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Biomedical subjects

K Kumaran

Publications and source records attributed to K Kumaran.

At least 37 records · Page 2Linked to original sources
PubMed1989

Pathways of hepatic glycogen formation in humans following ingestion of a glucose load in the fed state.

The relative contributions of the direct and the indirect pathways to hepatic glycogen formation following a glucose load given to humans four hours after a substantial breakfast have been examined. Glucose loads labeled with [6-(14)C]glucose were given to six healthy volunteers along with diflunisal (1 g) or acetaminophen (1.5 g), drugs excreted in urine as glucuronides. Distribution of 14C in the glucose unit of the glucuronide was taken as a measure of the extent to which glucose was deposited directly in liver glycogen (ie, glucose----glucose-6-phosphate----glycogen) rather than indirectly (ie, glucose----C3-compound----glucose-6-phosphate----glycogen). The maximum contribution to glycogen formation by the direct pathway was estimated to be 77% +/- 4%, which is somewhat higher than previous estimates in humans fasted overnight (65% +/- 1%, P less than 0.05). Thus, the indirect pathway of liver glycogen formation following a glucose load is operative in both the overnight fasted and the fed state, although its contribution may be somewhat less in the fed state.

Acetaminophen↗
PubMed1989

Testing of the assumptions made in estimating the extent of futile cycling.

In estimating glucose and fructose 6-phosphate futile cycling in vivo, complete detritiation of [2-3H]glucose is assumed at the glucose 6-phosphate level, [3-3H]glucose at triose phosphate formation, and [6-3H]glucose in its conversion to glucose via pyruvate. [3-3H]glucose detritiation via the pentose cycle is assumed to be negligible. Normal and non-insulin-dependent diabetic subjects, in the basal state and infused with glucose, were given [2-3H,2-14C]galactose, and 3H-to-14C ratios in blood glucose were determined. [2-3H,2-14C]glucose was given with acetaminophen, and 3H/14C in urinary glucuronide was determined. Detritiation at glucose 6-phosphate was approximately 80%. [3-3H,1-14C]fructose was infused, and 3H/14C was determined in blood glucose and urinary glucuronide. At triose phosphate, 75-90% of the 3H was removed. The pentose cycle contribution was only a few percent. [6-3H,6-14C]glucose was infused, and 3H/14C in blood lactate was determined. [3-3H,3-14C]lactate was infused, and ratios in blood glucose were determined. Maximally, 10% of 3H from [6-3H]glucose was retained. If glucose and galactose are metabolized in the same hepatic site(s), glucose conversion to three-carbon intermediates in the indirect pathway of glycogen formation occurs in extrahepatic tissue(s). Reported estimates of futile cycling, although qualitatively correct, quantitatively require correction.

Adult↗
PubMed1988

Pentose pathway in human liver.

[1-14C]Ribose and [2-14C]glucose were given to normal subjects along with glucose loads (1 g per kg of body weight) after administration of diflunisal and acetaminophen, drugs that are excreted in urine as glucuronides. Distributions of 14C were determined in the carbons of the excreted glucuronides and in the glucose from blood samples drawn from hepatic veins before and after glucagon administration. Eighty percent or more of the 14C from [1-14C]ribose incorporated into the glucuronic acid moiety of the glucuronides was in carbons 1 and 3, with less than 8% in carbon 2. In glucuronic acid from glucuronide excreted when [2-14C]glucose was given, 3.5-8.1% of the 14C was in carbon 1, 2.5-4.3% in carbon 3, and more than 70% in carbon 2. These distributions are in accord with the glucuronides sampling the glucose unit of the glucose 6-phosphate pool that is a component of the pentose pathway and is intermediate in glycogen formation. It is concluded that the glucuronic acid conjugates of the drugs can serve as a noninvasive means of sampling hepatic glucose 6-phosphate. In human liver, as in animal liver, the classical pentose pathway functions, not the L-type pathway, and only a small percentage of the glucose is metabolized via the pathway.

Acetaminophen↗
PubMed1987

Quantitation of the pathways of hepatic glycogen formation on ingesting a glucose load.

Diflunisal, 5-(2',4'-difluorophenyl)salicylic acid, excreted in urine as its glucuronide, was given to normal humans (n = 6) along with a glucose load specifically labeled with 14C. Glucuronide excreted by each subject was reduced to its glucoside and glucose from it degraded to yield the distribution of 14 C in its six carbons. Randomization of the 14C from the specifically labeled glucose was taken as a measure of the extent to which glucose was deposited indirectly (i.e., glucose----lactate----glucose----6-P----glycogen), rather than directly (i.e., glucose----glucose-6-P----glycogen). The maximum contribution to glycogen formation by the direct pathway was estimated to be 65 +/- 1%, on the assumption that glucuronide and glycogen are derived from the same hepatic pool of glucose-6-P in liver. Evidence that supports that assumption was obtained by comparing the randomization of 14C in the urinary glucuronide with that in glucose in blood from the hepatic vein of four of the subjects before and after they were given glucagon. Other evidence supporting the assumption was obtained by comparing in two subjects 3H/14C ratios in glucose from hepatic vein blood before and after glucagon administration with that in urinary glucuronide, having labeled the uridine diphosphate (UDP)-glucose in their livers with 14C by giving them 1-[14C]galactose and their circulating glucose with 3H by giving a 5-[3H]glucose-labeled load. It is concluded that glucuronide formation in humans can be used to trace glucose metabolism in the liver, and that in humans the indirect pathway of glucose metabolism is active.

Administration, Oral↗
PubMed1986

Determinants in the pathways followed by the carbons of acetone in their conversion to glucose.

[2-14C]Acetone was infused into rats that were fed or fasted. Each was infused with either a trace quantity of acetone or a large quantity that resulted in a blood concentration of acetone of at least 4 mM. The distribution of 14C in the carbons of glucose from each rat was determined. Two of the rats were given acetone in their drinking water and one was diabetic. Whether a rat was chronically exposed to acetone, fed or fasted, normal or diabetic, if given the trace dose, over 80% of the 14C in the glucose it formed was in carbons 1, 2, 5, and 6 of the glucose. If a rat was given the large dose, about 50% was in carbons 3 and 4. Thus, the major determinant of the pathways followed by acetone when it is metabolized is its concentration and not the prior dietary state of the animal or its previous exposure to acetone. Incorporation into carbons 1, 2, 5, and 6 occurs in the conversion of the carbons of [2-14C]lactate into glucose, whereas incorporation into carbons 3 and 4 occurs in the conversion of the carbons of [1-14C]acetate into glucose. Therefore, at high acetone concentration, the pathway that has been proposed for acetone's metabolism via acetate predominates, and via acetate there can be no net synthesis of glucose from acetone. When rats were given cyanamide and then the large dose of acetone, 74% of the 14C in the glucose they formed was in carbons 3 and 4 of the glucoses. Thus, the relative contribution of the pathway to lactate, or its metabolic equivalent, that has been proposed appears to be lessened by the administration of an aldehyde dehydrogenase inhibitor.

Acetates↗
PubMed1986

Pathways of acetone's metabolism in the rat.

Distributions of 14C were different from those of 13C in glucoses formed by livers of rats in diabetic ketosis and perfused with [2-14C]acetone and [2-13C]lactate. There was 32-73% of the 14C and 8-12% of the 13C in carbons 3 and 4 of the glucoses with the remaining 14C and 13C distributed about equally in the other carbons. Incorporations of 14C from [2-14C]acetone (14-39%) also exceeded those from [2-14C]pyruvate (8-10%) into carbons 3 and 4 of glucoses formed by hepatocytes from rats fed acetone or fasted. [2-14C]Acetone and [2-14C]pyruvate were infused into rats that were fed, fasted, given acetone in their drinking water, or in diabetic ketosis. Thirty-seven to 52% of the 14C in the glucoses formed was in their carbons 3 and 4 when the acetone was infused and 8 to 14% when the pyruvate was infused. [1,3-14C]Hydroxybutyrate was formed by the rats in diabetic ketosis given [2-14C]acetone. It is concluded that acetone is metabolized in rats to a large extent by a pathway in which lactate or its metabolic equivalent is not an intermediate and that pathway is via acetyl-CoA. via acetyl-CoA.

Acetone↗
PubMed1985

The nature of the pentose pathway in liver.

[2-14C]Glucose, [3,4-14C]glucose, [5-14C]glucose, [4,5,6-14C]glucose, and [1-14C]ribose were perfused through livers of rats. The rats were fed or fasted and refed. In one experiment the liver perfused was regenerating and in another phenazine methosulfate was in the perfusate. Perfusion was for 30 or 90 min. Glucose from each perfusate and liver glucose-6-P and glycogen were isolated, purified, and degraded. The distributions of 14C in the carbons of the glucoses from the glycogens are similar to the distributions from the glucose 6-phosphates. The distributions of 14C are in accord with metabolism of glucose by the classical pentose pathway and not by the L-type pathway that has been proposed to function in liver.

Animals↗
PubMed1985

Quantitative estimation of the pathways followed in the conversion to glycogen of glucose administered to the fasted rat.

When [6-3H,6-14C]glucose was given in glucose loads to fasted rats, the average 3H/14C ratios in the glycogens deposited in their livers, relative to that in the glucoses administered, were 0.85 and 0.88. When [3-3H,3-14C]lactate was given in trace quantity along with unlabeled glucose loads, the average 3H/14C ratio in the glycogens deposited was 0.08. This indicates that a major fraction of the carbons of the glucose loads was converted to liver glycogen without first being converted to lactate. When [3-3H,6-14C]glucose was given in glucose loads, the 3H/14C ratios in the glycogens deposited averaged 0.44. This indicates that a significant amount of H bound to carbon 3, but not carbon 6, of glucose is removed within liver in the conversion of the carbons of the glucose to glycogen. This can occur in the pentose cycle and by cycling of glucose-6-P via triose phosphates: glucose----glucose-6-P----triose phosphates----glucose-6-P----glycogen. The contributions of these pathways were estimated by giving glucose loads labeled with [1-14C]glucose, [2-14C]glucose, [5-14C]glucose, and [6-14C]glucose and degrading the glucoses obtained by hydrolyzing the glycogens that deposited. Only a few per cent of the glucose carbons deposited in glycogen were deposited in liver via glucose-6-P conversion to triose phosphates. Between 4 and 9% of the glucose utilized by the liver was utilized in the pentose cycle. While these are relatively small percentages, since three NADP3H molecules are formed from each molecule of [3-3H]glucose-6-P utilized in the cycle, a major portion of the difference between the ratios obtained with [3-3H]glucose and with [6-3H]glucose is attributable to metabolism in the pentose cycle. Because 3H of [3-3H]glucose is extensively removed during the conversion of the glucose to glycogen within liver the extent of incorporation of the 3H into liver glycogen is not the measure of glucose's metabolism in other tissues before its carbons are deposited in liver glycogen. The distributions of 14C from the 14C-labeled glucoses into the carbons of the liver glycogens mean that at a minimum about 30% of the carbons of the glucose deposited in the glycogen were first converted to lactate or its metabolic equivalent.

Acetyl Coenzyme A↗
PubMed1983

Ketone body production in diabetic ketosis by other than liver.

To determine if ketone bodies, synthesized from fatty acids by tissues other than the liver, enter the circulation, rats in diabetic ketosis were injected with sodium [6,13-14C]palmitate. Hydroxybutyrate was isolated from the urine excreted by each rat and from an aqueous extract of its carcass. The distribution of 14C in the four carbons of hydroxybutyrate in the extract was the same as in the urine. The ratio of 14C in carbon 1 to carbon 3 of the hydroxybutyrate averaged 1.80 and averaged 1.31 in carbon 2 to carbon 4. Hydroxybutyrate when formed by perfused liver has the same carbon 1-to-carbon 3 ratio as carbon 2-to-carbon 4 ratio. The results indicate that hydroxybutyrate synthesized by tissues other than the liver mixes in the circulation with that synthesized by the liver and a portion of the mix is then excreted in the urine. The difference between the carbon 1-to-3 carbon ratio 3 and carbon 2-to-carbon 4 ratio calculates to an estimated minimum of 15% to 17% of the hydroxybutyrate in the circulation of the ketotic diabetic rat having tissues other than the liver as its source. Assuming the liver and kidneys are the sources of the ketone bodies in diabetic ketosis, the ketone bodies produced by the kidneys are not excreted into the urine without first entering the circulation.

Animals↗
PubMed1982

The tracing of the pathway of mevalonate's metabolism to other than sterols.

Specifically 14C-labeled mevalonic acids were administered to rats in diabetic ketosis, and the distribution of 14C was determined in the hydroxybutyric acid each rat excreted. Also, the distributions of 14C were determined in hydroxybutyric acid formed by slices of livers and kidneys from rats in diabetic ketosis and incubated with the specifically labeled mevalonic acids. The distributions found are in accord with the conversion of mevalonate to hydroxymethylglutaryl-CoA by the shunt pathway proposed by J. Edmond and G. Popják ((1974) J. Biol. Chem. 249, 66-71). That is, carbon 5 of mevalonate was metabolized to form the carboxyl of acetyl-CoA and carbons 2 and 3 of mevalonate were converted in large measure to hydroxybutyric acid without acetyl-CoA as an intermediate, i.e. the bond between carbon 2 and 3 was not cleaved, while the bond between 1 and 2, traced with [1,2-14C]mevalonate, was cleaved. Similar distributions of 14C were found in hydroxybutyric acid excreted by rats in diabetic ketosis administered specifically 14C-labeled isovaleric acids, isovaleric acid having in its metabolism intermediates common to those in the shunt pathway.

Animals↗
PubMed1982

A method for quantitating the contributions of the pathways of acetoacetate formation and its application to diabetic ketosis in vivo.

A method has been developed for estimating in the intact cell the contribution of deacylation of acetoacetyl-CoA to the formation of acetoacetate relative to acetoacetate's formation via hydroxymethylglutaryl (HMG)-CoA. Estimates depend upon the fraction of the terminal four carbons of an even carbon-containing fatty acid that are converted to acetoacetate without prior conversion to acetyl-CoA, since in the formation of acetoacetate via HMG-CoA the omega-2 and omega-3 carbons of the fatty acid are converted to acetyl-CoA. Incorporation of 14C from [16-14C]palmitic acid into carbon 2 relative to carbon 4 of acetoacetate is used as the measure of the formation of the acetoacetate from the omega and omega-1 carbons of the fatty acid without acetyl-CoA as an intermediate. Incorporation of 14C from [13-14C]palmitic acid into carbon 1 relative to carbon 3 of acetoacetate is the measure of the formation of acetoacetate from the omega-2 and omega-3 carbons without acetyl-CoA as an intermediate. Comparison of these incorporations is made with incorporation into the carbons of acetoacetate of 14C from palmitic acid labeled with 14C in any of its first 12 carbons since such incorporation must proceed via acetyl-CoA as an intermediate. In an application of this approach, the specifically 14C-labeled palmitic acids were injected into rats in diabetic ketosis. Hydroxybutyric acid that each rat excreted was isolated and degraded. From the ratios of incorporation into the carbons of the hydroxybutyrates, as a minimum, 11% of the total quantity of hydroxybutyrate excreted by the rats was formed from acetoacetyl-CoA without HMG-CoA as an intermediate.

Acetoacetates↗
PubMed1982

Pathways of acetoacetate's formation in liver and kidney.

Specifically 14C-labeled palmitic acids were perfused through livers and incubated with slices of kidneys from rats in diabetic ketosis. The distribution of 14C in the hydroxybutyric acid formed was determined. In liver, the ratio of incorporation of 14C from [13-14C]palmitic acid into carbon 1 to carbon 3 of the hydroxybutyric acid was the same as the ratio in carbon 2 to carbon 4 from [6-14C]palmitic acid. In kidney, the carbon 1-to-carbon 3 ratio was more than twice the carbon 2-to-carbon 4 ratio. In both tissues, 14C from [16-14C] palmitic acid was preferentially incorporated into carbon 4 compared to carbon 2 of the hydroxybutyric acid, but more so in liver than kidney. These results mean that in liver, the sole pathway of acetoacetate formation is via hydroxymethylglutaryl-CoA, while in kidney it is not. Rather in kidney, acetoacetyl-CoA is converted to acetoacetate to a large extent by direct deacylation, presumably via a transferase- and/or deacylase-catalyzed reaction. In liver, most of the palmitic acid utilized is converted to acetoacetate while in kidney it is not. We previously estimated that, as a minimum, 11% of the hydroxybutyric acid excreted by the rat in diabetic ketosis is formed without hydroxymethylglutaryl-CoA as an intermediate. The kidney appears to be the source of this hydroxybutyric acid if the pathways operative in these tissues in vitro are those that also operate in vivo.

Acetoacetates↗
PubMed1979

omega-Oxidation of fatty acids and the acetylation p-aminobenzoic acid.

p-Aminobenzoic acid was fed to normal and alloxan-induced diabetic rats injected with [omega-14C]labeled and [2-14C]labeled fatty acids. The p-acetamidobenzoic acid that was excreted was hydrolyzed to yield acetate which was degraded. The distribution of 14C in the acetates formed when an [omega-14C]labeled fatty acid was injected was similar to that when a [2-14C]labeled fatty acid was injected. This contrasts with the finding that in acetates from 2-acetamido-4-phenylbutyric acid excreted when 2-amino-4-phenylbutyric acid was fed, there was a difference in the distributions of 14C, a difference attributable to omega-oxidation of the fatty acid. Acetylation of p-aminobenzoic acid is then concluded to occur in a different cellular environment than that of 2-amino-4-phenylbutyric acid, one in which omega-oxidation is not functional. When 2-amino-4-phenylbutyric acid was fed and [6-14C]palmitic acid injected, rather than [16-14C]palmitic acid, the distribution of 14C in acetate was the same as when [2-14C]palmitic acid was injected. This indicates that the dicarboxylic acid formed on omega-oxidation of palmitic acid does not undergo beta-oxidation to form succinyl-CoA. Thus, glucose is not formed via omega-oxidation of long-chain fatty acid.

4-Aminobenzoic Acid↗
PubMed1978

Contribution of omega-oxidation to fatty acid oxidation by liver of rat and monkey.

Contributions of omega-oxidation to overall fatty acid oxidation in slices from livers of ketotic alloxan diabetic rats and of fasted monkeys are estimated. Estimates are made from a comparison of the distribution of 14C in glucose formed by the slices from omega-14C-labeled compared to 2-14C-labeled fatty acids of even numbers of carbon atoms and from [1-14C]acetate compared to [2-14C]acetate. These estimates are based on the fact that 1) the dicarboxylic acid formed via omega-oxidation of a omega-14C-labeled fatty acid will yield [1-14C]acetate and [1-14C]succinate on subsequent beta-oxidation, if beta-oxidation is assumed to proceed to completion; 2) only [2-14C]acetate will be formed if the fatty acid is metabolized solely via beta-oxidation; and 3) 14C from [1-14C]acetate and [1-14C]succinate is incorporated into carbons 3 and 4 of glucose and 14C from [2-14C]acetate is incorporated into all six carbons of glucose. From the distributions found, the contribution of omega-oxidation to the initial oxidation of palmitate by liver slices is estimated to between 8% and 11%, and the oxidation of laurate between 17% and 21%. Distributions of 14C in glucose formed from 14C-labeled palmitate infused into fasted and diabetic rats do not permit quantitative estimation of the contribution of omega-oxidation to fatty acid oxidation in vivo. However, the distributions found also indicate that, of the fatty acid metabolized by the whole animal in the environment of glucose formation, at most, only a minor portion is initially oxidized via omega-oxidation. As such, omega-oxidation cannot contribute more than a small extent to the formation of glucose.

Acetates↗