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.

Multiple metabolic effects of CGRP in conscious rats: role of glycogen synthase and phosphorylase

1993 ◽  
Vol 264 (1) ◽  
pp. E1-E10 ◽  
Author(s):  
L. Rossetti ◽  
S. Farrace ◽  
S. B. Choi ◽  
A. Giaccari ◽  
L. Sloan ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glycogen Synthase ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Plasma Concentrations ◽  
Glucose Production ◽  
Glucose Disposal ◽  
Hepatic Glucose ◽  
Intracellular Glucose

Calcitonin gene-related peptide (CGRP) is a neuropeptide that is released at the neuromuscular junction in response to nerve excitation. To examine the relationship between plasma CGRP concentration and intracellular glucose metabolism in conscious rats, we performed insulin (22 pmol.kg-1.min-1) clamp studies combined with the infusion of 0, 20, 50, 100, 200, and 500 pmol.kg-1.min-1 CGRP (plasma concentrations ranging from 2 x 10(-11) to 5 x 10(-9) M). CGRP antagonized insulin's suppression of hepatic glucose production at plasma concentrations (approximately 10(-10) M) that are only two- to fivefold its basal portal concentration. Insulin-mediated glucose disposal was decreased by 20-32% when CGRP was infused at 50 pmol.kg-1.min-1 (plasma concentration 3 x 10(-10) M) or more. The impairment in insulin-stimulated glycogen synthesis in skeletal muscle accounted for all of the CGRP-induced decrease in glucose disposal, while whole body glycolysis was increased despite the reduction in total glucose uptake. The muscle glucose 6-phosphate concentration progressively increased during the CGRP infusions. CGRP inhibited insulin-stimulated glycogen synthase in skeletal muscle with a 50% effective dose of 1.9 +/- 0.36 x 10(-10) M. This effect on glycogen synthase was due to a reduction in enzyme affinity for UDP-glucose, with no changes in the maximal velocity. In vitro CGRP stimulated both hepatic and skeletal muscle adenylate cyclase in a dose-dependent manner. These data suggest that 1) CGRP is a potent antagonist of insulin at the level of muscle glycogen synthesis and hepatic glucose production; 2) inhibition of glycogen synthase is its major biochemical action in skeletal muscle; and 3) these effects are present at concentrations of the peptide that may be in the physiological range for portal vein and skeletal muscle. These data underscore the potential role of CGRP in the physiological modulation of intracellular glucose 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

scholarly journals Caffeamide 36-13 Regulates the Antidiabetic and Hypolipidemic Signs of High-Fat-Fed Mice on Glucose Transporter 4, AMPK Phosphorylation, and Regulated Hepatic Glucose Production

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Yueh-Hsiung Kuo ◽  
Cheng-Hsiu Lin ◽  
Chun-Ching Shih
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Glucose Transporter ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hypolipidemic Effect ◽  
Glucose Transporter 4 ◽  
High Fat ◽  
Amide Derivatives ◽  
Hepatic Glucose

This study was to investigate the antidiabetic and antihyperlipidemic effects of (E)-3-[3, 4-dihydroxyphenyl-1-(piperidin-1-yl)prop-2-en-1-one] (36-13) (TS), one of caffeic acid amide derivatives, on high-fat (HF-) fed mice. The C57BL/6J mice were randomly divided into the control (CON) group and the experimental group, which was firstly fed a HF diet for 8 weeks. Then, the HF group was subdivided into four groups and was given TS orally (including two doses) or rosiglitazone (Rosi) or vehicle for 4 weeks. Blood, skeletal muscle, and tissues were examined by measuring glycaemia and dyslipidemia-associated events. TS effectively prevented HF diet-induced increases in the levels of blood glucose, triglyceride, insulin, leptin, and free fatty acid (FFA) and weights of visceral fa; moreover, adipocytes in the visceral depots showed a reduction in size. TS treatment significantly increased the protein contents of glucose transporter 4 (GLUT4) in skeletal muscle; TS also significantly enhanced Akt phosphorylation in liver, whereas it reduced the expressions of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Moreover, TS enhanced phosphorylation of AMP-activated protein kinase (phospho-AMPK) both in skeletal muscle and liver tissue. Therefore, it is possible that the activation of AMPK by TS resulted in enhanced glucose uptake in skeletal muscle, contrasting with diminished gluconeogenesis in liver. TS exhibits hypolipidemic effect by decreasing the expressions of fatty acid synthase (FAS). Thus, antidiabetic properties of TS occurred as a result of decreased hepatic glucose production by PEPCK and G6Pase downregulation and improved insulin sensitization. Thus, amelioration of diabetic and dyslipidemic state by TS in HF-fed mice occurred by regulation of GLUT4, G6Pase, and FAS and phosphorylation of AMPK.

scholarly journals Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes

2002 ◽  
Vol 173 (3) ◽  
pp. 465-473 ◽  
Author(s):  
MA Luque ◽  
N Gonzalez ◽  
L Marquez ◽  
A Acitores ◽  
A Redondo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Human Skeletal Muscle ◽  
Glycogen Synthase ◽  
Second Messengers ◽  
Glycogen Synthesis ◽  
Human Muscle ◽  
Camp Content ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) has been shown to have insulin-like effects upon the metabolism of glucose in rat liver, muscle and fat, and on that of lipids in rat and human adipocytes. These actions seem to be exerted through specific receptors which, unlike that of the pancreas, are not - at least in liver and muscle - cAMP-associated. Here we have investigated the effect, its characteristics, and possible second messengers of GLP-1 on the glucose metabolism of human skeletal muscle, in tissue strips and primary cultured myocytes. In muscle strips, GLP-1, like insulin, stimulated glycogen synthesis, glycogen synthase a activity, and glucose oxidation and utilization, and inhibited glycogen phosphorylase a activity, all of this at physiological concentrations of the peptide. In cultured myotubes, GLP-1 exerted, from 10(-13) mol/l, a dose-related increase of the D-[U-(14)C]glucose incorporation into glycogen, with the same potency as insulin, together with an activation of glycogen synthase a; the effect of 10(-11) mol/l GLP-1 on both parameters was additive to that induced by the equimolar amount of insulin. Synthase a was still activated in cells after 2 days of exposure to GLP-1, as compared with myotubes maintained in the absence of peptide. In human muscle cells, exendin-4 and its truncated form 9-39 amide (Ex-9) are both agonists of the GLP-1 effect on glycogen synthesis and synthase a activity; but while neither GLP-1 nor exendin-4 affected the cellular cAMP content after 5-min incubation in the absence of 3-isobutyl-1-methylxantine (IBMX), an increase was detected with Ex-9. GLP-1, exendin-4, Ex-9 and insulin all induced the prompt hydrolysis of glycosylphosphatidylinositols (GPIs). This work shows a potent stimulatory effect of GLP-1 on the glucose metabolism of human skeletal muscle, and supports the long-term therapeutic value of the peptide. Further evidence for a GLP-1 receptor in this tissue, different from that of the pancreas, is also illustrated, suggesting a role for an inositolphosphoglycan (IPG) as at least one of the possible second messengers of the GLP-1 action in human muscle.

Skeletal muscle glucose metabolism in obesity-prone and obesity-resistant rats

1993 ◽  
Vol 264 (6) ◽  
pp. R1224-R1228 ◽  
Author(s):  
M. J. Pagliassotti ◽  
K. A. Shahrokhi ◽  
J. O. Hill
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Weight Gain ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Glycogen Synthase ◽  
Body Weight Gain ◽  
Glycogen Synthesis ◽  
Insulin Resistant ◽  
Wide Range

Ad libitum access to a high-fat (HF) diet produces a wide range of weight gain in rats. Rats most susceptible to weight gain on such a diet (obesity prone; OP) are more insulin resistant after 4-5 wk of diet exposure than are those most resistant (obesity resistant; OR) to weight gain. To investigate whether skeletal muscle glucose metabolism contributes to insulin resistance in this model, insulin-stimulated glucose metabolism was assessed in the perfused hindquarter of rats exposed to either a low-fat (LF, n = 6) or HF diet for 5 wk. Delineation of OP (n = 6) and OR (n = 6) rats was based on body weight gain. OP rats gained 60% more body weight while eating only 10% more energy than OR rats. Single-pass perfusions were carried out for 2 h in the presence of glucose, insulin, and [U-14C]glucose. Insulin-stimulated glucose uptake (mumol.100 g-1.min-1) was 14.2 +/- 0.9 in LF, 11.1 +/- 0.8 in OR, and 6.2 +/- 0.6 in OP. Glucose oxidation (mumol.100 g-1.min-1) was 1.7 +/- 0.3 and 1.2 +/- 0.3 in LF and OR, respectively, but was 0.2 +/- 0.1 in OP. Net glycogen synthesis was significantly reduced in OP compared with OR and LF despite similar glycogen synthase I activity. Muscle triglyceride concentration was not significantly different in OR and OP rats. These results demonstrate significant defects in skeletal muscle glucose uptake and disposal in rats most susceptible to HF diet-induced obesity. Clearly, the heterogeneous response to a HF diet involves not only body weight gain but also skeletal muscle fuel metabolism.

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.

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.

More marked stimulation by lithium than insulin of the glycogenic pathway in rat skeletal muscle.

1997 ◽  
Vol 273 (3) ◽  
pp. E514 ◽  
Author(s):  
C Fürnsinn ◽  
C Noe ◽  
R Herdlicka ◽  
M Roden ◽  
P Nowotny ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Zucker Rats ◽  
Kinase Activation ◽  
Insulin Resistant ◽  
Primary Deficit ◽  
Rat Soleus Muscle ◽  
Glycogen Synthase Activity

Lithium's impact on glucose metabolism was compared with that of insulin in isolated rat soleus muscle. Lithium chloride (20 mmol/l) induced a 4.8-fold more pronounced increment over basal glycogen synthase activity than insulin (10 nmol/l) (nmol UDP-glucose into glycogen in synthase activity assay.g-1.min-1: lithium, +22.1 +/- 1.8 vs. insulin, +4.6 +/- 3.9; P < 0.01). In parallel, lithium was less efficient than insulin in stimulating glucose transport (counts per minute 2-deoxy-D-[3H]glucose.mg-1.h-1: lithium, +211 +/- 19 vs. insulin, +311 +/- 57; P < 0.05) and lactate release (mumol.g-1.h-1: lithium, +1.0 +/- 0.5 vs. insulin, +3.9 +/- 0.5; P < 0.01), and similar increments were induced in glycogen synthesis (mumol glucose into glycogen.g-1.h-1: lithium, +3.32 +/- 0.43 vs. insulin, +3.46 +/- 0.47; not significant). Full additivity of glycogenic effects and divergent dependency on phosphatidylinositol 3-kinase activation provided further evidence for different mechanisms of action. In muscle from insulin-resistant obese Zucker rats (fa/fa), failure of lithium to reverse deficits in glucose metabolism suggested a primary deficit in muscle glucose uptake rather than glycogen synthesis. Hence lithium distinctly stimulates glycogen synthase activity in skeletal muscle and may therefore be regarded as a candidate for the treatment of disorders associated with primary deficits in the glycogenic pathway.

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.

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