Low Carbohydrate Keto Diets Induce Insulin Resistance and Fatty Liver

Low carbohydrate high fat diets, which are now marketed as keto diets, have been around for a long time. Indeed, the "father" of the keto diet craze might well be considered Dr. Robert Atkins, a cardiologist who developed a low carbohydrate high fat diet in the late 1990's.

But well before the Atkins diet first appeared on the scene the use of ketogenic diets for clinical reasons has been around for over 70 years. The longest use of ketogenic diets has been in patients with medically intractable epilepsy. Infants who inherit a non-functional glucose transporter 1 (GLUT1) have severely impaired energy generation in the brain due to a lack of glucose transport. These infants are effectively treated with a ketogenic diet given that the ketones, acetoacetate and beta-hydroxybutyrate (BHB) freely enter the brain and can be used for energy production. Ketogenic diets have also been used in the clinical treatment of diabetes, cancer, Alzheimer disease, and Parkinson disease.

The current non-clinical setting for ketogenic diets is in the area of weight loss diets. However, as I reported earlier, long-term adherence to ketogenic diets may be associated with cardiac pathology:

KETO DIETS: BEWARE OF POTENTIAL CARDIAC PROBLEMS

Now another study has just been published demonstrating that keto diets are likely to induce fatty liver and resistance to the effects of insulin in the liver:

A low-carbohydrate diet induces hepatic insulin resistance and metabolic associated fatty liver disease in mice

Granted this study was carried out in laboratory animals, the results are, nonetheless, of potential significance in humans.

Indeed, as pointed out by the authors of this study there are often differences in caloric content divided between protein, carbohydrate, and fat in ketogenic diets consumed by humans and those used in studies in laboratory mice. In humans the clinical use of ketogenic diets are restricted to total protein content of between 5% and 10% of total calories where a normal diet contains 15% to 20% of total calories. In rodent studies the most common ketogenic diets contain less than 5% of total calories from protein. Therefore, in the current study the researchers used ketogenic diets containing between 8% and 10% of total calories from protein as a means to ensure that the observations were due to low carbohydrate content, rather than due to protein restriction.

The published studies involved providing mice a standard diet of chow, or a high fat diet, or a ketogenic diet. The total caloric content of the ketogenic diet was 8.5% protein, 4.3% fibers, 79.1% fat, 4.3% ashes, and 3.8% carbohydrate. The total caloric content of the high-fat diet (HFD) 35% fat, 23.9% protein, 3% fibers, 5.7% ashes, and 23.2% carbohydrate. Now I will point out that the total calories of the HFD listed in this paper do not add up to 100% (only 90.8%) so not certain what was missing from their reporting.

Results from the study found that after three days on the ketogenic diet the mice had reduced body weight compared to chow and HFD mice. This is in line with what has been shown in other studies and compares to results of keto dieting by humans. After 16 weeks, mice on standard chow and those fed the ketogenic diet had similar body weight gain compared

to HFD mice. This result indicates that long term ketogenic dieting does not affect body weight in lean mice. In comparison the HFD mice exhibited significantly increased fat mass and liver mass as would be expected from this type of diet. However, the ketogenic diet led to significantly increased liver weight compared to chow-fed mice. In addition, the ketogenic diet resulted in increased hepatic lipid droplet accumulation demonstrating that the ketogenic diet accelerated diet-induced hepatic steatosis.

The development of hepatic steatosis is associated with increased liver inflammation and with impaired glucose metabolism. When fasting blood glucose levels were analyzed in the various feeding groups it was found that they were lower on the ketogenic diet compared to chow or HFD. However, following 3-7 days of feeding the ketogenic diet the mice had significantly impaired glucose tolerance compared to chow or HFD mice. After 5 or 16 weeks on the ketogenic diet the mice exhibited glucose intolerance, demonstrating that impaired glucose tolerance on a ketogenic diet is progressive and comparable to a that resulting from a high fat diet. Given that other studies have found that glucose intolerance is associated with sustained inflammation these researchers examined for the levels of various inflammation promoting molecules (cytokines). What they found was that plasma levels of interferon-gamma, interleukin-5 (IL-5), IL-6, and tumor necrosis factor-alpha were all markedly elevated in long

term ketogenic diet and HFD mice. Of significance was that only plasma IL-6 (an acute phase cytokine released by the liver) was also found significantly increased in short-term ketogenic diet mice. The pattern of these inflammatory cytokines was sustained in long-term ketogenic diet fed mice.

TAKE HOME: Whereas, the typical ketogenic diet has been shown to result in weight loss, hence the popularity of this type of diet, there needs to be caution with respect to potential complications related to glucose homeostasis which can lead to serious liver pathology.