Gluconeogenesis as a Stress Response: Regulation by Cortisol | MWM 2.31

The last lesson covered how insulin, glucagon, and allosteric regulators from within the liver ensure that the liver only engages in gluconeogenesis when it can and when it needs to. This lesson focuses on an additional layer of regulation: cortisol. Cortisol is the principal glucocorticoid in humans. Glucocorticoids are steroid hormones produced by the adrenal cortex that increase blood glucose. Cortisol has multiple actions on the liver, muscle, adipose, and pancreas that all converge on making glucose more available to the brain. Among them, it increases movement of fatty acids from adipose to the liver, which provide the energy for gluconeogenesis, and the movement of amino acids from skeletal muscle to the liver, which provide the building blocks for gluconeogenesis. Cortisol serves both to antagonize insulin, thereby acutely increasing gluconeogenesis, and to increase the synthesis of gluconeogenic enzymes, which amplifies all other pro-gluconeogenic signaling and increases the total capacity for gluconeogenesis. In fact, even the day-to-day regulation of gluconeogenesis by glucagon is strongly dependent on normal healthy levels of cortisol in the background. Since gluconeogenesis is an extremely expensive investment with a negative return, it makes sense that the body would regulate it as a stress response, and thus place it under control by cortisol. This raises the question of whether carbohydrate restriction increases cortisol. Several studies are reviewed in this lesson that indicate that 1) there may be an extreme level of carbohydrate restriction that always increases cortisol, and 2) carbohydrate restriction definitely increases cortisol in some people. It may be the case that other stressors in a person’s “stress bucket” determine whether and how strongly the person reacts to carbohydrate restriction with elevated cortisol.

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  1. Conventional medical textbooks tell you that gluconeogenesis kicks in when glycogen stores are runnign down. I’ve never believed this: does the body somehow measure how much glycogen is left and invoke gluconeogensis at a certain given point (very unlikely). The more likely scenario is that when blood glucose falls below the normal default level, this triggers glucagon which in turn triggers gluconeogenesis. And this can happen at any time (emphasis on ‘any time’) providing insulin is ‘too low’ and glucagon is triggered. Thus gluconeogenesis can readily occur in paralell with glycogen depletion as a fail-safe to ensure that blood glucose does not risk drying up altogether. What do you think? I would appreciate any comments. Russell

    1. Hepatic glycogen stores need to be depleted to allow the blood glucose to fall, if things are properly regulated.

      1. My understanding is that dietary glucose must fall first. Then glucose from liver glycogen kicks in. Then soon afterwards (within 30 minutes or so), glucose from gluconeogenesis kicks in. So the first thing to happen is a fall in blood glucose. Put another way: Hepatic glucose needs to fall first to allow muscle & liver glycogen to be depleted, if things are properly regulated. Please correct me if I am wrong.

        1. That’s a more or less correct sequence, but you don’t necessarily see the drop in blood glucose if it is properly compensated for.

  2. I long suspected this to be the case as a low carb follower for many years. I initially had extreme inflammatory skin conditions which I was able to get under control through a low carbohydrate nutrient dense protocol. Unfortunately, I continued the protocol for years longer than necessary. I wonder how often this is the case for low carb zealots??? I believe Atkins himself explained that his protocol was a means of “temporary” therapeutic intervention.

  3. Chris, have you looked at Type 2 Diabetic overnight gluconeogenesis despite normal or higher serum glucose? If so, please point me to your thoughts on it.
    (Sleep or night related as daytime fasting doesn’t trigger it.)


  4. Brilliant. Understood about insulin and glucagon, but the role of cortisol is news to me. This is great stuff.

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