Intermittent Fasting: Effects on Diabetes and Cancer

"Caloric restriction, undernutrition without malnutrition is the only known approach to consistently prolong survival in animal models"

This is a space that attracts people that are distrustful of authority. Some of the pros are free speech, some of the cons are lack of reliable review. One of the subjects that attract people that like alternatives views are diets. The one I will review briefly today is intermittent fasting.

My professions motto is "Do no harm" so...

First the harms:

There's a lack of quality studies to assess the harms of Intermittent Fasting. However, there are some theoretical concerns for people with a regular weight of behavioral nature, like binge eating. In mice models, there seems to be a deleterious effect on fertility but on Humans, there has not been shown any alterations in the hypothalamic-pituitary-gonadal axis.¹

Introduction

Our bodies have mechanisms to deal with excess and scarcity of energetic resources. At the cellular level, roughly speaking, we use either routes that require oxygen by mitochondrial activity or anaerobic routes that don't.
This is of extreme importance because in here a source of longevity we can control.

In modern life, carbohydrates are readily available but our ancestors evolved in carbohydrate scarce scenarios. As a species we had to adapt to swings of availability thus we found a way to store excess in our liver in the form of fat (triglycerides) later in other tissues in our body. This system creates insulin resistance, being insulin the signal to store more and more fat.

If you think about it, is a concept easy to grasp. Insulin resistance is a way for our bodies to protect itself from excessive carbohydrates in the form of deposited fat in organs. This by resisting the high levels of insulin during this process. If the compensatory mechanism is overwhelmed, this leads to Hepatic scarring (the fat changes the permanently the structure of the liver), later pancreatic scarring (which destroy the cells that produce insulin), diabetes and all the complications that come with it like heart disease, kidney failure and even some types of cancer.

Depending on how advanced is the process the consequences could be reversible (particularly in non-insulin dependent diabetes). Here's where fasting comes into play.

Fasting.

Fasting as a therapy is highly controversial. Continuous caloric restriction (CCR) by hypocaloric diets is the recommended therapy by most doctors as of today.

In the early stages, before the scarring due to excessive fat deposits occurs. Mobilization of fat is a lot easier to achieve
. You can either increase the use of it or decrease the intake.

• Decrease intake by changing the energy sources, frequency and quantity of intake.

• Increase usage by high metabolic activity states like exercise, heat challenges or disease, as they force the body to alter the usage of the energy sources as it acquires them and of the ones it has stored.

Out of the many approaches, one of them is smaller average intakes. By reducing the portions of food and thus the caloric intake the body lowers the metabolism to maintain a resting metabolic rate. The change of RMR can be seen in the long term, but in the short term is exhausting and has relatively high non-compliance.²

What happens if instead of smaller portions you stop eating.

This is controversial and intuition tells us cramming your diet doesn't sound like a good idea. Fortunately, we can prescind of intuition in favor of evidence.³

When you fast for periods 10-16 hours your body depletes its carbohydrate liver storage and starts using fat reserves. Unlike with averaging low CCR, this is a desperate measure. It doesn't slow down your metabolism, in fact, it increases it slightly. It gives your brain and heart a boost in order for you to find that food before you die.¹

There's an interesting unintended consequence. The microbiome is extremely sensitive to abrupt changes. The bacteria in the gut increase slightly their fermentation, this comes at the expense of glycan rich mucins in the intestinal epithelium.⁴ There's a complex signaling bacteria-epithelium being mediated. Selecting overall bacterial populations that are non-pathogenic.⁵

The effects on lean muscle mass loss appear to be lower in Intermittent fasting when compared to CCR, a relative conservation of 4x as much muscle.⁶ Another benefit appears to be that lowers the reperfusion injury in the myocardium by autophagy.⁷ The control of hunger appears to be achieved by lowering and saturating the mechanisms for ghrelin production regulating the circadian rythm which diminishes the hunger sensation over time.⁸ It also appears to have a neuroprotective effect by different routes like GABAergic stabilization and stimulus for neurogenesis in the hippocampal region.⁹

While the effects on weight when comparing CCR to intermittent fasting appear similar, the impact on loss in the central axis is higher for intermittent fasting. Also, there seems to be an overall continuous lowering in the concentration of circulating insulin in blood with fasting, while CCR seems to reach faster a plateau.¹⁰

Overall, it looks like an excellent empirically tested and theoretically consistent way of preventing and dealing with early stages of diabetes, as well as obesity. The known benefits far outweigh the known risks of a therapy. This subtype of hypocaloric diet can be used in combination with other regimes or alone.

If fasting is controversial, this is gonna be a little bit more.

Cancer

Obesity has been linked to several types of cancer, Particularly for Breast cancer and Gastrointestinally derived cancers. with as high as 1.5 relative risk increases compared to the general population. This could account for 1/5 of all cancers in the general population¹¹

You should always be wary of the idea alone of a singular approach to cancer treatment, as cancer is the burden of multicellular life and will be with us for a long time. Most of us have ticking bombs whose countdown we ignore, but there are a couple strategies to slow it down for most people.

One of this appears to be a slight increase in products derived from bacterial fermentation, particularly acetate. At low levels seems to have a positive effect on the aerobic metabolism by stimulating mitochondrial activity but constant intake and high concentrations increase the risk of metabolic syndrome ¹²
A practical example of this is mild consumption of alcohol since ethanol is converted to acetate in the body. At small concentrations is beneficial but at high concentrations is deleterious¹³

The microscopic fine-tuning of energetic input for life extension seems to be improved even if slightly by intermittent fasting. It is a viable type of hypocaloric diet.

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The correct regime for fasting is unknown, the most common regime is 16-24 hours. The frequency of those cycles is currently once a week, although is merely based on cultural empiric practices

In summary:

• Probably better control of weight and depletion of abdominal fat deposits
• Reversal of early effects in non-insulin dependent diabetes
• At least in overweight patients better control of appetite
• Mild Neuroprotection over several years
• Cardioprotection against reperfusion injury after ischemic events
• Indirect lowering of the relative risk of some types of cancer

Reminder, this can also be achieved over time with almost any other hypocaloric regime. There's no significantly higher harm in this one so is an interesting complement to the arsenal of lifestyle interventions.

Remember, before starting any drastic change to your diet you should consult your doctor.

Thanks for reading.

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1 Harvie, M., & Howell, A. (2017). Potential Benefits and Harms of Intermittent Energy Restriction and Intermittent Fasting Amongst Obese, Overweight and Normal Weight Subjects—A Narrative Review of Human and Animal Evidence. Behavioral Sciences, 7(1), 4.

2 D E Kelley R Wing C Buonocore J Sturis K Polonsky M Fitzsimmons Relative effects of calorie restriction and weight loss in noninsulin-dependent diabetes mellitus. The Journal of Clinical Endocrinology & Metabolism, Volume 77, Issue 5, 1 November 1993, Pages

3 Collier, R. (2013). Intermittent fasting: the science of going without. CMAJ : Canadian Medical Association Journal, 185(9), E363–E364. http://doi.org/10.1503/cmaj.109-4451

4 Turnbaugh, P. J., Ridaura, V. K., Faith, J. J., Rey, F. E., Knight, R., & Gordon, J. I. (2009). The Effect of Diet on the Human Gut Microbiome: A Metagenomic Analysis in Humanized Gnotobiotic Mice. Science Translational Medicine, 1(6), 6ra14.

5 Sharma, R., Young, C., & Neu, J. (2010). Molecular Modulation of Intestinal Epithelial Barrier: Contribution of Microbiota. Journal of Biomedicine and Biotechnology, 2010, 305879.

6 Catenacci VA, Pan Z, Ostendorf D, Brannon S, Gozansky WS, Mattson MP, Martin B, MacLean PS, Melanson EL, Troy Donahoo W. A randomized pilot study comparing zero-calorie alternate-day fasting to daily caloric restriction in adults with obesity. Obesity (Silver Spring). 2016 Sep;24(9):1874-83.

7 Godar, R. J., Ma, X., Liu, H., Murphy, J. T., Weinheimer, C. J., Kovacs, A., … Diwan, A. (2015). Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury. Autophagy, 11(9), 1537–1560.

8 Stengel, A., Wang, L., & Taché, Y. (2011). Stress-related alterations of acyl and desacyl ghrelin circulating levels: mechanisms and functional implications. Peptides, 32(11), 2208–2217. http://doi.org/10.1016/j.peptides.2011.07.002

9 Silvia Manzanero, Joanna R Erion, Tomislav Santro. Intermittent Fasting Attenuates Increases in Neurogenesis after Ischemia and Reperfusion and Improves Recovery. First Published February 19, 2014

10 Harvie, M. N., Pegington, M., Mattson, M. P., Frystyk, J., Dillon, B., Evans, G., … Howell, A. (2011). The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomised trial in young overweight women. International Journal of Obesity (2005), 35(5), 714–727.

11 Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003 Apr 24;348(17):1625-38.

12 Perry, R. J., Peng, L., Barry, N. A., Cline, G. W., Zhang, D., Cardone, R. L., … Shulman, G. I. (2016). Acetate mediates a microbiome-brain-β cell axis promoting metabolic syndrome. Nature, 534(7606), 213–217. http://doi.org/10.1038/nature18309

13 Krenz, M., & Korthuis, R. J. (2012). Moderate Ethanol Ingestion and Cardiovascular Protection: From Epidemiologic Associations to Cellular Mechanisms. Journal of Molecular and Cellular Cardiology, 52(1), 93–104.

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