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)

1. Liver mitochondrial outer membranes were pre-exposed to media of low (20 mM phosphate) or high salt concentration (20 mM phosphate + 0.3 M KCl) before assay of carnitine palmitoyltransferase (CPT) at 25 degrees C. 2. With membranes from fed rats, exposure to high salt decreased sensitivity of CPT to malonyl-CoA whereas high salt increased sensitivity of CPT to malonyl-CoA in membranes from 48 hr-fasted rats. These changes were paralleled by alterations in the KD for high affinity binding of [14C]malonyl-CoA to outer membranes. 3. Decreasing the CPT assay temperatures from 25 to 10 degrees C caused qualitatively similar changes to those seen on exposure to high salt. 4. The relative content of sphingomyelin was increased 2-fold and 4-fold in liver mitochondrial outer membranes from fasted and diabetic rats respectively. Fasting had no effect on the content of cholesterol whereas diabetes decreased this by a third.
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PMID:Physiological state and the sensitivity of liver mitochondrial outer membrane carnitine palmitoyltransferase to malonyl-CoA. Correlations with assay temperature, salt concentration and membrane lipid composition. 139 5

Epidemiological studies have clearly shown that the so-called metabolic syndrome which is linked to insulin resistance and a reduced glucose utilization of muscle represents an important risk factor for cardiovascular disease. However, only little is known of the intracellular consequences of insulin resistance. An important feature of an altered substrate utilization is related to signal transduction of gene expression. For the example of myosin heavy chain expression, it is shown that metabolic signals exist which reflect the fuel flux and substrate utilization of the heart muscle cell. The signals were characterized in functional states of the heart associated with altered metabolic influences (fasting, diabetes, sucrose feeding, increased calorie intake, carnitine palmitoyltransferase inhibition). In the pressure-overloaded heart, metabolic interventions which are expected to increase glucose utilization (sucrose feeding, captopril treatment) have a pronounced effect. Although a link with gene expression remains to be established, it should be noted that the sarcoplasmic reticulum Ca(2+)-pump activity seems to be affected in a functionally comparable manner. It is concluded that metabolic signals alter the protein phenotype of heart muscle and it is expected that a deranged signal transduction affects, not only the heart, but also vascular muscle.
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PMID:The metabolic syndrome and signal transduction of gene expression. 183 54

Saponin-permeabilization (30 micrograms/ml) of the platelet plasma membrane, which enables access of added compounds to mitochondrial overt carnitine palmitoyltransferase (CPT I), was applied to allow the rapid determination of CPT I activity in situ. The effects of diabetes and short-term incubation with insulin in vitro on the kinetic parameters and malonyl-CoA sensitivity of CPT I were also studied in rat platelets. CPT I exhibited ordinary Michaelis-Menten kinetics when platelets were incubated with palmitoyl-CoA. Malonyl-CoA showed an I50 (concentration giving 50% inhibition of CPT activity) of 0.92 +/- 0.11 microM in permeabilized platelets. Platelets obtained from diabetic rats (induced by streptozotocin injection) exhibited an increased Vmax and I50 for malonyl-CoA, and an unaltered Km for palmitoyl-CoA. In contrast, preincubation of platelets prepared from both fed control rats and diabetic rats with insulin (100 and 150 microU/ml) led to a decrease in enzyme activity when assayed with 75 microM palmitoyl-CoA and 0.5 mM L-carnitine as substrates. These in vivo and in vitro results suggested that insulin directly modulated rat platelet CPT I activity, as it does in the liver.
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PMID:Characterization of overt carnitine palmitoyltransferase in rat platelets; involvement of insulin on its regulation. 185 44

1. Liver mitochondrial outer and inner membranes were isolated from normal, 48 h-fasted, streptozotocin-diabetic and hypothyroid rats. 2. Relative to membrane protein, fasting and diabetes substantially increased the activity of carnitine palmitoyltransferase (CPT) in outer membranes. Inner-membrane CPT specific activity was only slightly altered, being increased in diabetes and decreased in hypothyroidism. Abundance of an inner-membrane Mr-68,000 polypeptide that cross-reacted with an anti-CPT serum was significantly increased in diabetes and hypothyroidism. Relative to inner-membrane CPT activity, this cross-reactivity was increased by 37% in diabetes and by 400% in hypothyroidism, suggesting modification of the intrinsic activity of the CPT in these states. 3. CPT in outer membranes was inhibitable by malonyl-CoA, whereas inner-membrane CPT was insensitive to malonyl-CoA. Fasting and diabetes increased the IC50 (concentration of malonyl-CoA causing 50% inhibition) for outer-membrane CPT, whereas the IC50 was decreased in hypothyroidism. 4. Binding of [14C]malonyl-CoA was observed with both outer and inner membranes and was fitted to two-site models in each case. Fasting, diabetes and hypothyroidism changed the KD for binding at the higher-affinity site in outer membranes in a manner that correlated closely with changes in IC50 for inhibition of outer-membrane CPT by malonyl-CoA. Fasting and diabetes increased the abundance of this outer-membrane high-affinity malonyl-CoA-binding site, whereas hypothyroidism decreased its abundance.
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PMID:A study of properties and abundance of the components of liver carnitine palmitoyltransferases in mitochondrial inner and outer membranes. Effects of hypothyroidism, fasting and a ketotic diabetic state. 187 97

The profile of the changes in the peroxisomal fatty acid oxidation activity in rat liver was compared with that in microsomal omega-oxidation under various conditions such as a 2-week administration of phenoxyacetic acid derivatives and perfluorinated compounds, short and long-term administration of clofibrate and bezafibrate, high-fat diet feeding, starvation and diabetes. The results were summarized as follows: 1) when phenoxyacetic acid derivatives and perfluorinated compounds were administered, there was a significant correlation in the increase of the activities between peroxisomal fatty acid oxidation and microsomal omega-oxidation. 2) On the long-term administration (79 weeks) of peroxisome proliferators the activities of the enzymes were significantly reduced, but the levels were still higher than the control level in a similar manner. 3) On high-fat diet feeding the patterns of the changes in the activities of peroxisomal fatty acid oxidation, carnitine acetyltransferase and microsomal omega-oxidation were similar to each other, differing from the changes in the activities of microsomal aminopyrin demethylase and mitochondrial carnitine palmitoyltransferase. 4) Under starved and diabetic conditions, co-induction of peroxisomal fatty acid oxidation and microsomal omega-oxidation was observed. From these results it is suggested that 1) the biosynthesis of these enzymes would be regulated on the gene expression of the nearby domain and 2) peroxisomal fatty acid oxidation and microsomal omega-oxidation were co-operatively regulated in order to achieve fatty acid metabolism smoothly.
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PMID:Characteristics of peroxisome proliferation: co-induction of peroxisomal fatty acid oxidation-related enzymes with microsomal laurate hydroxylase. 191 1

We recently demonstrated a marked inhibitory effect of high physiological concentrations of free fatty acids (FFAs) on insulin binding, degradation, and action in isolated rat hepatocytes. To elucidate the mechanism, male rats were treated for 3 days with saline (control) or etomoxir (ethyl 2-[6-(p-chlorophenoxy)hexyl]-glycidate), a prodrug, which in vivo is converted to a specific competitive inhibitor of carnitine palmitoyltransferase, and thus, lipid oxidation. Oleic acid (0.4 mM) reduced both 125-I-labeled insulin binding and insulin-stimulated [14C]aminoisobutyric acid transport approximately 40% in cells from control animals. However, this FFA concentration was without effect in cells from etomoxir-treated animals. Etomoxir increased EC50 for the inhibitory effect of oleic acid on insulin binding approximately threefold. The data indicate that the mitochondrial oxidation of fatty acids may be important for their inhibitory effect on insulin binding and action in isolated rat hepatocytes.
Diabetes 1991 Jun
PMID:Prevention of inhibitory effect of free fatty acids on insulin binding and action in isolated rat hepatocytes by etomoxir. 204 Mar 95

The long-term regulation of hepatic mitochondrial carnitine palmitoyltransferase (CPT) was studied in control, insulin-treated, and untreated spontaneously diabetic BB Wistar rats. The activity of CPT was elevated approximately twofold in the untreated diabetic rats. This corresponded to an approximately equivalent elevation in the immunoreactive CPT activity. mRNACPT was assayed by reticulocyte lysate translation and by dot blot to a CPT oligonucleotide probe. The level of mRNACPT was approximately proportional to the observed CPT activity. A cDNA probe to CPT was developed, and transcriptional activity for CPT was assessed in isolated hepatic nuclei. Again, transcription of CPT mRNA was approximately proportional to the observed activity. We therefore conclude that at least part of the long-term regulation of hepatic CPT in spontaneously diabetic BB Wistar rats is the product of increased de novo synthesis of CPT protein brought about by regulation at the transcriptional level. Additional control of the amount of CPT may be via the regulation of RNA processing and turnover and enzyme insertion into the mitochondrial membrane.
Diabetes 1989 Jan
PMID:Regulation of carnitine palmitoyltransferase synthesis in spontaneously diabetic BB Wistar rats. 290 13

Administration to normal rats of 100 mg of streptozotocin/kg body weight produced ketotic diabetic rats in which the affinity of carnitine palmitoyltransferase for malonyl-CoA was decreased by 10-fold and its activity was increased by 30%, but the injection of insulin brought the affinity and the activity back to normal within 4 h. Administration of 60 mg of streptozotocin/kg produced non-ketotic diabetic rats and caused a less substantial change in the affinity of carnitine palmitoyltransferase for malonyl-CoA. In the BB Wistar diabetic rat, the onset of diabetes also increased the activity of carnitine palmitoyltransferase and decreased its affinity for malonyl-CoA. Injection of insulin brought both of these values back to normal within 2 h. The total activity of mitochondrial carnitine palmitoyltransferase (outer + inner activities) was 40% greater in the BB Wistar diabetic rat, but treatment with insulin did not decrease the total activity to normal values within 2 h. The elevated activity and decreased affinity for malonyl-CoA found in fasting rats did not respond to short-term insulin treatment. The evaluation of a previous report that cycloheximide blocks the effects of starvation indicated that cycloheximide did not act by inhibiting protein synthesis, but produced its effect by preventing gastric emptying. Current data suggest that diabetes increases the activity of carnitine palmitoyltransferase and greatly diminishes the affinity of the enzyme for malonyl-CoA and that the severity of diabetes is associated with differences in the affinity of the enzyme for its inhibitor. Insulin acts on the outer carnitine palmitoyltransferase to reverse these effects very rapidly, but diabetes produces some change in the total activity that is not reversed by short-term treatment with insulin.
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PMID:Regulation of carnitine palmitoyltransferase by insulin results in decreased activity and decreased apparent Ki values for malonyl-CoA. 295 85

Although carnitine palmitoyltransferase (CPT) has received considerable attention, particularly its regulation by malonyl CoA, most studies have monitored the forward reaction, ie, the formation of acylcarnitine. We examined the opposite or reverse reaction, in which palmitoyl CoA is generated, in osmotically-disrupted rat hepatic mitochondria. Specifically, the effects of pH, fasting, and untreated recent-onset diabetes were investigated. As with the forward (f) reaction, the CPT reverse (r) velocity v pH curve was somewhat parabolic with a pH maximum at approximately 7.2 (except the CPT that was from the diabetic rats). However, as the pH rose, the CPT reverse and forward curves diverged due to a precipitous decline in the forward reaction. This discordance in rates in the alkaline range was apparent in all three groups of CPT but was most prominent in the diabetic preparation (for example, as the pH increased from 7.3 to 8.8, the respective declines in the f and r velocities were 74% and 2%). In addition, under our assay conditions the CPTr from diabetic rats not only had a higher velocity (55.4 +/- 1.4 nmol/min/mg protein) than that from the fed (32.1 +/- 3.1) or fasted (43.1 +/- 3.4) animals, but also the Vmax was found to be twofold greater, even though there was no difference in the Km for palmitoylcarnitine. In summary, diabetes affects the kinetics of the reverse reaction and, regardless of the animal's premortem condition, but more so in the diabetes, this reaction is less attenuated than the forward one as the pH rises.
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PMID:Carnitine palmitoyltransferase: effects of diabetes, fasting, and pH on the reaction that generates acyl CoA. 318 91

1. The kinetic properties of overt carnitine palmitoyltransferase (CPT I, EC 2.3.1.21) were studied in rat liver mitochondria isolated from untreated, diabetic and insulin-treated diabetic animals. A comparison was made of the time courses required for the changes in these properties of CPT I to occur and for the development of ketosis during the induction of chronic diabetes and its reversal by insulin treatment. 2. The development of hyperketonaemia over the first 5 days of insulin withdrawal from streptozotocin-treated rats was accompanied by parallel increases in the activity of CPT I and in the I0.5 (concentration required to produce 50% inhibition) of the enzyme for malonyl-CoA. 3. The rapid reversal of the ketotic state by treatment of chronically diabetic rats with 6 units of regular insulin was not accompanied by any change in the properties of CPT I over the first 4 h. Higher doses of insulin (15 units), delivered throughout a 4 h period, resulted in an increase in the affinity of CPT I for malonyl-CoA, but the sensitivity of the enzyme to the inhibitor was still significantly lower than in mitochondria from normal animals. 4. Conversely, when insulin treatment was continued over a 24 h period, full restoration of the sensitivity of the enzyme to malonyl-CoA was achieved. However, the activity of the enzyme was only decreased marginally. 5. These results are discussed in terms of the possibility that the major regulatory sites of the rate of hepatic oxidation may vary in different phases of the induction and reversal of chronic diabetes.
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PMID:Role of carnitine palmitoyltransferase I in the regulation of hepatic ketogenesis during the onset and reversal of chronic diabetes. 327 23


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