Hormonal and Metabolic Profiles of Fasting
Physiologically, what happens when we fast? How does our metabolism respond to a changing external circumstance (no caloric input)? What hormones are increased and/or decreased? How do these hormones affect our metabolism? How does our body maintain appropriate blood glucose levels? What substrates and fuel sources in the blood increase/decrease? To answer these questions, the duration of the fast must be considered.
Post-prandial (following a meal)
After a meal is ingested and digested, the beta cells (of the islets of Langerhans) in the pancreas can sense the increased arterial blood glucose concentration via GLUT2. This triggers insulin secretion from the beta cells. Glucose-induced insulin secretion is increased with increasing blood glucose concentrations, as the ATP produced from the glucose within the beta cell binds to Kir6.2, preventing potassium efflux and causing depolarization, a voltage-dependent increase in calcium, and vesicular exocytosis of insulin (alongside equimolar amounts of C-peptide). Ideally, the rise in insulin - whose function as an anabolic hormone is to increase glucose uptake (via GLUT4 on skeletal muscle and adipose tissue) and increase glycolysis, triglyceride synthesis, glycogen synthesis, and protein synthesis (amongst other things) - lowers the blood glucose to normal levels following digestion of a meal. In a metabolically healthy individual, 2 hours after an OGTT (oral glucose tolerance test), the blood glucose should be below 140 mg/dL. If it is above 140 and below 200 mg/dL, this is an indication of impaired glucose tolerance, an initial sign of insulin resistance and pre-diabetes. If it is above 200 mg/dL, this is considered diabetes. Fatty acid and glycerol concentrations in the blood should be low post-prandially, as these are markers of lipolysis, which is suppressed by insulin (i.e. downstream phosphorylation of PKB and PPi by insulin binding to its receptor, tyrosine phosphorylation of the receptor, IRS1 docking, p110 activity, and PDK1 activity). Ketones are undetectable in the blood following a meal, and RER is closer to 1.00, indicating a higher percentage of carbohydrates being metabolized (than lipids).
Overnight fast (10-12 hours)
An overnight fast of 10-12 hours is the shortest amount of time in which significant hormonal and metabolic changes associated with fasting will be seen in individuals. Although insulin and glucose decrease in a post-absorptive state, they do not return to basal levels until the morning after an overnight fast (or after 10-12 hours). A fasted blood glucose concentration should be below 110 mg/dL, ideally between 80 and 90 mg/dL. Anything higher indicates either impaired fasting glucose, or if above 125 mg/dL, diabetes. After an overnight fast, insulin should be below 10 uU/mL, ideally between 5 - 8 uU/mL. Although clinicians often only routinely screen for type 2 diabetes using an OGTT or HbA1c test, fasting insulin levels might be a better indicator to determine an increasing risk of insulin resistance and/or type 2 diabetes. Type 2 diabetes is a gradually-progressing disease that can be reversed if caught early, but often, it is not diagnosed until years of accumulated hyperinsulinemia-induced damage.
Glucagon, insulin’s opposing hormone, should be slightly elevated after an overnight fast to compensate for the decrease in blood glucose concentration. Glucagon induces gluconeogenesis and ketogenesis in the liver to provide the body with alternate fuel sources. However, ketones remain relatively low until around 48-72 hours of fasting. Interestingly enough, despite its role as a catabolic hormone, glucagon also stimulates insulin to offset any risk of hyperglycemia.
Despite norepinephrine remaining steady following an overnight fast, epinephrine may have increased slightly, alongside a slight increase in cortisol. These catabolic hormones stimulate lipolysis, glycogenolysis, and gluconeogenesis to maintain an adequate blood glucose concentration and provide the body with alternate fuel substrates, working synergistically with glucagon. The increased rate of lipolysis and beta-oxidation is responsible for a slightly higher level of fatty acids and glycerol in the blood, as well the slight drop in RER to somewhere between 0.8 and 0.9. Individuals whose RER’s do not drop and remain closer to 1.00 (burning a higher percentage of carbohydrates to lipids) following an overnight fast are considered less metabolically flexible and are at a higher risk of type 2 diabetes.
24 hour fast
After 24 hours without caloric input, the body continues to break down its storage of substrates to fuel its activity. Insulin will still be below 10 uU/mL, most likely at undetectable quantities. Glucagon will have increased even further, perhaps to around 130 pg/mL. Epinephrine will be at a similar concentration as during the overnight fast, and norepinephrine will remain steady. RER drops as glycogen stores are depleted and the body uses a greater percentage of lipids for energy production; maintenance of the blood glucose concentration becomes even more reliant on hepatic glucose production (gluconeogenesis) over glycogenolysis.
48 fast
Insulin levels will be remain undetectable at this point, which is logical considering the body continues to be dominated by a catabolic state (breaking down stored substrates) rather than an anabolic state (synthesis and growth as associated with insulin). Norepinephrine finally begins to increase, alongside the continued increase in epinephrine. Cortisol will also increase slightly. Glucagon, catecholamines, and cortisol account for the continued rise in the concentration of blood fatty acids and glycerol (still due to increased lipolysis via phosphorylation of HSL and increased beta oxidation). The RER will have dropped further, as the body relies even more heavily on lipids over carbohydrates.
72 hour fast (“starvation”)
Gut endothelial cells have long been cited to turn over every 3-5 days; this claim encouraged the proposal of 3-day fasts for IBS sufferers in hopes that a complete turnover of enterocytes may strengthen the intestinal barrier and provide protection against IBS symptoms. New research, however, has found that some gut endothelial cells, in particular those that are connected to neural input and nerve fibers, can persist for weeks or even months. Although 3-day fasts may offer relief by allowing a “rest” period without additional triggers of inflammation for a highly permeable intestinal lining, it does not provide relief by means of a complete endothelial cell turnover.
At 72 hours of fasting, the body is considered to be in “starvation.” Around this time, the most dramatic hormonal and metabolic changes have taken place, including a major spike in norepinephrine, increased epinephrine, an RER near 0.7 (almost 100% lipid utilization for ATP production), and a dramatic increase in circulating ketones. Fatty acid and glycerol concentration likely plateaued, but glucagon will be further elevated, as a result of the low blood glucose (which is likely below one’s typical overnight fasted blood glucose, perhaps below 70 mg/dL). Insulin is still undetectable (as it was even in a 12-24 hour fast and will continue to be).
Cortisol has also probably reached a range of 40-50 ug/dL. Whereas insulin stimulates protein synthesis (via mTOR), cortisol induces protein breakdown, reducing skeletal muscle content to provide amino acids to fuel gluconeogenesis. However, GH can offset the cortisol-induced protein breakdown. In the short term, cortisol can lead to an increase in GH. But, extending the already-long list of the negatives of chronic cortisol elevation, GH is decreased when cortisol remains elevated for long periods of time. Other articles will explore other effects of chronic cortisol elevation (i.e. in women on hormonal birth control).
The body can continue breaking down lipids and adipose tissue (which far exceeds glucose storage) for days, or even weeks, in order to survive. While fasting (and the associated fat metabolism and ketogenesis) has been routinely used as a weight loss and/or longevity tool, the potential protein breakdown while fasting has been hotly debated and yields mixed results. This article aimed to analyze the various hormonal and metabolic profiles associated with increasing fasting durations. Future posts will examine the applications of these profiles to metabolic disease progression.