MADRID — During the International Scientific Symposium “New Frontiers in Scientific Research” that recently took place in Barcelona, specialists analyzed the role of the very-low-calorie ketogenic diet. This analysis was in relation to three comorbidities that have a higher incidence among overweight and obese patients: polycystic ovary syndrome, nonalcoholic fatty liver disease, and type 2 diabetes. The experts’ aim? To analyze and update the latest evidence on the benefits of this dietary choice.

Polycystic Ovary Syndrome

Alessandra Gambineri, MD, PhD, associate professor at the Department of Medicine and Surgery (DIMEC) at the University of Bologna, Bologna, Italy, addressed the link between obesity and polycystic ovary syndrome, which she described as a chronic disease that affects about 10% of women of childbearing age and that presents diverse phenotypes with different characteristics.

“The pathophysiology of this syndrome is characterized by the interaction of three factors: androgen excess, adipose tissue dysfunction, and insulin resistance. These factors interact with each other and are expressed differently in each phenotype,” said Gambineri.

She indicated that adipose tissue dysfunction is central to this pathology. This centrality results from its association with secretions, such as free fatty acids, proinflammatory cytokines, certain adipokines that promote insulin resistance, glucocorticosteroids, androgens, and oxidative stress.

“Similarly, the oxidative stress that characterizes this syndrome is increasingly present in obese individuals,” said Gambineri. “This oxidative stress also produces ovary hypotoxicity that aggravates ovulatory function. In this context, the very-low-calorie ketogenic diet can be useful in several ways: weight reduction, promoting the loss of mainly visceral/abdominal fat, decreasing lipotoxicity, and improving inflammation, hyperinsulinemia, and insulin resistance.”

This was the path followed to carry out a study that aimed to analyze the effects of the very-low-calorie ketogenic diet on manifestations of polycystic ovary syndrome in the obesity phenotype. Gambineri presented its results.

“The objective was to compare the effects of a very-low-calorie ketogenic diet and the standard low-calorie (hypocaloric) diet as a control group,” she said. “The effects studied include body weight, insulin resistance, menstrual cycle, ovulation, ovarian morphology, and hyperandrogenism in a population of 30 obese women with polycystic ovary syndrome and insulin resistance.”

Study participants had a diagnosis of polycystic ovary syndrome as defined by the National Institutes of Health (NIH) criteria and were aged 18-45 years. These women were randomly assigned to two groups of equal size: experimental (very-low-calorie ketogenic diet) and control (hypocaloric diet). “The women assigned to the experimental group followed the ketogenic stage for eight weeks and then moved to the second, low-calorie diet phase for an additional eight weeks, while those in the control group (hypocaloric diet) followed the low-calorie diet for all 16 weeks.”

The primary outcomes were changes in weight and body composition, specifically fat mass and lean mass, measured by bioimpedance. “The changes observed in the following aspects were considered secondary outcomes: abdominal fat distribution, metabolic parameters, ovulation, ovarian morphology, hirsutism, hyperandrogenism, psychological well-being, and psychological distress,” said Gambineri. “Any reduction in the ovarian stroma, the area where androgens are synthesized, was also analyzed.”

The study authors found that although BMI decreased in both groups, this reduction was greater in the group that followed the very-low-calorie ketogenic diet. Significant weight loss was observed in both groups, 12.4 kg vs. 4.7 kg. Significant differences were also observed in waist circumference (−8.1% in the experimental group vs. −2.2% in the control group), fat mass (−15.1% vs. −8.5%), and free testosterone (−30.3% vs. +10.6%). Only the experimental group saw a reduction in insulin.

“A key point regarding hyperandrogenism, especially regarding what’s referred to as free testosterone, there was only a significant reduction in the very-low-calorie ketogenic diet group,” said Gambineri. “This reduction was especially evident in the first part of the study, coinciding with the ketogenic period. The reason for this effect lies in the significant increase in the concentration of sex hormone-binding globulins, SHB6. Said globulins bind to the testosterone present in female blood, producing a reduction in free testosterone, a very important effect considering that this syndrome is an androgenic disorder. Furthermore, current treatments for polycystic ovary syndrome do not reduce free testosterone as much as this dietary approach does.”

For the specialist, among all these positive effects in these patients, perhaps most important is the notable improvement that occurs in ovulation. “At the beginning of the study, only 38.5% of the participants in the experimental group and 14.3% of those in the control group had ovulatory cycles. After the intervention, 84.6% managed to ovulate, compared to 35.7% who achieved this goal in the other group.”

Gambineri suggested that this method is “valid for reducing fat mass and rapidly improving hyperandrogenism and ovulatory dysfunction in women with obesity and polycystic ovary syndrome.”

Reversing Type 2 Diabetes?

Daniela Sofrà, MD, an endocrinologist specializing in diabetology at La Source Clinic in Lausanne, Switzerland, reviewed the current evidence on the role of the very-low-calorie ketogenic diet in the management of type 2 diabetes.

“It’s time to rethink diabetes treatment and focus efforts on managing obesity as an associated factor,” she said. “One of the hypotheses being examined in this regard is the twin cycle, which postulates that type 2 diabetes is the result of excess fat in the liver. This in turn is associated with insulin resistance with pancreas dysfunction.”

Sofrà added that there is a study documenting for the first time the reversibility of the morphology of the diabetic pancreas after caloric restriction with the very-low-calorie ketogenic diet. “The reason for this effect is the use of visceral and intrahepatic fat, which can lead to the remission of the clinical manifestation of type 2 diabetes, understanding as such the definition made by the American Diabetes Association: glycosylated hemoglobin < 6.5% without pharmacological therapy.”

Specifically, the results of this research showed that after following the very-low-calorie ketogenic diet and achieving a 15% weight loss (mean weight loss of the participants), liver glucose levels returned to normal levels within 7 days. Beta cell function returned to near normal within 8 weeks.

“Subsequent studies have shown the durability of remission of type 2 diabetes, thanks to the reactivation of the insulin-secreting function of beta cells that had become dedifferentiated in the face of chronic nutrient excess. Specifically, 6 out of 10 patients maintained glycosylated hemoglobin < 6% after 6 months without the need for pharmacological therapy,” Sofrà added.

Likewise, she highlighted that the probability of achieving remission is mainly determined by the duration of the disease. “The years with diabetes are one of the main predictors of the response that the patient will have with this dietary intervention. Studies have shown that remission is possible in patients with diabetes for less than 6 years, although there are other projects that indicate that it can be achieved with up to 10 years’ duration.”

Based on these data, Sofrà emphasized the pleiotropic effects of the very-low-calorie ketogenic diet on glycemic control, favoring the possible remission of diabetes or the reduction of drugs, as well as the reduction of the HOMA-IR index (insulin resistance) and waist circumference in people with type 2 diabetes.

Nonalcoholic Fatty Liver Disease

The third comorbidity of obesity that may benefit from the very-low-calorie ketogenic diet is hepatic steatosis, or nonalcoholic fatty liver disease, said Hardy Walle, MD, an internal medicine specialist and director/founder of the Bodymed center, Kirkel, Germany and one of the authors of this research.

“Recent research shows that ectopic fat and nonalcoholic fatty liver disease could be considered a cause, or at least one of the causes, of most of the diseases that affect the population as a consequence of overweight and obesity,” said Walle. “Some authors have stated that without fatty liver, there is no type 2 diabetes.”

Walle pointed out that between 30% and 40% of the adult population has nonalcoholic fatty liver disease, a percentage that increases considerably in people with obesity, reaching 70% prevalence and increasing, in the case of type 2 diabetes, to almost 90%. “Even normal weight does not rule out fatty liver; in fact, about 15% of people with nonalcoholic fatty liver disease are not overweight.”

In a setting where there are no approved drugs for the treatment of fatty liver (the current standard approach focuses on lifestyle interventions), a short-term hypocaloric diet (or liver fasting) is considered an effective method for management of this pathology. This principle was demonstrated by a study by the Saarland University, Saarbrücken, Germany, that Walle used to illustrate this statement.

“The participants (60 patients with hepatic steatosis) followed a hypocaloric diet (less than 1000 kcal/day) for 14 days with a formula rich in protein and fiber specially developed for the treatment of nonalcoholic fatty liver disease. A fibroscan was then performed with controlled attenuation parameter measurement to quantify fatty liver disease. The results showed not only a significant improvement in nonalcoholic fatty liver disease parameters, but also a marked improvement in all relevant metabolic parameters (serum lipids, liver enzymes),” explained Walle.

“This evidence leads us to affirm that the concept of hepatic fasting (by means of a hypocaloric diet) marks a point of reference for a future treatment approach for nonalcoholic fatty liver disease,” he concluded.

The study that Gambineri presented was carried out with the collaboration of the Pronokal Group (Nestlé Health Science). Gambineri, Sofrà, and Walle disclosed no relevant financial relationships.

This article was translated from the Medscape Spanish edition.

Follow Carla Nieto Martinez of Medscape Spanish Edition on Twitter @carlanmartinez . For more news, follow Medscape on Facebook, Twitter, Instagram, YouTube, and LinkedIn

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