Physiological adaptation to prolonged starvation (2023)

This is a summary of the physiological responses to the total or near-total absence of nutrition.

  • The metabolic response to starvation is characterised by a switch from carbohydrate metabolism to fat cmetabolism, in the context of a hypometabolic state, with minimised catabolism.
  • Initially, stores of carbohydrate precursors (eg. glycogen) are depleted.
  • Then, in the first 24-48 hours there is increased gluconeogenesis from amino acids and glycerol.
  • Subsequently, ketogenesis takes over, and much of the body metabolic needs are met by ketone bodies and free fatty acids.
  • This is the consequence of decreasing insulin levels, and relatively increased influence from catecholamines and cortisol.
  • Over prolonged starvation, protein catabolism begins, resulting in degradation of structurally important proteins, and organ system dysfunction.

The physiological adaptation to starvation has been asked about in Question 27 from the second paper of 2013. Specifically, the college wanted to know about the metabolic changes of starvation and the stress response.

Composition and quantity of nutrients stored in the human body

George F Cahill is the guru of food deprivation physiology. His 1970 article "Starvation in Man" remains a masterpiece of scientific writing. Therein one may find a table entitled "Fuel Composition Of Normal Man" which I have uselessly interpreted into another weird cylinder diagram.
Whatever the value of that may be.

Anyway, each of us has about 20-25g of circulating fuel (of which the majority is glucose), worth about 113 calories. If we take this Homo vulgaris to be a 20 year old specimen measuring 70kg and 170cm, we can calculate that at their basal metabolic rate of 1800kcal/day they go through one blood volume worth of calories every 90 minutes.

Physiological adaptation to prolonged starvation (1)

(Video) 8:Metabolic adaptations in Fasting & Starvation | Metabolism-8 | Biochemistry

Thus, the circulating nutrient volume is constantly being consumed and replenished.

Then, we have a rapidly available glycogen storehouse, of which two thirds resides in the muscle. There is a total 900kcal of this stuff, and it is also constantly being consumed and replenished. It is replenished after meals (when insulin drives glucose into cells and promotes glyconeogenesis) and it is consumed between meals (when glucagon activated glycogenolysis, releasing glucose out of cells).

Glycogen is a poor means of storing energy. It is a starch-like branching molecule, has a low calorie density, only about 4 kcal per gram. Cahill reminds us that this density is actually measured in dried glycogen - in reality, 2g of water is stored together with each 1g of glycogen (in order to maintain intracellular isotonicity) and this dilutes its energy density even further.

Fat, on the other hand, is stored in blobs which are essentially free of water. It is a much more efficient energy storage system. And the vast majority of the fat in the body is available as a metabolic fuel, if push comes to shove. Those blobs are cushioning, they serve a purely cosmetic role and if you need to burn them to survive, so be it- they will not be missed. Not only that, but fat has a far higher energy density - something like 9.4 kcal per gram.

Protein does not come in a fuel storage form. It is structurally important; all of your protein has some function, and to burn it as fuel would be a gesture of desperation. An organism which is consuming its own protein is truly struggling. That said, if your organism is struggling it has some 6kg or so of protein to get through before it dies.

    Metabolic adaptation to a brief period of fasting

    The main change from the normal pattern is the refusal of the myocardium and skeletal muscle to use glucose. Instead, they switch over exclusively to free fatty acid and ketone metabolism.

    The glycogen reserves in humans never get completely depleted. There is at all times a hepatic reserve, waiting to mobilise and rescue the organism from some sort of horrible situation.

    (Video) How does the body adapt to starvation?

    The diagram below is again a paraphrase of Cahill; the mass of nutrients given in it is the amount consumed in a 24 hour period.

    Physiological adaptation to prolonged starvation (2)

      Furthermore, the Cori cycle plays a more important role. 36g of the daily glucose is converted into lactate, which shuttles back to the liver.
      The liver uses free fatty acids to power the process of gluconeogenesis.
      Thus, any lactate converted back to glucose is really free fatty acid energy converted to glucose. In essence, all these Cori-cycling anaerobic glycolysis tissues are running on free fatty acid energy, and glucose and lactate merely act as vessels which contain that energy.

      Hormones responsible for the metabolic adaptation to brief fasting

      Well, its all about increasing the rate of lipolysis, is it not. And the rate of lipolysis in fatty tissues is governed by the intracellular content of cAMP, which responds to both insulin and noradrenaline.

      Physiological adaptation to prolonged starvation (3)

      The major hormonal player in this adaptation is insulin, or rather, its lack. With the absence of regular glucose peaks (given the lack of eating) insulin levels drop. Insulin is the primary inhibitor of lipolysis, because the tyrosine kinase activity of its intracellular domain activates a phosphodiesterase, which keeps intracellular cAMP levels low. As insulin levels drop, the background sympathetic activity becomes unopposed, and the hormone sensitive lipase begins to dismantle their triglyceride stores, releasing delicious fatty acids into the bloodstream.
      (Yes, there are three lipases in the pathway, because there are three fatty acid molecules attached to the glycerol. Only the first lipase is hormone-sensitive.)

      So, noradrenaline increases the rate of lipolysis (by affecting the bored and lonely beta-3 receptor, which doesn't seem to have much of a function outside of lipolysis), and insulin decreases the rate of lipolysis. Which effect is dominant in ICU patients who are frequently marinading in infusions of both noradrenaline and insulin? Hard to say. The catecholamine excess associated with critical illness definitely causes lipolysis, even in absence of exogenous catecholamines.

      (Video) Physiologic adaptations to fasting/starvation #viveksirsphysiology #vsp

      Proteolysis in fasting is not studied as well as lipolysis, but it is clear that an insulin deficit also activates proteolytic pathways (because the administration of small amounts of intravenous dextrose seems to inhibit proteolysis)

      Which brings up an interesting question. Nobody ever just lies there and starves quietly for their first few days in the ICU. What happens to these patients?

      They still starve.
      But, if 150g (600kcal) or so of simple carbohydrate is delivered every day (which is 3 litres of 5% dextrose, or around 600ml of Jevity), the proteolytic pathway is switched off. Lipolysis continues, but the exogenous glucose results in enough insulin release to abort the ketogenesis.

      In short, feeding your patient even a tiny amount of carbohydrate will prevent ketosis and protein catabolism.

      Sneakily, one can achieve the same effect by administering insulin as a part of an insulin-dextrose infusion. At protocol rate (80ml/hr) one ends up giving only 1920ml of 5% dextrose in 24 hours, which is just short of 100g (or 400kCal); but the exogenous insulin switches off the ketogenesis and proteolysis anyway.

      Adaptation to prolonged fasting

      Proteolysis cannot continue at a rate of 75 grams per day. This would be insane, and all of the protein would be depleted very quickly.
      Thus, with prolonged starvation, the rate of protein catabolism reduces. This can be seen from experiments, as a decreased rate of urinary nitrogen (urea) excretion. Because the rate if urea production is so low, the obligatory rate of urine production is also lower.

      A fasting person requires much less fluid this way, which must have been an evolutionary advantage.

      (Video) How does the body adapt to starvation

      Physiological adaptation to prolonged starvation (4)

      The adaptation to prolonged starvation is primarily a change in the pattern of ketone use. The brain gives up its addiction to glucose, and survives on a diet of ketones. At this stage, nothing else uses glucose- every tissue in the body either burns fatty acids, burns ketones, or uses the Cori cycle. Because there is a decreased need for glucose, there is a decreased need for gluconeogenesis, and thus a decreased need for protein catabolism.

      in summary, there are 3 phases of fasting:

      Physiological adaptation to prolonged starvation (5)

      Weight loss due to fasting

      Physiological adaptation to prolonged starvation (6)With total acaloric fasting, a certain healthy 41 yr old member of a cloistered religious community lost 0.9kg per day for the first few days of the fast, a rate which decreased to a stable 0.3kg/day towards the third week of fasting.

      This rate seems consistent among various experimentally fasted subjects. Most seem to lose about 20% of their body weight during a 30 day fast.

      The total amount of weight lost in the course of a fasting experiment is not representative of the critical care population. Our patients are infrequently monastic ovolactovegetarians with a normal BMI. Additionally, in a critical care setting the metaboPhysiological adaptation to prolonged starvation (7)lic demands are greatly increased. One can only estimate that the ICU patient loses weight at a much faster rate, especially if burns, trauma or sepsis are involved.

      (Video) Metabolic changes during starvation

      Electrolyte changes during prolonged starvation

      The 41 yr old monk lost 0.9kg per day for the first few days of the fast. This initial rapid weight loss is not totally due to the loss of dry nutrient mass. Think about it: the burning of 0.9kg of fat protein and carbohydrate in one day day would yield 3150 kcal in total, which is insane (given that a basal metabolic rate we agreed on is 1800 kcal/day).

      The extra weight loss is actually due to diuresis and natriuresis. The urinary loss of the sodium cation is obligatory loss. As ketone anions are lost in the urine, they require a cation to accompany them; initially this is sodium, and later in the fast it is ammonium.

      • Potassium decreases initially, and remains stable at around 3.0 mmol/L. There is a constant rate of urinary potassium loss, which is thought to be the result of lean tissue dissolving. It seems to parallel the rate of proteolysis, and it seems related to lean body mass.
      • Magnesium remains surprisingly stable.
      • Calcium remains stable
      • Phosphate remains stable
      • Uric acid levels increase, perhaps as a product of protein catabolism; not only that but urate seems to compete with ketoacids for renal tubular transport sites.

      Cardiovascular effects of prolonged starvation

      • Heart rate decreases, and healthy fasted volunteers may get as bradycardic as 35 BPM.
        The heart rate increases again (slightly ) after the 4th week.
      • Blood pressure decreases, and in the 1982 study by Kerndt et al the subject terminated his fast because the postural hypotension was interfering with his monastic duties.
      • ECG changes occur: most commonly, a right axis deviation and a decrease in T wave and QRS amplitude. Extreme starvation and malnutrition (eg. in long term prisoners of war) also results in QT interval prolongation, T wave inversion and ST depression.


      How does the body adapt to prolonged starvation? ›

      Circulating ketone body concentrations rise during prolonged starvation. During starvation, most tissues utilise fatty acids and/or ketone bodies to spare glucose for the brain. Glucose utilisation by the brain is decreased during prolonged starvation as the brain utilises ketone bodies as the major fuel.

      What are the physiological consequences of prolonged starvation? ›

      The end-stage of starvation usually brings with it one of two different diseases - kwashiorkor and marasmus. Marasmus happens due to extreme energy deficiency, often from inadequate amounts of calories and protein. The person's body weight reaches dangerously low levels and infections are common.

      What is the physiological response to starvation? ›

      In humans. Ordinarily, the body responds to reduced energy intake by burning fat reserves and consuming muscle and other tissues. Specifically, the body burns fat after first exhausting the contents of the digestive tract along with glycogen reserves stored in liver cells and after significant protein loss.

      What does the body break down during starvation? ›

      Protein turnover. While considerable amounts of body fat may be lost during starvation, the main danger comes from the breakdown of protein. The obvious general muscle wasting is an ominous feature that points to the parallel loss of functional proteins in heart, liver, kidneys, and other tissues.

      What is the best energy source during a prolonged state of starvation? ›

      After several days of starvation, ketone bodies become the major source of fuel for the heart and other organs. As starvation continues, fatty acids and triglyceride stores are used to create ketones for the body. This prevents the continued breakdown of proteins that serve as carbon sources for gluconeogenesis.

      What is the body's highest priority during starvation? ›

      Starvation. When the body is deprived of nourishment for an extended period of time, it goes into “survival mode.” The first priority for survival is to provide enough glucose or fuel for the brain. The second priority is the conservation of amino acids for proteins.

      What organs shut down first when starving? ›

      The body attempts to protect the brain, says Zucker, by shutting down the most metabolically intense functions first, like digestion, resulting in diarrhea. “The brain is relatively protected, but eventually we worry about neuronal death and brain matter loss,” she says.

      How long can the body tolerate starvation? ›

      With no food and no water, the maximum time the body can survive is thought to be about one week . With water only, but no food, survival time may extend up to 2 to 3 months. Over time, a severely restricted food intake can reduce the lifespan.

      How does the body maintain homeostasis during starvation? ›

      Ketones play a central role in prolonged starvation, replacing glucose as the primary fuel for the brain and signaling a reduction in protein catabolism and alanine output from muscle. Protein conservation is achieved and glucose homeostasis is maintained.

      Does your body get used to starvation? ›

      The body's systems do not “reset” after starvation.

      Yet, once a person returns to a normal calorie level, the body cannot adapt. The body cannot adapt from dropping to an ultra-low caloric intake to lose weight and return to a higher caloric intake to maintain the weight loss.

      What hormones are released during starvation? ›

      Our results support the following sequence: (1) Starvation lowers blood glucose; (2) glucose-sensing neurons respond by activating sympathetic neurons; (3) norepinephrine, released in the stomach, stimulates ghrelin secretion; (4) ghrelin releases GH, which maintains blood glucose.

      How can a person obtain energy during starvation? ›

      The brain and red blood cells use glucose as a fuel (the brain uses approximately 600 kcal d1). The glucose that is synthesized (gluconeogenesis) during starvation uses amino acids as a source of carbon.

      How does the brain respond to starvation? ›

      Restricted eating, malnourishment, and excessive weight loss can lead to changes in our brain chemistry, resulting in increased symptoms of depression and anxiety (Centre for Clinical Interventions, 2018b). These changes in brain chemistry and poor mental health outcomes skew reality.

      What happens to hormones during starvation? ›

      Starvation and obesity cause characteristic changes in appetite hormones, such as low leptin levels in starvation and high leptin and low ghrelin levels in obesity. Starvation can lead to death but the exact cause of this is often unclear.


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