scholarly journals Effects of starvation and exercise on concentrations of citrate, hexose phosphates and glycogen in skeletal muscle and heart. Evidence for selective operation of the glucose-fatty acid cycle

1985 ◽  
Vol 232 (2) ◽  
pp. 585-591 ◽  
Author(s):  
A Zorzano ◽  
T W Balon ◽  
L J Brady ◽  
P Rivera ◽  
L P Garetto ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Ketone Bodies ◽  
Recovery Period ◽  
Moderate Intensity ◽  
Glycogen Depletion ◽  
Acid Cycle ◽  
Glucose Fatty Acid Cycle ◽  
Fructose 1,6 Bisphosphate ◽  
Hexose Phosphates

Concentrations of citrate, hexose phosphates and glycogen were measured in skeletal muscle and heart under conditions in which plasma non-esterified fatty acids and ketone bodies were physiologically increased. The aim was to determine under what conditions the glucose-fatty acid cycle might operative in skeletal muscle in vivo. In keeping with the findings of others, starvation increased the concentrations of glycogen, citrate and the fructose 6-phosphate/fructose 1,6-bisphosphate ratio in heart, indicating that the cycle was operative. In contrast, it decreased glycogen and had no effect on the concentration of citrate or the fructose 6-phosphate/fructose 1,6-bisphosphate ratio in the soleus, a slow-twitch red muscle in which the glucose-fatty acid cycle has been demonstrated in vitro. In fed rats, exercise of moderate intensity caused glycogen depletion in the soleus and red portion of gastrocnemius muscle, but not in heart. In starved rats the same exercise had no effect on the already diminished glycogen contents in skeletal muscle, but it decreased cardiac glycogen by 25-30%. After exercise, citrate and the fructose 6-phosphate/fructose 1,6-bisphosphate ratio were increased in the soleus of the starved rat. Significant changes were not observed in fed rats. The data suggest that in the resting state the glucose-fatty acid cycle operates in the heart, but not in the soleus muscle, of a starved rat. In contrast, the metabolite profile in the soleus was consistent with activation of the glucose-fatty acid cycle in the starved rat during the recovery period after exercise. Whether the cycle operates during exercise itself is unclear.

Skeletal muscle pyruvate dehydrogenase activity during acetate infusion in humans

1995 ◽  
Vol 268 (5) ◽  
pp. E1007-E1017 ◽  
Author(s):  
C. T. Putman ◽  
L. L. Spriet ◽  
E. Hultman ◽  
D. J. Dyck ◽  
G. J. Heigenhauser
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Dehydrogenase Activity ◽  
Pyruvate Dehydrogenase ◽  
Acetate Metabolism ◽  
Acetyl Coa ◽  
Acid Cycle ◽  
Citrate Accumulation ◽  
Acetyl Group ◽  
Glucose Fatty Acid Cycle

Pyruvate dehydrogenase activity (PDHa), acetyl group, and citrate accumulation were examined in human skeletal muscle at rest and during cycling exercise while acetate was infused. Eight subjects received 400 mmol of sodium acetate (Ace) at a constant rate during 20 min of rest, 5 min of cycling at 40% maximal O2 uptake (VO2max) and 15 min of cycling at 80% VO2max. Two weeks later experiments were repeated while 400 mmol of sodium bicarbonate was infused in the control condition (CON). Ace infusion increased muscle acetyl-coenzyme A (acetyl-CoA), citrate, and acetylcarnitine. A decline in resting PDHa during 20 min of Ace infusion (0.37 +/- 0.08 vs. 0.16 +/- 0.03 mmol.min-1.kg wet wt-1) coincided with an elevation in the acetyl-CoA-to-free CoA ratio (acetyl-CoA/CoASH; 0.28 +/- 0.04 to 0.73 +/- 0.14). After 20 min of CON infusion, resting PDHa (0.32 +/- 0.06 mmol.min-1.kg wet wt-1) was similar to PDHa before Ace infusion. During exercise, acetyl-CoA, citrate, and acetyl-CoA/CoASH were further elevated, and the differences that existed at rest were resolved. PDHa increased to the same extent in Ace and CON, in which it was 44-47% transformed after 5 min at 40% VO2max and completely transformed after 15 min at 80% VO2max. At rest PDHa was regulated by variations in acetyl-CoA/CoASH secondary to enhanced acetate metabolism. Conversely, during exercise PDHa regulation appeared independent of variations in acetyl-CoA/CoASH. The resting data are consistent with a central role for PDHa and citrate in the regulation of the glucose-fatty acid cycle in skeletal muscle, as classically proposed. However, in the present study Ace infusion was not effective in perturbing the glucose-fatty acid cycle during exercise.

Contribution of muscle and liver to glucose-fatty acid cycle in humans

1993 ◽  
Vol 264 (4) ◽  
pp. E599-E605 ◽  
Author(s):  
C. Saloranta ◽  
V. Koivisto ◽  
E. Widen ◽  
K. Falholt ◽  
R. A. DeFronzo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Glucose Metabolism ◽  
Glycogen Synthase ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Acid Cycle ◽  
Glucose Fatty Acid Cycle ◽  
Plasma Ffa

To examine the influence of elevated free fatty acid (FFA) levels on hepatic glucose production (HGP) and oxidative and nonoxidative pathways of glucose metabolism, 12 healthy subjects participated in two euglycemic insulin-clamp studies performed with and without infusion of Intralipid plus heparin. To elucidate the role of skeletal muscle in this putative interaction, we performed muscle biopsies for the measurement of activities of glycogen synthase (GS), pyruvate dehydrogenase (PDH), and carnitine palmitoyltransferase (CPT). Infusion of Intralipid plus heparin caused an increase in plasma FFA concentrations and rate of lipid oxidation (measured by indirect calorimetry) that was not inhibited by insulin. Suppression of HGP by insulin was impaired by elevated plasma FFA levels. Furthermore, the increase in plasma FFA was associated with a 20% reduction in total glucose metabolism (P < 0.01), which was completely accounted for by a reduction in the rate of glucose oxidation. Although the fractional activity of GS was increased by insulin, elevation of plasma FFA had no influence on this key enzyme of glycogen synthesis. In addition, the activities of PDH and CPT were uninfluenced by the elevation of FFA, suggesting that oxidative processes in skeletal muscle were not a major target for the operative glucose-fatty acid cycle under the current conditions. Taken together, the data indicate that the interaction between FFA and glucose metabolism also involves impaired suppression of HGP by insulin.

scholarly journals Palmitate inhibits liver glycolysis. Involvement of fructose 2,6-bisphosphate in the glucose/fatty acid cycle

1988 ◽  
Vol 251 (2) ◽  
pp. 541-545 ◽  
Author(s):  
L Hue ◽  
L Maisin ◽  
M H Rider
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Ketone Bodies ◽  
Acid Cycle ◽  
Glucose Fatty Acid Cycle ◽  
Inhibition Of Glycolysis ◽  
Beta Hydroxybutyrate ◽  
Fasted Rats

In hepatocytes from overnight-fasted rats incubated with glucose, palmitate decreased the production of lactate, the detritiation of [2-3H]- and [3-3H]-glucose, and the concentration of fructose 2,6-bisphosphate. Similarly, perfusion of hearts from fed rats with beta-hydroxybutyrate resulted in an inhibition of the detritiation of [3-3H]glucose and a fall in fructose 2,6-bisphosphate concentration. This fall could result from an increase in citrate (hepatocytes and heart) and sn-glycerol 3-bisphosphate concentration. It is suggested that a fall in fructose 2,6-bisphosphate concentration participates in the inhibition of glycolysis by fatty acids and ketone bodies.

Malonyl-CoA regulation in skeletal muscle: its link to cell citrate and the glucose-fatty acid cycle

1997 ◽  
Vol 272 (4) ◽  
pp. E641-E648 ◽  
Author(s):  
A. K. Saha ◽  
D. Vavvas ◽  
T. G. Kurowski ◽  
A. Apazidis ◽  
L. A. Witters ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Pancreatic Beta Cell ◽  
Acid Oxidation ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Acid Cycle ◽  
Citrate Lyase ◽  
Malonyl Coa ◽  
Glucose Fatty Acid Cycle

Malonyl-CoA is an inhibitor of carnitine palmitoyltransferase I, the enzyme that controls the oxidation of fatty acids by regulating their transfer into the mitochondria. Despite this, knowledge of how malonyl-CoA levels are regulated in skeletal muscle, the major site of fatty acid oxidation, is limited. Two- to fivefold increases in malonyl-CoA occur in rat soleus muscles incubated with glucose or glucose plus insulin for 20 min [Saha, A. K., T. G. Kurowski, and N. B. Ruderman. Am. J. Physiol. 269 (Endocrinol. Metab. 32): E283-E289, 1995]. In addition, as reported here, acetoacetate in the presence of glucose increases malonyl-CoA levels in the incubated soleus. The increases in malonyl-CoA in all of these situations correlated closely with increases in the concentration of citrate (r2 = 0.64) and to an even greater extent the sum of citrate plus malate (r2 = 0.90), an antiporter for citrate efflux from the mitochondria. Where measured, no increase in the activity of acetyl-CoA carboxylase (ACC) was found. Inhibition of ATP citrate lyase with hydroxycitrate markedly diminished the increases in malonyl-CoA in these muscles, indicating that citrate was the major substrate for the malonyl-CoA precursor, cytosolic acetyl-CoA. Studies with enzyme purified by immunoprecipitation indicated that the observed increases in citrate could have also allosterically activated ACC. The results suggest that in the presence of glucose, insulin and acetoacetate acutely increase malonyl-CoA levels in the incubated soleus by increasing the cytosolic concentration of citrate. This novel mechanism could complement the glucose-fatty acid cycle in determining how muscle chooses its fuels. It could also provide a means by which glucose acutely modulates signal transduction in muscle and other cells (e.g., the pancreatic beta-cell) in which its metabolism is determined by substrate availability.

Bypassing the glucose/fatty acid cycle: AMP-activated protein kinase

2003 ◽  
Vol 31 (6) ◽  
pp. 1157-1160 ◽  
Author(s):  
D. Carling ◽  
L.G.D. Fryer ◽  
A. Woods ◽  
T. Daniel ◽  
S.L.C. Jarvie ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Metabolic Regulation ◽  
Muscle Activation ◽  
Glycogen Metabolism ◽  
Acid Oxidation ◽  
Acid Cycle ◽  
Glucose Fatty Acid Cycle ◽  
Amp Activated Protein Kinase

The AMPK (AMP-activated protein kinase) cascade plays a key role in regulating energy metabolism. Conditions which cause a decrease in the ATP/AMP ratio lead to activation of AMPK. Once activated, AMPK initiates a series of responses that act to restore the energy balance of the cell. In skeletal muscle, activation of AMPK increases both glucose uptake and fatty acid oxidation, raising the possibility that AMPK can bypass the glucose/fatty acid cycle. This review focuses on the role of AMPK in the regulation of glucose and fatty acid metabolism in muscle. Recently, naturally occurring mutations within the γ isoforms have been identified which lead to altered metabolic regulation in cardiac and skeletal muscle and suggest an important role for the kinase in regulating glycogen metabolism.

Glucose–fatty acid cycle operates in humans at the levels of both whole body and skeletal muscle during low and high physiological plasma insulin concentrations

1994 ◽  
Vol 130 (1) ◽  
pp. 70-79 ◽  
Author(s):  
Allan A Vaag ◽  
Aase Handberg ◽  
Peter Skøtt ◽  
Erik A Richter ◽  
Henning Beck-Nielsen
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Pyruvate Dehydrogenase ◽  
Plasma Insulin ◽  
Activity Ratio ◽  
Whole Body ◽  
Acid Cycle ◽  
Glucose Fatty Acid Cycle

Vaag, AA, Handberg A, Skøtt P, Richter EA, Beck-Nielsen H. Glucose-fatty acid cycle operates in humans at the levels of both whole body and skeletal muscle during low and high physiological plasma insulin concentrations. Eur J Endocrinol 1994;130:70–9. ISSN 0804–4643 Plasma non-esterified fatty acid concentrations were elevated acutely (Intralipid + heparin infusion) in 14 normal humans in order to study the effects of fatty acids on whole-body basal and insulin-stimulated glucose metabolism, and on activities of skeletal muscle key enzymes. Whole-body glucose metabolism was assessed using [3-3H]glucose and indirect calorimetry. Biopsies were taken from the vastus lateralis muscle during basal and insulin-stimulated (3 h, 40 mU·m−2·min1) steady-state periods. Total peripheral glucose uptake was unaffected by Intralipid infusion in the basal state, whereas it decreased during Intralipid infusion in the hyperinsulinemic state (10.7±0.7 vs 8.7±0.8 mg · kg−1 fat-free mass · min−1, p < 0.02). Intralipid infusion decreased whole-body glucose oxidation in the basal state (1.3±0.2 vs 0.8±0.1 mg·kg−1 fat-free mass·min−1, p<0.001) and during hyperinsulinemia (3.6±0.2 vs 1.7±0.2 mg·kg−1 fat-free mass·min−1 p<0.001). Whole-body non-oxidative glucose uptake increased during Intralipid infusion in the basal state and was unaffected in the hyperinsulinemic state. The skeletal muscle pyruvate dehydrogenase activity ratio decreased in the basal state during Intralipid infusion (55±6 vs 43±5%, p<0.05), whereas no statistical significant decrease in the pyruvate dehydrogenase activity ratio was observed during insulin infusion (57±8 vs 47 ± 5%, NS). Insulin increased the activity of the active form of pyruvate dehydrogenase on the control day, but not during Intralipid infusion. Activities of phosphofructokinase and glycogen synthase were unaffected by Intralipid infusion. Plasma glucose concentrations were similar during Intralipid infusion and on the control day, whereas Intralipid infusion increased the muscle glucose content in the basal state (1.36±0.09 vs 1.77±0.12 mmol/kg dry wt, p<0.05) and in the hyperinsulinemic state (1.23 ± 0.09 vs 1.82 ± 0.16 mmol/kg dry wt, p <0.05). Insulin increased the muscle lactate content on the control day (6.50±0.95 vs 8.65±0.77 mmol/kg dry wt, p<0.05), but not during Intralipid infusion. In conclusion, the glucose–fatty acid cycle operates in humans in vivo at the levels of both whole body and skeletal muscle during both low and high physiological insulin concentrations. Allan Vaag, Department of Internal Medicine M, Odense University Hospital, Sdr. Boulevard, DK-5000, Odense C, Denmark

Respiratory capacity and glycogen depletion in thyroid-deficient muscle

1980 ◽  
Vol 49 (1) ◽  
pp. 102-106 ◽  
Author(s):  
K. M. Baldwin ◽  
A. M. Hooker ◽  
R. E. Herrick ◽  
L. F. Schrader
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Plasma Free Fatty Acid ◽  
Endurance Capacity ◽  
Glycogen Depletion ◽  
Respiratory Capacity ◽  
Rest And Exercise

This study was undertaken to determine the effects of propylthiouracil-induced thyroid deficiency on a) the capacity of muscle homogenates to oxidize [2-14C]pyruvate and [U-14C]palmitate and b) glycogen depletion during exercise in liver and in fast-oxidative-glycogenolytic (FOG), fast-glycogenolytic (FG), and slow-oxidative (SO) muscle. Relative to the rates for normal rats, oxidation with pyruvate was reduced by 53, 68, and 58%, and palmitate by 40, 50, and 48% in FOG, FG, and SO muscle, respectively (P less than 0.05). Normal rats ran longer than thyroid-deficient rats at 26.7 m/min (87 ± 8 vs. 37 ± 5 min). After 40 min of running (22 m/min), the amount of glycogen consumed in normal FOG, FG, and SO muscle and in liver amounted to only 23, 12, 66, and 52%, respectively, of that for their thyroid-deficient counterparts. Also, normal rats maintained higher plasma free fatty acid levels than thyroid-deficient rats during both rest and exercise (P less than 0.05). These findings suggest that thyroid deficiency causes a reduced potential for FFA utilization in skeletal muscle that enhances its consumption of glycogen, thereby limiting endurance capacity.

Role of the AMP-activated protein kinase in regulating fatty acid metabolism during exerciseThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 34 (3) ◽  
pp. 315-322 ◽  
Author(s):  
Gregory R. Steinberg
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Moderate Intensity ◽  
Amp Activated Protein Kinase

During moderate-intensity exercise, fatty acids are the predominant substrate for working skeletal muscle. The release of fatty acids from adipose tissue stores, combined with the ability of skeletal muscle to actively fine tune the gradient between fatty acid and carbohydrate metabolism, depending on substrate availability and energetic demands, requires a coordinated system of metabolic control. Over the past decade, since the discovery that AMP-activated protein kinase (AMPK) was increased in accordance with exercise intensity, there has been significant interest in the proposed role of this ancient stress-sensing kinase as a critical integrative switch controlling metabolic responses during exercise. In this review, studies examining the role of AMPK as a regulator of fatty acid metabolism in both adipose tissue and skeletal muscle during exercise will be discussed. Exercise induces activation of AMPK in adipocytes and regulates triglyceride hydrolysis and esterfication through phosphorylation of hormone sensitive lipase (HSL) and glycerol-3-phosphate acyl-transferase, respectively. In skeletal muscle, exercise-induced activation of AMPK is associated with increases in fatty acid uptake, phosphorylation of HSL, and increased fatty acid oxidation, which is thought to occur via the acetyl-CoA carboxylase-malony-CoA-CPT-1 signalling axis. Despite the importance of AMPK in regulating fatty acid metabolism under resting conditions, recent evidence from transgenic models of AMPK deficiency suggest that alternative signalling pathways may also be important for the control of fatty acid metabolism during exercise.

scholarly journals GH replacement causing acute hyperglycaemia and ketonuria in a type 1 diabetic patient

2013 ◽  
Vol 2013 ◽  
Author(s):  
Dominic Cavlan ◽  
Shanti Vijayaraghavan ◽  
Susan Gelding ◽  
William Drake
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Type 1 Diabetes ◽  
Fatty Acid ◽  
Diabetic Patient ◽  
Acid Cycle ◽  
Gh Replacement ◽  
Glucose Fatty Acid Cycle ◽  
Gh Excess

Summary A state of insulin resistance is common to the clinical conditions of both chronic growth hormone (GH) deficiency and GH excess (acromegaly). GH has a physiological role in glucose metabolism in the acute settings of fast and exercise and is the only anabolic hormone secreted in the fasting state. We report the case of a patient in whom knowledge of this aspect of GH physiology was vital to her care. A woman with well-controlled type 1 diabetes mellitus who developed hypopituitarism following the birth of her first child required GH replacement therapy. Hours after the first dose, she developed a rapid metabolic deterioration and awoke with hyperglycaemia and ketonuria. She adjusted her insulin dose accordingly, but the pattern was repeated with each subsequent increase in her dose. Acute GH-induced lipolysis results in an abundance of free fatty acids (FFA); these directly inhibit glucose uptake into muscle, and this can lead to hyperglycaemia. This glucose–fatty acid cycle was first described by Randle et al. in 1963; it is a nutrient-mediated fine control that allows oxidative muscle to switch between glucose and fatty acids as fuel, depending on their availability. We describe the mechanism in detail. Learning points There is a complex interplay between GH and insulin resistance: chronically, both GH excess and deficiency lead to insulin resistance, but there is also an acute mechanism that is less well appreciated by clinicians. GH activates hormone-sensitive lipase to release FFA into the circulation; these may inhibit the uptake of glucose leading to hyperglycaemia and ketosis in the type 1 diabetic patient. The Randle cycle, or glucose–fatty acid cycle, outlines the mechanism for this acute relationship. Monitoring the adequacy of GH replacement in patients with type 1 diabetes is difficult, with IGF1 an unreliable marker.

Regulation of fat-carbohydrate interaction in skeletal muscle during intense aerobic cycling

1993 ◽  
Vol 265 (6) ◽  
pp. E852-E859 ◽  
Author(s):  
D. J. Dyck ◽  
C. T. Putman ◽  
G. J. Heigenhauser ◽  
E. Hultman ◽  
L. L. Spriet
Keyword(s):  
Skeletal Muscle ◽  
Pyruvate Dehydrogenase ◽  
Saline Control ◽  
Elevated Plasma ◽  
O2 Uptake ◽  
Muscle Lactate ◽  
Acid Cycle ◽  
Glucose Fatty Acid Cycle ◽  
Male Subjects ◽  
Muscle Biopsies

Six male subjects received either a saline (control) or Intralipid infusion during 30 min rest and 15 min cycling at 85% maximal O2 uptake (VO2max) to examine the regulation of fat-carbohydrate interaction (glucose-fatty acid cycle) in skeletal muscle. Muscle biopsies were sampled immediately before and at 3 and 15 min of exercise in both trials. A muscle biopsy was also taken at -30 min rest in the Intralipid trial. Intralipid infusion significantly elevated plasma free fatty acids above control during rest (0.21 +/- 0.04 to 0.94 +/- 0.09 mM) and exercise (5 min: 1.27 +/- 0.15 mM; 15 min: 1.42 +/- 0.13 mM). Muscle glycogen degradation was significantly lower in the Intralipid trial (109.7 +/- 29.3 vs. 194.7 +/- 32.1 mmol/kg dry muscle). Muscle lactate accumulation after 15 min was similar in both trials (control, 60.7 +/- 12.2 and Intralipid, 60.9 +/- 12.4 mmol/kg dry muscle). Muscle citrate increased at rest during Intralipid (0.32 +/- 0.06 to 0.58 +/- 0.06 mmol/kg dry muscle) but was not different between trials at 3 min (control, 0.73 +/- 0.07 and Intralipid, 0.68 +/- 0.06 mmol/kg dry muscle) and 15 min of cycling. Resting acetyl-CoA was unaffected by Intralipid and increased similarly in both trials at 3 min of cycling (control, 59.0 +/- 10.3 and Intralipid, 50.7 +/- 13.6 mumol/kg dry muscle) and remained unchanged at 15 min. Pyruvate dehydrogenase activity increased five- to sevenfold during exercise and was similar in both trials (15 min: control, 2.42 +/- 0.30 and Intralipid, 2.79 +/- 0.41 mmol.min-1 x kg wet wt-1).(ABSTRACT TRUNCATED AT 250 WORDS)

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