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PubMed1976

Propionic acidemia and hyperlysinemia in a case with ornithine transcarbamylase (OTC) deficiency.

A female infant with episodic hyperammonemia due to a disorder of the urea cycle and who had hyperlysinemia and an unusual elevation of short chain fatty acids, mainly propionate, is described. Both occurred apparently only during attacks of hyperammonemia. Propionic acidemia was ruled out by enzyme studies. OTC deficiency was diagnosed on the basis of: 1) decreased enzyme activity in leukocytes;2) hyperammonemia in response to protein intakes in excess of 2.0 g/kg/day; 3) orotic aciduria in the patient and her asymptomatic mother; 4) suggestive evidence of x-linked dominant inheritance; and 5) exclusion of citrullinemia, argininosuccinic aciduria, argininemia, and disorders of lysine metabolism that are associated with hyperammonemia. Homocitrullinuria, presence of epsilon-N-acetyl-l-lysine in urine, and absence of saccharopine indicate deficiency of the saccharopine pathway of lysine degradation. However, alpha-ketoglutarate reductase was normal in fibroblasts. Since these metabolites were observed only in conjunction with hyperammonemia but not after a lysine load, we suggest that there was competition between ammonia and lysine for alpha-ketoglutarate. The link between disorders of the urea cycle and short chain fatty acid metabolism remains unexplained..

Acid-Base Imbalance↗

PubMed1989

Adult-onset chorea and dementia with propionic acidemia.

Propionic acidemia usually presents in the newborn period with severe metabolic acidosis and lethargy. A 31-year-old man with adult onset chorea and dementia had propionic acidemia due to propionyl CoA carboxylase deficiency. Metabolic investigations may prove useful in patients with movement disorder of unknown etiology.

Adult↗

PubMed2001

Synthesis, absolute configuration and biological activity of both enantiomers of 2-(5,6-dichloro-3-indolyl)propionic acid: new dichloroindole auxins.

Racemic 2-(5,6-dichloro-3-indolyl)propionic acid (5,6-Cl2-2-IPA) was synthesized from 5,6-dichloroindole-3-acetic acid (5,6-Cl2-IAA) by successive esterification, methoxycarbonylation, methylation, and double hydrolysis. The racemate was converted to the diastereomeric esters of (S)-(-)-1-phenylethyl alcohol. These were separated by HPLC into two optically active diastereomers and then hydrolyzed with p-TsOH to the optically active enantiomers of 5,6-Cl2-2-IPA. The absolute configurations of both the 5,6-Cl2-2-IPA enantiomers were determined by comparing the 1H-NMR spectra of their diastereomeric (S)-(-)-1-phenylethyl esters with those of the diastereomeric (S)-(-)-1-phenylethyl esters of 2-(3-indolyl)propionic acid (2-IPA) whose absolute configurations are already known. There was no essential difference between (S)-(+)- and (R)-(-)-5,6-Cl2-2-IPA in hypocotyl growth-inhibiting activity toward Chinese cabbage, but their inhibitory activities were stronger than that of the potent mother auxin, 5,6-Cl2-IAA. No essential difference in the coleoptile elongating activity of Avena sativa was apparent for the enantiomers, this activity being about one-third that of 5,6-Cl2-IAA.

Avena↗

PubMed1975

Decidualization in rats given 5alpha-dihydrotestosterone or its propionate neonatally.

In Experiment 1, female rats were given a single subcutaneous injection of 1.25 mg 5alpha-dihydrotestosterone (DHT) or its propionate (DHTP) on day 5 of postnatal life. All of them showed regular estrous cycles as adults like untreated control animals. At about 60 days of age, the rats were ovariectomized and given 7 daily injections of 2 mg progesterone (P) plus 0.2 mug estradiol-17beta (ED). Uterine trauma applied on the 4th day of P-ED injections resulted in well developed deciduomata in all animals by the day after the last injection. This made a sharp contrast to the failure of female rats receiving testosterone propionate (TP) neonatally to give a positive response under similar experimental conditions (Takewaki and Ohta, 1974). The mean weight of traumatized horns was significantly larger in DHTP-treated rats (but not in DHT-treated rats) than in controls. In Experiment 2, rats were ovariectomized on day 4 and given a dose of 1.25 mg DHT or DHTP on day 5. Controls were ovariectomized on day 4 but not given any steroid on the next day. A series of 7 daily injections of 2 mg P plus 0.2 mug ED was started at about 60 days of age, after the animals had received 3 daily injections of 0.2 mug ED or 30 daily injections of 0.1 mug ED. Incidence of deciduomata following uterine traumatization was markedly lowered only in animals treated with DHTP neonatally and given 0.1 mug ED for 30 days as adults, no significant differences being found in both incidence and size of deciduomata among the other groups. It was suggested that the effects of neonatal steroid administration on uterine responsiveness in adulthood are specific to the steroid. The previous conclusion that persistent estrus in androgen-sterilized rats plays a part in the reduction of uterine responsiveness was confirmed. An exposure of rats to estrogen for a prolonged postpuberal period was without effect, unless the animals had received enough androgen neonatally.

Animals↗

PubMed1987

Inhibition of mitochondrial carnitine acylcarnitine translocase-mediated uptake of carnitine by 2-(3-methyl-cinnamyl-hydrazono)-propionate. Hydrazonopropionic acids, a new class of hypoglycaemic substances, VI.

The rate of mitochondrial carnitine-carnitine exchange mediated by carnitine acylcarnitine translocase was measured by following the uptake of L-[methyl-14C]carnitine. It was demonstrated that the hypoglycaemic compound 2-(3-methyl-cinnamyl-hydrazono)-propionate causes a concentration-dependent decrease in the rate of the translocase-mediated transport of carnitine in guinea pig liver mitochondria. Apparent initial influx rates were decreased by 20% at 0.3 mmol/1 2-(3-methyl-cinnamyl-hydrazono)-propionate, 38% at 0.5 mmol/l, and 75% at 2.0 mmol/l of this compound. This finding may explain the previously observed inhibitory effects of this substance on long-chain fatty acid oxidation, ketone body production and gluconeogenesis.

Animals↗

PubMed2004

Odd-numbered long-chain fatty acids in erythrocyte phospholipids as long-term follow-up parameter in propionic acidemia.

Odd-numbered long-chain fatty acids (OLCFAs) increase in total erythrocyte lipids or plasma in patients with propionic acidemia and have been proposed as a useful parameter of metabolic control. However, up to now no parameter for long-term metabolic control has been available for this disorder. In contrast to previous investigations, we investigated OLCFAs with particular reference to differences for two phospholipid fractions of erythrocyte lipids. The phosphatidylethanolamine (PE) fraction of erythrocyte lipids has a slow turnover rate and might reflect the metabolic propionyl-CoA burden over a period of some weeks. Distinct increases in OLCFA of up to 200% in the phosphatidylcholine fraction were observed after episodes of metabolic decompensation and maximum OLCFA levels were found 3 weeks after the onset of a crisis. As a sign of poor metabolic control, OLCFA levels in PE steadily increased after recurrent episodes of decompensation, but not in clinically stable patients. However, in one patient with clinically good metabolic control, OLCFAs continually increased after the second year of life for an as yet unknown reason. In conclusion, data from this study indicate the usefulness of OLCFA analysis in the PE fraction of erythrocyte lipids, in particular with regard to the need for such a parameter for evidence-based improvement of management strategies in propionic acidemia.

Biomarkers↗

PubMed1983

Dietary therapy in a girl with propionic acidemia: supplement with leucine resulted in catch up growth.

A 15-month-old girl with propionic acidemia presented a failure to thrive and muscular hypotonia, who had been treated with diets low in leucine, valine, isoleucine, threonine and methionine. Supplementation with leucine gave her a catch up growth and brought about an improvement in muscular hypotonia in parallel with restoration of plasma leucine which had been below normal range during the treatment with the above diets. Oral loading test of leucine produced no ketoacidosis. These findings indicate that the restriction of leucine is not necessary in the dietary management of propionic acidemia.

Amino Acid Metabolism, Inborn Errors↗

PubMed2003

Effects of hydrochloric, acetic, butyric, and propionic acids on pathogenesis of ulcers in the nonglandular portion of the stomach of horses.

OBJECTIVE: To identify the pathogenesis of gastric ulcers by comparing injury to the nonglandular gastric mucosa of horses caused by hydrochloric acid (HCl) or volatile fatty acids (VFAs). SAMPLE POPULATION: Gastric tissues from 30 horses. PROCEDURE: Nonglandular gastric mucosa was studied by use of Ussing chambers. Short-circuit current (Isc) and potential difference were measured and electrical resistance calculated for tissues after addition of HCl and VFAs to normal Ringer's solution (NRS). Tissues were examined histologically. RESULTS: Mucosa exposed to HCl in NRS (pH, 1.5) had a significant decrease in Isc, compared with Isc for mucosa exposed to NRS at pH 4.0 or 7.0. Also, exposure to 60mM acetic, propionic, and butyric acids (pH, 4.0 or 1.5) caused an immediate significant decrease in Isc. Recovery of sodium transport was detected only in samples exposed to acetic acid at pH 4.0. Recovery of sodium transport was not seen in other mucosal samples exposed to VFAs at pH < or = 4.0. CONCLUSIONS AND CLINICAL RELEVANCE: Acetic, butyric, and propionic acids and, to a lesser extent, HCl caused decreases in mucosal barrier function of the nonglandular portion of the equine stomach. Because of their lipid solubility at pH < or = 4.0, undissociated VFAs penetrate cells in the nonglandular gastric mucosa, which causes acidification of cellular contents, inhibition of sodium transport, and cellular swelling. Results indicate that HCl alone or in combination with VFAs at gastric pH < or = 4.0 may be important in the pathogenesis of gastric ulcers in the nonglandular portion of the stomach of horses.

Acetic Acid↗

PubMed1991

Effects of propionate infusion and dietary energy on dry matter intake in sheep.

Four nonlactating, nonpregnant, mature ewes equipped with multiple venous and arterial catheters were used to evaluate the influence of propionate as a satiety signal in ruminants. Our experiment was a 4 x 4 Latin square with portal infusion (physiological saline [Sa] or sodium propionate [Pr]) and DE intake (Lo, 63% of maintenance requirement, or Hi, 200% of maintenance requirement) as factors. One 240-min infusion of Pr (1 mmol/min) or Sa into the portal vein began at approximately 0800 on d 8 of each 8-d period. Feed intake was measured and hepatic blood was sampled every 30 min during infusion. Intake of DM and digestible energy (DEI) during infusion were not affected by infusion or diet and were most rapid at 30 min postfeeding. Average 30-min DMI and DEI were 539 g and 1,484 kcal, respectively, at 240 min. Cumulative DMI and DEI were unaffected by infusion but tended to be greater with Lo. After 30 min, animals tended to consume Lo at a greater rate than Hi, suggesting that satiety was delayed. Insulin concentration was increased (P less than .02) when animals consumed Hi (36.1 mU/liter) vs Lo (16.8 mU/liter) and was elevated (P less than .01) at 30 and 60 min postfeeding when animals were infused with Pr. Plasma acetate tended to be reduced with Pr infusion. Plasma Pr tended to increase with Pr infusion, especially when sheep were fed Lo. Satiety, DMI, and DEI were not affected by Pr infusion in this study.

Animal Feed↗

PubMed1993

The effects of ruminally undegradable protein, propionic acid, and monensin on puberty and pregnancy in beef heifers.

Two hundred ten spring-born English crossbred beef heifers were used in two experiments in consecutive years using a randomized complete block design. The objectives were to determine the effects of increasing dietary intake of ruminally undegradable protein or propionic acid on the occurrence of puberty and to elucidate the mechanism by which monensin decreases age of puberty in beef heifers. Diets were fed for 120 d beginning in mid-November and consisted of mature grass hay and barley straw with .45 kg.animal-1 x d-1 supplement (CON) formulated to obtain .4 kg.animal-1 x d-1 of BW gain; .5 kg of supplement similar to CON and containing an additional 250 g of ruminally undegradable intake protein supplied from blood and corn gluten meal (UIP); .45 kg of supplement similar to CON composition and containing 400 g.animal-1 x d-1 of a 50% water and 50% propionic acid mixture (PROP); or .45 kg of supplement similar to CON supplying 200 mg.animal-1 x d-1 of monensin (MON). The hay:straw ratio in each diet was adjusted biweekly, to maintain similar BW gains for heifers fed each dietary treatment. As planned, BW gains were similar (P > .1) for all heifers. The heifers fed MON were 21 d younger (P < .05) at first estrus than heifers fed UIP; CON and PROP were intermediate and similar to heifers fed MON and UIP. The heifers fed UIP were 7 to 8 kg heavier (P < .05) at puberty than CON- or PROP-treated heifers. The heifers fed PROP were 6 kg heavier (P < .1) at puberty than heifers fed MON. Heifers that received UIP required less (P < .05) TDN than did heifers that received CON or PROP to achieve similar gain. Pregnancy rate was similar for all treatment groups. Feeding UIP in excess of NRC CP requirements may improve energy utilization of heifers fed mature roughages but may delay the onset of puberty compared with heifers fed monensin. This study demonstrated that nutrient composition of the diet may influence age of puberty independent of growth rate.

Animal Feed↗

PubMed2000

Net portal appearance of volatile fatty acids in sheep intraruminally infused with mixtures of acetate, propionate, isobutyrate, butyrate, and valerate.

The net portal appearance of volatile fatty acids (VFA) was investigated in four ruminally fistulated and multicatheterized sheep. During the experiments, the sheep were fed once every hour for 14 h and intraruminally infused with mixtures of VFA for the 12 h commencing 2 h after the initiation of the hourly feeding protocol. Paired arterial and portal blood samples were obtained hourly during the last 6 h of the experiments. In the control treatment (1), only water was infused intraruminally. In Treatments 2 through 4, the intraruminal infusion rates of propionate (40 mmol/h), isobutyrate (5 mmol/h), and valerate (5 mmol/h) were unchanged. In Treatments 2, 3, and 4, the acetate infusion rate was 100, 60, and 20 mmol/h, respectively, and the butyrate infusion rate was 10, 30, and 50 mmol/h, respectively. Thus, the infusion rate of VFA carbon was constant across Treatments 2 through 4. Portal recovery estimated from the increased net portal appearance in Treatments 2 through 4 compared to the control treatment was 85% for propionate and 60% for isobutyrate, and these recoveries were unaffected by treatment. The portal recovery of butyrate increased (from 21 to 32%) with increasing infusion rate of butyrate and decreasing infusion rate of acetate, as did the portal recovery of valerate (from 14 to 31%). The portal recovery of acetate was 55%, when measured as net portal appearance. Thus, it seems that the capacity for beta-oxidation in ruminal epithelium is limited, which would explain the increasing portal recovery of butyrate and valerate with increasing infusion rate of butyrate, when infusion rate of VFA carbon is unchanged.

Acetates↗

PubMed2003

Effect of chromium propionate on growth, carcass traits, pork quality, and plasma metabolites in growing-finishing pigs.

Two experiments were conducted to determine the effects of dietary Cr, as Cr propionate, on growth, carcass traits, pork quality, and plasma metabolites in growing-finishing swine. Ninety-six crossbred gilts (Exp. 1; initial and final BW of 28 [SEM = 0.41] and 109 [SEM = 2.11] kg) or 144 PIC Cambrough 22 barrows (Exp. 2; initial and final BW of 26 [SEM = 0.39] and 111 [SEM = 2.52] kg) were allotted to six or four dietary treatments, respectively, with six replications and four (Exp. 1) or six (Exp. 2) pigs in each replicate pen blocked by weight in randomized complete block designs. The six dietary treatments for Exp. 1 were 1) corn-soybean meal (C-SBM), 2) C-SBM + 50 ppb Cr, 3) C-SBM + 100 ppb Cr, 4) C-SBM + 200 ppb Cr, 5) C-SBM low NE diet, and 6) C-SBM low NE diet + 200 ppb Cr. The four dietary treatments for Exp. 2 were C-SBM with 0, 100, 200, or 300 ppb Cr. Growth, carcass traits, and plasma metabolite (collected on d 29 and at each phase change) data were taken at the end of both experiments and pork quality data were taken at the end of Exp. 1. There was no effect (P > 0.10) on overall growth performance when pigs were fed graded levels of Cr (Exp. 1 and 2) or Cr in the positive control or low NE diets (Exp. 1). Longissimus muscle area, ham weight, ham fat-free lean, and total carcass lean were increased in pigs fed 200 ppb in the positive control diets but decreased in pigs fed 200 ppb Cr in the low NE diets (Cr x NE, P < 0.08). There was no effect of Cr concentration (P > 0.10) on carcass traits in Exp. 2. In Exp. 1, cook loss of a fresh or a frozen chop was decreased (P < 0.10) by 200 ppb Cr. In Exp. 1, NEFA concentration was decreased (P < 0.05) in pigs fed Cr in the positive control or low NE diets during the early-finishing period. In Exp. 2, the addition of Cr decreased NEFA (quadratic, P < 0.09) and plasma urea N (linear, P < 0.02) concentrations and tended to increase total cholesterol and high density lipoproteins (quadratic, P < 0.09). In these experiments, Cr propionate had no effect on overall growth performance, variable effects on carcass traits and plasma metabolites, and some positive effects on pork quality, especially water holding capacity of a fresh or frozen chop.

Animal Feed↗

PubMed2003

Effect of chromium propionate and metabolizable energy on growth, carcass traits, and pork quality of growing-finishing pigs.

An experiment was conducted to evaluate the dietary effects of Cr propionate (CrProp) and metabolizable energy (ME) on growth, carcass traits, and pork quality of growing-finishing pigs. One hundred forty-four Cambrough-22 barrows were allotted to four dietary treatments in a randomized complete block design (six replicates of six pigs per replicate; average initial and final body weight were 27 and 113 kg, respectively). The dietary treatments were: 1) corn-soybean meal basal (B; low ME), 2) B + 200 ppb of Cr (as CrProp), 3) B + 200 kcal ME/kg (4.5% added fat; high ME), or 4) B + 200 kcal ME/kg + 200 ppb of Cr. At trial termination, three pigs per replicate were killed to determine dietary effects on carcass traits and pork quality. Overall average daily gain, average daily feed intake, and gain:feed ratio were not affected (P > 0.10) by diet. During the early growing period, average daily gain was increased in pigs fed the CrProp-low-ME diets, but decreased in pigs fed the CrProp-high ME diets (Cr x ME, P < 0.04). Feed intake was increased (P < 0.05) in pigs fed the high-ME diets during the early growing period. Forty-five min and 24 h pH were not affected (P > 0.10) by diet. The CIE L* tended (P = 0.07) to be increased and shear force tended (P = 0.06) to be decreased in pigs fed high-ME diets. Subjective marbling was increased (P < 0.03) and longissimus muscle percentage moisture and thaw loss were decreased (P < 0.04) in pigs fed CrProp. Chromium propionate had no consistent effect on growth and carcass traits in this experiment; however, CrProp did affect some aspects of pork quality.

Animal Feed↗

PubMed1987

Effects of dietary monensin and sodium propionate on net nutrient flux in steers fed a high-concentrate diet.

Four Holstein steers (mean body weight, 211 +/- 20 kg) were utilized in a Latin-square design with a 2 X 2 factorial arrangement of treatments to investigate the effects of monensin (0 or 220 mg/d) and sodium propionate (0 or 450 g/d) on net nutrient flux. Steers were surgically prepared with hepatic portal and mesenteric venous catheters and an elevated carotid artery, after which they were adjusted to their basal diet (85% concentrate) and initial treatment over 19 d. Samples of arterial and portal venous blood were taken hourly over 3 h for the final 3 d of each 2-wk period. Portal blood flow was determined by primed continuous infusion of para-aminohippurate. No changes were seen in dry matter intake, portal blood flow, or net portal flux of any of the volatile fatty acids with the exception of butyrate flux, which decreased with monensin addition. Addition of monensin decreased net portal flux of ammonia, decreased recycling of urea, and tended to increase the net portal flux of glucose. Addition of sodium propionate increased the net portal flux of glucose and decreased the net portal flux of alpha-amino-N. These results are interpreted to suggest that changes in the products of ruminal fermentation may not be exactly translated into the products appearing in the portal circulation, and more information is needed to describe these relationships.

Animal Nutritional Physiological Phenomena↗

PubMed2002

The effect of delayed ensiling and application of a propionic acid-based additive on the fermentation of barley silage.

Prolonged exposure to air can adversely affect the silage fermentation process. To investigate a possible method to overcome this problem, we determined if a buffered propionic acid-based additive, applied to chopped, whole-plant barley exposed to air before ensiling, would affect the subsequent fermentation. Wilted forage was chopped and treated with nothing, or with 0.1% (wt/wt wet forage) of a buffered propionic acid-based additive and ensiled immediately in quadruplicate 20-L laboratory silos. Portions of the chopped forage, untreated and treated, were left in loose piles in a barn for 24 h before ensiling. Another portion of the untreated silage exposed to air for 24 h was also treated with 0.1% of the additive just before ensiling. Prolonged exposure to air before ensiling increased the numbers of yeasts on forages by more than 1,000-fold. The concentrations of water-soluble carbohydrates decreased by more than 50%; the ammonia-N concentrations increased 40%, and pH increased by more than 1 unit as a result of exposure to air. These changes were less in forage that was treated with the additive at chopping. After 60 d, silages of forages that were exposed to air before ensiling had a higher pH, higher concentrations of ammonia-N and butyric acid, and lower concentrations of lactic and acetic acids than silages of forage that had been ensiled immediately after harvest. In situ DM digestibility was lowest in untreated silages that had been exposed to air before ensiling. In contrast, treatment with the additive, applied before or after exposure to air, prevented the reduction in in vitro digestion.

Acetic Acid↗

PubMed1984

Effects of propionic acid added to supplemental corn on utilization of complete ensiled diets by lactating dairy cows.

Two bottom unloading silos were filled with alternate loads of alfalfa (Medicago sativa L.) and ground shelled corn grain mix (1:5, grain:forage, wet basis) to determine effects of propionic acid added to supplemental corn on performance of lactating dairy cow consuming a complete ensiled diet. One silo received grain mix containing 1% propionic acid. Each of two groups of six lactating cows was fed one of the complete ensiled diets supplemented with high moisture corn, dried-shelled corn, or no supplemental corn for 4 mo. Cows that consumed the acid-treated diet produced less milk, fat, and protein than cows consuming the untreated diet. Supplemental high moisture corn and dried shelled corn increased milk and protein yields, and high moisture corn increased fat yields compared to the unsupplemented. Daily variation of the ratio of grain:forage indicated that alternate load additions of forage and grain resulted in poor mixing of ration components and may be related to some of the differences in performance.

Animal Feed↗

PubMed1991

Effects of energy balance on hepatic capacity for oleate and propionate metabolism and triglyceride secretion.

The purpose of this study was to identify conditions that could decrease accumulation of triglyceride in liver, preferably by increasing hepatic secretion of triglyceride-rich lipoproteins. Hepatocytes isolated from lactating goats were incubated in vitro, and the fate of [1-14C]oleate was measured to determine hepatic capacity for various routes of long-chain fatty acid metabolism. The effect of in vivo energy balance and modifications of the nutrients present in the culture media were tested. Addition of linoleic acid, isovalerate, niacin, propionate, or propylene glycol did not affect triglyceride accumulation or secretion. Pyruvate decreased intracellular triglyceride accumulation. Changes in oxidation of oleate through manipulation of carnitine acyl transferase activity did not influence oleate esterification rate. Livers and hepatocytes isolated from goats in negative energy balance contained more lipid and triglyceride. Liver cells from goats in negative energy balance had decreased capacity for converting propionate to glucose with no change in ketogenic capacity as judged by acid soluble product formation from oleate. Hepatocytes from goats in negative energy balance retained less oleate as cell triglyceride with no change in triglyceride export, indicating a decreased net rate of esterification. Lactating goats, either in negative or positive energy balance, demonstrated the same low capacity for export of newly synthesized triglyceride as previously reported for fed wethers.

Animals↗

PubMed1976

Effects of glucagon on gluconeogenesis from lactate and propionate in the perfused rat liver.

Quinolinic acid (Q.A.) which inhibits gluconeogenesis at the site of phosphoenolpyruvate (PEP) synthesis, reduced the content of PEP while elevating that of aspartate and malate in rat livers perfused with a medium containing 10 mM L-lactate. Glucagon at 10(-9) M did not affect Q.A. inhibition of lactate gluconeogenesis nor the depression of PEP level, but further elevated malate and aspartate accumulation. Exogenous butyrate had the same effect as glucagon on these parameters. Butylmalonate (BM), an inhibitor of mitochondrial malate transport, inhibited lactate and propionate gluconeogenesis to similar extents. The addition of 10(-9) M glucagon had no effect on BM inhibition of lactate gluconeogenesis, but almost completely reversed BM inhibition of propionate gluconeogenesis. These results suggest that glucagon may act on at least two sites, resulting in elevated hepatic gluconeogenesis. First, it may stimulate dicarboxylic acid synthesis (malate and oxaloacetate, specifically) through activation of pyruvate carboxylation. Secondly, it may stimulate synthesis of other dicarboxylic acids (fumarate, for example) by activating certain steps of the tricarboxylic acid cycle. The stimulatory effect of glucagon on gluconeogenesis in the perfused rat liver is well documented (1, 2). Exton et al., who earlier located the site of stimulation between pyruvate and PEP synthesis (3), proposed that glucagon stimulated PEP synthesis in the perfused rat liver (4), while reports from Williamson et al. (5) suggested the pyruvate-carboxylase reaction as the site of glucagon action. Stimulation at sites above PEP formation and of portions of the tricarboxylic acid cycle (4) by glucagon have also been suggested (6). In the present experiments, we have used substrates entering at different parts of the gluconeogenic pathway, and specific inhibitors to further resolve the action of glucagon.

Animals↗