In a recent study published in the journal Nutrients, researchers investigated the dynamics of fasting-induced ketosis.
Long-term fasting is an effective non-pharmacological intervention for the prevention and management of chronic diseases. It normalizes glucose and lipid metabolism, reduces oxidative stress, restores balance in the gut microbiota, and has anti-inflammatory effects. However, fasting-induced ketosis is often compared to diabetic ketoacidosis. Switching metabolism to endogenous energy sources is a hallmark of fasting.
When food intake is interrupted, glucose and insulin levels decrease, glucagon is secreted, and glycogen is broken down to glucose. When glycogen stores are depleted, lipolysis occurs, releasing fatty acids into the bloodstream as an energy source. In the liver, fatty acids are converted to ketone bodies, which are energy-rich, water-soluble, and transported to peripheral tissues where they are oxidized to enable ATP synthesis.
Study: Long-term fasting-induced ketosis in 1610 subjects: metabolic regulation and safety. Image credit: RHJPhtotos / Shutterstock
About the Research
In this study, researchers investigated individual differences in the dynamics of fasting-induced ketosis in people aged 18-91 years who participated in a fasting program at a clinic. Patients with type 1 diabetes, cachexia, dementia, anorexia nervosa, cerebrovascular insufficiency, or cognitive disorders were excluded.
Graphical Abstraction
Participants underwent a medical examination before the fast. They were provided with a 600 kcal vegetarian diet the day before the fast. A laxative was administered on the first day of the fast. During the fast, they were provided with fresh fruit juice (250 ml), vegetable soup (250 ml), and honey (20 g). Participants were encouraged to drink 2–3 liters of herbal tea or calorie-free water daily.
Daily caloric intake ranged from 75 kcal to 250 kcal. The program also consisted of alternating periods of rest and physical activity. A vegetarian, egg-lacto-lacto diet was resumed on the final fasting day. Blood samples were taken to measure ketonemia as β-hydroxybutyrate concentrations. Urinary acetoacetate excretion was assessed using the sodium nitroprusside test.
KetoStix strips were used to assess ketosis. Emotional and physical well-being was evaluated. Lipid profile, glycemic index, blood counts, thyroid stimulating hormone, and coagulation parameters were also measured. Post-ketogenic caloric loss was estimated using 24-hour urine volume and caloric value of ketone bodies.
Investigation result
The study involved 1,610 participants. First, the research team compared the correlation between ketonuria (urinary acetoacetate concentration) and ketonemia (blood beta-hydroxybutyrate concentration) in 32 subjects. They found that semi-quantitative measurement of urinary acetoacetate is a convenient, non-invasive method to accurately reflect ketosis induced by long-term fasting.
Additionally, the cumulative caloric loss during fasting in these 32 individuals ranged from 124 kcal to 1468 kcal. On average, 56.2 kcal were lost as ketones per day. Those who were most physically active during the fasting program experienced the most rapid increase in ketonemia. Across the cohort, some individuals excreted trace amounts of ketones, while others excreted higher levels.
Ketonuria was higher in those who did not consume fruit juice or honey. A subgroup of 179 participants with no missing data reported their intake during the first 5 days of the fast. The research team categorized their calorie intake into quartiles. The lowest quartile consisted of 45 people with an average daily intake of 98 kcal, with 31 people with high ketonuria and 14 people with low ketonuria. This group was matched with those who consumed only soup.
The highest quartile included 44 people (19 high ketonuria and 25 low ketonuria), with an average calorie intake of 228 kcal. The team also investigated whether other factors influenced ketonuria. Hyperketonurics were younger, male, had lower high-density lipoprotein and urea, and were heavier. Fasting reduced glycated hemoglobin and blood glucose levels less significantly in people with low ketonuria.
Changes in weight and waist circumference were more pronounced in subjects with high ketonuric levels. Uric acid levels increased by 206 µmol/L in subjects with high ketonuric levels and by 97 µmol/L in those with low ketonuric levels. Changes in ketonuria correlated well with changes in uric acid levels. Blood pressure, health status, cholesterol, and triglyceride levels did not differ between subjects with low and high ketonuric levels.
Conclusion
In summary, this study demonstrated that ketosis induced by long-term fasting does not lead to physiologically unhealthy levels. Gender, age, physiological state, and physical activity influenced ketosis. Carbohydrate intake regulated, not inhibited, ketosis. Overall, the results suggest that individual characteristics can predict the outcome of long-term fasting. This may lead to the establishment of personalized strategies for long-term fasting.
Journal References:
Grundler F, Mesnage R, Ruppert PMM, Kouretas D, Wilhelmi De Toledo F. Long-term fasting-induced ketosis in 1610 subjects: metabolic regulation and safety. Nutrients, 2024, DOI: 10.3390/nu16121849, https://www.mdpi.com/2072-6643/16/12/1849
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