scholarly journals The regulation of glutamine and ketone-body metabolism in the small intestine of the long-term (40-day) streptozotocin-diabetic rat

1987 ◽  
Vol 242 (1) ◽  
pp. 61-68 ◽  
Author(s):  
M Watford ◽  
E J Erbelding ◽  
E M Smith
Keyword(s):  
Small Intestine ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Streptozotocin Diabetes ◽  
Diabetic Rats ◽  
Glutamine Metabolism ◽  
Diabetic Rat ◽  
Coa Transferase ◽  
Glutaminase Activity

The small intestine is the major site of glutamine utilization in the mammalian body. During prolonged (40-day) streptozotocin-diabetes in the rat there is a marked increase in both the size and the phosphate-activated glutaminase activity of the small intestine. Despite this increased capacity, intestinal glutamine utilization ceases in diabetic rats. Mean arterial glutamine concentration fell by more than 50% in diabetic rats, suggesting that substrate availability is responsible for the decrease in intestinal glutamine use. When arterial glutamine concentrations in diabetic rats were elevated by infusion of glutamine solutions, glutamine uptake across the portal-drained viscera was observed. The effect of other respiratory fuels on intestinal glutamine metabolism was examined. Infusions of ketone bodies did not affect glutamine use by the portal-drained viscera of non-diabetic rats. Prolonged diabetes had no effect on the activity of 3-oxoacid CoA-transferase in the small intestine or on the rate of ketone-body utilization in isolated enterocytes. Glutamine (2 mM) utilization was decreased in enterocytes isolated from diabetic rats as compared with those from control animals. However, glutaminase activity in homogenates of enterocytes was unchanged by diabetes. In enterocytes isolated from diabetic rats the addition of ketone bodies or octanoate decreased glutamine use. It is proposed that during prolonged diabetes ketone bodies, and possibly fatty acids, replace glutamine as the major respiratory fuel of the small intestine.

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 The regulation of phosphate-activated glutaminase activity and glutamine metabolism in the streptozotocin-diabetic rat

1984 ◽  
Vol 224 (1) ◽  
pp. 207-214 ◽  
Author(s):  
M Watford ◽  
E M Smith ◽  
E J Erbelding
Keyword(s):  
Drinking Water ◽  
Small Intestine ◽  
Glutamine Metabolism ◽  
Diabetic Rat ◽  
Complete Suppression ◽  
Chemically Induced ◽  
Phosphate Activated Glutaminase ◽  
Kidney Liver ◽  
Nh4cl Solution ◽  
Glutaminase Activity

The activity of phosphate-activated glutaminase was increased in the kidney, liver and small intestine of rats made diabetic for 6 days with injection of streptozotocin (75 mg/kg body wt.). Insulin prevented this increase in all three tissues. Treatment with NaHCO3, to correct the acidosis that accompanies diabetes, prevented the increase in renal glutaminase activity, but not that in liver or small intestine. Chemically induced acidosis (NH4Cl solution as drinking water) or alkalosis (NaHCO3 solution as drinking water) increased and decreased, respectively, glutaminase activity in the kidney, but were without significant effect on the activity in liver and small intestine. The increase in glutaminase activity in the small intestine during diabetes was due to an overall increase in the size of this organ, and was only detectable when activity was expressed in terms of whole organ, not mucosal scrapings or isolated enterocytes. Prolonged diabetes (40 days) resulted in an even greater increase in the size and glutaminase activity of the small intestine. Despite this marked increase in capacity for glutamine catabolism, arteriovenous-difference measurements showed a complete suppression of plasma glutamine utilization by the small intestine during diabetes, confirming the report by Brosnan, Man, Hall, Colbourne & Brosnan [(1983) Am. J. Physiol. 235, E261-E265].

scholarly journals 3-oxo acid coenzyme A-transferase in normal and diabetic rat muscle

1976 ◽  
Vol 158 (2) ◽  
pp. 509-512 ◽  
Author(s):  
A Fenselau ◽  
K Wallis
Keyword(s):  
Skeletal Muscle ◽  
Coenzyme A ◽  
Substrate Inhibition ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Functional Parameters ◽  
Rat Muscle ◽  
Coa Transferase ◽  
Normal Rat ◽  
Streptozotocin Diabetic Rats

The amounts of succinyl-CoA--3-oxo acid CoA-transferase (EC 2.8.3.5) decrease progressively in skeletal muscle in streptozotocin-diabetic rats, reaching after 10 days about 50% of the value in normal rat muscle. Electrofocusing studies indicate the occurrence of partial proteolysis of the enzyme in diabetic muscle. However, several functional parameters relating to acetoacetate utilization, including substrate inhibition, are quite similar for muscle transferase preparations from normal and diseased rats. The development of pathological ketoacidosis is discussed in the light of these observations.

Changes in serotonin levels and 5-HT receptor activity in duodenum of streptozotocin-diabetic rats

2001 ◽  
Vol 281 (3) ◽  
pp. G798-G808 ◽  
Author(s):  
H. Takahara ◽  
M. Fujimura ◽  
S. Taniguchi ◽  
N. Hayashi ◽  
T. Nakamura ◽  
...  
Keyword(s):  
Small Intestine ◽  
Motor Activity ◽  
Serotonin Receptor ◽  
Ex Vivo ◽  
Diabetic Rats ◽  
Receptor Activity ◽  
Diabetic Rat ◽  
Receptor Subtype ◽  
Serotonin Content ◽  
Rat Duodenum

Few previous studies have discussed the changes in serotonin receptor activity in the small intestine of diabetic animals. Therefore, we examined serotonin content in duodenal tissue and dose-dependent effects of serotonin agonists and antagonists on the motor activity of ex vivo vascularly perfused duodenum of streptozotocin (STZ)-diabetic rats. Serotonin content was significantly increased in enterochromaffin cells but not altered in serotonin-containing neurons in STZ-diabetic rats. Motor activity assessed by frequency, amplitude, and percent motility index per 10 min of pressure waves was reduced in the duodenum of diabetic rats, and this reduction was reversed by insulin treatment. Serotonin dose dependently increased the motor activity in control rat duodenum but only a higher concentration of serotonin increased the motor activity in diabetic rats. The 5-hydroxytryptamine (5-HT) receptor subtype 4 (5-HT4) antagonist SB-204070 dose dependently reduced motor activity in both control and diabetic rats, whereas the 5-HT3receptor antagonist azasetron, even at a higher concentration, failed to affect motor activity in diabetic rat duodenum but dose dependently reduced motor activity in control rat duodenum. These results suggest that 5-HT3receptor activity was impaired but 5-HT4receptor activity was intact in STZ-diabetic rat duodenum. Such an impairment of 5-HT3receptor activity may induce the motility disturbance in the small intestine of diabetes mellitus.

scholarly journals Accumulation of diabetic rat peripheral nerve myelin by macrophages increases with the presence of advanced glycosylation endproducts.

1984 ◽  
Vol 160 (1) ◽  
pp. 197-207 ◽  
Author(s):  
H Vlassara ◽  
M Brownlee ◽  
A Cerami
Keyword(s):  
Steady State ◽  
Peripheral Nerve ◽  
Diabetic Rats ◽  
Myelin Proteins ◽  
Diabetic Rat ◽  
Striking Difference ◽  
Nonenzymatic Glycosylation ◽  
Advanced Glycosylation

We have previously shown that increased nonenzymatic glycosylation occurs in peripheral nervous tissue of diabetic humans and animals, primarily on the PO-protein of peripheral nerve myelin. The pathophysiologic mechanism by which this biochemical alteration leads to myelin breakdown and removal is not as yet understood. In the present study we show that advanced glycosylation end-product (AGE) adducts that form during long-term exposure of peripheral nerve myelin proteins to glucose in vitro and in vivo markedly alter the way in which myelin interacts with elicited macrophages. In this interaction, macrophages appear to specifically recognize AGEs on myelin, since AGE-BSA competes nearly as effectively as AGE-myelin, while neither unmodified BSA nor unmodified myelin compete. The failure of yeast mannan to interfere with macrophage recognition of AGE-myelin suggests that the mannose/fucose receptor does not mediate this process. Recognition of AGE-protein by macrophages is associated with endocytosis, as demonstrated by resistance of cell-associated radioactivity to removal by trypsin action, and by low temperature inhibition of ligand accumulation in the cellular fraction. 125I-labeled myelin that had been incubated in vitro with 50 mM glucose for 8 wk reached a steady state accumulation within thioglycolate-elicited macrophages that was five times greater than that of myelin incubated without glucose. Similarly, myelin isolated from rats having diabetes for 1.5-2.0 years duration had a steady state level that was 9 times greater than that of myelin from young rats, and 3.5 times greater than that of myelin from age-matched controls. In contrast, myelin isolated from rats having diabetes for 4-5 wk had the same degree of accumulation observed with myelin of age-matched normal rats. These data suggest that the amount of increased nonenzymatic glycosylation observed in the myelin of short-term diabetic rats had not yet resulted in the significant accumulation of AGE-myelin present both in vitro and in the long-term diabetic rats. The disappearance of acid-insoluble radioactivity from within the cells and the appearance of acid-soluble radioactivity released into the medium were very similar for the two groups, suggesting that the striking difference in accumulation seen between normal myelin and AGE-myelin is due primarily to increased uptake. Formation of irreversible AGE-adducts on myelin appears to promote the recognition and uptake of the modified myelin by macrophages. This interaction between AGE-myelin and macrophages may initiate or contribute to the segmental demyelination associated with diabetes and the normal aging of peripheral nerve.

scholarly journals Elevated glutamine metabolism in splenocytes from spontaneously diabetic BB rats

1991 ◽  
Vol 274 (1) ◽  
pp. 49-54 ◽  
Author(s):  
G Wu ◽  
C J Field ◽  
E B Marliss
Keyword(s):  
Diabetic Rats ◽  
Glutamine Metabolism ◽  
Co2 Production ◽  
Diabetic Rat ◽  
Bb Rat ◽  
Isolated Cells ◽  
Atp Production ◽  
Glutamate Production ◽  
Insulin Dependent ◽  
Diabetic Syndrome

To investigate the metabolic fates of glutamine in splenocytes from the BB rat with spontaneous immunologically mediated insulin-dependent diabetes, freshly isolated cells were incubated in Krebs-Ringer Hepes buffer with 1.0 mM-[U-14C]glutamine and 0, 4 mM- or 15 mM-glucose. (1) The major products of glutamine metabolism in splenocytes from normal and diabetic rats were ammonia, glutamate, aspartate and CO2. (2) The addition of glucose increased (P less than 0.01) glutamate production, but decreased (P less than 0.01) aspartate and CO2 production from glutamine, as compared with the values obtained in the absence of glucose. However, there were no differences in these metabolites of glutamine at 4 mM- and 15 mM-glucose. (3) At all glucose concentrations used, the productions of ammonia, glutamate, aspartate and CO2 from glutamine were all markedly increased (P less than 0.01) in splenocytes from diabetic rats. (4) Potential ATP production from glutamine in the splenocytes was similar to that from glucose, and was increased in cells from the diabetic rat. (5) ATP concentrations were increased (P less than 0.01) in diabetic-rat splenocytes in the presence of glutamine with or without glucose. (6) Our results demonstrate that glutamine is an important energy substrate for splenocytes and suggest that the increased glutamine metabolism may be associated with the activation of certain subsets of splenocytes in the immunologically mediated diabetic syndrome.

P3476High-resolution respirometry reveals enhanced myocardial mitochondrial ketone oxidation after fasting and ventricular unloading

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
E Zweck ◽  
V Burkart ◽  
C Wessel ◽  
D Scheiber ◽  
K H M Leung ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Ex Vivo ◽  
Oxidative Capacity ◽  
Left Ventricular ◽  
University Hospital ◽  
Oxygen Flux ◽  
Protective Effects ◽  
Coa Transferase

Abstract Background Impairment of myocardial mitochondrial function is regarded as an established pathomechanism in heart failure. Enhanced oxidation of ketone bodies may potentially exert protective effects on myocardial function. High-resolution respirometry (HRR) resembles a gold-standard methodology to determine myocardial mitochondrial metabolism and oxidative function but has not been validated for ketone substrates yet. Purpose We hypothesized that (1) quantification of ketone body oxidative capacity (OC) in myocardium utilizing ex-vivo HRR is feasible and that (2) ketone-associated OC is elevated after fasting and under conditions of chronic mechanical ventricular unloading. Methods We established new HRR (Oxygraph-2k) protocols, measuring oxygen flux generated by oxidation of the ketone substrates beta-hydroxybutyrate (HBA) and acetoacetate (ACA). Ketone protocols were then applied to twelve C57BL/6 mice' (of which six were fasted for 16h) left ventricular and right liver lobe tissue, as well as to eleven terminal heart failure patients' left ventricular tissue, harvested at heart transplantation. Heart transplant recipients were subdivided into patients with left ventricular assist device prior to transplantation (LVAD group, n=6) or no unloading prior to transplantation (HTX group, n=5). Results In non-fasted rodent hearts, HBA yielded an OC of 25±4 pmol/(s*mg tissue) above basal respiration, when applied as sole substrate (21±11 pmol/(s*mg) in liver). ACA alone did not induce oxygen flux, but ACA+succinate yielded 229% higher oxygen flux than succinate alone in state III (146±32 vs 44±12 pmol/(s*mg); p=0.0003). When titrated after succinate, ACA increased OC by 93±25 pmol/(s*mg) (p=0.0003). In 16h-fasted rodent hearts, HBA-supported OC was 27% higher (41±3 vs 52±9 pmol/(s*mg); p=0.04), while OC with ACA+succinate was unchanged (p=0.60). In rodent liver, no oxygen flux was induced by ACA, reflecting absence of 3-oxoacid CoA-transferase. However, HBA-supported OC was 118% higher in fasted liver (37±13 vs 57±13 pmol/(s*mg); p=0.03). In humans, left ventricular unloading was not associated with altered myocardial OC for fatty acids and glycolytic substrates (standard protocol, p=0.13), but HBA-supported OC was 39% higher in the LVAD group compared to the HTX group (54±12 vs 39±9 pmol/(s*mg), p=0.04). Conclusion Quantification of ketone body OC with HRR is feasible in permeabilized myocardial fibers. Applying this novel method revealed increased HBA-supported myocardial mitochondrial respiration after fasting and chronic left ventricular unloading. These data support a concept of enhanced ketone oxidation following ventricular unloading in myocardial mitochondria. Our findings facilitate new studies on myocardial ketone turnover and the interaction of mitochondrial ketone metabolism with cardiac performance. Acknowledgement/Funding CRC 1116, Research commission of the University Hospital Düsseldorf

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.

scholarly journals Activities of enzymes of ketone-body utilization in brain and other tissues of suckling rats

1971 ◽  
Vol 121 (1) ◽  
pp. 49-53 ◽  
Author(s):  
M. Ann Page ◽  
H. A. Krebs ◽  
D. H. Williamson
Keyword(s):  
Rat Brain ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Rat Kidney ◽  
Adult Brain ◽  
Suckling Period ◽  
Suckling Rats ◽  
Adult Rat ◽  
Coa Transferase ◽  
High Concentrations

1. The activities of 3-hydroxybutyrate dehydrogenase and 3-oxo acid CoA-transferase in rat brain at birth were found to be about two-thirds of those of adult rat brain, expressed per g wet wt. The activities rose throughout the suckling period and at the time of weaning reached values about three times higher than those for adult brain. Later they gradually declined. 2. At birth the activity of acetoacetyl-CoA thiolase in rat brain was about 60% higher than in the adult. During the suckling period there was no significant change in activity. 3. In rat kidney the activities of the three enzymes at birth were less than one-third of those at maturity. They gradually rose and after 5 weeks approached the adult value. Similar results were obtained with rat heart. 4. The activity of glutamate dehydrogenase (a mitochondrial enzyme like 3-hydroxybutyrate dehydrogenase and 3-oxo acid CoA-transferase) also rose in brain and kidney during the suckling period, but at no stage did it exceed the adult value. 5. Throughout the suckling period the total ketone-body concentration in the blood was about six times higher than in adult fed rats, and the concentration of free fatty acids in the blood was three to four times higher. 6. It is concluded that the rate of ketone-body utilization in brains of suckling rats is determined by both the greater amounts of the key enzymes in the tissue and the high concentrations of ketone bodies in the blood. In addition, the low activities of the relevant enzymes in kidney and heart of suckling rats may make available more ketone bodies for the brain.

scholarly journals Activities of enzymes involved in acetoacetate utilization in adult mammalian tissues

1971 ◽  
Vol 121 (1) ◽  
pp. 41-47 ◽  
Author(s):  
D. H. Williamson ◽  
Margaret W. Bates ◽  
M. Ann Page ◽  
H. A. Krebs
Keyword(s):  
Ketone Body ◽  
Alloxan Diabetes ◽  
Adrenal Glands ◽  
Ketone Bodies ◽  
Rat Tissues ◽  
Adult Rat ◽  
Coa Transferase ◽  
Mammalian Tissues ◽  
Fat Feeding ◽  
Low Activity

1. The activities in rat tissues of 3-oxo acid CoA-transferase (the first enzyme involved in acetoacetate utilization) were found to be highest in kidney and heart. In submaxillary and adrenal glands the activities were about one-quarter of those in kidney and heart. In brain it was about one-tenth and was less in lung, spleen, skeletal muscle and epididymal fat. No activity was detectable in liver. 2. The activities of acetoacetyl-CoA thiolase were found roughly to parallel those of the transferase except for liver and adrenal glands. The high activity in the latter two tissues may be explained by additional roles of thiolase, namely, the production of acetyl-CoA from fatty acids. 3. The activities of the two enzymes in tissues of mouse, gerbil, golden hamster, guinea pig and sheep were similar to those of rat tissues. The notable exception was the low activity of the transferase and thiolase in sheep heart and brain. 4. The activities of the transferase in rat tissues did not change appreciably in starvation, alloxan-diabetes or on fat-feeding, where the rates of ketone-body utilization are increased. Thiolase activity increased in kidney and heart on fat-feeding. 5. The activity of 3-hydroxybutyrate dehydrogenase did not change in rat brain during starvation. 6. The factors controlling the rate of ketone-body utilization are discussed. It is concluded that the activities of the relevant enzymes in the adult rat do not control the variations in the rate of ketone-body utilization that occur in starvation or alloxan-diabetes. The controlling factor in these situations is the concentration of the ketone bodies in plasma and tissues.

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