The Randle cycle revisited: a new head for an old hat

In 1963, Lancet published a paper by Randle et al. that proposed a “glucose-fatty acid cycle” to describe fuel flux between and fuel selection by tissues. The original biochemical mechanism explained the inhibition of glucose oxidation by fatty acids. Since then, the principle has been confirmed by many investigators. At the same time, many new mechanisms controlling the utilization of glucose and fatty acids have been discovered. Here, we review the known short- and long-term mechanisms involved in the control of glucose and fatty acid utilization at the cytoplasmic and mitochondrial level in mammalian muscle and liver under normal and pathophysiological conditions. They include allosteric control, reversible phosphorylation, and the expression of key enzymes. However, the complexity is formidable. We suggest that not all chapters of the Randle cycle have been written.

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Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle.

Journal of Clinical Investigation ◽

10.1172/jci117042 ◽

1994 ◽

Vol 93 (2) ◽

pp. 870-876 ◽

Cited By ~ 447

Author(s):

Y P Zhou ◽

V E Grill

Keyword(s):

Fatty Acids ◽

Insulin Secretion ◽

Fatty Acid ◽

Pancreatic Islets ◽

Acid Cycle ◽

Rat Pancreatic Islets ◽

Glucose Fatty Acid Cycle

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Lipids and infant formulas

Nutrition Research Reviews ◽

10.1079/nrr19980018 ◽

1998 ◽

Vol 11 (2) ◽

pp. 255-278 ◽

Cited By ~ 17

Author(s):

J. S. Forsyth

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Structured Lipids ◽

Infant Formulas ◽

Long Term Effects ◽

Term Infants ◽

Cholesterol Intake ◽

Short And Long Term ◽

Breast Fed

AbstractThe ultimate goal in the design of infant formula is to achieve the outcome seen in breast fed infants. This review of lipids in infant formulas for term infants begins by referring to the lipid composition of human milk, and relates that to differences in lipid digestion and metabolism which exist between breast fed and formula fed infants and which may significantly influence fatty acid bioavailability.Recommendations are made for the lipid content and fatty acid composition of term infant formulas (especially for lauric, linoleic, α-linolenic, long chain 20 and 22C n-3 and n-6 polyunsaturated fatty acids and thetransfatty acids).Further research is required to define more clearly the long term nutritional, growth and developmental effects of structured lipids in formulas for term infants. More information is required on the differential handling of LCPUFA and other fatty acids at the organ and cellular level. There is a need for large (multi-centre) randomized studies to determine the short and long term functional effects of LCPUFA supplementation. Further research and development is required to determine a commercial source of LCPUFA which is safe, effective and economic. Further information is required on the short and long term effects of cholesterol intake during infancy, and in particular its relationship to LCPUFA metabolism. Long term studies should be initiated to determine the relationship of infant diet (especially saturated fatty acid and cholesterol intake) to the development of cardiovascular disease.

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Effect of short- and long-term lipid enrichment on total lipids, lipid class and fatty acid composition in rotifers

Aquaculture International ◽

10.1007/bf00118530 ◽

1994 ◽

Vol 2 (1) ◽

pp. 19-32 ◽

Cited By ~ 59

Author(s):

Jose R. Rainuzzo ◽

Kjell I. Reitan ◽

Yngvar Olsen

Keyword(s):

Fatty Acid Composition ◽

Fatty Acid ◽

Lipid Class ◽

Acid Composition ◽

Total Lipids ◽

Short And Long Term ◽

Lipid Enrichment

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Short- and long-term repeatability of fatty acid composition of human plasma phospholipids and cholesterol esters. The Atherosclerosis Risk in Communities (ARIC) Study Investigators

American Journal of Clinical Nutrition ◽

10.1093/ajcn/62.3.572 ◽

1995 ◽

Vol 62 (3) ◽

pp. 572-578 ◽

Cited By ~ 60

Author(s):

J Ma ◽

A R Folsom ◽

J H Eckfeldt ◽

L Lewis ◽

L E Chambless

Keyword(s):

Fatty Acid Composition ◽

Fatty Acid ◽

Human Plasma ◽

Acid Composition ◽

Cholesterol Esters ◽

Atherosclerosis Risk In Communities ◽

Atherosclerosis Risk ◽

Short And Long Term ◽

Aric Study

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

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-13-0047 ◽

2013 ◽

Vol 2013 ◽

Cited By ~ 1

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.

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Atlantic salmon require long-chain n-3 fatty acids for optimal growth throughout the seawater period

Journal of Nutritional Science ◽

10.1017/jns.2016.10 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 26

Author(s):

Grethe Rosenlund ◽

Bente E. Torstensen ◽

Ingunn Stubhaug ◽

Nafiha Usman ◽

Nini H. Sissener

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Atlantic Salmon ◽

Fold Increase ◽

Optimal Growth ◽

Dietary Fatty Acids ◽

Nutritional Requirement ◽

Retention Efficiency ◽

Long Chain

AbstractThe nutritional requirement for n-3 long-chain PUFA in fast-growing Atlantic salmon (Salmo salar) during grow out in the sea is not well documented. Diets were formulated with levels of EPA (20 : 5n-3) and DHA (22 : 6n-3) ranging from 1·3 to 7·4 % of fatty acids (4–24 g/kg feed). Two long-term trials were conducted through the seawater phase, the first at 6 and 12°C, and the second at 12°C. In the first trial, growth at both temperatures was significantly lower in fish fed 1·4 % EPA+DHA of total fatty acids compared with the 5·2 % EPA+DHA group. In the second trial, growth was significantly lower in fish fed 1·3 and 2·7 % compared with 4·4 and 7·4 % EPA + DHA. Fatty acid composition in the fish reflected diet composition, but only after a 7-fold increase in body weight did the fatty acid profile of the fish stabilise according to dietary fatty acids (shown for EPA and DHA). The retention efficiency of DHA increased with decreasing dietary levels, and was 120–190 and 120–200 % in trials 1 and 2, respectively. The retention efficiency of EPA was lower (60–200 %), and values >100 % were only achieved at the lowest dietary levels in both trials. Temperature did not affect fatty acid retention efficiency. These results suggest that Atlantic salmon have a specific requirement for EPA + DHA >2·7 % of fatty acids for optimal long-term growth in seawater, and that short-term growth trials with less weight increase would not show these effects.

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Abstract 653: Muscle Ring Finger-1 (MuRF1) Expression Shifts Cardiomyocyte Substrate Utilization from Fatty Acids to Glucose

Circulation ◽

10.1161/circ.116.suppl_16.ii_120-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Monte S Willis ◽

Jon Schisler ◽

Holly McDonough ◽

Cam Patterson

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Glucose Oxidation ◽

Relative Proportion ◽

Substrate Utilization ◽

Acid Oxidation ◽

Protective Mechanism ◽

Dependent Manner ◽

Dose Dependent

Previous work has suggested that MuRF1, a cardiac-specific protein, regulates metabolism by its interactions with proteins that regulate ATP transport, glycolysis, and the electron transport chain. We recently identified that MuRF1 is cardioprotective in ischemia reperfusion injury. In the current study, we investigated the effects of MuRF1 expression on metabolic substrate utilization and found that MuRF1 shifts substrate utilization from fatty acids to glucose in a dose-dependent manner. Isolated neonatal ventricular cardiomyocytes were treated with an adenovirus expressing MuRF1 (Ad.MuRF1) or GFP (Ad.GFP) at a range of 0–25 MOI (Multiplicity Of Infection). 14C-Oleate or 14C-glucose were added to cells for 1 hour and 14C-CO2 release was determined using the CO2-trapping method. Trapped 14CO2 and acid soluble metabolites were used to calculate total fatty acid oxidation. Cardiomyocytes treated with 5–25 MOI Ad.MuRF1 demonstrated a dose dependent decrease in fatty acid oxidation of 10.5 +/− 2.3(5 MOI), 8.5 +/− 1.9 (10 MOI), 6.6 +/− 1.6 (15 MOI), and 5.1 +/− 1.3 (25 MOI) nmol oleate/mg protein/h. Compared with control cardiomyocytes treated with 5–25 MOI Ad.GFP (average of 5–25 MOI=13.5 +/− 0.7 nmol oleate/mg protein/h), this represents a 22.2%– 62.2% decrease in fatty acid oxidation. Inversely, glucose oxidation increased with increasing MuRF1 expression. Cardiomyocytes infected with 25 MOI Ad.MuRF1 oxidized 184% more glucose (28.9 +/− 4.6 nmol glucose/mg protein/h) compared to control cells treated with 25 MOI Ad.GFP (15.7 +/− 1.3 nmol glucose/mg protein/h). Increasing MuRF1 expression resulted in no net gain or loss of calculated ATP production (1699 +/− 157 vs. 1480 +/− 188 nmol ATP/mg protein/h). The co-utilization of glucose and fatty acids as substrates for the production of ATP allows the heart to adapt to both environmental stress and disease. Increasing the relative proportion of glucose oxidation in relationship to fatty acids is a known protective mechanism during cardiac stress, and may represent one mechanism by which MuRF1 is cardioprotective.

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Hepatic alpha 2 mu-globulin: a potential metabolic role in the rat proximal tubule

AJP Renal Physiology ◽

10.1152/ajprenal.1996.271.3.f527 ◽

1996 ◽

Vol 271 (3) ◽

pp. F527-F538 ◽

Cited By ~ 1

Author(s):

S. C. Borkan ◽

Y. H. Wang ◽

K. T. Lam ◽

P. Brecher ◽

J. H. Schwartz

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Proximal Tubule ◽

Glucose Oxidation ◽

Renal Cortex ◽

Female Rats ◽

Male Rats ◽

Normal Female ◽

Fatty Acid Binding ◽

Oxidation Rates

In the present study, we provide immunohistochemical and immunologic evidence to localize an abundant, 15.5-kDa protein to the soluble protein fraction of the proximal tubule. This 15.5-kDa protein binds fatty acids in vitro and has identity with amino acids 10-117 of alpha 2 mu-globulin (A2 fragment), a 19-kDa protein synthesized predominantly in the male liver. With reverse transcription-polymerase chain reaction, mRNA for A2 was detected in male liver but not in the male kidney. De novo accumulation of the 15.5-kDa protein was observed in the renal cortex of female rats given intravenous injections of purified 19-kDa protein (A2), suggesting intrarenal processing of the larger protein. The potential role of this protein in the proximal tubule, a site that utilizes fatty acids as an important metabolic substrate, was determined in isolated proximal tubule segments. Fatty acid and glucose oxidation rates were measured in three experimental models in which the 15.5-kDa protein was virtually absent: 1) uninephrectomized male rats treated with deoxycorticosterone acetate and salt, 2) male rats subjected to bilateral adrenalectomy, and 3) normal female rats. In the absence of the 15.5-kDa protein, fatty acid oxidation rates decreased by 30-55%, whereas glucose oxidation significantly increased in all three models. In female renal cortex, depletion of the 15.5-kDa protein was associated with a rise in heart fatty acid binding protein, an alternative intracellular transporter of fatty acids. These data support the hypothesis that a proteolytic cleavage product of hepatic alpha 2 mu-globulin may facilitate the oxidation of oleate, a hydrophobic ligand, in the proximal tubule.

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