The Glucose Fatty-Acid Cycle Its Role in Insulin Sensitivity and the Metabolic Disturbances of Diabetes Mellitus

Randle, P. J.; Garland, P. B.; Hales, C. N.; Newsholme, E. A.

doi:10.1016/s0140-6736(63)91500-9

Cited by 4,638 publications

(2,713 citation statements)

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“…It probably originates from the time of classic calorimetric studies that were being conducted by Benedict nearly 100 y ago, 16,17 and gained credence in the 1930s following the demonstration by Krebs 18 of competition between amino acids and glucose in kidney slices, followed by that of Waters et al 19 of competition between 3-hydroxybutyrate and glucose in dog heart-lung preparations. But it was not until the early 1960s, following the demonstration that lipid fuels inhibit glucose oxidation in rat diaphragm and in perfused heart 20,21 that Randle et al 22,23 proposed a 'glucose-fatty acid cycle' as an important set of mechanism by which carbohydrate and fat metabolism interact. The essential components of this cycle have recently been reiterated by Randle 24 as follows:…”

Section: Fatty Acids Amino Acids Glucosementioning

confidence: 99%

“…Glucose-fatty acid interactions in skeletal muscle: from reciprocality to dependency During the past 40 y, since the glucose-fatty acid cycle was first proposed, 22 several major facets of the complex interrelationship between glucose and lipid metabolism have been unraveled in skeletal muscle. As discussed below, they constitute various sets of mechanisms that underscore not only reciprocal relationships between glucose and lipid metabolism but also relationships that show dependency between these two major oxidative fuel substrates for mammalian metabolism.…”

Section: Fatty Acids Amino Acids Glucosementioning

confidence: 99%

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Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

et al. 2004

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Life is a combustion, but how the major fuel substrates that sustain human life compete and interact with each other for combustion has been at the epicenter of research into the pathogenesis of insulin resistance ever since Randle proposed a 'glucose-fatty acid cycle' in 1963. Since then, several features of a mutual interaction that is characterized by both reciprocality and dependency between glucose and lipid metabolism have been unravelled, namely:(i) the inhibitory effects of elevated concentrations of fatty acids on glucose oxidation (via inactivation of mitochondrial pyruvate dehydrogenase or via desensitization of insulin-mediated glucose transport), (ii) the inhibitory effects of elevated concentrations of glucose on fatty acid oxidation (via malonyl-CoA regulation of fatty acid entry into the mitochondria), and more recently (iii) the stimulatory effects of elevated concentrations of glucose on de novo lipogenesis, that is, synthesis of lipids from glucose (via SREBP1c regulation of glycolytic and lipogenic enzymes).This paper first revisits the physiological significance of these mutual interactions between glucose and lipids in skeletal muscle pertaining to both blood glucose and intramyocellular lipid homeostasis. It then concentrates upon emerging evidence, from calorimetric studies investigating the direct effect of leptin on thermogenesis in intact skeletal muscle, of yet another feature of the mutual interaction between glucose and lipid oxidation: that of substrate cycling between de novo lipogenesis and lipid oxidation. It is proposed that this energy-dissipating substrate cycling that links glucose and lipid metabolism to thermogenesis could function as a 'fine-tuning' mechanism that regulates intramyocellular lipid homeostasis, and hence contributes to the protection of skeletal muscle against lipotoxicity.

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Section: Fatty Acids Amino Acids Glucosementioning

confidence: 99%

Section: Fatty Acids Amino Acids Glucosementioning

confidence: 99%

Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

et al. 2004

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“…The Randle (glucose-fatty acid) cycle has often been used to explain the mechanism behind skeletal muscle insulin resistance induced by fatty acid (FA) [8]. More recent insights from various lipid infusion studies have led to an alternative mechanism [9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of adipose tissue lipolysis increases intramuscular lipid use in type 2 diabetic patients

et al. 2005

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Aims/hypothesis: In the present study, we investigated the consequences of adipose tissue lipolytic inhibition on skeletal muscle substrate use in type 2 diabetic patients. Materials and methods: We studied ten type 2 diabetic patients under the following conditions:(1) at rest; (2) during 60 min of cycling exercise at 50% of maximal workload capacity and subsequent recovery. Studies were done under normal, fasting conditions (control trial: CON) and following administration of a nicotinic acid analogue (low plasma non-esterified fatty acid trial: LFA). Continuous [U-13 C]palmitate and [6,6 -2 H 2 ]glucose infusions were applied to quantify plasma NEFA and glucose oxidation rates, and to estimate intramuscular triacylglycerol (IMTG) and glycogen use. Muscle biopsies were collected before and after exercise to determine net changes in lipid and glycogen content specific to muscle fibre type. Results: Following administration of the nicotinic acid analogue (Acipimox), the plasma NEFA rate of appearance was effectively reduced, resulting in lower NEFA concentrations in the LFA trial (p<0.001). Plasma NEFA oxidation rates were substantially reduced at rest, during exercise and subsequent recovery in the LFA trial.The lower plasma NEFA oxidation rates were compensated by an increase in IMTG and endogenous carbohydrate use (p<0.05). Plasma glucose disposal rates did not differ between trials. In accordance with the tracer data, a greater net decline in type I muscle fibre lipid content was observed following exercise in the LFA trial (p<0.05). Conclusions/interpretation: This study shows that plasma NEFA availability regulates IMTG use, and that adipose tissue lipolytic inhibition, in combination with exercise, could be an effective means of augmenting intramuscular lipid and glycogen use in type 2 diabetic patients in an overnight fasted state.

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“…In 1963, Randle and colleagues were among the first to investigate the pathophysiology of IR 7 , suggesting the elevation of free fatty acids (FFA) in the splenic circulation as the cornerstone of this disorder. They proposed the glucose fatty acid cycle, called the Randle cycle.…”

Section: Introductionmentioning

confidence: 99%

Optimal cutoff for the evaluation of insulin resistance through triglyceride-glucose index: A cross-sectional study in a Venezuelan population

et al. 2017

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Background: Insulin resistance (IR) evaluation is a fundamental goal in clinical and epidemiological research. However, the most widely used methods are difficult to apply to populations with low incomes. The triglyceride-glucose index (TGI) emerges as an alternative to use in daily clinical practice. Therefore the objective of this study was to determine an optimal cutoff point for the TGI in an adult population from Maracaibo, Venezuela. Methods: This is a sub-study of Maracaibo City Metabolic Syndrome Prevalence Study, a descriptive, cross-sectional study with random and multi-stage sampling. For this analysis, 2004 individuals of both genders ≥18 years old with basal insulin determination and triglycerides < 500 mg/dl were evaluated.. A reference population was selected according to clinical and metabolic criteria to plot ROC Curves specific for gender and age groups to determine the optimal cutoff point according to sensitivity and specificity.The TGI was calculated according to the equation: ln [Fasting triglyceride (mg / dl) x Fasting glucose (mg / dl)] / 2. Results: The TGI in the general population was 4.6±0.3 (male: 4.66±0.34 vs. female: 4.56±0.33, p=8.93x10 -10). The optimal cutoff point was 4.49, with a sensitivity of 82.6% and specificity of 82.1% (AUC=0.889, 95% CI: 0.854-0.924). There were no significant differences in the predictive capacity of the index when evaluated according to gender and age groups. Those individuals with TGI≥4.5 had higher HOMA2-IR averages than those with TGI <4.5 (2.48 vs 1.74, respectively, p<0.001). Conclusions: The TGI is a measure of interest to identify IR in the general population. We propose a single cutoff point of 4.5 to classify individuals with IR. Future studies should evaluate the predictive capacity of this index to determine atypical metabolic phenotypes, type 2 diabetes mellitus and even cardiovascular risk in our population.

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The Glucose Fatty-Acid Cycle Its Role in Insulin Sensitivity and the Metabolic Disturbances of Diabetes Mellitus

Cited by 4,638 publications

References 32 publications

Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

Inhibition of adipose tissue lipolysis increases intramuscular lipid use in type 2 diabetic patients

Optimal cutoff for the evaluation of insulin resistance through triglyceride-glucose index: A cross-sectional study in a Venezuelan population

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