tissue, we have studied the short- and long-term regulation of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) in the beta-cell. These enzymes catalyze the formation of malonyl-CoA and its usage for de novo fatty acid biogenesis. ACC mRNA, protein, and enzymatic activity are present at appreciable levels in rat pancreatic islets and clonal beta-cells (HIT cells). Glucose addition to HIT cells results in a marked increase in ACC activity that precedes the initiation of insulin release. Fasting does not modify the ACC content of islets, whereas it markedly downregulates that of lipogenic tissues. This indicates differential regulation of the ACC gene in lipogenic tissues and the islets of Langerhans. FAS is very poorly expressed in islet tissue, yet ACC is abundant. This demonstrates that the primary function of malonyl-CoA in the beta-cells is to regulate fatty acid oxidation, not to serve as a substrate for fatty acid biosynthesis. The anaplerotic enzyme pyruvate carboxylase, which allows the replenishment of citric acid cycle intermediates needed for malonyl-CoA production via citrate, is abundant in islet tissue. Glucose causes an elevation in beta (HIT)-cell citrate that precedes secretion, and only those nutrients that can elevate citrate induce effective insulin release. The results provide new evidence in support of the model and explain why malonyl-CoA rises markedly and rapidly in islets upon glucose stimulation: 1) glucose elevates citrate, the precursor of malonyl-CoA; 2) glucose enhances ACC enzymatic activity; and 3) malonyl-CoA is not diverted to lipids. The data suggest that ACC is a key enzyme in metabolic signal transduction of the beta-cell and provide evidence for the concept that an anaplerotic/malonyl-CoA pathway is implicated in insulin secretion.
Diabetes 1996 Feb
PMID:Evidence for an anaplerotic/malonyl-CoA pathway in pancreatic beta-cell nutrient signaling. 854 64


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