A recent opinion published in Clinical Nutrition ESPEN provides a highly detailed review of intermittent fasting and the ketogenic diet, as well as strategies to apply a combination of these approaches to manage chronic health conditions.

Study: Intermittent fasting with Ketogenic Diet: A combination approach for management of chronic diseases. Image Credit: EZ-Stock Studio/Shutterstock

What is intermittent fasting?

Intermittent fasting is a time- or food-restricted feeding pattern, in which foods and drinks are allowed within a defined period followed by fasting.  

In time-restricted fasting, an individual can consume meals and snacks one to three times each day, depending on the time-restricted eating pattern. The fasting period can vary between 12 and 23 hours a day. In periodic fasting, the duration of fasting can range from two to 21 days or longer.

Time-restricted fasting is used to gradually reduce calorie intake over time. This approach considers small eating windows in the morning and early afternoon to be better than late afternoon or evening eating windows in terms of reducing fat accumulation, insulin resistance, and inflammation.

Previous studies have shown that time-restricted fasting helps manage body weight and improve muscle mass. Moreover, prolonged time-restricted fasting has been shown to improve metabolism and protect against cardiovascular and metabolic diseases.

In diet-restricted fasting, the focus is given to the type and amount of food that can be consumed during the fasting period. There are many types of diet-restricted fasting, including water-only, drinks-only, and calorie-restricted fasting. In pure fasting, however, foods and drinks are completely prohibited.

Diet-restricted fasting can be used in conjunction with any type of diet plan, including vegan, vegetarian, paleo, ketogenic, or gluten-free diets. In fact, even water-only fasting has been shown to be safe and effective in managing certain diseases.

Both time- and diet-restricted fasting are equally effective in managing body weight. A combination of both approaches is also effective in managing chronic diseases.

What are the stages of intermittent fasting?

Intermittent fasting can be divided into four stages, including fed, post-absorptive to early fasting, fasting, and long-term fasting stages.

In the fed stage, which starts immediately after feeding, glucose acts as the fain fuel, whereas insulin acts as the regulatory hormone to metabolize glucose and inhibit lipolysis. Excess glucose is stored in the adipose tissue.

In the post-absorptive to early fasting stage, insulin levels decline, which subsequently leads to the initiation of glycogenolysis to provide glucose. Lipolysis can also be initiated in this stage.

In the fasting stage, glucose still acts as the main energy fuel; however, a shift of fuel source from glucose to fatty acid is initiated. This sometimes causes flu-like symptoms, commonly known as ‘ketoflu’.

During the long-term fasting stage, a complete metabolic switch occurs, where fatty acids become the main energy fuel. Moreover, branched-chain amino acid catabolism is inhibited in this stage, thus leading to protein-sparing and reduced insulin levels.  

In intermittent fasting, the fasting duration should not initially exceed 12 hours; however, the duration can be gradually increased to achieve a complete metabolic switch to fatty acids. This is called the maintenance phase, which can be continued for extended periods of time, ranging from weeks to months.

What is the ketogenic diet?

The classic ketogenic diet refers to a calorie-rich diet wherein fats, carbohydrates, and proteins constitute 70%, 10%, and 20% of daily calorie intake, respectively. Dietary fats include natural, as well as unprocessed monounsaturated and polyunsaturated fats, from different food sources. Saturated fats from animal-based foods can also be used, as they can be rapidly metabolized to increase high-density lipoprotein (HDL) cholesterol levels in the blood.

Modified ketogenic diets, such as the modified Atkins diet (MAD) and low glycemic index diet, were developed in the 2000s to reduce fat consumption and increase carbohydrate consumption.

In healthy individuals, a combination approach of intermittent fasting and the ketogenic diet can be applied without specific monitoring. However, in patients with chronic diseases, tolerability, and possible complications should be monitored. More specifically, continuous monitoring of body weight and blood levels of glucose, ketones, hemoglobin, lipid parameters, and inflammatory markers is crucial.

Combining intermittent fasting with ketogenic diet

Both intermittent fasting and the ketogenic diet induce a metabolic switch from glucose to fatty acids. Sirtuins, which are NAD+-dependent lysine-specific deacetylases, play vital roles in regulating glucose and fat metabolism. Intermittent fasting has been shown to induce Sirtuin expression. 

A combination of intermittent fasting and the ketogenic diet can be applied to manage various chronic diseases. Both strategies are effective in protecting against cerebral ischemia and hypoxia, as well as controlling intracranial pressure in conditions of traumatic brain injury, ischemic stroke, and status epilepticus.

This type of combination therapy could be beneficial in managing various diseases through metabolic remodeling, including diabetes, cardiovascular diseases, and autoimmune diseases. A successful application of this combination approach depends on various factors, including patient-related and diet factors.

Important considerations

Before implementing the combination of intermittent fasting and the ketogenic diet, patients’ medical and family history of disorders, as well as a social history of alcoholism and drug abuse, should be carefully analyzed.  

A professional discussion with patients about the health benefits of intermittent fasting and the ketogenic diet is vital for their motivation. Apps that track the duration of fasting, weight changes, and health parameters are also effective in motivating patients.    

Patients should be provided with adequate time to adapt to the changes in their dietary habits. Upon the achievement of desired outcomes, patients should be rewarded to support their continued motivation.

Regarding diet factors, accurate calculation of calorie requirements and the subsequent formulation of an appropriate diet plan is important before implementing the combination therapy. An appropriate ratio of macronutrients including carbohydrates, proteins, and fats should be maintained in the diet.

The monotony of diet can be avoided by choosing foods from different sources and recipes. Low glycemic index foods and vegetables are recommended.

Adequate hydration is also highly important. Patients considering water-only fasting should consume between two and three liters of water every day.

The combination therapy may not be appropriate for children, pregnant women, and breastfeeding women. In addition, patients with active infection, eating disorders, diabetic ketoacidosis, and acute or chronic pancreatic or liver disorders should avoid practicing a combination of intermittent fasting and the ketogenic diet.

Journal reference:

• Arora, N., Pulimamidi, S., Yadav, H., et al. (2023). Intermittent fasting with Ketogenic Diet: A combination approach for management of chronic diseases. Clinical Nutrition ESPEN. doi:10.1016/j.clnesp.2023.01.024.