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The Randle Cycle: case closed on refined carbohydrate

An average person has well in excess of 100,000 kcals of stored fatty acids (Cahill, 1970) allowing survival for weeks, months or years. Oxidation of long-chain-fatty acids, is the normal and resting state of metabolism. Glucose can be oxidised for energy, at the expense of stored adipose tissue. The cell in its resting state needs no further energy, due to a balance between molecules to be degraded and molecules available from adipose tissue.


ATP: Units of Energy

Glucose can provide around 36 ATP, protein can be degraded to amino acids to provide around 40 ATP, whereas fat provides well over 100 ATP (Berg, 2019). Fat is the energy source. By-products of fat metabolism, ketones, are the preferred fuel for the brain, and are preserved for the brain and nervous system, crossing the blood-brain barrier as a highly efficient fuel for neurons (Cunnane 2020).They provide a fuel source 28% more efficient per unit oxygen than glucose (Cox et al., 2016) which activate natural anti-inflammatory and longevity pathways for life extension (Veech et al., 2017) and have a glucose-lowering effect in the blood.


The Randle Cycle

An elegant and continually developed mechanism of regulating energy status between the muscle, plasma and adipose tissues was originally proposed in 1963 by Randle et al., demonstrating the control between glucose and fatty acids in their oxidation in organs and cells (Randle et al., 1963, Hue and Taegtmeyer, 2009).

A homeostatic mechanism to maintain energy regulation between glucose, and long-chain-fatty acids for oxidation by the organism. (Hue and Taegtmeyer, 2009).


Errors of Carbohydrate Metabolism:

Errors of carbohydrate metabolism include, glucose being stored as glycogen. If glycogen stores are full, glucose is converted to triglyceride and stored in adipose tissue. The long-term effect of glucose, which is in part mediated by insulin, is involved mainly in the control of lipogenesis. It focuses on carbohydrate storage into lipid rather than on glucose oxidation itself. In Obesity, excessive nutrient intake overwhelms the Krebs Cycle and is characterised by a glucose-dominant metabolism and loss of metabolic flexibility (Feinman et al., 2015).

Fat reduces carbohydrate oxidation. 'Carbohydrate Sparing' which is our normal and resting metabolism. (Hue and Taegtmeyer, 2009).

Carbohydrate blocks fat oxidation, through elevation of Malonyl-CoA. (Hue and Taegtmeyer, 2009).


Obesity and Carbohydrate Metabolism:

While Obesity is highly heterogenous, insulin resistance, hyperinsulinemia, characterised by frequent hunger, impaired glucose tolerance and an impaired or inability to oxidise adipose tissue for energy are common symptoms (Hyde et al., 2019). The Krebs cycle can no longer find a balance between the molecules to be degraded and the number of molecules available (Alabduladhem and Bordoni, 2021).


Malonyl-CoA: The key to fat oxidation

Malonyl-CoA blocks fat oxidation. Chronic and sustained elevations in Malonyl-CoA leads to an increase in LCFA-CoA outside of the cell, as LCFA-CoA can no longer enter the cell to be oxidised for energy. The cell can 'switch' to predominantly oxidising glucose at the expense of lipid sources, which then requires constant replenishment of glucose to provide ATP at a lower rate.


Insulin Resistance

Sustained or chronic increases in the concentrations of Malonyl-CoA and cytosolic LCFA-CoA, drives insulin resistance, manifesting itself as carbohydrate intolerance, leading to accelerated fat accumulation.


So what?

Carbohydrate tolerance, or the ability to oxidise glucose for energy, is individual and changes over time. An overconsumption of carbohydrate can switch the cell from being metabolically flexible, to being glucose-dominant, an abnormal state.


Take home:

Take the test: hand-held respirometers are available to monitor fuel use in the body, whether you are predominantly oxidising either fat or carbohydrate:

Lumen: https://www.lumen.com/en-us/home.html.


Carbohydrate can suppress normal fat oxidation of a cell and can switch metabolism to predominantly oxidising glucose.


Carbohydrate intake should be approached with caution.


References:

Alabduladhem T.O., Bordoni B. (2021). Physiology, Krebs Cycle. Feb 7. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing.


Berg, J.M., Tymoczko, J.L., Gatto, G. Stryer. (2019). Biochemistry, New York, NY: W H Freeman and Co.


Cahill GF Jr. (1970). Starvation in man. N Engl J Med. 19;282(12).


Cox, P.J., Kirk, T., Ashmore, T., Willerton, K., Evans, R., Smith, A., Murray, Andrew J., Stubbs, B., West, J., McLure, Stewart W., et al. (2016). Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metabolism 24, 1-13.


Cunnane, S.C., Trushina, E., Morland, C. et al. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing. (2020). Nat Rev Drug Discov 19, 609–633.


Feinman, R.D. Pogozelski, W.K., Astrup, A., Bernstein, R.K., Fine, E.J., Westman, E.C., Accurso, Frassetto, L., Gower, B.A., McFarlane, S.I., Nielsen, J.V., Krarup, T., Saslow, L., Roth, K.S., Vernon, M.C., Volek, J.S., Wilshire, G.B. Dahlqvist, A., Sundberg, R., Childers, A., Morrison, K., Manninen, A.H., Dashti, H.M., Wood, R.J., Wortman, J., Worm, N. (2015). Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition. 31(1):1-13.


Hue, L., & Taegtmeyer, H. (2009). The Randle cycle revisited: a new head for an old hat. American journal of physiology. Endocrinology and metabolism, 297(3), E578–E591.


Hyde, P. N., Sapper, T. N., Crabtree, C. D., LaFountain, R. A., Bowling, M. L., Buga, A., Fell, B., McSwiney, F. T., Dickerson, R. M., Miller, V. J., Scandling, D., Simonetti, O. P., Phinney, S. D., Kraemer, W. J., King, S. A., Krauss, R. M., & Volek, J. S. (2019). Dietary carbohydrate restriction improves metabolic syndrome independent of weight loss. JCI insight, 4(12), e128308.


Murray, A.J., Knight, N.S., Cole, M.A., Cochlin, L.E., Carter, E., Tchabanenko, K., Pichulik, T., Gulston, M.K., Atherton, H.J., Schroeder, M.A., et al. (2016). Novel ketone diet enhances physical and cognitive performance. FASEB J.


Randle PJ, Garland PB, Hales CN, Newsholme EA. (1963). The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet1: 785–789.


Veech, R.L., Bradshaw, P.C., Clarke, K., Curtis, W., Pawlosky, R., King, M.T. (2017). Ketone bodies mimic the life span extending properties of caloric restriction. Life; 69(5):305-314.



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