Mediation of Glucoregulation at Rest and During Exercise by the Glucose-Fatty Acid Cycle: In Vivo and In Vitro Studies

1998 ◽  
Vol 23 (6) ◽  
pp. 534-557 ◽  
Author(s):  
Carol D. Rodgers ◽  
Mladen Vranic
Keyword(s):  
Fatty Acid ◽  
Glucose Uptake ◽  
Carbohydrate Metabolism ◽  
In Vitro Studies ◽  
Degree Of Saturation ◽  
Diaphragm Muscle ◽  
Acid Cycle ◽  
Glucose Fatty Acid Cycle ◽  
The Impact

Himsworth (1934) demonstrated that increased fat consumption leads to decreased glucose tolerance due to decreased insulin sensitivity. Randle and colleagues (1964) named this interplay between fat and carbohydrate metabolism the glucose-fatty acid cycle (GFAC) and proposed a series of feedback mechanisms by which elevated levels of free fatty acids (FFAs) impair glucose uptake and oxidation in rat heart and diaphragm muscle. Numerous investigators have extended these studies to clarify the existence of GFAC and provide insight into the mechanisms and conditions under which it occurs. This paper reviews the literature and highlights other indirect means by which FFAs affect carbohydrate metabolism. Numerous in vitro studies are reviewed, emphasizing the importance of FFA concentration, carbon length, and degree of saturation. This article addresses evidence that the interplay between fat and carbohydrate metabolism is not a function of FFA concentration but a result of the impact that FFA levels have on insulin. Key words: glucose-fatty acid cycle, Randle cycle, carbohydrate metabolism, lipid metabolism, glucose uptake, glucose oxidation, fat oxidation

Human kidney free fatty acid and glucose uptake: evidence for a renal glucose-fatty acid cycle.

1997 ◽  
Vol 273 (3) ◽  
pp. E650 ◽  
Author(s):  
C Meyer ◽  
V Nadkarni ◽  
M Stumvoll ◽  
J Gerich
Keyword(s):  
Fatty Acid ◽  
Glucose Uptake ◽  
Renal Vein ◽  
Human Kidney ◽  
Glucose Disposal ◽  
Acid Cycle ◽  
Glucose Fatty Acid Cycle ◽  
Palmitate Uptake ◽  
The Relationship ◽  
Important Site

To determine the relationship between free fatty acids (FFA) and glucose uptake by the human kidney, 12 postabsorptive normal volunteers underwent renal vein catheterization and were infused to isotopic steady state with [6-3H]glucose and [9,10-3H]palmitate. Arterial and renal vein palmitate specific activities were not significantly different (3,533 +/- 219 vs. 3,549 +/- 220 dpm/mumol, P = 0.64). Palmitate renal fractional extraction and uptake determined isotopically (7.2 +/- 1.1% and 9.1 +/- 1.4 mumol/min) were not significantly different from those calculated by net balance measurements (8.3 +/- 1.2% and 9.7 +/- 1.2 mumol/min, P > 0.07 and P > 0.7, respectively). Renal palmitate uptake accounted for 8.7 +/- 1.3% of its systemic turnover. Renal linoleate and oleate fractional extraction calculated by net balance measurements (8.0 +/- 0.9 and 7.7 +/- 1.2%, respectively) were not significantly different from each other and that of palmitate (all P > 0.7). Renal uptake of palmitate, linoleate (7.9 +/- 1.0 mumol/min), and oleate (10.9 +/- 2.0 mumol/min) were all directly proportional to their arterial concentrations (r = 0.70, 0.68, and 0.63, respectively, all P < 0.025). Renal glucose uptake (93 +/- 10 mumol/min) accounted for 12.6 +/- 1.5% of its systemic turnover and was inversely related to the sum of palmitate, linoleate, and oleate uptake (r = -0.74, P < 0.01). These data indicate that in postabsorptive humans: 1) the kidney is an important site of FFA and glucose disposal, 2) a renal glucose-fatty acid cycle may exist, and 3) there appears to be little or no release into the circulation of stored renal FFA.

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 Interleukin-6 Increases Insulin-Stimulated Glucose Disposal in Humans and Glucose Uptake and Fatty Acid Oxidation In Vitro via AMP-Activated Protein Kinase

Diabetes ◽  
2006 ◽  
Vol 55 (10) ◽  
pp. 2688-2697 ◽  
Author(s):  
A. L. Carey ◽  
G. R. Steinberg ◽  
S. L. Macaulay ◽  
W. G. Thomas ◽  
A. G. Holmes ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Protein Kinase ◽  
Glucose Uptake ◽  
Fatty Acid Oxidation ◽  
Interleukin 6 ◽  
Glucose Disposal ◽  
Acid Oxidation ◽  
Amp Activated Protein Kinase

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.

Abstract 344: FNDC5, a PGC1-a-Dependent Myokine, Increases Glucose Utilization and Fatty-Acid Oxidation by AMPK Signaling Pathway

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Ling Tao ◽  
Yi Liu ◽  
Chao Xin ◽  
Weidong Huang ◽  
Lijian Zhang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glucose Uptake ◽  
Fatty Acid Oxidation ◽  
Glucose Utilization ◽  
C2c12 Cells ◽  
Time Dependent ◽  
Acid Oxidation ◽  
Ampk Signaling

FNDC5 is a hormone secreted by myocytes that could reduce obesity and insulin resistance, However, the exact effect of FNDC5 on glucose and lipid metabolism remain poorly identified; More importantly, the signaling pathways that mediate the metabolic effects of FNDC5 is completely unknown. Here we showed that FNDC5 stimulates β-oxidation and glucose uptake in C2C12 cells in a dose- and time-dependent fashion in vitro (n=8, all P<0.01). In vivo study revealed that FNDC5 also enhanced glucose tolerance in diabetic mice and increased the glucose uptake evidenced by increased [18F] FDG accumulation in hearts by PET scan (n=6, all P<0.05). FNDC5 decreased the expression of gluconeogenesis related molecules (PEPCK and G6Pase) and increased the phosphorylation of ACC, a key modulator of fatty-acid oxidation, both in hepatocytes and C2C12 cells (n=3, all P<0.05). In parallel with its stimulation of β-oxidation and glucose uptake, FNDC5 increased the phosphorylation of AMPK both in hepatocytes and C2C12 cells in a dose- and time-dependent fashion in vitro and in vivo. More importantly, the β-oxidation and glucose uptake, the expression of PEPCK and G6Pase and the phosphorylation of ACC induced by FNDC5 were attenuated by AMPK inhibitor in hepatocytes and C2C12 cells (P<0.05). Most importantly, the FNDC5 induced glucose uptake and phosphorylation of ACC were attenuated in AMPK-DN mice (n=6, all P<0.05). The glucose-lowering effect of FNDC5 in diabetic mice was also attenuated by AMPK inhibitor. Our data presents the direct evidence that FNDC5 stimulates glucose utilization and fatty-acid oxidation by AMPK signaling pathway, suggesting that FNDC5 be a novel pharmacological approach for type 2 diabetes.

Insulin sensitivity of rates of glycolysis and glycogen synthesis in soleus, stripped soleus, epitrochlearis, and hemi-diaphragm muscles isolated from sedentary rats

1983 ◽  
Vol 3 (7) ◽  
pp. 675-679 ◽  
Author(s):  
R. A. J. Challiss ◽  
J. Espinal ◽  
E. A. Newsholme
Keyword(s):  
Fatty Acid ◽  
Glucose Utilization ◽  
Glycogen Synthesis ◽  
Maximal Inhibition ◽  
Maximal Stimulation ◽  
Glucose Fatty Acid Cycle ◽  
Isolated Adipocytes ◽  
Stimulation Of

The effect of insulin concentrations on the rates of glycolysis and glycogen synthesis in four different in vitro rat muscle preparations (intact soleus, stripped soleus, epitrochlearis, and hemi-diaphragm) were investigated: the concentrations of insulin that produced half-maximal stimulation of the rates of these two processes in the four muscle preparations were similar – about 100 μunits/ml. This is at least 10-fold greater than the concentration that produced half-maximal inhibition of lipolysis in isolated adipocytes. Since 100 μunits/ml insulin is outside the normal physiological range in the rat, it is suggested that, in vivo, insulin influences glucose utilization in muscle mainly indirectly, via changes in the plasma fatty acid levels and the ‘glucose/fatty acid cycle’. Consequently the view that insulin stimulates glucose utilization in muscle mainly by a direct effect on membrane transport must be treated with caution.

THE EFFECT OF GROWTH HORMONE AND OF CORTISOL ON THE RESPONSE OF ISOLATED RAT DIAPHRAGM TO THE STIMULATING EFFECT OF INSULIN ON GLUCOSE UPTAKE AND ON INCORPORATION OF AMINO ACIDS INTO PROTEIN

1959 ◽  
Vol 18 (4) ◽  
pp. 395-408 ◽  
Author(s):  
K. L. MANCHESTER ◽  
P. J. RANDLE ◽  
F. G. YOUNG
Keyword(s):  
Amino Acids ◽  
Growth Hormone ◽  
Protein Synthesis ◽  
Glucose Uptake ◽  
Carbohydrate Metabolism ◽  
Rat Diaphragm ◽  
Pituitary Growth Hormone ◽  
Isolated Rat ◽  
Stimulation Of

SUMMARY 1. The effect of hypophysectomy, or of adrenalectomy, and injection of pituitary growth hormone (GH) or of cortisol, on the uptake of glucose and the incorporation of glycine into protein by isolated rat diaphragm, and the effect of the addition of insulin in vitro on these processes, has been studied. 2. Both hypophysectomy and adrenalectomy raised the uptake of glucose by isolated diaphragm, while treatment of the intact or of the hypophysectomized rat with GH, or of the intact or of the adrenalectomized rat with cortisol, depressed it. Although hypophysectomy and adrenalectomy did not influence the additional glucose uptake induced by 200 mu./ml. of insulin in vitro, both these operations enhanced the effect of 0·1–1·0 mu./ml. of insulin on glucose uptake by diaphragm in vitro. Treatment of the rat with GH or cortisol diminished the rise in glucose uptake of diaphragm induced by 0·1–1·0 mu./ml. insulin. 3. Hypophysectomy depressed, and administration of GH to the intact or hypophysectomized rat raised, the incorporation of glycine into protein of the isolated diaphragm, but neither of these operations altered the magnitude of the stimulation of incorporation induced by 1·0 mu./ml. insulin. 4. Adrenalectomy raised, and administration of cortisol to the intact or adrenalectomized rat depressed, the incorporation of glycine into protein of the isolated diaphragm; adrenalectomy enhanced, the injection of cortisol diminished, the effect of 1·0 mu./ml. insulin on these processes. 5. The possibility that GH directs insulin towards the stimulation of protein synthesis, in part by restraining the action of insulin on carbohydrate metabolism, is discussed.

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