scholarly journals A possible mechanism for the anti-ketogenic action of alanine in the rat

1980 ◽  
Vol 190 (2) ◽  
pp. 323-332 ◽  
Author(s):  
Romano Nosadini ◽  
Harish Datta ◽  
Alan Hodson ◽  
K. George M. M. Alberti
Keyword(s):  
Ketone Body ◽  
Ketone Bodies ◽  
Regulatory System ◽  
Glucagon Secretion ◽  
Diabetic Rats ◽  
Metabolic Clearance ◽  
Endogenous Insulin ◽  
Feedback Cycle ◽  
Insulin And Glucagon Secretion ◽  
Acetoacetate Infusion

1. The anti-ketogenic effect of alanine has been studied in normal starved and diabetic rats by infusing l-alanine for 90min in the presence of somatostatin (10μg/kg body wt. per h) to suppress endogenous insulin and glucagon secretion. 2. Infusion of alanine at 3mmol/kg body wt. per h caused a 70±11% decrease in [3-hydroxybutyrate] and a 58±9% decrease in [acetoacetate] in 48h-starved rats. [Glucose] and [lactate] increased, but [non-esterified fatty acid], [glycerol] and [3-hydroxybutyrate]/[acetoacetate] were unchanged. 3. Infusion of alanine at 1mmol/kg body wt. per h caused similar decreases in [ketone body] (3-hydroxybutyrate plus acetoacetate) in 24h-starved normal and diabetic rats, but no change in other blood metabolites. 4. Alanine [3mmol/kg body wt. per h] caused a 72±9% decrease in the rate of production of ketone bodies and a 57±8% decrease in disappearance rate as assessed by [3-14C]acetoacetate infusion. Metabolic clearance was unchanged, indicating that the primary effect of alanine was inhibition of hepatic ketogenesis. 5. Aspartate infusion at 6mmol/kg body wt. per h had similar effects on blood ketone-body concentrations in 48h-starved rats. 6. Alanine (3mmol/kg body wt. per h) caused marked increases in hepatic glutamate, aspartate, malate, lactate and citrate, phosphoenolpyruvate, 2-phosphoglycerate and glucose concentrations and highly significant decreases in [3-hydroxybutyrate] and [acetoacetate]. Calculated [oxaloacetate] was increased 75%. 7. Similar changes in hepatic [malate], [aspartate] and [ketone bodies] were found after infusion of 6mmol of aspartate/kg body wt. per h. 8. It is suggested that the anti-ketogenic effect of alanine is secondary to an increase in hepatic oxaloacetate and hence citrate formation with decreased availability of acetyl-CoA for ketogenesis. The reciprocal negative-feedback cycle of alanine and ketone bodies forms an important non-hormonal regulatory system.

Stimulatory effect of norepinephrine on ketogenesis in normal and insulin-deficient humans

1984 ◽  
Vol 247 (6) ◽  
pp. E732-E739 ◽  
Author(s):  
U. Keller ◽  
P. P. Gerber ◽  
W. Stauffacher
Keyword(s):  
Ketone Body ◽  
Ketone Bodies ◽  
Plasma Free Fatty Acid ◽  
Normal Subjects ◽  
Plasma Norepinephrine ◽  
Metabolic Clearance ◽  
Insulin Deficiency ◽  
Norepinephrine Infusion ◽  
Normal Humans ◽  
Body Production

Elevation of plasma norepinephrine concentrations to stress levels (1,800 pg/ml) resulted in normal subjects in a significant increase in ketone body production by 155% (determined by use of [14C]acetoacetate infusions), in a decrease of the metabolic clearance rate by 38%, hyperketonemia, and in increased plasma free fatty acid (FFA) levels by 57% after 75 min. Norepinephrine infusion during somatostatin-induced insulin deficiency resulted in an augmented and sustained increase in ketone body concentrations due to increased production and decreased peripheral clearance of ketone bodies. Norepinephrine's stimulatory effect on lipolysis waned with time, and its effect on ketogenesis in normal subjects was greater than its influence on plasma FFA levels, and thus presumably on hepatic FFA uptake, suggesting a direct stimulatory effect on hepatic ketogenesis. The data demonstrate that in normal humans the hyperketonemic effect of elevated plasma norepinephrine concentrations results from a combination of three factors: increased ketone body production from augmented FFA supply to the liver; accelerated hepatic ketogenesis; and modestly decreased metabolic clearance of ketone bodies. Acute insulin deficiency augments all these effects and results in progressive ketosis.

scholarly journals Glutamine and ketone-body metabolism in the gut of streptozotocin-diabetic rats

1988 ◽  
Vol 249 (2) ◽  
pp. 565-572 ◽  
Author(s):  
M S M Ardawi
Keyword(s):  
Small Intestine ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Diabetic Rats ◽  
Glutamine Metabolism ◽  
Gut Mucosa ◽  
Streptozotocin Induced Diabetes ◽  
Streptozotocin Diabetic Rats ◽  
Short And Long Term

1. In short- and long-term diabetic rats there is a marked increase in size of both the small intestine and colon, which was accompanied by marked decreases (P less than 0.001) and increases (P less than 0.001) in the arterial concentrations of glutamine and ketone bodies respectively. 2. Portal-drained viscera blood flow increased by approx. 14-37% when expressed as ml/100 g body wt., but was approximately unchanged when expressed as ml/g of small intestine of diabetic rats. 3. Arteriovenous-difference measurements for ketone bodies across the gut were markedly increased in diabetic rats, and the gut extracted ketone bodies at approx. 7 and 60 nmol/min per g of small intestine in control and 42-day-diabetic rats respectively. 4. Glutamine was extracted by the gut of control rats at a rate of 49 nmol/min per g of small intestine, which was diminished by 45, 76 and 86% in 7-, 21- and 42-day-diabetic rats respectively. 5. Colonocytes isolated from 7- or 42-day-diabetic rats showed increased and decreased rates of ketone-body and glutamine metabolism respectively, whereas enterocytes of the same animals showed no apparent differences in the rates of acetoacetate utilization as compared with control animals. 6. Prolonged diabetes had no effects on the maximal activities of either glutaminase or ketone-body-utilizing enzymes of colonic tissue preparations. 7. It is concluded that, although the epithelial cells of the small intestine and the colon during streptozotocin-induced diabetes exhibit decreased rates of metabolism of glutamine, such decreases were partially compensated for by enhanced ketone-body utilization by the gut mucosa of diabetic rats.

scholarly journals Relationship between plasma and muscle concentrations of ketone bodies and free fatty acids in fed, starved and alloxan-diabetic states

1973 ◽  
Vol 134 (2) ◽  
pp. 499-506 ◽  
Author(s):  
Oliver E. Owen ◽  
Helene Markus ◽  
Stuart Sarshik ◽  
Maria Mozzoli
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Free Fatty Acids ◽  
Plasma Glucose ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Water Concentration ◽  
Diabetic Rats ◽  
Muscle Membrane

1. Concentrations of ketone bodies, free fatty acids and chloride in fed, 24–120h-starved and alloxan-diabetic rats were determined in plasma and striated muscle. Plasma glucose concentrations were also measured in these groups of animals. 2. Intracellular metabolite concentrations were calculated by using chloride as an endogenous marker of extracellular space. 3. The mean intracellular ketone-body concentrations (±s.e.m.) were 0.17±0.02, 0.76±0.11 and 2.82±0.50μmol/ml of water in fed, 48h-starved and alloxan-diabetic rats, respectively. Mean (intracellular water concentration)/(plasma water concentration) ratios were 0.47, 0.30 and 0.32 in fed, 48h-starved and alloxan-diabetic rats respectively. The relationship between ketone-body concentrations in the plasma and intracellular compartments appeared to follow an asymptotic pattern. 4. Only intracellular 3-hydroxybutyrate concentrations rose during starvation whereas concentrations of both 3-hydroxybutyrate and acetoacetate were elevated in the alloxan-diabetic state. 5. During starvation plasma glucose concentrations were lowest at 48h, and increased with further starvation. 6. There was no significant difference in the muscle intracellular free fatty acid concentrations of fed, starved and alloxan-diabetic rats. Mean free fatty acid intramuscular concentrations (±s.e.m.) were 0.81±0.08, 0.98±0.21 and 0.91±0.10μmol/ml in fed, 48h-starved and alloxan-diabetic states. 7. The intracellular ketosis of starvation and the stability of free fatty acid intracellular concentrations suggests that neither muscle membrane permeability nor concentrations of free fatty acids per se are major factors in limiting ketone-body oxidation in these states.

Response of ketone body metabolism to exercise during transition from postabsorptive to fasted state

1986 ◽  
Vol 250 (5) ◽  
pp. E495-E501 ◽  
Author(s):  
F. Fery ◽  
E. O. Balasse
Keyword(s):  
Clearance Rate ◽  
Ketone Body ◽  
Turnover Rate ◽  
Ketone Bodies ◽  
Normal Subjects ◽  
Moderate Intensity ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Fasted State ◽  
The Brain

This study examines the effects of a 2-h exercise of moderate intensity (50% of VO2 max) on the tracer-determined turnover rate of ketone bodies (KB) in 21 normal subjects fasted for 16 h, 5 days, whose basal ketonemia ranged between 0.09 and 6.16 mM. The KB response observed at the end of exercise is a function of the initial degree of ketosis. When basal ketonemia is below 0.6 mM, exercise enhances ketogenesis (Ra), the amplitude of this process being positively correlated with KB level. There is a concomitant acceleration of the metabolic clearance rate (MCR) of KB attaining 40-50%. When ketonemia exceeds 2.5 mM, the stimulatory effects of exercise on Ra and on MCR become less marked as basal ketonemia rises and are completely abolished or even reversed when initial KB level is higher than 3-4 mM. The pattern of changes in the concentration and in the overall disposal rate of KB were similar to that of Ra. It is suggested that the parallel inhibition of the stimulatory effect of work on hepatic ketogenesis and on muscular extraction of ketones associated with increasing degrees of fasting hyperketonemia has two physiological implications: it maintains the preferential utilization of KB by nonmuscular tissues (presumably the brain) and prevents the development of uncontrolled hyperketonemia, despite the intense catabolic situation created by the combination of exercise and starvation.

scholarly journals Effect of ischaemic limb injury on the rates of metabolism of ketone bodies in starved rats

1976 ◽  
Vol 156 (2) ◽  
pp. 233-238 ◽  
Author(s):  
R N Barton
Keyword(s):  
Clearance Rate ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Whole Body ◽  
Metabolic Clearance ◽  
O2 Consumption ◽  
Clearance Rates ◽  
Metabolic Clearance Rate ◽  
Limb Injury ◽  
Blood Ketone Bodies

1. Rats starved for 30h were injected with trace amounts of [3-14C]acetoacetate and β-hydroxy[3-14C]butyrate 1h after ischaemic limb injury in a 20 °C environment, and the concentrations and radioactivities of blood ketone bodies were determined at intervals. 2. Starvation alone raised the rates of production and utilization of β-hydroxybutyrate plus acetoacetate about 3.7-fold, but lowered their metabolic clearance rates by about 50%. In the starved rat ketone-body oxidation could account for up to 30% of whole body O2 consumption. 3. Injury in starved rats lowered the rates of production and utilization of both β-hydroxybutyrate and acetoacetate, the combined fall of about 37% slightly exceeding the concomitant fall in whole-body O2 consumption. The concentration of β-hydroxybutyrate decreased after injury, but its metabolic clearance rate was unaltered; the concentration of acetoacetate rose slightly and its metabolic clearance rate fell.

scholarly journals Turnover rates of ketone bodies in normal, starved and alloxan-diabetic rats

1968 ◽  
Vol 110 (4) ◽  
pp. 655-661 ◽  
Author(s):  
Margaret W. Bates ◽  
H. A. Krebs ◽  
D. H. Williamson
Keyword(s):  
Ketone Body ◽  
Alloxan Diabetes ◽  
Ketone Bodies ◽  
Diabetic Rats ◽  
Turnover Rates ◽  
Blood Concentrations ◽  
Order Of Magnitude ◽  
The Mean ◽  
Body Production ◽  
Body Concentration

1. Rates of appearance and disappearance of total ketone bodies were determined in normal, starved and alloxan-diabetic rats by measuring specific radioactivities and concentrations of blood acetoacetate and 3-hydroxybutyrate at different times after injection of 3-hydroxy[14C]butyrate. 2. The mean rates of appearance were 1·7, 4·2 and 10·9μmoles/min./100g. body wt. respectively for normal, starved and alloxan-diabetic rats. The rates of disappearance were of the same order of magnitude as the rates of appearance. 3. There was a direct correlation between the rates of appearance and disappearance and the blood concentrations of the ketone bodies. 4. The results indicate that in the rat increased ketone-body production is paralleled by increased ketone-body utilization and that the raised ketone-body concentration in the blood in starvation and alloxan-diabetes is due to a slight imbalance between the rates of production and utilization. 5. The findings are discussed in relation to the concept that ketone bodies can serve as fuels of respiration when the supply of carbohydrate is limited.

Metabolism of ketone bodies by ovine brain in vivo

1976 ◽  
Vol 231 (5) ◽  
pp. 1490-1494 ◽  
Author(s):  
RG Kammula
Keyword(s):  
Lactic Acid ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Lactic Acid Production ◽  
Plasma Insulin Concentration ◽  
Blood Samples ◽  
Sagittal Sinus ◽  
Percent Conversion ◽  
Acetoacetate Infusion

Ketosis was produced by intravenous infusion (5 mmol/kg per h) of [3-14C]acetoacetate (sp act 0.5 muCi/mmol) into fed and 7-day-fasted sheep. Changes in arterial and sagittal sinus blood samples. During acetoacetate infusion, there was a significant increase in ketone body uptake (P less than 0.001) and conversion to 14CO2 in both fed and fasted sheep. Changes in arterial concentrations and cerebral removal of various metabolites were investigated by simultaneous collection of arterial and sagittal sinus blood samples. During acetoacetate infusion, there was a significant increase in ketone body uptake (P less than 0.001) and conversion to 14CO2 in both fed and fasted sheep when compared to control periods (saline infusion). The percent conversion of ketone bodies to 14CO2 was slightly higher in fasted sheep (22%) compared to fed sheep (18%). Blood glucose and free fatty acid concentrations were decreased, but there was a significant increase in blood lactic acid and lactic acid production by the brain. The plasma insulin concentration was increased significantly both in fed and fasted animals. These results indicate that ovine brain can utilize ketone bodies irrespective of nutritional state. In addition, ketone bodies stimulated the production of lactate by ovine brain.

Hepatic denervation does not significantly change the response of the liver to glucagon in conscious dogs

1995 ◽  
Vol 268 (2) ◽  
pp. E194-E203 ◽  
Author(s):  
M. Wada ◽  
C. C. Connolly ◽  
C. Tarumi ◽  
D. W. Neal ◽  
A. D. Cherrington
Keyword(s):  
Plasma Glucose Level ◽  
Metabolic Response ◽  
Control Period ◽  
Glucose Production ◽  
Glucagon Secretion ◽  
Sham Operation ◽  
Plasma Glucagon ◽  
Endogenous Insulin ◽  
Insulin And Glucagon Secretion ◽  
Glucose Clearance

In view of the increasing frequency of liver transplantation, and the importance of glucagon in the minute-to-minute regulation of glucose production, we assessed the effect of hepatic denervation on the liver's response to a physiological rise in glucagon in 18-h fasted dogs. Before study (2 wk), the dogs underwent liver denervation (DN; n = 6) or sham operation (SH; n = 5). Endogenous insulin and glucagon secretion were inhibited using somatostatin, and the two hormones were replaced intraportally in basal amounts. After the control period the glucagon infusion rate was tripled for 3 h. Glucagon increased from 41 +/- 8 to 128 +/- 8 and 54 +/- 4 to 129 +/- 9 pg/ml in SH and DN, respectively (P < 0.05), causing tracer-determined glucose production to increase from 2.5 +/- 0.1 to 4.9 +/- 0.5 and 2.3 +/- 0.1 to 5.8 +/- 0.8 mg.kg-1.min-1 by 15 min, respectively (P < 0.05). Glucose clearance fell slightly during glucagon infusion in DN, causing a somewhat greater increase in the plasma glucose level (to 175 +/- 15 vs. 207 +/- 20 mg/dl). The changes in gluconeogenic efficiency increased 65-90% in both groups (P < 0.05). In conclusion, denervation of the liver failed to significantly alter the metabolic response of that organ to a half-maximally effective increment in the plasma glucagon level.

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