Search
  • info7537153

The Randle Cycle: An Evolutionary Perspective

The 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).


It shows substrate availability in the plasma (blood) either as glucose or long-chain-fatty acids. A dominant hormone involved in regulating glucose homeostasis, is insulin. Carbohydrate stimulates insulin response. The insulin response is also the most dominant following carbohydrate ingestion, by comparison to the three macronutrients: proteins, fats, and carbohydrates. Of these three, carbohydrates are non-essential. Elevated insulin inhibits the release of long chain fatty acids into the plasma, inhibiting oxidation.

Indeed, post-prandial hypoglycaemia, in the time after a meal, is most pronounced following ingestion of carbohydrate, leading to a sensation of hunger and stress hormones, due the corresponding insulin response, often stimulating an intake of excess calories, rather than returning to and remaining in the post-prandial state (Chandler-Laney, 2014, Wyatt et al., 2021). Hyperinsulinism in response to ingested nutrients is wide-ranging and individual; it occurs most commonly with refined sugars, grains, and starches (Brand-Miller et al., 2009, Coulston et al., 1983, Galgani et al., 2006, Hertzler and Kim, 2003, Mayer, 1953, Nilsson et al., 2008, Reynolds et al., 2009, Wolever et al., 2006).


The capacity across a population to oxidise carbohydrate in the muscle tissue is wide-ranging, individual, and changes over time, depending on whether the cell is 'insulin resistant', and overall sensitivity to insulin, a signal a bit like a knock at the door.


Insulin Resistance Syndrome

In insulin resistance, the capacity of glucose to be oxidised in the muscle tissue is impaired, leading to a downstream effect of reduced energy production and regulation within the tissue and cell; 'the door', being the cell, is ignoring the signal of insulin, 'the knock'. This can lead to sensations of tiredness and fatigue after mealtimes, particularly after an energetically mixed or 'balanced' meals, containing both carbohydrate and fat together.


It has been suggested that the prevalence of insulin resistance in the general population is driven in part by our evolution (Brand-Miller et al., 2011, Ségurel et al., 2013) due to an extended period of low carbohydrate conditions, in our evolution where there was a near-exclusive reliance on animal products for approximately two million years (Ben-Dor et al., 2021).


Pathological insulin resistance differs from peripheral resistance, and develops in some individuals because of excess carbohydrate rather than total energy intake (Hussein et al., 2009) but the consumption of industrially processed and refined ‘hyper-palatable food’ (Monteiro et al., 2019) containing added sugars, refined flours and industrialised fats compounds the issue of insulin resistance, substantially increasing risk of all-cause mortality (Rauber et al., 2018, Marti, 2019) and certain types of cancer (Fiolet et al., 2018).


Both low carbohydrate intake and high energy expenditure improves insulin sensitivity (Volek et al., 2016) and historically, treatments to restrict CHO on a ‘protein diet’ for Obesity and Type 2 Diabetes were common and with good evidence base, hence the reason for their frequent reappearance in the literature and public view (Bistrian et al., 1977, Yang 1980, Feinman et al., 2015) an approach consistent with our evolution in a low CHO environment (Ben-Dor et al., 2021).


Lipid oxidation

Fritzen et al., 2020 have recently released a paper 'Tuning fatty acid oxidation in skeletal muscle with dietary fat and exercise' and state: both the consumption of a diet rich in fatty acids and exercise training result in similar adaptations in several skeletal muscle proteins. These adaptations are involved in fatty acid uptake and activation within the myocyte, the mitochondrial import of fatty acids and further metabolism of fatty acids by β-oxidation. Fatty acid availability is repeatedly increased postprandially during the day, particularly during high dietary fat intake and also increases during, and after, aerobic exercise.


Lipid and Glucose Oxidative Pathways

What this means is that the body will adjust, often in as little as 3-4 days, to increase the capability of the muscle tissue for lipid oxidation, and that a low-carbohydrate, high-fat diet is complimentary to energetic regulation in the tissue, cell, and aerobic activity and exercise.


Further: both the consumption of a diet rich in fatty acids and exercise training result in similar adaptations in several skeletal muscle proteins. These adaptations are involved in fatty acid uptake and activation within the myocyte, the mitochondrial import of fatty acids and further metabolism of fatty acids by β-oxidation. Fatty acid availability is repeatedly increased postprandially during the day, particularly during high dietary fat intake and also increases during, and after, aerobic exercise (Fritzen et al., 2020).


Summarised:

  • Both high fat intake and aerobic exercise training increase the abundance and activity of several lipid metabolic proteins in skeletal muscle related to fatty acid uptake, handling and mitochondrial import.

  • Mitochondrial biogenesis is induced primarily by aerobic exercise training and not by high fat intake in humans, probably due to increased ATP turnover occurring only during exercise.

  • Fatty acid availability seems to be a key signal for adaptations in muscle proteins involved in lipid metabolism as fatty acids act as ligands for peroxisome proliferator-activated receptors and through β-oxidation-driven sirtuin 1 signalling.

  • Obesity is characterized by impairments in fatty acid oxidation capacity, but aerobic exercise training is a potent tool to restore such impairments by induction of lipid metabolic proteins in muscle.

  • An efficient capacity to handle and oxidize fatty acids, and the ability to adapt fatty acid utilization to fatty acid availability, seem to be of great importance for both lipid and glucose homeostasis and insulin action.

Evolutionary Perspectives:

Prior to the introduction of agriculture, humans were near exclusive carnivores in low carbohydrate conditions for two million years during the Pleistocene Epoch (Ben-Dor et al., 2021) and the inclusion of nutrient-dense animal products provided the energy and nutrition necessary for extensive brain development and growth; development which has since been declining or showing no subsequent increase since the Holocene (Henneberg, 1988).

Easy to dismiss as a fad, simplistic. But, true. Difficult to replicate..


Our genome has not changed significantly since modern humans first emerged from East Africa between 50 – 100ka and we are best adapted for foods consumed then (Eaton, 2007). This is evidenced by a stomach that has adjusted to lower pH levels than obligate carnivores, such as cats (Widdowson, 1985). It is suggested that the strong stomach acidity enabled our survival as a scavenger rather than a forager to increase the tolerance for pathogen exposure (Ben-Dor et al., 2021).


Diets lower in animal products, and higher in plant and carbohydrate content contain anti-nutrients limiting full use by the brain and body for energy (Hervik & Svihus, 2019; Schnorr et al., 2015). Long-term exposure to higher carbohydrate conditions can lead to chronic high plasma fasting and post-prandial glucose levels, promote atrophy of the hippocampus and amygdala, even with blood glucose (BG) values within the normal range and in the absence of diabetes (Cherbuin, 2012).


It should not be surprising however, that some people may be better suited towards vegetarianism and plant-based diets and experience negligeable developmental issues of the brain (Crozier et al., 2019) and that some people may retain insulin sensitivity with dietary CHO and be better adapted toward starch-based diets, given the exposure to agricultural practice after the Pleistocene Epoch and into the Holocene (Ben-Dor et al., 2021). This exposure allows a hypothesis for the subsequent development and appearance of the AMY1 gene for starch digestion, although this is not conclusive (Fernández and Wiley, 2017).


It is clear that a good proportion of the population has higher tolerance to carbohydrate, and experiences no symptoms of insulin resistance across the lifespan. What is applicable to some, however, is not applicable to all, all of the time.


So What?

Research indicates we were scavenger apex predators for a period of nearly two million years, and adaptations to this period remains embedded in modern humans' biology, in the form of genetics, metabolism, and morphology.


Take Home:

The capacity across a population to oxidise carbohydrate in the muscle tissue is wide-ranging, individual, and changes over time. Insulin resistance syndrome manifests itself as glucose intolerance. A low-carbohydrate, higher fat diet is complimentary both to the understanding of energy regulation, evolution and the ability to improve aerobic function.


References:

Ben-Dor, M, Sirtoli, R, Barkai, R. The evolution of the human trophic level during the Pleistocene. Yearbook Phys Anthropol. 2021; 1– 30. https://doi.org/10.1002/ajpa.24247


Bistrian, D. R., Winterer, J., Blackburn, G. L., Young, V., & Sherman, M. (1977). Effect of a protein-sparing diet and brief fast on nitrogen metabolism in mildly obese subjects. The Journal of laboratory and clinical medicine, 89(5), 1030–1035.


Brand-Miller, J. C., Stockmann, K., Atkinson, F., Petocz, P., & Denyer, G. (2009). Glycemic index, postprandial glycemia, and the shape of the curve in healthy subjects: analysis of a database of more than 1,000 foods. The American journal of clinical nutrition, 89(1), 97–105. https://doi.org/10.3945/ajcn.2008.26354


Brand-Miller, J. C., Griffin, H. J., & Colagiuri, S. (2012). The carnivore connection hypothesis: revisited. Journal of obesity, 2012, 258624. https://doi.org/10.1155/2012/258624.


Chandler-Laney, P. C., Morrison, S. A., Goree, L. L., Ellis, A. C., Casazza, K., Desmond, R., & Gower, B. A. (2014). Return of hunger following a relatively high carbohydrate breakfast is associated with earlier recorded glucose peak and nadir. Appetite, 80, 236–241. https://doi.org/10.1016/j.appet.2014.04.031


Coulston, A. M., Liu, G. C., & Reaven, G. M. (1983). Plasma glucose, insulin and lipid responses to high-carbohydrate low-fat diets in normal humans. Metabolism: clinical and experimental, 32(1), 52–56. https://doi.org/10.1016/0026-0495(83)90155-5


FioletT, SrourB, SellemL, Kesse-GuyotE, AllèsB, MéjeanC et al. Consumption of ultra-processed foods and cancer risk: results from NutriNet-Santé prospective cohortBMJ 2018; 360 :k322 doi:10.1136/bmj.k322

Fritzen, A.M., Lundsgaard, AM. & Kiens, B. Tuning fatty acid oxidation in skeletal muscle with dietary fat and exercise. Nat Rev Endocrinol16, 683–696 (2020). https://doi.org/10.1038/s41574-020-0405-1.


Galgani, J., Aguirre, C., & Díaz, E. (2006). Acute effect of meal glycemic index and glycemic load on blood glucose and insulin responses in humans. Nutrition journal, 5, 22. https://doi.org/10.1186/1475-2891-5-22


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.


Hennenberg, M. (1988). Decrease of Human Skull Size in the Holocene. Human Biology,60(3), 395-405. Retrieved July 16, 2021, from http://www.jstor.org/stable/41464021


Hertzler, S. R., & Kim, Y. (2003). Glycemic and insulinemic responses to energy bars of differing macronutrient composition in healthy adults. Medical science monitor : international medical journal of experimental and clinical research, 9(2), CR84–CR90.


Mayer, J., Bates, M. W., and Van Itallie, T. B. (1952). Blood sugar and food intake in rats with lesions of anterior hypothalamus. Metabolism. 1:340-348.


Nilsson, A. C., Ostman, E. M., Holst, J. J., & Björck, I. M. (2008). Including indigestible carbohydrates in the evening meal of healthy subjects improves glucose tolerance, lowers inflammatory markers, and increases satiety after a subsequent standardized breakfast. The Journal of nutrition, 138(4), 732–739. https://doi.org/10.1093/jn/138.4.732


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.


Rauber F, da Costa Louzada ML, Steele EM, Millett C, Monteiro CA, Levy RB. Ultra-Processed Food Consumption and Chronic Non-Communicable Diseases-Related Dietary Nutrient Profile in the UK. (2018) Nutrients. 10(5):587.


Reynolds, A., Mann, J., Cummings, J., Winter, N., Mete, E., & Te Morenga, L. (2019). Carbohydrate quality and human health: a series of systematic reviews and meta-analyses. Lancet (London, England), 393(10170), 434–445. https://doi.org/10.1016/S0140-6736(18)31809-9.


Ségurel, L., Austerlitz, F., Toupance, B. et al. Positive selection of protective variants for type 2 diabetes from the Neolithic onward: a case study in Central Asia. Eur J Hum Genet21, 1146–1151 (2013). https://doi.org/10.1038/ejhg.2012.295


Wolever, T. M., Yang, M., Zeng, X. Y., Atkinson, F., & Brand-Miller, J. C. (2006). Food glycemic index, as given in glycemic index tables, is a significant determinant of glycemic responses elicited by composite breakfast meals. The American journal of clinical nutrition, 83(6), 1306–1312. https://doi.org/10.1093/ajcn/83.6.1306


(Widdowson, 1985)


Wyatt P, Berry S, Finlayson G, O’Driscoll R, Hadjigeorgiou G, Drew D, Khatib H, L, Linenberg I, Chan A, Spector T, Pranks P, Wolf J, Blundell J, Valdes A (2021) Nature Metabolism doi.org/10.1038/s42255-021-00383-x


Yang SP, Martin LJ, Schneider G. Weight reduction utilizing a protein-sparing modified fast. (1980). J Am Diet Assoc. Apr;76(4):343-6.

45 views0 comments

Recent Posts

See All