Acute Reversal of Experimental Diabetic Ketoacidosis in the Rat with (+)-Decanoylcarnitine

McGarry, Julie; Foster, Daniel W.

doi:10.1172/jci107252

Cited by 64 publications

(26 citation statements)

References 34 publications

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“…Accordingly, the current findings do not necessarily contraindicate the strategic use of CPT-1 inhibitors in certain clinical situations. For example, such agents might still prove useful in the acute reversal of diabetic ketoacidosis (63), in the prevention of myocardial injury or arrhythmia during reperfusion of the heart after ischemia (64), or in the treatment of congestive heart failure (65).…”

Section: Discussionmentioning

confidence: 99%

Prolonged Inhibition of Muscle Carnitine Palmitoyltransferase-1 Promotes Intramyocellular Lipid Accumulation and Insulin Resistance in Rats

et al. 2001

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Cross-sectional studies in human subjects have used 1 H magnetic resonance spectroscopy (HMRS) to demonstrate that insulin resistance correlates more tightly with the intramyocellular lipid (IMCL) concentration than with any other identified risk factor. To further explore the interaction between these two elements in the rat, we used two strategies to promote the storage of lipids in skeletal muscle and then evaluated subsequent changes in insulin-mediated glucose disposal. Normal rats received either a low-fat or a high-fat diet (20% lard oil) for 4 weeks. Two additional groups (lowfat + etoxomir and lard + etoxomir) consumed diets containing 0.01% of the carnitine palmitoyltransferase-1 inhibitor, R-etomoxir, which produced chronic blockade of enzyme activity in liver and skeletal muscle.

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Section: Discussionmentioning

confidence: 99%

Prolonged Inhibition of Muscle Carnitine Palmitoyltransferase-1 Promotes Intramyocellular Lipid Accumulation and Insulin Resistance in Rats

et al. 2001

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“…Animals were lightly anesthetized with ether for the placement of catheters in the femoral artery on one side and the inferior vena cava through the femoral vein on the other (14). They were then placed in individual restraining cages and allowed to awaken from the anesthesia before experiments were begun.…”

Section: Methodsmentioning

confidence: 99%

Hormonal control of ketogenesis. Rapid activation of hepatic ketogenic capacity in fed rats by anti-insulin serum and glucagon.

McGarry¹,

Wright²,

Foster³

1975

J. Clin. Invest.

218

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A B STR A CT The enhanced capacity for long-chain fatty acid oxidation and ketogenesis that develops in the rat liver between 6 and 9 h after the onset of starvation was shown to be inducible much more rapidly by administration of anti-insulin serum or glucagon to fed rats. After only 1 h of treatment with either agent, the liver had clearly switched from a "nonketogenic" to a "ketogenic" profile, as determined by rates of acetoacetate and 1-hydroxybutyrate production on perfusion with oleic acid. As was the case after starvation, the administration of insulin antibodies or glucagon resulted in depletion of hepatic glycogen stores and a proportional increase in the ability of the liver to oxidize long-chain fatty acids and (-)-octanoylcarnitine, suggesting that all three treatment schedules activated the carnitine acyltransferase system of enzymes. In contrast to anti-insulin serum, which produced marked elevations in plasma glucose, free fatty acid, and ketone body concentrations, glucagon treatment had little effect on any of these parameters, presumably due to enhanced insulin secretion after the initial stimulation of glycogenolysis. Thus, after treatment with glucagon alone, it was possible to obtain a "ketogenic" liver from a nonketotic animal. The results are consistent with the possibility that the activity of carnitine acyltransferase, and thus ketogenic capacity, is subject to bihormonal control through the relative blood concentrations of insulin and glucagon, as also appears to be the case with hepatic carbohydrate metabolism.

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“…The mitochondrial sites implicated have included the transport of acyl groups (12), the A-oxidation cycle (13), and product formation, (citrate and acetoacetate) (14). Recently, attention has been given to intrinsic changes in mitochondrial enzyme activity as a regulatory factor in ketosis (13,(15)(16)(17). Increased carnitine palmitoyltransferase activity (CPT)1 has been described in the ketosis of diabetes (15)(16)(17), starvation (15,18), and after growth hormone administration (19).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, attention has been given to intrinsic changes in mitochondrial enzyme activity as a regulatory factor in ketosis (13,(15)(16)(17). Increased carnitine palmitoyltransferase activity (CPT)1 has been described in the ketosis of diabetes (15)(16)(17), starvation (15,18), and after growth hormone administration (19). Bunyan and Greenbaum (13) have described an increase in acylCoA dehydrogenase activity in rat liver homogenates after treatment with growth hormone and used this finding to explain an observed increase in fatty acid oxidation.…”

Section: Introductionmentioning

confidence: 99%

Hepatic mitochondrial function in ketogenic states. Diabetes, starvation, and after growth hormone administration.

DiMarco¹,

Hoppel²

1975

J. Clin. Invest.

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A B S T R A C T The study was designed to evaluate hepatic mitochondrial function during ketotic states. The ketogenic models studied were streptozotocin-induced diabetic ketoacidosis, 48 h of starvation, and after growth hormone administration. In the last-mentioned model we observed increased free fatty acids but not ketonemia.Oxidative phosphorylation was measured using the citric acid cycle substrates pyruvate and succinate, the amino acid glutamate, a ketone body P-hydroxybutyrate, and a long-chain fatty acid palmitoyl-l-carnitine. State 3 (ADP stimulated) and state 4 (ADP limited) respiration, respiratory control ratio (state 3/state 4), and the ADP/O ratios were normal in the controls and the experimental groups. Uncoupled respiration produced by dinitrophenol with a variety of substrates was unchanged in the experimental groups compared to the controls.Fatty acid oxidation was studied in detail. The rate of utilization of palmitoyl-l-carnitine by controls or experimental groups did not depend on the product formed (citrate, acetoacetate). No significant changes were observed in the oxidation of palmitoyl-CoA (+ carnitine) or with an intermediate-chain fatty acid hexanoate. The specific activity of hepatic mitochondria carnitine palmitoyltransferase did not change in any of the three experimental groups.It is concluded that during diabetic ketoacidosis, starvation, and growth hormone administration, there is (a) no alteration in hepatic mitochondrial function; (b) no change in the intrinsic capacity of hepatic mitochondria to oxidize fatty acids; and (c) no change in the specific activity of mitochondrial carnitine pal-

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Acute Reversal of Experimental Diabetic Ketoacidosis in the Rat with (+)-Decanoylcarnitine

Cited by 64 publications

References 34 publications

Prolonged Inhibition of Muscle Carnitine Palmitoyltransferase-1 Promotes Intramyocellular Lipid Accumulation and Insulin Resistance in Rats

Prolonged Inhibition of Muscle Carnitine Palmitoyltransferase-1 Promotes Intramyocellular Lipid Accumulation and Insulin Resistance in Rats

Hormonal control of ketogenesis. Rapid activation of hepatic ketogenic capacity in fed rats by anti-insulin serum and glucagon.

Hepatic mitochondrial function in ketogenic states. Diabetes, starvation, and after growth hormone administration.

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